Clinical Oncology News - June 2009 - Special Edition Vol. 12 No. 1

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2009 • VOL. 12 • NO. 1

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The Medical Treatment Of Metastatic Colorectal Cancer Anthony B. El-Khoueiry, MD Heinz-Josef Lenz, MD

K-ras Testing and Its Implications in the Treatment of Metastatic Colorectal Cancer Tanios Bekall-Saab, MD NEWS

Treatment of Advanced Non-Small Cell Lung Cancer: First-Line Therapy And Future Directions

Breast Cancer Approach: Same For Young and Old Clinical Value of Genitourinary Cancer Markers Questioned

Edward S. Kim, MD Prashanth Adapala, MD Tomasz P. Srokowski, MD

HEMATOLOGIC DISEASE

Myelodysplastic Syndromes: Pharmacologic Agents That Extend Overall Survival Steven D. Gore, MD

Treatment of Multiple Myeloma Shaji Kumar, MD S. Vincent Rajkumar, MD Kenneth C. Anderson, MD

NEWS

Updated Results From Imatinib IRIS Study Reveals New Lessons

SUPPORTIVE CARE

Treatment of Nausea And Vomiting in the Oncology Setting David G. Frame, PharmD William Leslie, MD

NEWS

Intrathecal Therapy for the Management of Cancer Pain

Clinicians Losing Sleep Over Risk Evaluation and Mitigation Strategy for ESAs

Oscar de Leon-Casasola, MD

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From the EDITORS Dear Reader, We hope you enjoy this issue of Clinical Oncology News Special Edition, which features educational reviews and news articles. We also want to alert you that to receive Clinical Oncology News 12 times per year, you must sign up for our Digital Edition. Clinical Oncology News will come out in print six months during the year and Clinical Oncology News Digital Exclusive will be published online the other six months. The print version will also be available in digital format, as Clinical Oncology News Digital Edition. This move will help save trees and allow access to content from anywhere. To sign up, please visit www.clinicaloncology.com and click on the banner at the top of the home page.

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Avastin® (Bevacizumab) For Intravenous Use WARNINGS Gastrointestinal Perforations Avastin administration can result in the development of gastrointestinal perforation, in some instances resulting in fatality. Gastrointestinal perforation, sometimes associated with intra-abdominal abscess, occurred throughout treatment with Avastin (i.e., was not correlated to duration of exposure). The incidence of gastrointestinal perforation (gastrointestinal perforation, fistula formation, and/or intra-abdominal abscess) in patients with colorectal cancer and in patients with non-small cell lung cancer (NSCLC) receiving Avastin was 2.4% and 0.9%, respectively. The typical presentation was reported as abdominal pain associated with symptoms such as constipation and vomiting. Gastrointestinal perforation should be included in the differential diagnosis of patients presenting with abdominal pain on Avastin. Avastin therapy should be permanently discontinued in patients with gastrointestinal perforation. (See WARNINGS: Gastrointestinal Perforations and DOSAGE AND ADMINISTRATION: Dose Modifications.)

Wound Healing Complications Avastin administration can result in the development of wound dehiscence, in some instances resulting in fatality. Avastin therapy should be permanently discontinued in patients with wound dehiscence requiring medical intervention. The appropriate interval between termination of Avastin and subsequent elective surgery required to avoid the risks of impaired wound healing/wound dehiscence has not been determined. (See WARNINGS: Wound Healing Complications and DOSAGE AND ADMINISTRATION: Dose Modifications.)

Hemorrhage Fatal pulmonary hemorrhage can occur in patients with NSCLC treated with chemotherapy and Avastin. The incidence of severe or fatal hemoptysis was 31% in patients with squamous histology and 2.3% in patients with NSCLC excluding predominant squamous histology. Patients with recent hemoptysis (≥1/2 tsp of red blood) should not receive Avastin. (See WARNINGS: Hemorrhage, ADVERSE REACTIONS: Hemorrhage, and DOSAGE AND ADMINISTRATION: Dose Modifications.)

INDICATIONS AND USAGE Avastin®, in combination with intravenous 5-fluorouracil–based chemotherapy, is indicated for first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum.

Avastin®, in combination with carboplatin and paclitaxel, is indicated for first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non-squamous, non-small cell lung cancer.

Avastin®, in combination with paclitaxel is indicated for the treatment of patients who have not received chemotherapy for metastatic HER2 negative breast cancer.

The effectiveness of Avastin in metastatic breast cancer is based on an improvement in progression free survival. Avastin is not indicated for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease.

Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Avastin in breast cancer. (See CLINICAL STUDIES.) CONTRAINDICATIONS None.

WARNINGS Gastrointestinal Perforations (See DOSAGE AND ADMINISTRATION: Dose Modifications) Gastrointestinal perforation complicated by intra-abdominal abscesses or fistula formation and in some instances with fatal outcome, occurs at an increased incidence in patients receiving Avastin as compared to controls. In Studies 1, 2, and 3, the incidence of gastrointestinal perforation (gastrointestinal perforation, fistula formation, and/or intra-abdominal abscess) in patients receiving Avastin was 2.4%.

These episodes occurred with or without intra-abdominal abscesses and at various time points during treatment. The typical presentation was reported as abdominal pain associated with symptoms such as constipation and emesis.

In post-marketing clinical studies and reports, gastrointestinal perforation, fistula formation in the gastrointestinal tract (eg. gastrointestinal, enterocutaneous, esophageal, duodenal, rectal), and/or intra-abdominal abscess occurred in patients receiving Avastin for colorectal and for other types of cancer. The overall incidence in clinical studies was 1%, but may be higher in some cancer settings. Of the reported events, approximately 30% were fatal. Patients with gastrointestinal perforation, regardless of underlying cancer, typically present with abdominal pain, nausea and fever. Events were reported at various time points during treatment ranging from one week to greater than 1 year from initiation of Avastin, with most events occurring within the first 50 days.

Permanently discontinue Avastin in patients with gastrointestinal perforation (gastrointestinal perforation, fistula formation, and/or intra-abdominal abscess).

Non-Gastrointestinal Fistula Formation (See DOSAGE AND ADMINISTRATION: Dose Modifications) Non-gastrointestinal fistula formation has been reported in patients treated with Avastin in controlled clinical studies (with an incidence of <0.3%) and in post-marketing experience, in some cases with fatal outcome. Fistula formation involving the following areas of the body other than the gastrointestinal tract have been reported: tracheo-esophageal, bronchopleural, biliary, vagina and bladder. Events were reported throughout treatment with Avastin, with most events occurring within the first 6 months.

Permanently discontinue Avastin in patients with fistula formation involving an internal organ.

Wound Healing Complications (See DOSAGE AND ADMINISTRATION: Dose Modifications) Avastin impairs wound healing in animal models. In clinical studies of Avastin, patients were not allowed to receive Avastin until at least 28 days had elapsed following surgery. In clinical studies of Avastin in combination with chemotherapy, there were 6 instances of dehiscence among 788 patients (0.8%).

The appropriate interval between discontinuation of Avastin and subsequent elective surgery required to avoid the risks of impaired wound healing has not been determined. In Study 1, 39 patients who received bolus-IFL plus Avastin underwent surgery following Avastin therapy; of these patients, six (15%) had wound healing/bleeding complications. In the same study, 25 patients in the bolus-IFL arm underwent surgery; of these patients, one of 25 (4%) had wound healing/bleeding complications. The longest interval between last dose of study drug and dehiscence was 56 days; this occurred in a patient on the bolus-IFL plus Avastin arm.

The interval between termination of Avastin and subsequent elective surgery should take into consideration the calculated half-life of Avastin (approximately 20 days).

Discontinue Avastin in patients with wound healing complications requiring medical intervention.

Hemorrhage (See DOSAGE AND ADMINISTRATION: Dose Modifications) Two distinct patterns of bleeding have occurred in patients receiving Avastin. The first is minor hemorrhage, most commonly NCI-CTC Grade 1 epistaxis. The second is serious, and in some cases fatal, hemorrhagic events.

In Study 6, four of 13 (31%) Avastin-treated patients with squamous cell histology and two of 53 (4%) Avastin-treated patients with histology other than squamous cell, experienced serious or fatal pulmonary hemorrhage as compared to none of the 32 (0%) patients receiving chemotherapy alone. Of the patients experiencing pulmonary hemorrhage requiring medical intervention, many had cavitation and/or necrosis of the tumor, either pre-existing or developing during Avastin therapy. In Study 5, the rate of pulmonary hemorrhage requiring medical intervention for the PC plus Avastin arm was 2.3% (10 of 427) compared to 0.5% (2 of 441) for the PC alone arm. There were seven deaths due to pulmonary hemorrhage reported by investigators in the PC plus Avastin arm as compared to one in the PC alone arm. Generally, these serious hemorrhagic events presented as major or massive hemoptysis without an antecedent history of minor hemoptysis during Avastin therapy. Do not administer Avastin to patients with recent history of hemoptysis of ≥1/2 tsp of red blood. Other serious bleeding events occurring in patients receiving Avastin across all indications include gastrointestinal hemorrhage, subarachnoid hemorrhage, and hemorrhagic stroke.

Some of these events were fatal. (See ADVERSE REACTIONS: Hemorrhage.)

Interim data from two ongoing clinical studies in patients with non-small cell lung cancer, in which patients with CNS metastases had completed either radiation and/or

AVASTIN® (Bevacizumab) surgery more than 4 weeks prior to the start of Avastin and were evaluated on study with CNS imaging, documented symptomatic Grade 2 CNS hemorrhage in one of 83 Avastin-treated patients (rate 1.2 %, 95% CI 0.06% - 5.93%).

Discontinue Avastin in patients with serious hemorrhage (i.e., requiring medical intervention) and initiate aggressive medical management. (See ADVERSE REACTIONS: Hemorrhage.)

Arterial Thromboembolic Events (see DOSAGE AND ADMINISTRATION: Dose Modifications and PRECAUTIONS: Geriatric Use) Arterial thromboembolic events (ATE) occurred at a higher incidence in patients receiving Avastin in combination with chemotherapy as compared to those receiving chemotherapy alone. ATE included cerebral infarction, transient ischemic attacks (TIAs), myocardial infarction (MI), angina, and a variety of other ATE. These events were fatal in some instances.

In a pooled analysis of randomized, controlled clinical trials involving 1745 patients, the incidence of ATE was 4.4% among patients treated with Avastin in combination with chemotherapy and 1.9% among patients receiving chemotherapy alone. Fatal outcomes for these events occurred in 7 of 963 patients (0.7%) who were treated with Avastin in combination with chemotherapy, compared to 3 of 782 patients (0.4%) who were treated with chemotherapy alone.The incidences of both cerebrovascular arterial events (1.9% vs. 0.5%) and cardiovascular arterial events (2.1% vs. 1.0%) were increased in patients receiving Avastin compared to chemotherapy alone. The relative risk of ATE was greater in patients 65 and over (8.5% vs. 2.9%) as compared to those less than 65 (2.1% vs. 1.4%). (See PRECAUTIONS: Geriatric Use.) The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Permanently discontinue Avastin in patients who experience a severe ATE during treatment. (See DOSAGE AND ADMINISTRATION: Dose Modifications and PRECAUTIONS: Geriatric Use.) Hypertension (See DOSAGE AND ADMINISTRATION: Dose Modifications) The incidence of severe hypertension was increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of NCI-CTC Grade 3 or 4 hypertension ranged from 8-18%.

Medication classes used for management of patients with NCI-CTC Grade 3 hypertension receiving Avastin included angiotensin-converting enzyme inhibitors, beta blockers, diuretics, and calcium channel blockers. Development or worsening of hypertension can require hospitalization or require discontinuation of Avastin in up to 1.7% of patients.

Hypertension can persist after discontinuation of Avastin. Complications can include hypertensive encephalopathy (in some cases fatal) and CNS hemorrhage.

In the post-marketing experience, acute increases in blood pressure associated with initial or subsequent infusions of Avastin have been reported (see PRECAUTIONS: Infusion Reactions). Some cases were serious and associated with clinical sequelae.

Permanently discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. (See DOSAGE AND ADMINISTRATION: Dose Modifications.)

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) (See DOSAGE AND ADMINISTRATION: Dose Modifications) RPLS has been reported in clinical studies (with an incidence of <0.1%) and in post-marketing experience. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present, but is not necessary for diagnosis of RPLS. Magnetic Resonance Imaging (MRI) is necessary to confirm the diagnosis of RPLS. The onset of symptoms has been reported to occur from 16 hours to 1 year after initiation of Avastin.

In patients developing RPLS, discontinue Avastin and initiate treatment of hypertension, if present. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known.

Neutropenia and Infection (See PRECAUTIONS: Geriatric Use and ADVERSE REACTIONS: Neutropenia and Infection) Increased rates of severe neutropenia, febrile neutropenia, and infection with severe neutropenia (including some fatalities) have been observed in patients treated with myelosuppressive chemotherapy plus Avastin. (See PRECAUTIONS: Geriatric Use and ADVERSE REACTIONS: Neutropenia and Infection.)

Proteinuria (See DOSAGE AND ADMINISTRATION: Dose Modifications) The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to control. In Studies 1, 3 and 5 the incidence of NCI-CTC Grade 3 and 4 proteinuria, characterized as >3.5 gm/24 hours, ranged up to 3.0% in Avastin-treated patients.

Nephrotic syndrome occurred in seven of 1459 (0.5%) patients receiving Avastin in clinical studies. One patient died and one required dialysis. In three patients, proteinuria decreased in severity several months after discontinuation of Avastin. No patient had normalization of urinary protein levels (by 24-hour urine) following discontinuation of Avastin.

The highest incidence of proteinuria was observed in a dose-ranging, placebo-controlled, randomized study of Avastin in patients with metastatic renal cell carcinoma, an indication for which Avastin is not approved, 24-hour urine collections were obtained in approximately half the patients enrolled. Among patients in whom 24-hour urine collections were obtained, four of 19 (21%) patients receiving Avastin at 10 mg/kg every two weeks, two of 14 (14%) patients receiving Avastin at 3 mg/kg every two weeks, and none of the 15 placebo patients experienced NCI-CTC Grade 3 proteinuria (>3.5 gm protein/24 hours).

In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy.

Discontinue Avastin in patients with nephrotic syndrome. The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. In most clinical studies, Avastin was interrupted for ≥2 grams of proteinuria/24 hours and resumed when proteinuria was <2 gm/24 hours. Patients with moderate to severe proteinuria based on 24-hour collections should be monitored regularly until improvement and/or resolution is observed. (See DOSAGE AND ADMINISTRATION: Dose Modifications.)

Congestive Heart Failure NCI-CTC Grade 2–4 left ventricular dysfunction, was reported in 25 of 1459 (1.7%) patients receiving Avastin in clinical studies. In Study 7, the rate of congestive heart failure (defined as NCI-CTC Grade 3 and 4) in the Avastin plus paclitaxel arm was 2.2 % versus 0.3% in the control arm. Among patients receiving anthracyclines, the rate of CHF was 3.8% for Avastin treated patients and 0.6% for patients receiving paclitaxel alone. Congestive heart failure occurred in six of 44 (14%) patients with relapsed acute leukemia (an unlabelled indication) receiving Avastin and concurrent anthracyclines in a single arm study.

The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied.

PRECAUTIONS General Use Avastin with caution in patients with known hypersensitivity to Avastin or any component of this drug product.

Infusion Reactions In clinical studies, infusion reactions with the first dose of Avastin were uncommon (<3%) and severe reactions occurred in 0.2% of patients. Infusion reactions reported in the clinical trials and post-marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, NCI-CTC Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. Adequate information on rechallenge is not available. Avastin infusion should be interrupted in all patients with severe infusion reactions and appropriate medical therapy administered.

There are no data regarding the most appropriate method of identification of patients who may safely be retreated with Avastin after experiencing a severe infusion reaction.

Surgery Avastin therapy should not be initiated for at least 28 days following major surgery.

The surgical incision should be fully healed prior to initiation of Avastin. Because of the potential for impaired wound healing, Avastin should be suspended prior to elective surgery. The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half-life of Avastin is estimated to be 20

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AVASTIN® (Bevacizumab) days (see CLINICAL PHARMACOLOGY: Pharmacokinetics) and the interval chosen should take into consideration the half-life of the drug. (See WARNINGS: Gastrointestinal Perforations and Wound Healing Complications.)

Cardiovascular Disease Patients were excluded from participation in Avastin clinical trials if, in the previous year, they had experienced clinically significant cardiovascular disease. In an exploratory analysis pooling the data from five randomized, placebo-controlled, clinical trials conducted in patients without a recent history of clinically significant cardiovascular disease, the overall incidence of arterial thromboembolic events, the incidence of fatal arterial thromboembolic events, and the incidence of cardiovascular thromboembolic events were increased in patients receiving Avastin plus chemotherapy as compared to chemotherapy alone.

Laboratory Tests Blood pressure monitoring should be conducted every two to three weeks during treatment with Avastin. Patients who develop hypertension on Avastin may require blood pressure monitoring at more frequent intervals. Patients with Avastin-induced or -exacerbated hypertension who discontinue Avastin should continue to have their blood pressure monitored at regular intervals.

Patients receiving Avastin should be monitored for the development or worsening of proteinuria with serial urinalyses. Patients with a 2+ or greater urine dipstick reading should undergo further assessment, e.g., a 24-hour urine collection. (See WARNINGS: Proteinuria and DOSAGE AND ADMINISTRATION: Dose Modifications.)

Drug Interactions A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38.

In Study 6, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin. However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0.

Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity data are available for Avastin in animals or humans.

Avastin may impair fertility. Dose-related decreases in ovarian and uterine weights, endometrial proliferation, number of menstrual cycles, and arrested follicular development or absent corpora lutea were observed in female cynomolgus monkeys treated with 10 or 50 mg/kg of Avastin for 13 or 26 weeks. Following a 4- or 12-week recovery period, which examined only the high–dose group, trends suggestive of reversibility were noted in the two females for each regimen that were assigned to recover. After the 12-week recovery period, follicular maturation arrest was no longer observed, but ovarian weights were still moderately decreased. Reduced endometrial proliferation was no longer observed at the 12-week recovery time point, but uterine weight decreases were still notable, corpora lutea were absent in 1 out of 2 animals, and the number of menstrual cycles remained reduced (67%).

Pregnancy Category C Avastin has been shown to be teratogenic in rabbits when administered in doses that approximate the human dose on a mg/kg basis. Observed effects included decreases in maternal and fetal body weights, an increased number of fetal resorptions, and an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested.

Angiogenesis is critical to fetal development and the inhibition of angiogenesis following administration of Avastin is likely to result in adverse effects on pregnancy.

There are no adequate and well-controlled studies in pregnant women. Avastin should be used during pregnancy or in any woman not employing adequate contraception only if the potential benefit justifies the potential risk to the fetus. All patients should be counseled regarding the potential risk of Avastin to the developing fetus prior to initiation of therapy. If the patient becomes pregnant while receiving Avastin, she should be apprised of the potential hazard to the fetus and/or the potential risk of loss of pregnancy. Patients who discontinue Avastin should also be counseled concerning the prolonged exposure following discontinuation of therapy (half-life of approximately 20 days) and the possible effects of Avastin on fetal development.

Nursing Mothers It is not known whether Avastin is secreted in human milk. Because human IgG1 is secreted into human milk, the potential for absorption and harm to the infant after ingestion is unknown. Women should be advised to discontinue nursing during treatment with Avastin and for a prolonged period following the use of Avastin, taking into account the half-life of the product, approximately 20 days [range 11-50 days]. (See CLINICAL PHARMACOLOGY: Pharmacokinetics.)

Pediatric Use The safety and effectiveness of Avastin in pediatric patients has not been studied. However, physeal dysplasia was observed in juvenile cynomolgus monkeys with open growth plates treated for four weeks with doses that were less than the recommended human dose based on mg/kg and exposure.The incidence and severity of physeal dysplasia were doserelated and were at least partially reversible upon cessation of treatment.

Geriatric Use In Study 1, NCI-CTC Grade 3–4 adverse events were collected in all patients receiving study drug (396 bolus-IFL plus placebo; 392 bolus-IFL plus Avastin; 109 5-FU/LV plus Avastin), while NCI-CTC Grade 1 and 2 adverse events were collected in a subset of 309 patients. There were insufficient numbers of patients 65 years and older in the subset in which NCI-CTC Grade 1–4 adverse events were collected to determine whether the overall adverse event profile was different in the elderly as compared to younger patients. Among the 392 patients receiving bolus-IFL plus Avastin, 126 were at least 65 years of age. Severe adverse events that occurred at a higher incidence (≥2%) in the elderly when compared to those less than 65 years were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients.

In Study 3, patients age 65 and older receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue.

In Study 5 patients age 65 and older receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients.

In Study 7, there were insufficient numbers of patients ≥65 years old to determine whether the overall adverse event profile was different in the elderly as compared with younger patients.

Of the 742 patients enrolled in Genentech-sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older.Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration.

In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients age 65 or older and 1127 patients less than 65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients 65 and over (8.5% vs. 2.9%) as compared to those less than 65 (2.1% vs. 1.4%). (See WARNINGS: Arterial Thromboembolic Events.)

ADVERSE REACTIONS The most serious adverse reactions in patients receiving Avastin were: Gastrointestinal Perforations (see WARNINGS) Non-Gastrointestinal Fistula Formation (see WARNINGS) Wound Healing Complications (see WARNINGS) Hemorrhage (see WARNINGS) Arterial Thromboembolic Events (see WARNINGS)

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AVASTIN® (Bevacizumab) Hypertensive Crises (see WARNINGS: Hypertension) Reversible Posterior Leukoencephalopathy Syndrome (see WARNINGS) Neutropenia and Infection (see WARNINGS) Nephrotic Syndrome (see WARNINGS: Proteinuria) Congestive Heart Failure (see WARNINGS) Adverse Reactions in Clinical Trials Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

The data described below reflect exposure to Avastin in 1529 patients, including 665 receiving Avastin for at least 6 months and 199 receiving Avastin for at least one year.

Avastin was studied primarily in placebo- and active-controlled trials (n=501, and n=1028, respectively).

Gastrointestinal Perforation The incidence of gastrointestinal perforation across all studies ranged from 0–3.7%.

The incidence of gastrointestinal perforation, in some cases fatal, in patients with mCRC receiving Avastin alone or in combination with chemotherapy was 2.4% compared to 0.3% in patients receiving only chemotherapy. The incidence of gastrointestinal perforation in NSCLC patients receiving Avastin was 0.9% compared to 0% in patients receiving only chemotherapy. (See WARNINGS: Gastrointestinal Perforations and DOSAGE AND ADMINISTRATION: Dose Modifications.)

Non-Gastrointestinal Fistula Formation (See WARNINGS: Non-Gastrointestinal Fistula Formation, DOSAGE AND ADMINISTRATION: Dose Modifications.)

Wound Healing Complications The incidence of post-operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus-IFL plus Avastin as compared to 4% (1/25) of patients who received bolus-IFL alone. In the same study, the incidence of wound dehiscence was also higher in the Avastin-treated patients (1% vs. 0.5%).

Hemorrhage Severe or fatal hemorrhages, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to fivefold more frequently in Avastin-treated patients compared to patients treated with chemotherapy alone. NCI-CTC Grade 3–5 hemorrhagic events occurred in 4.7% of NSCLC patients and 5.2% of mCRC patients receiving Avastin compared to 1.1% and 0.7% for the control groups respectively. (See WARNINGS: Hemorrhage.)

The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus-IFL plus Avastin compared with patients receiving bolus-IFL plus placebo. These events were generally mild in severity (NCI-CTC Grade 1) and resolved without medical intervention. Additional mild to moderate hemorrhagic events reported more frequently in patients receiving bolus-IFL plus Avastin when compared to those receiving bolus-IFL plus placebo included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). (See WARNINGS: Hemorrhage and DOSAGE AND ADMINISTRATION: Dose Modifications.)

Arterial Thromboembolic Events The incidence of arterial thromboembolic events was increased in NSCLC patients receiving PC plus Avastin (3.0%) compared with patients receiving PC alone (1.4%).

Five events were fatal in the PC plus Avastin arm, compared with 1 event in the PC alone arm. This increased risk is consistent with that observed in patients with mCRC. (See WARNINGS: Arterial Thromboembolic Events, DOSAGE AND ADMINISTRATION: Dose Modifications, and PRECAUTIONS: Geriatric Use.) Venous Thromboembolic Events The incidence of NCI-CTC Grade 3–4 venous thromboembolic events was higher in patients with mCRC or NSCLC receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone. In addition, in patients with mCRC the risk of developing a second subsequent thromboembolic event in patients receiving Avastin and chemotherapy is increased compared to patients receiving chemotherapy alone.

In Study 1, 53 patients (14%) on the bolus-IFL plus Avastin arm and 30 patients (8%) on the bolus-IFL plus placebo arm received full dose warfarin following a venous thromboembolic event. Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus-IFL plus Avastin and 3% (1/30) of patients receiving bolus-IFL alone.

The overall incidence of NCI-CTC Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus-IFL plus Avastin and 13.6% in patients receiving bolus-IFL plus placebo. In Study 1, the incidence of the following NCI-CTC Grade 3 and 4 venous thromboembolic events was higher in patients receiving bolus-IFL plus Avastin as compared to patients receiving bolus-IFL plus placebo: deep venous thrombosis (34 vs. 19 patients) and intra-abdominal venous thrombosis (10 vs. 5 patients).

Hypertension Fatal CNS hemorrhage complicating Avastin induced hypertension can occur.

In Study 1, the incidences of hypertension and of severe hypertension were increased in patients with mCRC receiving Avastin compared to those receiving chemotherapy alone (see Table 4).

Table 4 Incidence of Hypertension and Severe Hypertension in Study 1 Arm 1 Arm 2 Arm 3 IFL+Placebo IFL+Avastin 5-FU/LV+ Avastin (n=394) (n=392) (n=109) 43% 60% 67% Hypertensiona (>150/100 mmHg) 2% 7% 10% Severe Hypertensiona (>200/110 mmHg) a

This includes patients with either a systolic or diastolic reading greater than the cutoff value on one or more occasions.

Among patients with severe hypertension in the Avastin arms, slightly over half the patients (51%) had a diastolic reading greater than 110 mmHg associated with a systolic reading less than 200 mmHg. Similar results were seen in patients receiving Avastin alone or in combination with FOLFOX4 or carboplatin and paclitaxel. (See WARNINGS: Hypertension and DOSAGE AND ADMINISTRATION: Dose Modifications.)

Neutropenia and Infection An increased incidence of neutropenia has been reported in patients receiving Avastin and chemotherapy compared to chemotherapy alone. In Study 1, the incidence of NCICTC Grade 3 or 4 neutropenia was increased in patients with mCRC receiving IFL+Avastin (21%) compared to patients receiving IFL alone (14%). In Study 5, the incidence of NCI-CTC Grade 4 neutropenia was increased in patients with NSCLC receiving PC plus Avastin (26.2%) compared with patients receiving PC alone (17.2%).

Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with NCI-CTC Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)].

Proteinuria (See WARNINGS: Proteinuria, DOSAGE AND ADMINISTRATION: Dose Modifications, and PRECAUTIONS: Geriatric Use.) Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity.The incidence of antibody development in patients receiving Avastin has not been adequately determined because the assay sensitivity was inadequate to reliably detect lower

AVASTIN® (Bevacizumab) titers. Enzyme-linked immunosorbent assays (ELISAs) were performed on sera from approximately 500 patients treated with Avastin, primarily in combination with chemotherapy. High titer human anti-Avastin antibodies were not detected.

Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading.

Metastatic Carcinoma of the Colon and Rectum The data in Tables 5 and 6 were obtained in Study 1. All NCI-CTC Grade 3 and 4 adverse events and selected NCI-CTC Grade 1 and 2 adverse events (hypertension, proteinuria, thromboembolic events) were reported for the overall study population.

The median age was 60, 60% were male, 79% were Caucasian, 78% had a colon primary lesion, 56% had extra-abdominal disease, 29% had prior adjuvant or neoadjuvant chemotherapy, and 57% had ECOG performance status of 0. The median duration of exposure to Avastin was 8 months in Arm 2 and 7 months in Arm 3.

Severe and life-threatening (NCI-CTC Grade 3 and 4) adverse events, which occurred at a higher incidence (≥2%) in patients receiving bolus-IFL plus Avastin as compared to bolus-IFL plus placebo, are presented in Table 5.

Table 5 NCI-CTC Grade 3 and 4 Adverse Events in Study 1 (Occurring at Higher Incidence (≥2%) in Avastin vs. Control) Arm 1 Arm 2 IFL+Placebo IFL+Avastin (n=396) (n=392) NCI-CTC Grade 3–4 Events 295 (74%) 340 (87%) Body as a Whole Asthenia 28 (7%) 38 (10%) Abdominal Pain 20 (5%) 32 (8%) Pain 21 (5%) 30 (8%) Cardiovascular Hypertension 10 (2%) 46 (12%) Deep Vein Thrombosis 19 (5%) 34 (9%) Intra-Abdominal Thrombosis 5 (1%) 13 (3%) Syncope 4 (1%) 11 (3%) Digestive Diarrhea 99 (25%) 133 (34%) Constipation 9 (2%) 14 (4%) Hemic/Lymphatic Leukopenia 122 (31%) 145 (37%) a Neutropenia 41 (14%) 58 (21%) a

AVASTIN® (Bevacizumab) Constitutional symptoms Fatigue Pain Abdominal pain Headache Cardiovascular (general) Hypertension Hemorrhage Hemorrhage

Arm 1 IFL+Placebo (n=98) Body as a Whole Pain Abdominal Pain Headache Cardiovascular Hypertension Hypotension Deep Vein Thrombosis Digestive Vomiting Anorexia Constipation Stomatitis Dyspepsia GI Hemorrhage Weight Loss Dry Mouth Colitis Hemic/Lymphatic Thrombocytopenia Nervous Dizziness Respiratory Upper Respiratory Infection Epistaxis Dyspnea Voice Alteration Skin/Appendages Alopecia Skin Ulcer Special Senses Taste Disorder Urogenital Proteinuria

Arm 2 IFL+Avastin (n=102)

Arm 3 5-FU/LV+Avastin (n=109)

54 (55%) 54 (55%) 19 (19%)

62 (61%) 62 (61%) 27 (26%)

67 (62%) 55 (50%) 30 (26%)

14 (14%) 7 (7%) 3 (3%)

23 (23%) 15 (15%) 9 (9%)

37 (34%) 8 (7%) 6 (6%)

46 29 28 18 15 6 10 2 1

53 44 41 33 25 25 15 7 6

51 38 32 33 19 21 18 4 1

(47%) (30%) (29%) (18%) (15%) (6%) (10%) (2%) (1%)

(52%) (43%) (40%) (32%) (24%) (24%) (15%) (7%) (6%)

(47%) (35%) (29%) (30%) (17%) (19%) (16%) (4%) (1%)

0

5 (5%)

5 (5%)

20 (20%)

27 (26%)

21 (19%)

38 10 15 2

48 36 26 9

44 35 27 6

(39%) (10%) (15%) (2%)

25 (26%) 1 (1%)

(47%) (35%) (26%) (9%)

33 (32%) 6 (6%)

(40%) (32%) (25%) (6%)

6 (6%) 7 (6%)

9 (9%)

14 (14%)

23 (21%)

24 (24%)

37 (36%)

39 (36%)

The data in Table 7 were obtained in Study 3. Only NCI-CTC Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events related to treatment were reported. The median age was a 61 years, 40% were female, 87% were Caucasian, 99% received prior chemotherapy for metastatic colorectal cancer, 26% had received prior radiation therapy, and the 49% had an ECOG performance status of 0. Selected NCI-CTC Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events which occurred at a higher incidence in patients receiving FOLFOX4 plus Avastin as compared to those who received FOLFOX4 alone, are presented in Table 7. These data are likely to under-estimate the true adverse event rates due to the reporting mechanisms used in Study 3.

Table 7 NCI-CTC Grade 3–5 Non-Hematologic and Grade 4–5 Hematologic Adverse Events in Study 3 (Occurring at Higher Incidence (≥2%) with Avastin + FOLFOX4 vs. FOLFOX4)

Patients with at least one event Gastrointestinal Diarrhea Nausea Vomiting Dehydration Ileus Neurology Neuropathy–sensory Neurologic–other

FOLFOX4 (n=285)

FOLFOX4 + Avastin (n=287)

Avastin (n=234)

171 (60%)

219 (76%)

87 (37%)

36 13 11 14 4

(13%) (5%) (4%) (5%) (1%)

26 (9%) 8 (3%)

51 35 32 29 10

(18%) (12%) (11%) (10%) (4%)

48 (17%) 15 (5%)

5 14 15 15 11

(2%) (6%) (6%) (6%) (5%)

2 (1%) 3 (1%)

56 (19%)

12 (5%)

24 (8%) 8 (3%)

19 (8%) 4 (2%)

5 (2%)

26 (9%)

19 (8%)

2 (1%)

15 (5%)

9 (4%)

Non-Squamous, Non-Small Cell Lung Cancer The data in Table 8 were obtained in Study 5. Only NCI-CTC Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events were reported. The median age was 63, 46% were female, no patients had received prior chemotherapy, 76% had Stage IV disease, 12% had Stage IIIB disease with malignant pleural effusion, 11% had recurrent disease, and 40% had an ECOG performance status of 0. The median duration of exposure to Avastin was 4.9 months.

NCI-CTC Grade 3, 4, and 5 adverse events that occurred at a ≥2% higher incidence in patients receiving PC plus Avastin as compared with PC alone are presented in Table 8.

Table 8 NCI-CTC Grade 3–5 Non-Hematologic and Grade 4 and 5 Hematologic Adverse Events in Study 5 (Occurring at a ≥2% Higher Incidence in Avastin-Treated Patients Compared with Control)

a

NCI-CTC Category Term Any event Blood/bone marrow Neutropenia Constitutional symptoms Fatigue Cardiovascular (general) Hypertension Vascular Venous thrombus/embolism Infection/febrile neutropenia Infection without neutropenia Infection with NCI-CTC Grade 3 or 4 neutropenia Febrile neutropenia Pulmonary/upper respiratory Pneumonitis/pulmonary infiltrates Metabolic/laboratory Hyponatremia Pain Headache Renal/genitourinary Proteinuria

Central laboratories were collected on Days 1 and 21 of each cycle. Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.

NCI-CTC Grade 1–4 adverse events which occurred at a higher incidence (≥5%) in patients receiving bolus-IFL plus Avastin as compared to the bolus-IFL plus placebo arm, are presented in Table 6.

Table 6 NCI-CTC Grade 1–4 Adverse Events in Study 1 (Occurring at Higher Incidence (≥5%) in IFL+Avastin vs. IFL)

37 (13%) 13 (5%) 0 (0%)

a

No. (%) of NSCLC Patients PC PC + Avastin (n=441) (n=427) 286 (65%) 334 (78%) 76 (17%)

113 (27%)

57 (13%)

67 (16%)

3 (0.7%)

33 (8%)

14

(3%)

12

(3%)

23 (5%) 30 (7%)

9 8

(2%) (2%)

19 (4%) 23 (5%)

11

(3%)

21 (5%)

5

(1%)

16 (4%)

2 (0.5%)

13 (3%)

0

13 (3%)

(0%)

Events were reported and graded according to NCI-CTC, Version 2.0. Per protocol, investigators were required to report NCI-CTC Grade 3–5 non-hematologic and Grade 4 and 5 hematologic events.

Metastatic Breast Cancer The data in Table 9 were obtained in Study 7. Only NCI-CTC Grade 3–5 nonhematologic and Grade 4–5 hematologic adverse events were reported. The median age was 55 years (range 27 - 85); 76% were white; 36% had received prior hormonal therapy for advanced disease, and 66% had received adjuvant chemotherapy, including 20% with prior taxane use and 50% with prior anthracyclines use. The median duration of exposure was 9 months with Avastin plus paclitaxel and 5 months for patients receiving paclitaxel alone Severe and life-threatening (NCI-CTC Grade 3 and 4) adverse events that occurred at a higher incidence (≥2%) in patients receiving paclitaxel plus Avastin compared with paclitaxel alone, are presented in Table 9.

Table 9 NCI-CTC Grade 3–5 Non-Hematologic and Grade 4 and 5 Hematologic Adverse Events in Study 7 (Occurring at Higher Incidence (≥2%) in Paclitaxel + Avastin vs. Paclitaxel alone) NCI-CTC Terminology Patients with at least one event Neuropathy—sensory Cerebrovascular ischemia Hypertension Headache Bone pain Nausea Vomiting Diarrhea Dehydration Fatigue Infection w/o neutropenia Infection w/ unknown ANC Neutrophils Rash/desquamation Proteinuria

Paclitaxel (n=348) 176 (50.6%) 61 (17.5%) 0 (0%) 5 (1.4%) 2 (0.6%) 6 (1.7%) 5 (1.4%) 8 (2.3%) 5 (1.4%) 3 (0.9%) 18 (5.2%) 16 (4.6%) 1 (0.3%) 11 (3.2%) 1 (0.3%) 0 (0.0%)

Paclitaxel + Avastin (n=363) 258 (71.1%) 88 (24.2%) 9 (2.5%) 58 (16.0%) 13 (3.6%) 14 (3.9%) 15 (4.1%) 20 (5.5%) 17 (4.7%) 12 (3.3%) 39 (10.7%) 33 (9.1%) 11 (3.0%) 21 (5.8%) 9 (2.5%) 11 (3.0%)

Sensory neuropathy, hypertension, and fatigue were reported at a ≥5% higher absolute incidence in the paclitaxel+ Avastin arm compared with the paclitaxel alone arm.

Fatal adverse reactions occurred in 6/363 (1.7%) of patients who received paclitaxel plus Avastin. Causes of death were gastrointestinal perforation (2), myocardial infarction (2), diarrhea/abdominal pain/weakness/hypotension (2).

Other Adverse Events The following adverse events occurred either in Avastin clinical studies or post-marketing experience: Body as a Whole: polyserositis Cardiovascular: pulmonary hypertension Digestive: intestinal necrosis, mesenteric venous occlusion, anastomotic ulceration Hemic and lymphatic: pancytopenia Respiratory: nasal septum perforation, dysphonia Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) OVERDOSAGE The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

Avastin® (Bevacizumab) For Intravenous Use Manufactured by: Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990

7453211 4835704 Initial U.S. Approval: February 2004 Code Revision Date: November 2008 ©2008 Genentech, Inc.

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APPROVED for first-line metastatic NSCLC and first- and second-line MCRC

Raising the survival standard

as observed in pivotal Phase III trials1-4 NSCLC

First-line

MCRC

First-line

Second-line

Primary Endpoint: OS

Primary Endpoint: OS

Primary Endpoint: OS

10.3 12.3 months months vs

Chemotherapy*

Avastin + chemotherapy*

19%

MCRC

15.6 20.3 months months

10.8 13.0 months months

vs

Chemotherapy*

vs

Avastin + chemotherapy*

Chemotherapy*

30%

Avastin + chemotherapy*

20%

increase†

increase†

increase†

P=0.013 Study E4599

P<0.001 Study 2107

P=0.001 Study E3200

*Chemotherapy regimens with Avastin-based therapy: Study E4599, paclitaxel/carboplatin; Study 2107, IFL; Study E3200, FOLFOX4. † Difference statistically significant. Hazard ratios for survival: Study E4599, HR=0.80; Study 2107, HR=0.66; Study E3200, HR=0.75. ‡ National Comprehensive Cancer Network.

Avastin is recognized by the NCCN‡ as a standard of care for appropriate patient types in combination with first-line IV chemotherapy5,6

Indications Avastin, in combination with carboplatin and paclitaxel, is indicated for first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non-squamous, non-small cell lung cancer.

Avastin, in combination with intravenous 5-fluorouracil–based chemotherapy, is indicated for first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum.

Boxed WARNINGS and additional important safety information Gastrointestinal (GI) perforation: Avastin administration can result in the development of GI perforation, in some cases resulting in fatality.

GI perforation, sometimes associated with intra-abdominal abscess, occurred throughout treatment with Avastin. Permanently discontinue Avastin therapy in patients with GI perforation.

Wound healing complication: Avastin administration can result in the development of wound dehiscence, in some instances resulting in fatality. Permanently discontinue Avastin therapy in patients with wound dehiscence requiring medical intervention. The appropriate interval between termination of Avastin and subsequent elective surgery has not been determined.

Hemorrhage: Severe, and in some cases fatal, pulmonary hemorrhage can occur in patients with NSCLC treated with chemotherapy and Avastin.

Do not administer Avastin to patients with recent hemoptysis (≥1/2 tsp of red blood). Permanently discontinue Avastin in patients with serious hemorrhage and initiate aggressive medical management.

Additional serious adverse events included non-GI fistula formation, arterial thromboembolic events, hypertensive crisis, reversible posterior leukoencephalopathy syndrome, neutropenia and infection, nephrotic syndrome, and congestive heart failure.

The most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events that may have occurred in Avastin indications (first-line NSCLC, first- and second-line MCRC) included neutropenia, fatigue, hypertension, infection, hemorrhage, asthenia, abdominal pain, pain, deep vein thrombosis, intra-abdominal thrombosis, syncope, diarrhea, constipation, leukopenia, nausea, vomiting, dehydration, ileus, neuropathy–sensory, neurologic–other, and headache.

Please see following brief summary of Prescribing Information, including Boxed WARNINGS, for additional safety information.

References: 1. Avastin Prescribing Information. Genentech, Inc. March 2008. 2. Sandler A, Gray R, Perry MC, et al. N Engl J Med. 2006;355:2542-2550.

3. Hurwitz H, Fehrenbacher L, Novotny W, et al. N Engl J Med. 2004;350:2335-2342. 4. Giantonio BJ, Catalano PJ, Meropol NJ, et al. J Clin Oncol. 2007;25:1539-1544.

5. The NCCN Colon Cancer Clinical Practice Guidelines in Oncology (Version 1.2008). ©2007 National Comprehensive Cancer Network, Inc. Available at: http://www.nccn.org. Accessed February 8, 2008. To view the most recent and complete version of the guideline, go online to www.nccn.org. 6. The NCCN Non-Small Cell Lung Cancer Clinical Practice Guidelines in Oncology (Version2.2008). ©2008 National Comprehensive Cancer Network, Inc. Available at: http://www.nccn.org. Accessed February 8, 2008. To view the most recent and complete version of the guideline, go online to www.nccn.org.

©2008 Genentech, Inc.

All rights reserved.

9151100

Printed in USA.

www.avastin.com

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TABLE of CONTENTS

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News Features 47 New Lessons From the Imatinib IRIS Study in CML 48 Some Clinicians Losing Sleep Over REMS for ESAs 50 Breast Cancer Approach: Same for Young and Old 59 Clinical Value of Genitourinary Cancer Markers Questioned

Solid Tumors

11

Hematologic Disease

54

The Medical Treatment of Metastatic Colorectal Cancer Anthony B. El-Khoueiry, MD Assistant Professor of Medicine University of Southern California Keck School of Medicine Norris Comprehensive Cancer Center Los Angeles, California

Steven D. Gore, MD Professor of Oncology Sidney Kimmel Comprehensive Cancer Center Johns Hopkins University School of Medicine Baltimore, Maryland

Heinz-Josef Lenz, MD Professor of Medicine University of Southern California Keck School of Medicine Norris Comprehensive Cancer Center Los Angeles, California

25

61

K-ras Testing and Its Implications In the Treatment of Metastatic Colorectal Cancer

Professor of Medicine Division of Hematology Mayo Clinic Rochester, Minnesota

Kenneth C. Anderson, MD Kraft Family Professor of Medicine Harvard Medical School Jerome Lipper Myeloma Center Dana-Farber Cancer Institute Boston, Massachusetts

Treatment of Advanced NonSmall Cell Lung Cancer: First-Line Therapy and Future Directions Fellow University of Texas Medical Branch Galveston, Texas

Shaji Kumar, MD

S. Vincent Rajkumar, MD

Assistant Professor of Medicine and Pharmacology Department of Medicine Division of Hematology and Oncology The Ohio State University-Arthur James Cancer Hospital Department of Pharmacology The Ohio State University Columbus, Ohio

Prashanth Adapala, MD

Treatment of Multiple Myeloma Associate Professor of Medicine Division of Hematology Mayo Clinic Rochester, Minnesota

Tanios Bekall-Saab, MD

33

Myelodysplastic Syndromes: Pharmacologic Agents That Extend Overall Survival

Supportive Care

79

Tomasz P. Srokowski, MD

Treatment of Nausea and Vomiting in the Oncology Setting

Clinical Associate Department of Cancer Medicine The University of Texas M.D. Anderson Cancer Center Houston, Texas

David G. Frame, PharmD

Edward S. Kim, MD

William Leslie, MD

Assistant Professor of Medicine Department of Thoracic/Head and Neck Medical Oncology The University of Texas M.D. Anderson Cancer Center Houston, Texas

Assistant Professor of Medicine Rush University Medical Center Chicago, Illinois

Clinical Assistant Professor of Pharmacy The University of Michigan College of Pharmacy Ann Arbor, Michigan

87

Intrathecal Therapy for the Management of Cancer Pain Oscar de Leon-Casasola, MD

WWW.CMEZONE.COM

Professor and Vice-chair for Clinical Affairs Department of Anesthesiology University at Buffalo School of Medicine and Biomedical Sciences Chief, Pain Medicine and Professor of Oncology Roswell Park Cancer Institute Buffalo, New York

CLINICAL ONCOLOGY NEWS SPECIAL EDITION 2009 â&#x20AC;˘ NO. 1

7

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BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

Irinotecan Hydrochloride Injection only For Intravenous Use Only

WARNINGS

Irinotecan Hydrochloride Injection should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available. Irinotecan Hydrochloride Injection can induce both early and late forms of diarrhea that appear to be mediated by different mechanisms.

Both forms of diarrhea may be severe. Early diarrhea (occurring during or shortly after infusion of Irinotecan Hydrochloride Injection) may be accompanied by cholinergic symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal hyperperistalsis that can cause abdominal cramping.

Early diarrhea and other cholinergic symptoms may be prevented or ameliorated by atropine (see PRECAUTIONS, General). Late diarrhea (generally occurring more than 24 hours after administration of Irinotecan Hydrochloride Injection) can be life threatening since it may be prolonged and may lead to dehydration, electrolyte imbalance, or sepsis. Late diarrhea should be treated promptly with loperamide. Patients with diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated or antibiotic therapy if they develop ileus, fever, or severe neutropenia (see WARNINGS). Administration of Irinotecan Hydrochloride Injection should be interrupted and subsequent doses reduced if severe diarrhea occurs (see DOSAGE AND ADMINISTRATION).

Severe myelosuppression may occur (see WARNINGS).

INDICATIONS AND USAGE

Irinotecan Hydrochloride Injection is indicated for patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy.

CONTRAINDICATIONS

Irinotecan Hydrochloride Injection is contraindicated in patients with a known hypersensitivity to the drug or its excipients.

WARNINGS General

Outside of a well-designed clinical study, Irinotecan Injection should not be used in combination with the “Mayo Clinic” regimen of 5-FU/LV (administration for 4-5 consecutive days every 4 weeks) because of reports of increased toxicity, including toxic deaths. Irinotecan hydrochloride injection should be used as recommended (see DOSAGE AND ADMINISTRATION).

Diarrhea

Irinotecan Hydrochloride Injection can induce both early and late forms of diarrhea that appear to be mediated by different mechanisms. Early diarrhea (occurring during or shortly after infusion of Irinotecan Hydrochloride Injection) is cholinergic in nature. It is usually transient and only infrequently is severe. It may be accompanied by symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal hyperperistalsis that can cause abdominal cramping. Early diarrhea and other cholinergic symptoms may be prevented or ameliorated by administration of atropine (see PRECAUTIONS, General, for dosing recommendations for atropine).

Late diarrhea (generally occurring more than 24 hours after administration of Irinotecan Hydrochloride Injection) can be life threatening since it may be prolonged and may lead to dehydration, electrolyte imbalance, or sepsis.

Late diarrhea should be treated promptly with loperamide (see PRECAUTIONS, Information for Patients, for dosing recommendations for loperamide). Patients with diarrhea should be carefully monitored, should be given fluid and electrolyte replacement if they become dehydrated, and should be given antibiotic support if they develop ileus, fever, or severe neutropenia. After the first treatment, subsequent weekly chemotherapy treatments should be delayed in patients until return of pretreatment bowel function for at least 24 hours without need for anti-diarrhea medication. If grade 2, 3, or 4 late diarrhea occurs subsequent doses of Irinotecan Hydrochloride Injection should be decreased within the current cycle (see DOSAGE AND ADMINISTRATION).

Neutropenia

Deaths due to sepsis following severe neutropenia have been reported in patients treated with Irinotecan Hydrochloride Injection. Neutropenic complications should be managed promptly with antibiotic support (see PRECAUTIONS).

Therapy with Irinotecan Hydrochloride Injection should be temporarily omitted during a cycle of therapy if neutropenic fever occurs or if the absolute neutrophil count drops <1000/mm3. After the patient recovers to an

absolute neutrophil count t1000/mm3, subsequent doses of Irinotecan Hydrochloride Injection should be reduced depending upon the level of neutropenia observed (see DOSAGE AND ADMINISTRATION).

Routine administration of a colony-stimulating factor (CSF) is not necessary, but physicians may wish to consider CSF use in individual patients experiencing significant neutropenia.

Patients with Reduced UGT1A1 Activity

Individuals who are homozygous for the UGT1A1*28 allele are at increased risk for neutropenia following initiation of Irinotecan Hydrochloride Injection treatment. A reduced initial dose should be considered for patients known to be homozygous for the UGT1A1*28 allele (see DOSAGE AND ADMINISTRATION). Heterozygous patients (carriers of one variant allele and one wild-type allele which results in intermediate UGT1A1 activity) may be at increased risk for neutropenia; however, clinical results have been variable and such patients have been shown to tolerate normal starting doses.

Hypersensitivity

Hypersensitivity reactions including severe anaphylactic or anaphylactoid reactions have been observed.

Colitis/Ileus

Cases of colitis complicated by ulceration, bleeding, ileus, and infection have been observed. Patients experiencing ileus should receive prompt antibiotic support (see PRECAUTIONS).

Renal Impairment/Renal Failure

Rare cases of renal impairment and acute renal failure have been identified, usually in patients who became volume depleted from severe vomiting and/or diarrhea.

Thromboembolism

Thromboembolic events have been observed in patients receiving irinotecan-containing regimens; the specific cause of these events has not been determined.

Pregnancy

Irinotecan Hydrochloride Injection may cause fetal harm when administered to a pregnant woman. Radioactivity related to 14C-irinotecan crosses the placenta of rats following intravenous administration of 10 mg/kg (which in separate studies produced an irinotecan Cmax and AUC about 3 and 0.5 times, respectively, the corresponding values in patients administered 125 mg/m2). Administration of 6 mg/kg/day intravenous irinotecan to rats (which in separate studies produced an irinotecan Cmax and AUC about 2 and 0.2 times, respectively, the corresponding values in patients administered 125 mg/m2) and rabbits (about one-half the recommended human weekly starting dose on a mg/m2 basis) during the period of organogenesis, is embryotoxic as characterized by increased post-implantation loss and decreased numbers of live fetuses. Irinotecan was teratogenic in rats at doses greater than 1.2 mg/kg/day (which in separate studies produced an irinotecan Cmax and AUC about 2/3 and 1/40th, respectively, of the corresponding values in patients administered 125 mg/m2) and in rabbits at 6.0 mg/kg/day (about one-half the recommended human weekly starting dose on a mg/m2 basis). Teratogenic effects included a variety of external, visceral, and skeletal abnormalities. Irinotecan administered to rat dams for the period following organogenesis through weaning at doses of 6 mg/kg/day caused decreased learning ability and decreased female body weights in the offspring. There are no adequate and well-controlled studies of irinotecan in pregnant women. If the drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Irinotecan Hydrochloride Injection.

PRECAUTIONS General

Care of Intravenous Site: Irinotecan Hydrochloride Injection is administered by intravenous infusion. Care should be taken to avoid extravasation, and the infusion site should be monitored for signs of inflammation. Should extravasation occur, flushing the site with sterile water and applications of ice are recommended.

Premedication with Antiemetics: Irinotecan is emetigenic.

It is recommended that patients receive premedication with antiemetic agents. In clinical studies of the weekly dosage schedule, the majority of patients received 10 mg of dexamethasone given in conjunction with another type of antiemetic agent, such as a 5-HT3 blocker (e.g., ondansetron or granisetron). Antiemetic agents should be given on the day of treatment, starting at least 30 minutes before administration of Irinotecan Hydrochloride Injection.

Physicians should also consider providing patients with an antiemetic regimen (e.g., prochlorperazine) for subsequent use as needed.

Treatment of Cholinergic Symptoms: Prophylactic or therapeutic administration of 0.25 to 1 mg of intravenous or subcutaneous atropine should be considered (unless clinically contraindicated) in patients experiencing rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, abdominal cramping, or diarrhea (occurring during or shortly after infusion of Irinotecan Hydrochloride Injection). These symptoms are expected to occur more frequently with higher irinotecan doses.

Patients at Particular Risk: The use of Irinotecan Hydrochloride Injection in patients with significant hepatic dysfunction has not been established. In clinical trials of either dosing schedule, irinotecan was not administered to patients with serum bilirubin >2.0 mg/dL, or transaminase >3 times the upper limit of normal if no liver metastasis, or transaminase >5 times the upper limit of normal with liver metastasis. In clinical trials of the weekly dosage schedule, patients with modestly elevated baseline serum total bilirubin levels (1.0 to 2.0 mg/dL) had a significantly greater likelihood of experiencing first-cycle, grade 3 or 4 neutropenia than those with bilirubin levels that were less than 1.0 mg/dL (50% [19/38] versus 18% [47/226]; p<0.001). Also see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations: Hepatic Insufficiency. Patients with deficient glucuronidation of bilirubin, such as those with Gilbert’s syndrome, may be at greater risk of myelosuppression when receiving therapy with Irinotecan Hydrochloride Injection.

Ketoconazole, enzyme-inducing anticonvulsants and St. John’s Wort are known to have drug-drug interactions with irinotecan therapy. (See Drug-Drug Interactions sub-section under CLINICAL PHARMACOLOGY).

Irinotecan commonly causes neutropenia, leucopenia, and anemia, any of which may be severe and therefore should not be used in patients with severe bone marrow failure.i Patients must not be treated with irinotecan until resolution of the bowel obstruction. Patients with hereditary fructose intolerance should not be given Irinotecan Hydrochloride Injection, as this product contains sorbitol.

Information for Patients

Patients and patients’ caregivers should be informed of the expected toxic effects of Irinotecan Hydrochloride Injection, particularly of its gastrointestinal complications, such as nausea, vomiting, abdominal cramping, diarrhea, and infection. Each patient should be instructed to have loperamide readily available and to begin treatment for late diarrhea (generally occurring more than 24 hours after administration of Irinotecan Hydrochloride Injection) at the first episode of poorly formed or loose stools or the earliest onset of bowel movements more frequent than normally expected for the patient. One dosage regimen for loperamide used in clinical trials consisted of the following (Note: This dosage regimen exceeds the usual dosage recommendations for loperamide.): 4 mg at the first onset of late diarrhea and then 2 mg every 2 hours until the patient is diarrhea-free for at least 12 hours. Loperamide is not recommended to be used for more than 48 consecutive hours at these doses, because of the risk of paralytic ileus.

During the night, the patient may take 4 mg of loperamide every 4 hours. Premedication with loperamide is not recommended. The use of drugs with laxative properties should be avoided because of the potential for exacerbation of diarrhea. Patients should be advised to contact their physician to discuss any laxative use.

Patients should be instructed to contact their physician or nurse if any of the following occur: diarrhea for the first time during treatment; black or bloody stools; symptoms of dehydration such as lightheadedness, dizziness, or faintness; inability to take fluids by mouth due to nausea or vomiting; inability to get diarrhea under control within 24 hours; or fever or evidence of infection.

Patients should be warned about the potential for dizziness or visual disturbances which may occur within 24 hours following the administration of Irinotecan Hydrochloride Injection, and advised not to drive or operate machinery if these symptoms occur.

Patients should be alerted to the possibility of alopecia.

Laboratory Tests

Careful monitoring of the white blood cell count with differential, hemoglobin, and platelet count is recommended before each dose of Irinotecan Hydrochloride Injection.

Drug Interactions

The adverse effects of Irinotecan Hydrochloride Injection, such as myelosuppression and diarrhea, would be expected to be exacerbated by other antineoplastic agents having similar adverse effects.

Patients who have previously received pelvic/ abdominal irradiation are at increased risk of severe myelosuppression following the administration of Irinotecan Hydrochloride Injection. The concurrent administration of Irinotecan Hydrochloride Injection with irradiation has not been adequately studied and is not recommended.

Lymphocytopenia has been reported in patients receiving Irinotecan Hydrochloride Injection, and it is possible that the administration of dexamethasone as antiemetic prophylaxis may have enhanced the likelihood of this effect. However, serious opportunistic infections have not been observed, and no complications have specifically been attributed to lymphocytopenia.

Hyperglycemia has also been reported in patients receiving Irinotecan Hydrochloride Injection. Usually, this has been observed in patients with a history of diabetes mellitus or evidence of glucose intolerance prior to administration of Irinotecan Hydrochloride Injection.

It is probable that dexamethasone, given as antiemetic prophylaxis, contributed to hyperglycemia in some patients.

The incidence of akathisia in clinical trials of the weekly dosage schedule was greater (8.5%, 4/47 patients) when prochlorperazine was administered on the same day as Irinotecan Hydrochloride Injection than when these drugs were given on separate days (1.3%, 1/80 patients). The 8.5% incidence of akathisia, however, is within the range

reported for use of prochlorperazine when given as a premedication for other chemotherapies.

It would be expected that laxative use during therapy with Irinotecan Hydrochloride Injection would worsen the incidence or severity of diarrhea, but this has not been studied.

In view of the potential risk of dehydration secondary to vomiting and/or diarrhea induced by Irinotecan Hydrochloride Injection, the physician may wish to withhold diuretics during dosing with Irinotecan Hydrochloride Injection and, certainly, during periods of active vomiting or diarrhea.

Drug-Laboratory Test Interactions

There are no known interactions between Irinotecan Hydrochloride Injection and laboratory tests.

Carcinogenesis, Mutagenesis & Impairment of Fertility

Long-term carcinogenicity studies with irinotecan were not conducted. Rats were, however, administered intravenous doses of 2 mg/kg or 25 mg/kg irinotecan once per week for 13 weeks (in separate studies, the 25 mg/kg dose produced an irinotecan Cmax and AUC that were about 7.0 times and 1.3 times the respective values in patients administered 125 mg/m2 weekly) and were then allowed to recover for 91 weeks. Under these conditions, there was a significant linear trend with dose for the incidence of combined uterine horn endometrial stromal polyps and endometrial stromal sarcomas. Neither irinotecan nor SN-38 was mutagenic in the in vitro Ames assay. Irinotecan was clastogenic both in vitro (chromosome aberrations in Chinese hamster ovary cells) and in vivo (micronucleus test in mice). No significant adverse effects on fertility and general reproductive performance were observed after intravenous administration of irinotecan in doses of up to 6 mg/kg/day to rats and rabbits. However, atrophy of male reproductive organs was observed after multiple daily irinotecan doses both in rodents at 20 mg/kg (which in separate studies produced an irinotecan Cmax and AUC about 5 and 1 times, respectively, the corresponding values in patients administered 125 mg/m2 weekly) and dogs at 0.4 mg/kg (which in separate studies produced an irinotecan Cmax and AUC about one-half and 1/15th, respectively, the corresponding values in patients administered 125 mg/m2 weekly).

Pregnancy

Pregnancy Category D—see WARNINGS.

Nursing Mothers

Radioactivity appeared in rat milk within 5 minutes of intravenous administration of radiolabeled irinotecan and was concentrated up to 65-fold at 4 hours after administration relative to plasma concentrations. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued when receiving therapy with Irinotecan Hydrochloride Injection.

Pediatric Use

The effectiveness of irinotecan in pediatric patients has not been established. Results from two open-label, single arm studies were evaluated. One hundred and seventy children with refractory solid tumors were enrolled in one phase 2 trial in which 50 mg/m2 of irinotecan was infused for 5 consecutive days every 3 weeks. Grade 3-4 neutropenia was experienced by 54 (31.8%) patients. Neutropenia was complicated by fever in 15 (8.8%) patients. Grade 3-4 diarrhea was observed in 35 (20.6%) patients. This adverse event profile was comparable to that observed in adults.

In the second phase 2 trial of 21 children with previously untreated rhabdomyosarcoma, 20 mg/m2 of irinotecan was infused for 5 consecutive days on weeks 0, 1, 3 and 4. This single agent therapy was followed by multimodal therapy.

Accrual to the single agent irinotecan phase was halted due to the high rate (28.6%) of progressive disease and the early deaths (14%). The adverse event profile was different in this study from that observed in adults; the most significant grade 3 or 4 adverse events were dehydration experienced by 6 patients (28.6%) associated with severe hypokalemia in 5 patients (23.8%) and hyponatremia in 3 patients (14.3%); in addition Grade 3-4 infection was reported in 5 patients (23.8%) (across all courses of therapy and irrespective of causal relationship).

Pharmacokinetic parameters for irinotecan and SN-38 were determined in 2 pediatric solid-tumor trials at dose levels of 50 mg/m2 (60-min infusion, n=48) and 125 mg/m2 (90-min infusion, n=6). Irinotecan clearance (mean r S.D.) was 17.3 r 6.7 L/h/m2 for the 50 mg/m2 dose and 16.2 r 4.6 L/h/m2 for the 125 mg/m2 dose, which is comparable to that in adults. Dose-normalized SN-38 AUC values were comparable between adults and children. Minimal accumulation of irinotecan and SN-38 was observed in children on daily dosing regimens [daily x 5 every 3 weeks or (daily x 5) x 2 weeks every 3 weeks].

Geriatric Use

Patients greater than 65 years of age should be closely monitored because of a greater risk of late diarrhea in this population (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations and ADVERSE REACTIONS, Overview of Adverse Events). The starting dose of Irinotecan Hydrochloride Injection in patients 70 years and older for the once every 3 week dosage schedule should be 300 mg/m2 (see DOSAGE AND ADMINISTRATION).

Ref.Brf. 483649-R1

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ADVERSE REACTIONS

Once Every 3 Week Dosage Schedule

Second-Line Single-Agent Therapy

Weekly Dosage Schedule In three clinical studies evaluating the weekly dosage schedule, 304 patients with metastatic carcinoma of the colon or rectum that had recurred or progressed following 5-FU-based therapy were treated with Irinotecan Hydrochloride Injection. Seventeen of the patients died within 30 days of the administration of Irinotecan Hydrochloride Injection; in five cases (1.6%, 5/304), the deaths were potentially drug-related. These five patients experienced a constellation of medical events that included known effects of Irinotecan Hydrochloride Injection. One of these patients died of neutropenic sepsis without fever.

Neutropenic fever occurred in nine (3.0%) other patients; these patients recovered with supportive care.

One hundred nineteen (39.1%) of the 304 patients were hospitalized a total of 156 times because of adverse events; 81 (26.6%) patients were hospitalized for events judged to be related to administration of Irinotecan Hydrochloride Injection. The primary reasons for drugrelated hospitalization were diarrhea, with or without nausea and/or vomiting (18.4%); neutropenia/leukopenia, with or without diarrhea and/or fever (8.2%); and nausea and/or vomiting (4.9%).

Adjustments in the dose of Irinotecan Hydrochloride Injection were made during the cycle of treatment and for subsequent cycles based on individual patient tolerance. The first dose of at least one cycle of Irinotecan Hydrochloride Injection was reduced for 67% of patients who began the studies at the 125-mg/m2 starting dose. Within-cycle dose reductions were required for 32% of the cycles initiated at the 125-mg/m2 dose level. The most common reasons for dose reduction were late diarrhea, neutropenia, and leukopenia. Thirteen (4.3%) patients discontinued treatment with Irinotecan Hydrochloride Injection because of adverse events. The adverse events in Table 5 are based on the experience of the 304 patients enrolled in the three studies described in the CLINICAL STUDIES, Studies Evaluating the Weekly Dosage Schedule, section.

A total of 535 patients with metastatic colorectal cancer whose disease had recurred or progressed following prior 5-FU therapy participated in the two phase 3 studies: 316 received irinotecan, 129 received 5-FU, and 90 received best supportive care. Eleven (3.5%) patients treated with irinotecan died within 30 days of treatment. In three cases (1%, 3/316), the deaths were potentially related to irinotecan treatment and were attributed to neutropenic infection, grade 4 diarrhea, and asthenia, respectively. One (0.8%, 1/129) patient treated with 5-FU died within 30 days of treatment; this death was attributed to grade 4 diarrhea.

Hospitalizations due to serious adverse events (whether or not related to study treatment) occurred at least once in 60% (188/316) of patients who received irinotecan, 63% (57/90) who received best supportive care, and 39% (50/129) who received 5-FU-based therapy. Eight percent of patients treated with irinotecan and 7% treated with 5-FUbased therapy discontinued treatment due to adverse events.

Of the 316 patients treated with irinotecan, the most clinically significant adverse events (all grades, 1-4) were diarrhea (84%), alopecia (72%), nausea (70%), vomiting (62%), cholinergic symptoms (47%), and neutropenia (30%). Table 6 lists the grade 3 and 4 adverse events reported in the patients enrolled to all treatment arms of the two studies described in the CLINICAL STUDIES, Studies Evaluating the Once Every 3 Week Dosage Schedule, section.

Table 6. Percent Of Patients Experiencing Grade 3 & 4 Adverse Events In Comparative Studies Of Once Every 3 Week Irinotecan Therapya Study 1 Adverse Event

Table 5. Adverse Events Occurring in >10% of 304 Previously Treated Patients with Metastatic Carcinoma of the Colon or Rectuma % of Patients Reporting NCI Grades NCI Grades 1-4 3&4

Body System & Event GASTROINTESTINAL Diarrhea (late)b 88 31 7-9 stools/day (grade 3) (16) t10 stools/day (grade 4) (14) Nausea 86 17 Vomiting 67 12 Anorexia 55 6 Diarrhea (early)c 51 8 Constipation 30 2 Flatulence 12 0 Stomatitis 12 1 Dyspepsia 10 0 HEMATOLOGIC 63 28 Leukopenia 60 7 Anemia 54 26 Neutropenia 500 to <1000/mm3 (grade 3) (15) <500/mm3 (grade 4) (12) BODY AS A WHOLE Asthenia 76 12 Abdominal cramping/pain 57 16 Fever 45 1 Pain 24 2 Headache 17 1 Back pain 14 2 Chills 14 0 Minor infectiond 14 0 Edema 10 1 Abdominal enlargement 10 0 METABOLIC & NUTRITIONAL pBody weight 30 1 Dehydration 15 4 nAlkaline phosphatase 13 4 nSGOT 10 1 DERMATOLOGIC Alopecia 60 NAe 0 Sweating 16 1 Rash 13 RESPIRATORY Dyspnea 22 4 nCoughing 17 0 Rhinitis 16 0 NEUROLOGIC Insomnia 19 0 Dizziness 15 0 CARDIOVASCULAR Vasodilation (flushing) 11 0 a Severity of adverse events based on NCI CTC (version 1.0) b Occurring > 24 hours after administration of Irinotecan Hydrochloride Injection c Occurring d 24 hours after administration of Irinotecan Hydrochloride Injection d Primarily upper respiratory infections e Not applicable; complete hair loss = NCI grade 2

Study 2

Irinotecan BSC b Irinotecan 5-FU N=189 N=90 N=127 N=129

TOTAL Grade 3/4 Adverse Events

79

67

69

54

GASTROINTESTINAL Diarrhea Vomiting Nausea Abdominal pain Constipation Anorexia Mucositis

22 14 14 14 10 5 2

6 8 3 16 8 7 1

22 14 11 9 8 6 2

11 5 4 8 6 4 5

22 7 5 1

0 6 3 0

14 6 1 4

2 3 3 2

8 1

3 0

1 2

4 0

2 2

1 0

2 4

0 2

BODY AS A WHOLE Pain Asthenia

19 15

22 19

17 13

13 12

METABOLIC & NUTRITIONAL Hepatic c

9

7

9

6

DERMATOLOGIC Hand & foot syndrome Cutaneous signs d

0 2

0 0

0 1

5 3

RESPIRATORY e

10

8

5

7

NEUROLOGIC

HEMATOLOGIC Leukopenia/Neutropenia Anemia Hemorrhage Thrombocytopenia Infection without grade 3/4 neutropenia with grade 3/4 neutropenia Fever without grade 3/4 neutropenia with grade 3/4 neutropenia

12

13

9

4

CARDIOVASCULAR g

9

3

4

2

OTHER h

32

28

12

14

a b c d e f g h

f

Severity of adverse events based on NCI CTC (version 1.0) BSC = best supportive care Hepatic includes events such as ascites and jaundice Cutaneous signs include events such as rash Respiratory includes events such as dyspnea and cough Neurologic includes events such as somnolence Cardiovascular includes events such as dysrhythmias, ischemia, and mechanical cardiac dysfunction Other includes events such as accidental injury, hepatomegaly, syncope, vertigo, and weight loss

Overview of Adverse Events

Gastrointestinal: Nausea, vomiting, and diarrhea are common adverse events following treatment with Irinotecan Hydrochloride Injection and can be severe. When observed, nausea and vomiting usually occur during or shortly after infusion of Irinotecan Hydrochloride Injection. In the clinical studies testing the every 3 week dosage schedule, the median time to the onset of late diarrhea was 5 days after irinotecan infusion. In the clinical studies evaluating the weekly dosage schedule, the median time to onset of late diarrhea was 11 days following administration of Irinotecan Hydrochloride Injection. For patients starting treatment at the 125-mg/m2 weekly dose, the median duration of any grade of late diarrhea was 3 days. Among those patients treated at the 125-mg/m2 weekly dose who experienced grade 3 or 4 late diarrhea, the median duration of the entire episode of diarrhea was 7 days. The frequency of grade 3 or 4 late diarrhea was somewhat greater in patients starting treatment at 125 mg/m2 than in patients given a 100-mg/m2 weekly starting dose (34% [65/193] versus 23% [24/102]; p=0.08). The frequency of grade 3 and 4 late diarrhea by age was significantly greater in patients t65 years than in

patients <65 years (40% [53/133] versus 23% [40/171]; p=0.002). In one study of the weekly dosage treatment, the frequency of grade 3 and 4 late diarrhea was significantly greater in male than in female patients (43% [25/58] versus 16% [5/32]; p=0.01), but there were no gender differences in the frequency of grade 3 and 4 late diarrhea in the other two studies of the weekly dosage treatment schedule.

Colonic ulceration, sometimes with gastrointestinal bleeding, has been observed in association with administration of Irinotecan Hydrochloride Injection.

Hematology: Irinotecan Hydrochloride Injection commonly causes neutropenia, leukopenia (including lymphocytopenia), and anemia. Serious thrombocytopenia is uncommon. When evaluated in the trials of weekly administration, the frequency of grade 3 and 4 neutropenia was significantly higher in patients who received previous pelvic/abdominal irradiation than in those who had not received such irradiation (48% [13/27] versus 24% [67/277]; p=0.04). In these same studies, patients with baseline serum total bilirubin levels of 1.0 mg/dL or more also had a significantly greater likelihood of experiencing first-cycle grade 3 or 4 neutropenia than those with bilirubin levels that were less than 1.0 mg/dL (50% [19/38] versus 18% [47/266]; p<0.001). There were no significant differences in the frequency of grade 3 and 4 neutropenia by age or gender. In the clinical studies evaluating the weekly dosage schedule, neutropenic fever (concurrent NCI grade 4 neutropenia and fever of grade 2 or greater) occurred in 3% of the patients; 6% of patients received G-CSF for the treatment of neutropenia. NCI grade 3 or 4 anemia was noted in 7% of the patients receiving weekly treatment; blood transfusions were given to 10% of the patients in these trials.

Body as a Whole: Asthenia, fever, and abdominal pain are generally the most common events of this type.

Cholinergic Symptoms: Patients may have cholinergic symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal hyperperistalsis that can cause abdominal cramping and early diarrhea. If these symptoms occur, they manifest during or shortly after drug infusion. They are thought to be related to the anticholinesterase activity of the irinotecan parent compound and are expected to occur more frequently with higher irinotecan doses.

Hepatic: In the clinical studies evaluating the weekly dosage schedule, NCI grade 3 or 4 liver enzyme abnormalities were observed in fewer than 10% of patients. These events typically occur in patients with known hepatic metastases.

Dermatologic: Alopecia has been reported during treatment with Irinotecan Hydrochloride Injection. Rashes have also been reported but did not result in discontinuation of treatment.

Respiratory: Severe pulmonary events are infrequent. In the clinical studies evaluating the weekly dosage schedule, NCI grade 3 or 4 dyspnea was reported in 4% of patients.

Over half the patients with dyspnea had lung metastases; the extent to which malignant pulmonary involvement or other preexisting lung disease may have contributed to dyspnea in these patients is unknown.

Interstitial pulmonary disease presenting as pulmonary infiltrates is uncommon during irinotecan therapy.

Interstitial pulmonary disease can be fatal. Risk factors possibly associated with the development of interstitial pulmonary disease include pre-existing lung disease, use of pneumotoxic drugs, radiation therapy, and colony stimulating factors. Patients with risk factors should be closely monitored for respiratory symptoms before and during irinotecan therapy.

Neurologic: Insomnia and dizziness can occur, but are not usually considered to be directly related to the administration of Irinotecan Hydrochloride Injection. Dizziness may sometimes represent symptomatic evidence of orthostatic hypotension in patients with dehydration.

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compromised pulmonary function, significant ascites, or pleural effusions.

Post-Marketing Experience

The following events have been identified during postmarketing use of Irinotecan Hydrochloride Injection in clinical practice. Infrequent cases of ulcerative and ischemic colitis have been observed. This can be complicated by ulceration, bleeding, ileus, obstruction, and infection, including typhlitis. Patients experiencing ileus should receive prompt antibiotic support (see PRECAUTIONS). Rare cases of intestinal perforation have been reported. Rare cases of symptomatic pancreatitis or asymptomatic elevated pancreatic enzymes have been observed.

Hypersensitivity reactions including severe anaphylactic or anaphylactoid reactions have also been observed (see WARNINGS).

Rare cases of hyponatremia mostly related with diarrhea and vomiting have been reported. Transient and mild to moderate increases in serum levels of transaminases (i.e., AST and ALT) in the absence of progressive liver metastasis; transient increase of amylase and occasionally transient increase of lipase have been very rarely reported.

Infrequent cases of renal insufficiency including acute renal failure, hypotension or circulatory failure have been observed in patients who experienced episodes of dehydration associated with diarrhea and/or vomiting, or sepsis (see WARNINGS).

Early effects such as muscular contraction or cramps and paresthesia have been reported.

OVERDOSAGE

In U.S. phase 1 trials, single doses of up to 345 mg/m2 of irinotecan were administered to patients with various cancers. Single doses of up to 750 mg/m2 of irinotecan have been given in non-U.S. trials. The adverse events in these patients were similar to those reported with the recommended dosage and regimen. There have been reports of overdosage at doses up to approximately twice the recommended therapeutic dose, which may be fatal.

The most significant adverse reactions reported were severe neutropenia and severe diarrhea. There is no known antidote for overdosage of Irinotecan Hydrochloride Injection.

Maximum supportive care should be instituted to prevent dehydration due to diarrhea and to treat any infectious complications.

HOW SUPPLIED

Each mL of Irinotecan Hydrochloride Injection contains 20 mg irinotecan (on the basis of the trihydrate salt); 45 mg sorbitol; 0.9 mg lactic acid; and Water for Injection, USP. When necessary, pH has been adjusted to 3.5 (range, 3.0 to 3.8) with sodium hydroxide or hydrochloric acid.

Irinotecan Hydrochloride Injection is available in single-use amber glass vials in the following package sizes: NDC 61703-349-16 NDC 61703-349-09

40 mg/2 mL 100 mg/5 mL

Store at 20°-25° C (68°-77° F). See USP Controlled Room Temperature (excursions permitted to 15°-30° C (59°-86° F)). Protect from light. It is recommended that the vial should remain in the carton until the time of use. Protect from freezing. Store Upright.

Hospira, Inc. Lake Forest, IL 60045 Product of Australia Rev. February 2008 i Addendum to the Expert Report on the clinical documentation, in patients with impaired hepatic function.

D. Larrey, February 2001.

Cardiovascular: Vasodilation (flushing) may occur during administration of Irinotecan Hydrochloride Injection.

Bradycardia may also occur, but has not required intervention. These effects have been attributed to the cholinergic syndrome sometimes observed during or shortly after infusion of Irinotecan Hydrochloride Injection.

Thromboembolic events have been observed in patients receiving Irinotecan Hydrochloride Injection; the specific cause of these events has not been determined.

Other Non-U.S. Clinical Trials

Irinotecan has been studied in over 1,100 patients in Japan.

Patients in these studies had a variety of tumor types, including cancer of the colon or rectum, and were treated with several different doses and schedules. In general, the types of toxicities observed were similar to those seen in U.S. trials with Irinotecan Hydrochloride Injection. There is some information from Japanese trials that patients with considerable ascites or pleural effusions were at increased risk for neutropenia or diarrhea. A potentially life-threatening pulmonary syndrome, consisting of dyspnea, fever, and a reticulonodular pattern on chest x-ray, was observed in a small percentage of patients in early Japanese studies. The contribution of irinotecan to these preliminary events was difficult to assess because these patients also had lung tumors and some had preexisting nonmalignant pulmonary disease. As a result of these observations, however, clinical studies in the United States have enrolled few patients with Ref.Brf. 483649-R1

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Irinotecan

Hydrochloride Injection Catalog Listing Hospira List No.

NDC#

PRODUCT DESCRIPTION

6170334916

IRINOTECAN HYDROCHLORIDE INJECTION 40 mg 2 mL SDV

6170334909

IRINOTECAN HYDROCHLORIDE INJECTION 100 mg 5 mL SDV

0349-16 0349-09 0349-36

6170334936

Units Per Minimum Order

Case Size

Onco-Tain™ Vial

1

120

�

1

120

�

1

90

�

IRINOTECAN HYDROCHLORIDE INJECTION 500 mg 25 mL SDV

Please see boxed warning and brief summary on following page.

WARNING Irinotecan HCl Injection should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents.

Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available. Irinotecan HCl Injection can induce both early and late forms of diarrhea that appear to be mediated by different mechanisms. Both forms of diarrhea may be severe. Early diarrhea (occurring during or shortly after infusion of irinotecan HCl injection) may be accompanied by cholinergic symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal hyperperistalsis that can cause abdominal cramping. Early diarrhea and other cholinergic symptoms may be prevented or ameliorated by

atropine (see PRECAUTIONS, General). Late diarrhea (generally occurring more than 24 hours after administration of irinotecan HCl injection) can be life threatening since it may be prolonged and may lead to dehydration, electrolyte imbalance, or sepsis. Late diarrhea should be treated promptly with loperamide. Patients with diarrhea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated or antibiotic therapy if they develop ileus, fever, or severe neutropenia (see WARNINGS). Administration of irinotecan HCl injection should be interrupted and subsequent doses reduced if severe diarrhea occurs (see DOSAGE AND ADMINISTRATION). Severe myelosuppression may occur (see WARNINGS).

INDICATION: Irinotecan HCl Injection is indicated for patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy.

ADDITIONAL SAFETY INFORMATION: Common adverse events include: diarrhea (early and late), neutropenia, leukopenia, anemia, thrombocytopenia, nausea, vomiting, abdominal cramping, cholinergic symptoms, dizziness, visual disturbances, alopecia, mucositis, pain, weakness, fever, colitis, thromboemolism, asthenia, insomnig and bradycardia.

1 Onco-Tain™ packaging for safe handling

Hospira, Inc.

P09-2064-Apr., 09

1Data on file at Hospira.

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The Medical Treatment of

Metastatic Colorectal Cancer ANTHONY B. EL-KHOUEIRY, MD Assistant Professor of Medicine

HEINZ-JOSEF LENZ, MD Professor of Medicine University of Southern California Keck School of Medicine Norris Comprehensive Cancer Center Los Angeles, California

C

olorectal cancer is the third leading cause of cancer deaths in men and women in the United States, with an estimated total of 49,960 deaths in 2008.1 The high

number of deaths can be attributed to the inability to achieve cures in a substantial number of patients with metastatic disease.

In the United States, until the year 2000, the only first-line chemotherapeutic option for patients with metastatic colorectal cancer (mCRC) was 5-fluorouracil (5-FU), mostly in combination with leucovorin (LV), with an average survival of 12 months.2 However, in the years since then, there has been a significant increase in the number of approved chemotherapeutic and targeted biologic agents for the treatment of mCRC. These advances have brought new hope to patients and a clear improvement in overall survival (OS), which has surpassed 20 months.3 At the same time, clinicians continue to face the challenge of formulating a complex plan of care from a large pool of therapeutic options. Whereas combination chemotherapy regimens that incorporate a biologic targeted agent, such as bevacizumab (Avastin, Genentech), became the most commonly used first-line treatment for patients with mCRC, new data show that sequencing the active agents after first-line single-agent fluoropyrimidine therapy may be a feasible approach for some patients. In contrast, the potential to cure patients with metastases to the liver

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or lung that may be resectable requires the administration of the combination regimen most likely to induce a response first line, with the aim of converting the metastatic disease to resectable disease. Emerging data about the utility of predictive markers of efficacy for the targeted biologic agents, such as cetuximab (Erbitux, Bristol-Myers Squibb), offer a novel tool to begin to tailor therapy to specific patients. This review provides an overview of the large body of available data on the treatment of patients with mCRC and serves as a tool for oncologists as they strive to maximize therapeutic benefit for every patient.

First-Line Therapy FLUOROPYRIMIDINES The response rate to monotherapy with 5-FU in patients with mCRC is 11%.4 5-FU/LV became a commonly used regimen, with an improved response rate (RR) of 21%. The increased RR is accompanied by a modest, but statistically significant, survival benefit in comparison with 5-FU monotherapy (11.7 vs 10.5

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Legend to Regimens AIO: LV 500 mg/m2 over 2 h, 5-FU 2,600 mg/m2 by 24-h infusion weekly for 6 wk; repeat every 8 wk bFOL: Oxaliplatin 85 mg/m2, d 1 and 15, LV 20 mg/m2 and 5-FU bolus 500 mg/m2, d 1, 8, and 15; repeat every 4 wk bFOL-B: Oxaliplatin 85 mg/m2, d 1 and 15, LV 20 mg/m2 and 5-FU bolus 500 mg/m2, d 1, 8, and 15, bevacizumab 5 mg/kg every 2 wk; repeat every 4 wk CapIri: Capecitabine 1,000 mg/m2 twice daily for 14 d, irinotecan 100 mg/m2 on d 1 and 8; repeat every 22 d23 or Capecitabine 1,000 mg/m2 twice daily for 14 d, irinotecan 250 mg/m2 on d 1; repeat every 3 wk12 CapOx: Capecitabine 1,000 mg/m2 twice daily for 14 d, oxaliplatin 70 mg/m2 on d 1 and 8; repeat every 22 d CapOx-B: Capecitabine 850 mg/m2 twice daily for 14 d, oxaliplatin 130 mg/m2 on d 1, bevacizumab 7.5 mg/kg on d 1; repeat every 3 wk Chronomodulated FOLFOX: 5-FU 700 mg/m2 over 12 h, LV 300 mg/m2 over 12 h, oxaliplatin 125 mg/m2 over 6 h; repeat every 3 wk FOLFIRI: Irinotecan 180 mg/m2 on d 1, LV 200 mg/m2 on d 1, 5-FU bolus 400 mg/m2 on d 1, followed by 5-FU 2.4-3.0 g/m2 by continuous infusion; repeat every 2 wk FOLFOX-B: Oxaliplatin 85 mg/m2, LV 350 mg, 5-FU bolus 400 mg/m2 and 5-FU 2,400 mg/m2 continuous infusion over 46 h, bevacizumab 5 mg/kg; repeat every 2 wk FOLFOX-4: LV 200 mg/m2/d, 5-FU bolus 400 mg/m2/d, then 5-FU 600 mg/m2/d by 22-h infusion for 2 d consecutively, oxaliplatin 85 mg/m2 on d 1 only; repeat every 2 wk FOLFOX-6: LV 200 mg/m2 over 2 h on d 1, followed by 5-FU bolus 400 mg/m2, then 5-FU 2,400-3,000 mg/m2 by 46-h infusion, oxaliplatin 100 mg/m2 on d 1 only; repeat every 2 wk FUFOX: 5-FU 2,000 mg/m2 over 24 h, LV 500 mg/m2, oxaliplatin 50 mg/m2 weekly for 4 wk; repeat every 6 wk IFL: Irinotecan 125 mg/m2 over 90 min, LV bolus 20 mg/m2, 5-FU bolus 500 mg/m2 weekly for 4 wk; repeat every 6 wk IROX: Oxaliplatin 85 mg/m2 and irinotecan 200 mg/m2; repeat every 3 wk LV5FU2 (de Gramont regimen): LV 200 mg/m2 over 2 h, 5-FU bolus 400 mg/m2 followed by 5-FU 600 mg/m2 by 22-h infusion, d 1 and 2; repeat every 2 wk Mayo Clinic regimen: LV 20 mg/m2 followed by 5-FU 425 mg/m2 on d 1-5; repeat every 4 wk Modified IFL (mIFL): Irinotecan 125 mg/m2 over 90 min, LV bolus 20 mg/m2, 5-FU bolus 500 mg/m2 weekly for 2 wk; repeat every 3 wk Roswell Park regimen: LV 500 mg/m2 over 2 h, 5-FU bolus 500 mg/m2 1 h into LV infusion weekly for 6 wk; repeat every 8 wk XELOX: Capecitabine 1,000 mg/m2 twice daily for 14 d, oxaliplatin 130 mg/m2 on d 1; repeat every 3 wk

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months; P=0.004).2 Capecitabine (Xeloda, Roche) is an oral fluoropyrimidine that is converted to 5-FU by the enzyme thymidilate phosphorylase, which is expressed predominantly in tumor tissue.5 Capecitabine was shown to be at least equivalent to 5-FU/LV as first-line therapy for mCRC in 2 Phase III randomized trials (Table 1).6,7 In both studies, patients in the capecitabine arm had a significantly lower incidence of diarrhea, stomatitis, nausea, and alopecia but a higher incidence of hand–foot syndrome.

COMBINATION REGIMENS Irinotecan-Based Combinations. Irinotecan (Camptosar, Pfizer), a prodrug of SN 38, achieves its antitumor effects by inhibiting topoisomerase I, an enzyme involved in the relaxation of supercoiled DNA.8 Irinotecan, in combination with 5-FU/LV, has been evaluated in the first-line setting in 2 Phase III randomized trials. Saltz et al compared the Mayo Clinic regimen (see Legend for a detailed description of this and other regimens discussed) with single-agent irinotecan and with irinotecan plus 5-FU/bolus LV (IFL). IFL resulted in statistically significant improvements in RR (39% vs 21%; P<0.001), progression-free survival (PFS; 7 vs 4.3 months; P=0.004), and OS (14.8 vs 12.6 months; P=0.04).9 Douillard et al compared infusional 5-FU/LV (de Gramont or AIO regimen) with irinotecan plus infusional 5-FU/LV (FOLFIRI).10 FOLFIRI conferred a statistically significant survival benefit of 17.4 months versus 14.1 months (P=0.031 by log-rank test; Table 2). Fuchs et al reported the results of a multicenter randomized trial that compared the efficacy and safety of 3 different combinations of fluoropyrimidine and irinotecan.11 Patients were randomly assigned to receive FOLFIRI, modified IFL (mIFL), or CapIri (capecitabine 1,000 mg/ m2 twice daily for 14 days and irinotecan 250 mg/m2 on day 1). Using a 3 × 2 factorial design, the investigators also evaluated the effect of celecoxib (Celebrex, Pfizer) on the efficacy and safety of chemotherapy. The trial design was modified to incorporate bevacizumab.

(This review focuses on the results of the first period of enrollment, before the addition of bevacizumab.)

CapIri resulted in a higher rate of grade 3 or higher toxicities (nausea, vomiting, diarrhea, dehydration, and hand–foot syndrome) than did FOLFIRI or mIFL; mIFL resulted in a higher rate of febrile neutropenia, diarrhea, myocardial infarction/stroke, and 60-day mortality than did FOLFIRI. In regard to efficacy, the overall response rates (ORRs) for FOLFIRI, mIFL, and CapIri were 46.6%, 41.9%, and 38%, respectively, with the differences not statistically significant. FOLFIRI demonstrated a statistically significant superior time to progression (TTP) of 8.2 months, versus 6 months for mIFL and 5.7 months for CapIri. Thus, FOLFIRI appears to be the winner of this head-to-head comparison.

Oxaliplatin-Based Combinations. Oxaliplatin (Eloxatin, Sanofi-Aventis) is a platinum analog that inhibits

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Table 1. Comparison of Oral Capecitabine and Bolus 5-FU/LV Study

N

Treatment

Response Rate, %

Median Time to Progression, mo

Overall Survival, mo

Hoff et al7

605

Capecitabinea

25.8

4.3

12.5

b

5-FU/LV (Mayo Clinic) 11.6

4.7

13.3

a

5.2

13.2

4.7

12.1

8

Van Cutsem et al

602

Capecitabine

18.9

5-FU/LV (Mayo Clinic) 15 a

2

b

Capecitabine administration: 1,250 mg/m twice daily for 2 weeks; P=0.005.

5-FU, 5-fluorouracil; LV, leucovorin; see Legend for regimen descriptions.

Table 2. Irinotecan-Based Combinations in First-Line Therapy Study

Response Rate, %

Progression-Free Survival, mo

Overall Survival, mo

IFL vs 5-FU/LV (Mayo Clinic)10

39 vs 21 P<0.001

7 vs 4.3 P=0.004

14.8 vs 12.6 P=0.04

FOLFIRI vs infusional 5-FU/LV11

35 vs 22 P<0.005

6.7 vs 4.4 P<0.001

17.4 vs 14.1 P=0.031

5-FU, 5-fluorouracil; LV, leucovorin; see Legend for regimen descriptions.

Table 3. Oxaliplatin-Based Combinations in First-Line Therapy Response Rate, %

Progression-Free Survival, mo

FOLFOX-4 vs LV5FU2

50 vs 21.9 P<0.001

8.2 vs 6 P<0.001

16.2 vs 14.7

Chr FOLFOX vs Chr 5-FU15

53 vs 16 P<0.001

8.7 vs 6.1 P<0.05

19.1 vs 19.4

FUFOX vs 5-FU/LV (Mayo Clinic)16

49.1 vs 22.6 P<0.001

7.8 vs 5.3 P<0.001

21.4 vs 16.1

Study 14

Overall Survival, mo

Chr, chronomodulated; 5-FU, 5-fluorouracil; LV, leucovorin; see Legend for regimen descriptions.

DNA synthesis through the formation of intra-strand DNA adducts. The diaminocyclohexane moiety, which distinguishes oxaliplatin from other platinum compounds, is thought to enhance its cytotoxicity through the formation of bulkier adducts.12 Three trials have evaluated oxaliplatin with varying doses and modes of administration of 5-FU in first-line therapy and have demonstrated a significant advantage in disease-free survival (Table 3).13-15 The first-line combination of oxaliplatin and capecitabine (XELOX or CapOx) has been evaluated in several Phase II studies, with RRs ranging from 37% to 55% and median OS between 17.1 and 19.5 months.16-18 More

recently, the capecitabine plus oxaliplatin combination has been shown to be equivalent to the 5-FU/folinic acid plus oxaliplatin (FOLFOX type) combination. In a randomized Phase III study with a 2 x 2 factorial design, patients were randomly assigned to receive XELOX or FOLFOX-4, and then bevacizumab or placebo. In a pooled analysis of the XELOX versus FOLFOX-4 arms, XELOX was non-inferior to FOLFOX-4, with a PFS of 8 months versus 8.5 months, respectively, and a median OS of 19.8 months versus 19.6 months, respectively.17 Similar results have been reported by Ducreux et al, who compared XELOX with FOLFOX-6.18 Three different combinations of fluoropyrimidine

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Table 4. Bevacizumab-Based Combinations in First-Line Therapy Study

Response Rate, %

Progression-Free Survival, mo

Median Overall Survival, mo

IFL + BV vs IFL30

26

10.6

20.3 vs 15.6 (P=0.0003)

5-FU/LV/BV vs 5-FU/LV31,32

40 vs 17 (P=0.029)31 26 vs 15 (P=0.05)32

9.0 vs 5.2 (P=0.005)31 9.2 vs 5.5 (P=0.002)32

16.6-21.531,32

FOLFOX + BV vs FOLFOX + placebo17,33 OR XELOX + BV vs XELOX + placebo17,33

38 vs 38a

9.4 vs 8 (P=0.0023)a

21.3 vs 19.9 (P=0.077)a

FOLFIRI + BV11

63.2

11.2

Not reached

mIFL + BV11

53.3

8.3

19.2

BV, bevacizumab; 5-FU, 5-fluorouracil; LV, leucovorin; see Legend for regimen descriptions. a

Response rate, progression-free survival, and overall survival based on analysis combining both BV-containing arms vs both arms containing chemotherapy + placebo.

and oxaliplatin were evaluated for safety and efficacy in the TREE (Three Regimens of Eloxatin Evaluation) study.19 In TREE-1 (the first period of enrollment before the addition of bevacizumab), 150 patients were randomly assigned to receive FOLFOX, bFOL, or CapOx. There were no major differences in efficacy or tolerability among the 3 regimens, but bFOL appeared to have the lowest ORR and TTP. Oxaliplatin Versus Irinotecan: Is There a Winning Combination? A trial conducted by the North Central Cancer Treatment Group (N9741) compared FOLFOX-4, IFL, and IROX in 796 patients.20 FOLFOX-4 resulted in a significantly higher overall RR than did IFL (45.2% vs 32.5%; P=0.0075). The updated OS and TTP at a median of 5 years confirmed the superiority of FOLFOX-4 in comparison to IFL and IROX. FOLFOX-4 resulted in an OS of 20.2 months versus 14.6 months and 17.3 months for IFL and IROX, respectively.21 It is unclear whether the superiority of FOLFOX-4 should be attributed solely to the addition of oxaliplatin or also to the influence of the infusional mode of administration of 5-FU. Another potentially confounding factor is the imbalance in the type of second-line therapy patients received after progression; 60% of patients treated with FOLFOX-4 received second-line irinotecan, whereas 24% of patients treated with IFL received second-line oxaliplatin.20 There is no significant difference between oxaliplatin- and irinotecan-based combinations when the same mode of fluoropyrimidine administration is used.

FOLFOX and FOLFIRI administered in sequence led to similar response and survival rates (see later discus-

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sion).22 Similarly, in a randomized Phase II trial of CapIri versus CapOx (N=161), there were no significant differences in median PFS (8.2 vs 6.6+ months) and median OS (15.8+ months for both).23 Another randomized Phase II study compared CapIri and bevacizumab with CapOx and bevacizumab and reported comparable RR, PFS, and OS for both arms. Of note, the CapIri regimen used in this study had lower doses of irinotecan (200 mg/m2 every 3 weeks) and capecitabine (800 mg/m2 orally twice daily for 14 days every 3 weeks), which resulted in a favorable toxicity profile in comparison with other CapIri regimens.24 Which Combination Should Patients Receive First?

Given that the oxaliplatin (FOLFOX or CapOx) and irinotecan (FOLFIRI or CapIri) combinations appear to be equivalent when the fluoropyrimidine is administered the same way, questions remain about which regimen to administer first. Tournigand et al randomized 226 patients to FOLFOX-6 followed by FOLFIRI, or vice versa, at the time of progression.22 The choice of the first-line regimen did not lead to any difference in RR (54% vs 56%) or OS, which reached 21 months for both arms. A similar conclusion was reached by Grothey et al, who reported an OS that approached 18 months in patients who received CapOx after they failed CapIri or vice versa.23 The Combination of Oxaliplatin and Irinotecan, With and Without 5-FU. As noted earlier, IROX was noted to have clinical activity in mCRC in N9741. The FIRE trial compared infusional 5-FU and irinotecan with IROX; the RRs were 45% and 48%, respectively.25 The PFS and OS with IROX were 7 months and 19.3

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months, respectively, versus 8.2 months and 21.9 months, respectively, with infusional 5-FU and irinotecan (difference not statistically significant). Thus, IROX appears to be a reasonable first-line therapeutic option for mCRC, especially for patients who may be resistant to or intolerant of 5-FU. Pharmacogenomics and molecular profiling are 2 methods by which patients who would not benefit from 5-FU can be identified.

This is an area of active ongoing research.

The combination of oxaliplatin and irinotecan along with 5-FU and leucovorin, known as FOLFOXIRI, represents another feasible therapeutic option, as shown in a Phase III study comparing it with FOLFIRI.26 FOLFOXIRI resulted in an RR of 66% versus 45% with FOLFIRI (P=0.0002), a PFS of 9.8 months versus 6.9 months (P=0.0006), and a median OS of 22.6 months versus 16.7 months (P=0.032). The number of deaths within 60 days after the start of treatment and the rate of febrile neutropenia were similar in both arms, but FOLFOXIRI resulted in a significantly higher incidence of grade 3 and 4 peripheral neuropathy (19% vs 0%; P<0.0001) and neutropenia (50% vs 28%; P=0.0006). This regimen may not be useful in patients older than 75 years or patients with a poor performance status and diffusely metastatic disease, but it may be particularly relevant for patients with unresectable liver metastases who could achieve enough downstaging to undergo potentially curative resection. In this study, the rate of R0 resection in the subset of patients with liver-only metastases was 36% with FOLFOXIRI versus 12% with FOLFIRI (P=0.018).

TARGETED AGENTS Bevacizumab. Bevacizumab is a humanized antibody directed against the vascular endothelial growth factor (VEGF),27 which is highly expressed in colorectal cancer. VEGF has a central role in tumor angiogenesis—it is recognized as the single most important angiogenic mediator in tumor biology.28 Bevacizumab inhibits VEGF-induced angiogenesis and tumor cell growth.27 Bevacizumab is FDA-approved for the first-line treatment of mCRC in combination with IV 5-FU–based chemotherapy.29 Approval was based on 2 randomized, active-controlled trials.

The first trial compared IFL plus placebo with IFL plus bevacizumab and with 5-FU/LV plus bevacizumab.30 The third arm was discontinued once the safety of IFL plus bevacizumab had been established. The addition of bevacizumab to IFL resulted in a significantly higher median survival than did IFL alone (20.3 vs 15.6 months; P=0.0003). An OS of 18.3 months was observed in the 110 patients in the 5-FU/LV-plus-bevacizumab arm.

The second study revealed a significantly improved RR (40% vs 17%; P=0.029) and PFS (9.0 vs 5.2 months; P=0.005) in patients receiving bevacizumab (5 mg/kg) and 5-FU/LV.31 A trend toward improved survival was also observed (21.5 vs 13.8 months). It is not clear why a

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higher dose of bevacizumab (10 mg/kg) did not confer the same benefits. Similar results were reported in a larger study of 209 patients who were unsuitable for first-line irinotecan (Table 4).32 The addition of bevacizumab to the more commonly used combinations, such as FOLFOX and FOLFIRI, has also been evaluated. NO16966 is a Phase III study in which patients were randomly assigned to receive XELOX or FOLFOX-4 and then bevacizumab or placebo, in a 2 x 2 factorial design.33 Patients in the bevacizumab-containing arms had a median PFS of 9.4 months, versus 8 months in the placebo group. RRs were similar in the 2 arms, and there was no statistically significant difference in median OS (20 months).

The lack of improvement in RR and the modest improvement in PFS appeared to be below expectations, especially when compared with the benefit derived from the addition of bevacizumab to IFL in the pivotal trial discussed previously. One of the potential explanations for the modest benefit may be that the number of patients treated with bevacizumab until progression was markedly lower than in previous studies; 29% and 47% of bevacizumab and placebo recipients, respectively, were treated until progression.

The safety and efficacy of bevacizumab in combination with 2 different fluoropyrimidine and irinotecan regimens were evaluated during the second period of enrollment in the BICC-C trial, reported by Fuchs et al (Table 5).11 As noted previously, the trial had been initiated as a comparison of FOLFIRI, mIFL, and CapIri. The results from the first period of enrollment (before the addition of bevacizumab) were reviewed earlier.

After the approval of bevacizumab, the CapIri arm was discontinued, given the lack of safety data when it is combined with bevacizumab; the trial continued with bevacizumab added to FOLFIRI or mIFL. The RRs for FOLFIRI-bevacizumab and mIFL-bevacizumab were comparable (54.4% vs 53.3%). The PFS times were 11.2 and 8.3 months, respectively. Median OS was not reached in the FOLFIRI-bevacizumab arm versus 19.2 months in the mIFL-bevacizumab arm.11 However, mIFL appeared to have a less favorable toxicity profile, with a 60-day mortality of 6.8%, versus 1.8% with FOLFIRI-bevacizumab. Based on these data, one can conclude that FOLFIRI-bevacizumab is one of the standard options for first-line treatment of mCRC. The safety data for the mIFL regimen with or without bevacizumab imply that it should be abandoned.

Preliminary safety results from an ongoing Phase II study comparing CapIri and bevacizumab with FOLFIRI and bevacizumab suggest that the former is a feasible and tolerable regimen.34 Cetuximab. Cetuximab (Erbitux, ImClone Systems/ Bristol-Myers Squibb), a chimeric immunoglobulin G1 monoclonal antibody, binds to the epidermal growth factor receptor (EGFR), inhibits its phosphorylation,

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and prevents the initiation of several intracellular events related to angiogenesis, apoptosis, proliferation, and invasion.35 The role of cetuximab in the treatment of mCRC was first established in patients whose disease had progressed on irinotecan-based therapy (see later discussion). More recently, emerging data have been showing a clinical benefit from the addition of cetuximab to FOLFOX and FOLFIRI in first-line therapy. In the CRYSTAL (Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer) trial, the addition of cetuximab to FOLFIRI resulted in a superior median PFS of 8.9 months versus 8 months for FOLFIRI alone (P=0.0479), as well as a superior RR of 46.9% versus 38.7% (P=0.0038).36 The combination of FOLFOX and cetuximab was compared with FOLFOX alone in a randomized Phase II study, OPUS (Oxaliplatin and Cetuximab in First-Line Treatment of Metastatic Colorectal Cancer).37 The RRs were 45.6% and 35.7%, respectively. As will be discussed later, the benefit from the addition of cetuximab was restricted to patients with wild-type KRAS status. These data led the European Medicines Agency to extend approval of cetuximab to patients with mCRC whose tumors express EGFR and wild-type KRAS, in combination with chemotherapy. Cetuximab was previously restricted to patients who had failed oxaliplatin- or irinotecan-based therapy or who were irinotecan-intolerant.

Bevacizumab and Cetuxiumab Combinations First Line: Feasibility and Efficacy. Two studies have evaluated the impact of the addition of both cetuximab and bevacizumab to first-line chemotherapy. In the PACCE trial, the addition of panitumumab to chemotherapy and bevacizumab was compared to chemotherapy and bevacizumab in two cohorts. In the first cohort, patients were randomly assigned to receive FOLFOX plus bevacizumab, with or without panitumumab. Another cohort of patients received FOLFIRI plus bevacizumab with or without panitumumab. At a planned interim analysis, the number of serious adverse events was 60% in the FOLFOX-bevacizumab-panitumumab arm versus 38% in the FOLFOX-bevacizumab arm. All-cause deaths were also more frequent in the panitumumab arm. The RRs were similar in both arms, while median PFS (9.5 vs 11 months; HR, 1.29; 95% CI, 1.06-1.56) and OS (19.3 vs 20.6 months; HR, 1.4; 95% CI, 1.09-1.81) were inferior in the panitumumab-containing arm. It was the authors’ conclusion that FOLFOX-bevacizumab-panitumumab had an unfavorable benefit-to-risk ratio in unselected patients with mCRC.38 In the irinotecan-based chemotherapy cohort, there were again more serious adverse events and deaths in the panitumumab-containing arm, while the PFS and OS were similar.39 The Dutch Colorectal Cancer Group conducted a randomized Phase III study of capecitabine, oxaliplatin, and bevacizumab, with or without cetuximab in advanced CRC. The RRs were similar between both

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arms, while the PFS was superior in the arm without cetuximab (10.7 vs. 9.4 months; P=0.01). There was no significant difference in OS between the 2 arms. The cetuximab-containing arm had a higher rate of grade 3 and 4 toxicities (82% vs 73%; P=0.0013).40 Based on these studies, the addition of both targeted agents, bevacizumab and cetuximab, to first-line chemotherapy appears to result in higher toxicity and no obvious clinical benefit. The risk for worsened PFS with both targeted agents appears to be worse in the KRAS-mutant group, as discussed later.

Is More Always Better? Up-front Combination Therapy Versus Sequencing. The standard approach to the treatment of patients with mCRC in the United States involves combination first-line chemotherapy, which usually incorporates a biologic targeted agent, most commonly bevacizumab. However, such an aggressive approach may not be needed or even appropriate for every patient. Two European studies evaluated the approach of sequential therapy, starting with a fluoropyrimidine alone, in comparison with upfront combination treatment. The FOCUS (Fluorouracil, Oxaliplatin, and CPT-11 [irinotecan] Use and Sequencing) trial was designed to evaluate whether first-line combination therapy is superior to single-agent therapy with 5-FU followed by the addition of irinotecan or oxaliplatin at the time of progression.41 FOCUS revealed a higher RR and PFS with first-line combination therapy but a similar OS in patients who received single-agent 5-FU followed by combination therapy on progression.

In the CAIRO (Capecitabine, Irinotecan, and Oxaliplatin in Advanced Colorectal Cancer) study, 820 previously untreated patients were randomly assigned to receive capecitabine followed by second-line irinotecan and third-line capecitabine and oxaliplatin, versus the combination of capecitabine plus irinotecan followed by capecitabine plus oxaliplatin on progression.42 There was no statistically significant difference in OS between the sequential and combination groups (16.43 vs 17.4 months, respectively; P=0.33). However, the combination arm had a superior median PFS (7.8 vs 5.8 months; P=0.0002), as well as a higher overall RR. Grade 3 and 4 toxicities in first line were more common in the combination arm except for hand–foot syndrome, which occurred more frequently in the capecitabine-alone arm. Quality-of-life scores were similar in the sequential and combination arms. Until molecular predictors of response become accessible and validated, clinicians will have to rely on their judgment to identify patients who may benefit from combination therapy first and those who may have a similar outcome with 5-FU monotherapy followed by the addition of other agents on progression. For example, one could consider using combination therapy in the first-line treatment of patients who may undergo resection of metastases, are symptomatic, or have

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Table 5A. Toxicity Concerns: First-Line Combination Regimens Without BV Grade 3 or 4 Toxicity, %

FOLFOX-622

Neutropenia

44

Febrile neutropenia

CapOx23

IROX21

FOLFIRI22

FOLFIRI11

0

36

26

43

0

NR

11

7

Diarrhea

11

13.6

24

Vomiting

3

2.4

Mucositis

1

Paresthesias

CapIri23,a

CapIri11,b

mIFL11

0

30.7

41

3.6

NR

5

14

13.9

12.7

47.5

19

22

10

8.8

3.8

15.6

7.3

NR

NR

10

NR

NR

NR

NR

34

6.2

7

0

NR

1.3

NR

NR

MI/stroke

NR

NR

NR

NR

NR

NR

NR

NR

60-Day mortality

NR

NR

NR

NR

3.6

NR

3.5

5.8

12.4

Table 5B. Toxicity Concerns: First-Line Combination Regimens With BV Grade 3 or 4 Toxicity, %

FOLFOX-B20

bFOL-B20

CapOx-B20

FOLFIRI-BV11

mIFL-BV11

Diarrhea

10

26

17

10.7

11.9

Dehydration

6

11

8

5.4

1.7

Neutropenia

35

13

4

53.6

28.8

Neurotoxicity

3

4

7

NR

NR

Hypertension

9

4

10

12.5

1.7

MI/stroke

NR

NR

NR

NR

NR

60-Day mortality

NR

NR

NR

1.8

6.8

a

Based on the following CapIri regimen: capecitabine 1,000 mg/m2 twice daily for 14 d, irinotecan 100 mg/m2 d 1 and 8; repeat every 22 d.

b

Based on the following CapIri regimen: capecitabine 1,000 mg/m2 twice daily for 14 d, irinotecan 250 mg/m2 d 1; repeat every 3 wk.12

BV, bevacizumab; MI, myocardial infarction; NR, not reported; see Legend for regimen descriptions.

peritoneal carcinomatosis. Otherwise, both FOCUS and CAIRO suggest that sequential therapy is appropriate for certain patients. The limitation of both of these studies is that they do not incorporate targeted agents or address the option of an approach in which patients start with combination therapy but then receive a maintenance-type treatment, as was the case in the OPTIMOX (FOLFOX-7/LV5FU2 Compared to FOLFOX-4 in Patients With Advanced Colorectal Cancer) studies.43,44

Second-Line Therapy IRINOTECAN FAILURE Bevacizumab. The addition of bevacizumab to FOLFOX-4 was found to confer a statistically significant survival benefit versus FOLFOX-4 alone in patients who had received 5-FUâ&#x20AC;&#x201C;based therapy and irinotecan (12.5 vs 10.7 months; P=0.0018).45 It is

important to note that the combination of FOLFOX-4 plus bevacizumab was evaluated as a second-line regimen in patients who had not received bevacizumab as first-line therapy. At this point, there are no prospective, randomized data to support the continued use of bevacizumab as part of a second-line regimen in patients who have progression of disease on a regimen containing bevacizumab. In BRiTE (Bevacizumab Regimens Investigation of Treatment Effects and Safety), an observational registry started in early 2004 that was designed to evaluate the efficacy and safety of bevacizumab in combination with chemotherapy, 44% of 1,445 patients who had progression of disease on first-line chemotherapy and bevacizumab received bevacizumab beyond progression (BBP); in other words, this group of patients received bevacizumab as second-line therapy, after having progressed on a first-line regimen containing bevacizumab.46 The median OS of patients who received BBP reached 31.8

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months, whereas patients who did not receive BBP had a median OS of 19.9 months. The median OS for all patients in the registry was 25.1 months. These data are considered to be hypothesis-generating but are limited by several potential inherent biases given the observational nature of the study.

Cetuximab. Several studies have established the role of cetuximab in the treatment of patients who have failed irinotecan-based therapy. The RR with a cetuximab-plus-irinotecan combination after irinotecan failure was 17% in a Phase II study of 121 patients.47 Cetuximab monotherapy in the same setting produced an RR of 10.5%.48 Cunningham et al randomized 329 patients with disease progression after irinotecanbased therapy to cetuximab plus irinotecan or to cetuximab alone in the BOND (Bowel Oncology With Cetuximab Antibody) Phase II trial.49 The RR was 22.9% for the combination arm versus 10.8% for the cetuximab monotherapy arm (P=0.007). A significant improvement in the rate of disease control (complete response [CR] + partial response [PR] + stable disease [SD]) was also noted (55.5% vs 36%; P<0.001).

PFS was significantly better in the combination arm (4.1 vs 1.5 months), but the difference in median OS was not statistically significant (8.6 vs 6.9 months).

This may be partly related to the fact that 50% of patients in the monotherapy group received combination therapy with irinotecan after progression. Lastly, the degree of EGFR overexpression did not correlate with clinical response, and the RR in patients with skin reactions was higher (25.8% vs 6.3%; P=0.005).

Recently, mutant-KRAS status has been shown to confer resistance to anti-EGFR therapy with cetuximab or panitumumab (see following text). The studies discussed in this paragraph did not account for the predictive value of KRAS, which had not been established when they were designed.

Bevacizumab Plus Cetuximab. The combination of bevacizumab plus cetuximab and the combination of bevacizumab plus cetuximab and irinotecan (CBI) were evaluated in a Phase II trial known as BOND-2.50 Patients had not received prior anti-VEGF or anti-EGFR therapy. The RR and TTP noted in patients treated with bevacizumab plus cetuximab or CBI were compared with those in historical controls treated with cetuximab alone or cetuximab plus irinotecan. Bevacizumab plus cetuximab resulted in a significant improvement in the RR (23% vs 11%; P=0.05) and TTP (6.9 vs 1.5 months; Pâ&#x2030;¤0.01) in comparison with cetuximab alone. Similarly, CBI improved the RR (38% vs 23%; P=0.03) and TTP (8.5 vs 4 months; P<0.01) in comparison with the cetuximab-and-irinotecan combination alone. Both regimens were well tolerated, and no evidence was found of synergistic toxicity in patients given bevacizumab plus cetuximab. Among patients receiving CBI, the incidence rates of grade 3/4 neutropenia and diarrhea were 18%

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and 26%, respectively. Bevacizumab plus cetuximab was well tolerated; 17% of patients had a grade 3 skin rash, and no patients had grade 4 toxicities. These data from 74 patients suggest that the addition of bevacizumab improves the efficacy of cetuximab alone and of the cetuximab-and-irinotecan combination in patients with irinotecan-refractory disease.

Oxaliplatin Combinations. Oxaliplatin-based combinations are established options for patients with disease progression after irinotecan-based therapy. FOLFOX-6 yielded an RR of 15% in patients who failed FOLFIRI.22 In patients with disease progression on CapIri, CapOx yielded an RR of 12.7%, PFS of 4.3 months, and OS of 10.6 months after the start of second-line therapy.51

OXALIPLATIN FAILURE Irinotecan Combinations. FOLFIRI and CapIri are established combination regimens that can be used in patients whose disease has progressed on oxaliplatinbased therapy, such as FOLFOX and bevacizumab.

An RR of 20.6% and a PFS of 5.1 months have been achieved with CapIri.51 FOLFIRI has produced an RR of 4% and a PFS of 2.5 months.22 Irinotecan Monotherapy. It is unclear whether irinotecan monotherapy after oxaliplatin failure is equivalent to the combination of 5-FU and irinotecan. The FOCUS trial mentioned previously suggests that irinotecan may be more effective as second-line therapy if 5-FU is continued rather than stopped (RR, 21% vs 11%).

Although this observation is worth noting, the final answer regarding the use of irinotecan alone versus 5-FU and irinotecan after oxaliplatin failure is not available at this point. FOCUS is a 5-arm trial powered to look for differences in OS among several sequencing modalities, but not specifically powered to compare irinotecan monotherapy versus 5-FU and irinotecan as second-line therapy.

Irinotecan Plus Cetuximab (for patients with wildtype KRAS). The combination of irinotecan and cetuximab was compared with irinotecan alone in a randomized Phase III study of 1,298 patients who had received first-line treatment with a fluoropyrimidine and oxaliplatin. The median OS of 10 months was comparable between the 2 arms. However, the combination of irinotecan and cetuximab resulted in a superior PFS of 4 months versus 2.6 months with irinotecan alone (HR, 0.692; P=0.0001), as well as a superior RR (16.4% vs 4.2%; P<0.0001). The combination was significantly more effective in maintaining overall quality of life, with superior results in 10 of 15 domains, including fatigue, diarrhea, and physical and emotional functioning. This study failed to meet its primary end point, given the lack of difference in OS, but this may be partly attributed to the fact that 47% of patients who received irinotecan alone subsequently received a cetuximab-containing treatment.52

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The superior RR, PFS, and quality-of-life scores seen with the combination suggest that it is a reasonable second-line option; the higher RR provides a theoretical rationale for using the combination for patients who are symptomatic or patients who could benefit from downstaging and subsequent resection of metastases in the liver or lung.

IRINOTECAN

AND

OXALIPLATIN FAILURE

Cetuximab (only for patients with wild-type KRAS). Cetuximab was compared with best supportive care (BSC) in a randomized Phase III study that included 572 patients who had failed treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. The majority of patients had received 3 or more lines of therapy.

Cetuximab treatment was associated with a significant improvement in OS (6.1 vs 4.6 months; HR for death, 0.77; P=0.005); 8% of patients treated with cetuximab had a PR and 31.4% had SD, versus no PR and 10.9% with SD in the BSC group.53 Panitumumab (only for patients with wild-type KRAS). In contrast to the chimeric antibody cetuximab, panitumumab is a fully human monoclonal antibody that binds to the EGFR. Panitumumab resulted in a PR rate of 10% in 148 patients who had failed therapy with 5-FU and either oxaliplatin or irinotecan or both.54 Panitumumab recently received FDA approval for the treatment of patients with EGFR-expressing mCRC with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens. This approval was granted based on the results of a trial that randomized 463 patients to BSC alone or BSC and IV panitumumab at a dosage of 6 mg/kg every other week.55 The investigators found that 19 (8%) of 231 patients assigned to panitumumab had a PR. The mean PFS was 96 days with panitumumab and 60 days with BSC alone.

These studies have established cetuximab and panitumumab as potential single-agent third-line options for patients with mCRC after failure of fluoropyrimidine, oxaliplatin, and irinotecan. However, recent data about the predictive role of KRAS status indicate that treatment with anti-EGFR antibodies should be restricted to patients with wild-type KRAS, as discussed later.

The Concept of Tailored Therapy: The Beginning of a New Era KRAS STATUS

AND

ANTI-EGFR THERAPY

KRAS is a member of the downstream signaling pathway of EGFR. Mutations of KRAS lead to constitutive activation of KRAS, therefore bypassing the need for EGFR activation by ligand binding.56 Several retrospective studies showed that the activity of cetuximab and panitumumab as single agents is restricted to patients with wild-type KRAS (Table 6).56-60 In the

CRYSTAL trial, patients with previously untreated mCRC were randomly assigned to FOLFIRI or to FOLFIRI plus cetuximab. Based on the data highlighting the impact of KRAS mutational status in codons 12 and 13 on sensitivity to anti-EGFR antibody therapy, a retrospective analysis examined the impact of KRAS on PFS and RR in patients randomly assigned to the 2 arms of the CRYSTAL trial; 587 of 1,198 patients treated had their tumor samples analyzed for KRAS mutation status. The KRAS-evaluable population was comparable with the intent-to-treat population of the study.

In the KRAS wild-type population, the PFS was 9.9 months for FOLFIRI plus cetuximab versus 8.7 months for FOLFIRI alone (HR, 0.68; P=0.017). In contrast, there was no difference in PFS between the 2 arms in the KRAS-mutant population (PFS, 7.6 vs 8.1 months; HR, 1.07; P=0.47).57 When patients were randomized to receive FOLFOX with cetuximab versus FOLFOX alone in the OPUS trial, the improvement in RR was restricted to patients with wild-type KRAS (RR, 61% for FOLFOX + cetuximab vs 37% for FOLFOX alone).

In contrast, patients with mutated KRAS manifested a trend toward a lower RR when treated with FOLFOX and cetuximab compared with FOLFOX alone (33% vs 49%; P=0.106).60 Other potential predictive markers of cetuximab activity, such as the EGFR ligands epiregulin and amphiregulin and the PTEN gene, have been examined in a retrospective manner in small studies.56,61 Although further discussion of these results is beyond the scope of this review, the addition of these entities to the armamentarium of predictive markers may further refine the selection of patients who would benefit from anti-EGFR antibody therapy.

KRAS STATUS

AND

ANTI-VEGF THERAPY

Data regarding the impact of KRAS status on the efficacy of bevacizumab in combination with chemotherapy are limited to a retrospective analysis of a subgroup of patients who were treated with IFL verus IFL and bevacizumab in a randomized Phase III study. The median PFS was significantly longer in bevacizumab-treated patients with wild-type (13.5 vs 7.4 months; P=0.0001) and mutant KRAS (9.3 vs 5.5 months; P=0.0008). The response rate was the same in both arms for the patients with mutant KRAS. These data suggest that bevacizumab provides significant clinical benefit in patients with either wild-type or mutant KRAS. 62 Further data are needed to assess the impact of KRAS status on the efficacy of bevacizumab, especially when given in combination with FOLFOX as is most commonly done in the United States. There are otherwise no established predictive markers for bevacizumab efficacy, but an ongoing retrospective study has examined the potential role of genomic polymorphisms in predicting sensitivity to bevacizumab.63 Validation of such preliminary results and others is pending.

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Table 6. Partial List of Studies Highlighting Predictive Role of KRAS Mutational Status in Patients Treated With Anti-EGFR Antibody Therapy

Study

Treatment

56

No. of Patients With Evaluable KRAS (%Wt : %Mt)

Response Rate, %

Progression-Free Survival

Wt KRAS

Mt KRAS

Wt KRAS

Mt KRAS

0

61 d

59 d

Khambata-Ford et al

Cetuximab

80 (62.5:37.5)

10

Van Cutsem et al (CRYSTAL)57

FOLFIRI + cetuximab vs FOLFIRI

540 (64.4:35.6)

59.3 36.2 vs vs 43.2; 40.2; P=0.0025 P=0.46

9.9 vs 8.7 mo; P=0.017

7.6 vs 8.1 mo; P=0.47

Lievre et al58

Mostly irinotecan/ cetuximab

114 (68:32)

43.6

0

32 wk

9 wk

Amado et al59

Panitumumab vs BSC

208 (59.6:40.4)

17

0

12.3 vs 7.3 wka

7.4 vs 7.3 wka

Bokemeyer et al (OPUS)60

FOLFOX + cetuximab vs FOLFOX

233 (58:42)

60.7 vs 37; P=0.011

32.7 vs 48.9; P=0.106

7.7 vs 7.2 mo; P=0.016

5.5 vs 8.6 mo; P=0.0192

a Progression-free survival in panitumumab-treated group versus BSC group.

BSC, best supportive care; Mt, mutant; Wt, wild-type; see Legend for regimen descriptions.

Participation in Clinical Trials Patients with progressive disease after treatment with a fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and cetuximab benefit from participation in a clinical trial. Several targeted biologic agents are undergoing evaluation alone or in combination with chemotherapy. Furthermore, there is a new urgent need to identify agents that may restore sensitivity to anti-EGFR therapy or bypass the resistance to antiEGFR therapy in patients with mutant KRAS. At this time, these patients do not benefit from cetuximab- or panitumumab-based therapy, which limits their treatment options after progression on 5-FU, oxaliplatin, irinotecan, and bevacizumab.

Conclusion The treatment of mCRC has been revolutionized with the advent of new active cytotoxic and biologic agents. Although significant strides have been made in improving survival and allowing some patients with metastatic disease to be potentially cured, significant challenges remain in our ability to tailor therapy to the individual patient. At this time, clinical judgment and patient preferences may influence the approach to treatment; for example, a patient with potentially

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resectable mCRC would benefit from a combination regimen that would maximize the chance of a response. In contrast, a patient with widely metastatic disease with no chance of cure might prefer a sequential approach that could reduce the risk for toxicity.

KRAS mutation status offers a new tool to restrict treatment with anti-EGFR antibodies to patients with wild-type KRAS, which in turn will prevent patients with mutant KRAS from being exposed to this therapy and its toxicities unnecessarily. The concept of lines of therapy that have been used to plan the treatment of mCRC must be supplemented by the emerging approach in which the lines of treatment may be blurred, and the focus is on tailored therapy to optimize the outcomes of individual patients.

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42. Punt CJ, Koopman M, Douma J, et al. Sequential compared to combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (ACC): a Dutch Colorectal Cancer Group (DCCG) phase III study. J Clin Oncol.

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43. Tournigand C, Cervantes A, Figer A, et al. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer—a GERCOR study. J Clin Oncol. 2006;24:394-400.

44. Maindrault-Goebel F, Lledo G, Chibaudel B, et al. Final results of OPTIMOX2, a large randomized phase II study of maintenance therapy or chemotherapy-free intervals (CFI) after FOLFOX in patients with metastatic colorectal cancer (MRC): a GERCOR study. J Clin Oncol. 2007;25(18 suppl):abstract 4013.

45. Giantonio BJ, Catalano PJ, Meropol NJ, et al. High dose bevacizumab improves survival when combined with FOLFOX4 in previously treated advanced colorectal cancer: results from the Eastern Cooperative Oncology Group (ECOG) study E3200.

J Clin Oncol. 2005;23(18 suppl):abstract 2.

46. Grothey A, Sugrue M, Hedrick D, et al. Association between exposure to bevacizumab (BV) beyond first progression (BBP) and overall survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC): results from a large observational study (BRiTE). J Clin Oncol. 2007;25(18 suppl):abstract 4036.

47. Saltz L, Rubin M, Hochster H, et al. Cetuximab (IMC-C225) plus irinotecan (CPT-11) is active in CPT-11–refractory colorectal cancer (CRC) that expresses epidermal growth factor receptor (EGFR). Clin Oncol. 2001;19(18 suppl):abstract 7.

48. Saltz LB, Meropol NJ, Loehrer PJ Sr, Needle MN, Kopit J, Mayer RJ. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor.

J Clin Oncol. 2004;22(7):1201-1208, PMID: 14993230.

49. Cunningham D, Humblet Y, Siena S, et al. Cetuximab (C225) alone or in combination with irinotecan (CPT-11) in patients with epidermal growth factor (EGFR) positive, irinotecan refractory

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metastatic colorectal cancer (mCRC). J Clin Oncol. 2003; 21(18 suppl):abstract 1012.

50. Saltz LB, Lenz HJ, Kindler H, et al. Interim report of randomized Phase II trial of cetuximab/bevacizumab/irinotecan (CBI) versus cetuximab/bevacizumab (CB) in irinotecan-refractory colorectal cancer. Presented at: ASCO Gastrointestinal Cancers Symposium; January 27-29, 2005; Miami, FL. Abstract 169b.

51. Grothey A, Jordan K, Kellner O, et al. Capecitabine/irinotecan (CapIri) and capecitabine/oxaliplatin (CapOx) are active second-line protocols in patients with advanced colorectal cancer (ACRC) after failure of first-line combination therapy: results of a randomized Phase II study. J Clin Oncol. 2004; 22(18 suppl):abstract 3534.

52. Sobrero A, Maurel J, Fehrenbacher L, et al. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer.

J Clin Oncol. 2008;26(14):2311-2319, PMID: 18390971.

53. Jonker DJ, O’Callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;357(20):2040-2048, PMID: 18003960.

54. Malik I, Hecht JR, Patnaik A, et al. Safety and efficacy of panitumumab monotherapy in patients with metastatic colorectal cancer. J Clin Oncol. 2005;23(18 suppl): abstract 3520.

55. Peeters M, Van Cutsem E, Siena S, et al. A phase 3, multicenter, randomized controlled trial of panitumumab plus best supportive care (BSC) vs BSC alone in patients with metastatic colorectal cancer. Presented at: 97th Annual Meeting of the American Association for Cancer Research; April 1-5, 2006; Washington, DC. Abstract CP-1.

56. Khambata-Ford S, Garrett CR, Meropol NJ. Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol. 2007;25(22):3230-3237, PMID: 17664471.

57. Van Cutsem E, Lang I, D’haens G, et al. KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: the CRYSTAL experience. J Clin Oncol.

2008;26(18 suppl):abstract 2.

58. Lievre A, Bachet JB, Boige V, et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol.

2008;26(3):374-379, PMID: 18202412.

59. Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol.

2008;26(10):1626-1634.

60. Bokemeyer C, Bondarenko I, Hartmann T, et al. KRAS status and efficacy of first-line treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: the OPUS experience. J Clin Oncol.

26(18 suppl):abstract 4000.

61. Loupakis F, Pollina L, Stasi I, et al. Evaluation of PTEN expression in colorectal cancer (CRC) metastases (mets) and in primary tumors as predictors of activity of cetuximab plus irinotecan treatment. J Clin Oncol. 2008;26(18 suppl):abstract 4003.

62. Hurwitz HI, Yi J, Ince W, et al. The clinical benefit of bevacizumab in metastatic colorectal cancer is independent of KRAS mutation status: analysis of a Phase III study of bevacizumab with chemotherapy in previously untreated metastatic colorectal cancer. Oncologist. 2009;14:22-28, PMID: 19144677.

63. Manegold P, El-Khoueiry AB, Lurje G. ICAM-1, GRP-78, and NFkB gene polymorphisms and clinical outcome in patients (pts) with metastatic colorectal cancer (mCRC) treated with first line 5-FU or capecitabine in combination with oxaliplatin and bevacizumab (FOLFOX/BV or XELOX/BV). J Clin Oncol.

2008;26(18 suppl):abstract 4134.

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Vectibix® (panitumumab) Injection for Intravenous Use Brief Summary of Prescribing Information.

For complete prescribing information consult official package insert.

WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONS Dermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 and higher) in 12% of patients receiving Vectibix® monotherapy. [see Dosage and Administration, Warnings and Precautions, and Adverse Reactions].

Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. [see Warnings and Precautions and Adverse Reactions]. Although not reported with Vectibix®, fatal infusion reactions have occurred with other monoclonal antibody products. [see Dosage and Administration].

INDICATIONS AND USAGE Vectibix® is indicated as a single agent for the treatment of EGFR-expressing, metastatic colorectal carcinoma (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.

The effectiveness of Vectibix® as a single agent for the treatment of EGFR-expressing, metastatic colorectal carcinoma is based on progression-free survival [see Clinical Studies (14) in Full Prescribing Information]. Currently, no data demonstrate an improvement in disease-related symptoms or increased survival with Vectibix®.

DOSAGE AND ADMINISTRATION Recommended Dose and Dose Modifications The recommended dose of Vectibix® is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. Doses higher than 1000 mg should be administered over 90 minutes [see Preparation and Administration].

Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix® infusions.

Dose Modifications for Infusion Reactions [see Adverse Reactions] • Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion.

• Immediately and permanently discontinue Vectibix® infusion in patients experiencing severe (grade 3 or 4) infusion reactions.

Dose Modifications for Dermatologic Toxicity [see Adverse Reactions] • Withhold Vectibix® for dermatologic toxicities that are grade 3 or higher or are considered intolerable. If toxicity does not improve to ≤ grade 2 within 1 month, permanently discontinue Vectibix®.

• If dermatologic toxicity improves to ≤ grade 2, and the patient is symptomatically improved after withholding no more than two doses of Vectibix®, treatment may be resumed at 50% of the original dose.

– If toxicities recur, permanently discontinue Vectibix®.

– If toxicities do not recur, subsequent doses of Vectibix® may be increased by increments of 25% of the original dose until the recommended dose of 6 mg/kg is reached.

Preparation and Administration Do not administer Vectibix® as an intravenous push or bolus.

Preparation Prepare the solution for infusion, using aseptic technique, as follows: • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Although Vectibix® should be colorless, the solution may contain a small amount of visible translucent-to-white, amorphous, proteinaceous, panitumumab particulates (which will be removed by filtration; see below). Do not shake. Do not administer Vectibix® if discoloration is observed.

• Withdraw the necessary amount of Vectibix® for a dose of 6 mg/kg.

• Dilute to a total volume of 100 mL with 0.9% sodium chloride injection, USP. Doses higher than 1000 mg should be diluted to 150 mL with 0.9% sodium chloride injection, USP. Do not exceed a final concentration of 10 mg/mL. • Mix diluted solution by gentle inversion. Do not shake.

Administration • Administer using a low-protein-binding 0.2 μm or 0.22 μm in-line filter.

• Vectibix® must be administered via infusion pump.

– Flush line before and after Vectibix® administration with 0.9% sodium chloride injection, USP, to avoid mixing with other drug products or intravenous solutions. Do not mix Vectibix® with, or administer as an infusion with, other medicinal products. Do not add other medications to solutions containing panitumumab.

– Infuse over 60 minutes through a peripheral intravenous line or indwelling intravenous catheter. Doses higher than 1000 mg should be infused over 90 minutes.

Use the diluted infusion solution of Vectibix® within 6 hours of preparation if stored at room temperature, or within 24 hours of dilution if stored at 2° to 8°C (36° to 46°F). DO NOT FREEZE. Discard any unused portion remaining in the vial.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Dermatologic Toxicity In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 16% of patients with mCRC receiving Vectibix®. The clinical manifestations included, but were not limited to, dermatitis acneiform, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, and abscesses requiring incisions and drainage were reported. Withhold Vectibix® for severe or life-threatening dermatologic toxicity [see Boxed Warning, Adverse Reactions, and Dosage and Administration].

Infusion Reactions In Study 1, 4% of patients experienced infusion reactions and in 1% of patients, these reactions were graded as severe (NCI-CTC grade 3–4).

Across all clinical studies, severe infusion reactions occurred with the administration of Vectibix® in approximately 1% of patients. Severe infusion reactions included anaphylactic reactions, bronchospasm, and hypotension [see Boxed Warning and Adverse Reactions]. Although fatal infusion reactions have not been reported with Vectibix®, fatalities have occurred with other monoclonal antibody products. Stop infusion if a severe infusion reaction occurs. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix® [see Dosage and Administration].

Increased Toxicity With Combination Chemotherapy Vectibix® is not indicated for use in combination with chemotherapy. In an interim analysis of Study 2, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased overall survival and increased incidence of NCI-CTC grade 3–5 (87% vs 72%) adverse reactions [see Clinical Studies (14) in Full Prescribing Information]. NCI-CTC grade 3–4 adverse drug reactions occurring at a higher rate in Vectibix®-treated patients included rash/dermatitis/acneiform (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs <1%), and hypomagnesemia (4% vs 0). NCI-CTC grade 3–5 pulmonary embolism occurred at a higher rate in Vectibix®-treated patients (7% vs 4%) and included fatal events in three (<1%) Vectibix®-treated patients.

As a result of the toxicities experienced, patients randomized to Vectibix®, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study, compared with those randomized to bevacizumab and chemotherapy.

In a single-arm study of 19 patients receiving Vectibix® in combination with IFL, the incidence of NCI-CTC grade 3–4 diarrhea was 58%; in addition, grade 5 diarrhea occurred in one patient. In a single-arm study of 24 patients receiving Vectibix® plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%.

Pulmonary Fibrosis Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. Following the initial fatality, patients with a history of interstitial pneumonitis, pulmonary fibrosis, evidence of interstitial pneumonitis, or pulmonary fibrosis were excluded from clinical studies. Therefore, the estimated risk in a general population that may include such patients is uncertain.

One case occurred in a patient with underlying idiopathic pulmonary fibrosis who received Vectibix® in combination with chemotherapy and resulted in death from worsening pulmonary fibrosis after four doses of Vectibix®. The second case was characterized by cough and wheezing 8 days following the initial dose, exertional dyspnea on the day of the seventh dose, and persistent symptoms and CT evidence of pulmonary fibrosis following the 11th dose of Vectibix® as monotherapy. An additional patient died with bilateral pulmonary infiltrates of uncertain etiology with hypoxia after 23 doses of Vectibix® in combination with chemotherapy. Permanently discontinue Vectibix® therapy in patients developing interstitial lung disease, pneumonitis, or lung infiltrates.

Electrolyte Depletion/Monitoring In Study 1, median magnesium levels decreased by 0.1 mmol/L in the panitumumab arm; hypomagnesemia (NCI-CTC grade 3 or 4) requiring oral or intravenous electrolyte repletion occurred in 2% of patients. Hypomagnesemia occurred 6 weeks or longer after the initiation of Vectibix®.

In some patients, both hypomagnesemia and hypocalcemia occurred. Patients’ electrolytes should be periodically monitored during and for 8 weeks after the completion of Vectibix® therapy. Institute appropriate treatment, eg, oral or intravenous electrolyte repletion, as needed.

Photosensitivity Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix®.

EGF Receptor Testing Detection of EGFR protein expression is necessary for selection of patients appropriate for Vectibix® therapy because these are the only patients studied and for whom benefit has been shown [see Indications and Usage, and Clinical Studies (14) in Full Prescribing Information]. Patients with colorectal cancer enrolled in Study 1 were required to have immunohistochemical evidence of EGFR expression using the Dako EGFR pharmDx® test kit.

Assessment for EGFR expression should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specific reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. Refer to the package insert for the Dako EGFR pharmDx® test kit, or other test kits approved by FDA, for identification of patients eligible for treatment with Vectibix® and for full instructions on assay performance.

ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Dermatologic Toxicity [see Boxed Warning and Warnings and Precautions] • Infusion Reactions [see Boxed Warning and Warnings and Precautions] • Increased Toxicity With Combination Chemotherapy [see Warnings and Precautions] • Pulmonary Fibrosis [see Warnings and Precautions] • Electrolyte Depletion/Monitoring [see Warnings and Precautions] • Photosensitivity [see Warnings and Precautions] The most common adverse events of Vectibix® are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including diarrhea resulting in dehydration.

The most serious adverse events of Vectibix® are pulmonary fibrosis, pulmonary embolism, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation. Adverse reactions requiring discontinuation of Vectibix® were infusion reactions, severe skin toxicity, paronychia, and pulmonary fibrosis.

Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates in the clinical studies of a drug cannot be directly compared to rates in clinical studies of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Safety data are available from 15 clinical trials in which 1467 patients received Vectibix®; of these, 1293 received Vectibix® monotherapy and 174 received Vectibix® in combination with chemotherapy [see Warnings and Precautions].

The data described in Table 1 and in other sections below, except where noted, reflect exposure to Vectibix® administered as a single agent at the recommended dose and schedule (6 mg/kg every 2 weeks) in 229 patients with mCRC enrolled in Study 1, a randomized, controlled trial. The median number of doses was five (range: one to 26 doses), and 71% of patients received eight or fewer doses. The population had a median age of 62 years (range: 27 to 82 years), 63% were male, and 99% were white with < 1% black, < 1% Hispanic, and 0% other.

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Table 1. Per-Patient Incidence of Adverse Reactions Occurring in ≥ 5% of Patients with a Between-Group Difference of ≥ 5% (Study 1) Patients Treated With Vectibix® Plus BSC (n = 229) Best Supportive Care (BSC) Alone (n = 234) Grade* All Grades Grade 3–4 All Grades Grade 3–4 % % % % Body as a Whole Fatigue 26 4 15 3 General Deterioration 11 8 4 3 Digestive Abdominal Pain 25 7 17 5 Nausea 23 1 16 <1 Diarrhea 21 2 11 0 Constipation 21 3 9 1 Vomiting 19 2 12 1 Stomatitis 7 0 1 0 Mucosal Inflammation 6 <1 1 0 Metabolic/Nutritional Hypomagnesemia (Lab) 38 4 2 0 Peripheral Edema 12 1 6 <1 Respiratory Cough 14 <1 7 0 Skin/Appendages All Skin/Integument Toxicity 90 16 9 0 Skin 90 14 6 0 Erythema 65 5 1 0 Acneiform Dermatitis 57 7 1 0 Pruritus 57 2 2 0 Nail 29 2 0 0 Paronychia 25 2 0 0 Skin Exfoliation 25 2 0 0 Rash 22 1 1 0 Skin Fissures 20 1 <1 0 Eye 15 <1 2 0 Acne 13 1 0 0 Dry Skin 10 0 0 0 Other Nail Disorder 9 0 0 0 Hair 9 0 1 0 Growth of Eyelashes 6 0 0 0 *Version 2.0 of the NCI-CTC was used for grading toxicities. Skin toxicity was coded based on a modification of the NCI-CTCAE, version 3.0.

Body System

Dermatologic, Mucosal, and Ocular Toxicity In Study 1, dermatologic toxicities occurred in 90% of patients receiving Vectibix®. Skin toxicity was severe (NCI-CTC grade 3 and higher) in 16% of patients. Ocular toxicities occurred in 15% of patients and included, but were not limited to: conjunctivitis (4%), ocular hyperemia (3%), increased lacrimation (2%), and eye/eyelid irritation (1%). Stomatitis (7%) and oral mucositis (6%) were reported. One patient experienced a NCI-CTC grade 3 event of mucosal inflammation.The incidence of paronychia was 25% and was severe in 2% of patients. Nail disorders occurred in 9% of patients [see Warnings and Precautions].

Median time to the development of dermatologic, nail, or ocular toxicity was 14 days; the time to most severe skin/ocular toxicity was 15 days after the first dose of Vectibix®; and the median time to resolution after the last dose of Vectibix® was 84 days. Severe toxicity necessitated dose interruption in 11% of Vectibix®-treated patients [see Dosage and Administration].

Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, and abscesses requiring incisions and drainage, were reported.

Infusion Reactions Infusional toxicity was defined as any event described at any time during the clinical study as allergic reaction or anaphylactoid reaction, or any event occurring on the first day of dosing described as allergic reaction, anaphylactoid reaction, fever, chills, or dyspnea. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Vectibix® infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across several clinical trials of Vectibix® monotherapy, 3% (43/1336) experienced infusion reactions of which approximately 1% (6/1336) were severe (NCI-CTC grade 3–4). In one patient, Vectibix® was permanently discontinued for a serious infusion reaction [see Dosage and Administration].

Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity.The immunogenicity of Vectibix® has been evaluated using two different screening immunoassays for the detection of anti-panitumumab antibodies: an acid dissociation bridging enzyme-linked immunosorbent assay (ELISA) (detecting high-affinity antibodies) and a Biacore® biosensor immunoassay (detecting both high- and low-affinity antibodies). The incidence of binding antibodies to panitumumab (excluding predose and transient positive patients), as detected by the acid dissociation ELISA, was 3/613 (< 1%) and as detected by the Biacore® assay was 28/613 (4.6%).

For patients whose sera tested positive in screening immunoassays, an in vitro biological assay was performed to detect neutralizing antibodies. Excluding predose and transient positive patients, 10 of the 613 patients (1.6%) with postdose samples and 3/356 (0.8%) of the patients with follow-up samples tested positive for neutralizing antibodies.

No evidence of altered pharmacokinetic profile or toxicity profile was found between patients who developed antibodies to panitumumab as detected by screening immunoassays and those who did not.

The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to panitumumab with the incidence of antibodies to other products may be misleading.

DRUG INTERACTIONS No formal drug-drug interaction studies have been conducted with Vectibix®.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. There are no studies of Vectibix® in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring.

[See Reproductive and Developmental Toxicology]. Vectibix® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, panitumumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women.

Women who become pregnant during Vectibix® treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-772-6436 (1-800-77-AMGEN) to enroll.

Nursing Mothers It is not known whether panitumumab is excreted into human milk; however human IgG is excreted into human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Vectibix® [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Pediatric Use The safety and effectiveness of Vectibix® have not been established in pediatric patients. The pharmacokinetic profile of Vectibix® has not been studied in pediatric patients.

Geriatric Use Of 229 patients with mCRC who received Vectibix® in Study 1, 96 (42%) were ≥age 65. Although the clinical study did not include a sufficient number of geriatric patients to determine whether they respond differently from younger patients, there were no apparent differences in safety and effectiveness of Vectibix® between these patients and younger patients.

OVERDOSAGE Doses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity or mutagenicity studies of panitumumab have been conducted. It is not known if panitumumab can impair fertility in humans. Prolonged menstrual cycles and/or amenorrhea occurred in normally cycling, female cynomolgus monkeys treated weekly with 1.25 to 5 times the recommended human dose of panitumumab (based on body weight). Menstrual cycle irregularities in panitumumab-treated female monkeys were accompanied by both a decrease and delay in peak progesterone and 17 -estradiol levels. Normal menstrual cycling resumed in most animals after discontinuation of panitumumab treatment.A no-effect level for menstrual cycle irregularities and serum hormone levels was not identified.The effects of panitumumab on male fertility have not been studied. However, no adverse effects were observed microscopically in reproductive organs from male cynomolgus monkeys treated for 26 weeks with panitumumab at doses of up to approximately 5-fold the recommended human dose (based on body weight).

Animal Toxicology and/or Pharmacology Weekly administration of panitumumab to cynomolgus monkeys for 4 to 26 weeks resulted in dermatologic findings, including dermatitis, pustule formation and exfoliative rash, and deaths secondary to bacterial infection and sepsis at doses of 1.25 to 5-fold higher (based on body weight) than the recommended human dose.

Reproductive and Developmental Toxicology Pregnant cynomolgus monkeys were treated weekly with panitumumab during the period of organogenesis (gestation day [GD] 20–50). While no panitumumab was detected in serum of neonates from panitumumab-treated dams, anti-panitumumab antibody titers were present in 14 of 27 offspring delivered at GD 100. There were no fetal malformations or other evidence of teratogenesis noted in the offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.25 to 5 times the recommended human dose (based on body weight).

PATIENT COUNSELING INFORMATION Advise patients to contact a healthcare professional for any of the following: • Skin and ocular/visual changes [see Boxed Warning and Warnings and Precautions], • Signs and symptoms of infusion reactions including fever, chills, or breathing problems [see Boxed Warning and Warnings and Precautions], • Persistent or recurrent coughing, wheezing, or dyspnea [see Warnings and Precautions], • Pregnancy or nursing [see Use in Specific Populations].

Advise patients of the need for: • Periodic monitoring of electrolytes [see Warnings and Precautions], • Limitation of sun exposure (use sunscreen, wear hats) while receiving Vectibix® and for 2 months after the last dose of Vectibix® therapy. [see Warnings and Precautions], • Adequate contraception in both males and females while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy [see Use in Specific Populations].

This brief summary is based on the Vectibix® prescribing information v4, 6/2008.

Rx Only This product, its production, and/or its use may be covered by one or more US Patents, including US Patent No. 6,235,883, as well as other patents or patents pending. © 2006–2008 Amgen Inc.All rights reserved.

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Important Safety Information Including Boxed WARNINGS: Safety data are available from 15 clinical trials in which 1467 patients received Vectibix®; of these, 1293 received Vectibix® monotherapy and 174 received Vectibix® in combination with chemotherapy.

WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONS

Dermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 and higher) in 12% of patients receiving Vectibix® monotherapy. Withhold Vectibix® for dermatologic toxicities that are grade 3 or higher or are considered intolerable. If toxicity does not improve to ≤grade 2 within 1 month, permanently discontinue Vectibix®. The clinical manifestations included, but were not limited to, dermatitis acneiform, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures.

Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, and abscesses requiring incisions and drainage were reported.

Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. Severe infusion reactions included anaphylactic reactions, bronchospasm, and hypotension. Although not reported with Vectibix®, fatal infusion reactions have occurred with other monoclonal antibody products. Stop infusion if a severe infusion reaction occurs. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix®.

* Correlation with safety and efficacy is unknown

Vectibix® is indicated as a single agent for the treatment of EGFR-expressing, metastatic colorectal carcinoma (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.

The effectiveness of Vectibix® as a single agent for the treatment of EGFR-expressing mCRC is based on progression-free survival (PFS). Currently, no data demonstrate an improvement in disease-related symptoms or increased survival with Vectibix®.

Based on independent review of disease progression, a statistically significant prolongation in PFS was observed with Vectibix®1 100%

Convenient dosing1 Q2W dosing, typically administered over 60 minutes (doses >1000 mg administered over 90 minutes), with no loading dose required†

Kaplan-Meier Estimate of PFS Time

90%

Vectibix® + BSC‡ (n=231) (Mean PFS: 96 days)

80%

3 available vial sizes: 400 mg (20 mL), 200 mg (10 mL), 100 mg (5 mL)

BSC‡ Alone (n=232) (Mean PFS: 60 days)

70% Proportion Event Free

Vectibix® is not indicated for use in combination with chemotherapy. In an interim analysis of a randomized (1:1) clinical trial of patients with previously untreated metastatic colorectal cancer, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased overall survival and increased incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions.

In a single-arm study of 19 patients receiving Vectibix® in combination with IFL, the incidence of NCI-CTC grade 3-4 diarrhea was 58%; in addition, grade 5 diarrhea occurred in 1 patient. In a single-arm study of 24 patients receiving Vectibix® plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%.

Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix®. Following the initial fatality, patients with a history of interstitial pneumonitis, pulmonary fibrosis, evidence of interstitial pneumonitis, or pulmonary fibrosis were excluded from clinical studies. Therefore, the estimated risk in such patients is uncertain. Permanently discontinue Vectibix® therapy in patients developing interstitial lung disease, pneumonitis, or lung infiltrates.

In the randomized, controlled clinical trial, median magnesium levels decreased by 0.1 mmol/L in the Vectibix® arm. Additionally, hypomagnesemia (NCI-CTC grade 3 or 4) requiring electrolyte repletion occurred in 2% of patients 6 weeks or longer after the initiation of Vectibix®. In some patients, both hypomagnesemia and hypocalcemia occurred.

Patients’ electrolytes should be periodically monitored during and for 8 weeks after the completion of Vectibix® therapy, and appropriate treatment instituted, as needed.

Exposure to sunlight can exacerbate dermatologic toxicity. It is recommended that patients wear sunscreen and hats and limit sun exposure while receiving Vectibix®.

Dermatologic, mucosal, and ocular toxicities were also reported.

Adequate contraception in both males and females must be used while receiving Vectibix® and for 6 months after the last dose of Vectibix® therapy.

The most common adverse events of Vectibix® are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including diarrhea resulting in dehydration. The most serious adverse events of Vectibix® are pulmonary fibrosis, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation.

The first fully human* anti-EGFR monoclonal antibody

60%

P < 0.0001

50% 40% 30%

†

20% 10% 0%

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 Weeks

‡

best supportive care

No difference in overall survival observed between study arms ©2008 Amgen. All rights reserved.

41900-B

7-08

Dose modifications may be needed if toxicity occurs; appropriate medical resources for the treatment of severe infusion reactions should be available.

Reference: 1. Vectibix® (panitumumab) prescribing information. Amgen.

Please see brief summary of Prescribing Information on next page.

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K-ras Testing and Its Implications In the Treatment of Metastatic Colorectal Cancer TANIOS BEKAII-SAAB, MD Assistant Professor of Medicine and Pharmacology Department of Medicine Division of Hematology and Oncology The Ohio State University-Arthur James Cancer Hospital Department of Pharmacology The Ohio State University Columbus, Ohio

C

olorectal cancer (CRC) is the third most common malignancy and the second leading cause of cancer-

related deaths in the United States.1 During the past decade, and with the introduction of new cytotoxic and biologic agents, the median duration of survival among patients with metastatic CRC (mCRC) has more than doubled.2,3

Epidermal Growth Factor Receptor Inhibition in mCRC Epidermal growth factor receptor (EGFR) often is overexpressed in CRC.4,5 EGFR activation promotes increased tumor cell proliferation, prevents tumor apoptosis, and promotes metastasis.6 Cetuximab (Erbitux, Bristol-Myers Squibb/ImClone) and panitumumab (Vectibix, Amgen) are monoclonal antibodies that target EGFR with documented activity in mCRC.7-9 Although EGFR expression was initially used for patient selection in several studies, clinical evidence has shown that EGFR expression, as measured by immunohistochemistry, does not

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

C L I N I C A L O N CO LO GY N E WS S P E C I A L E D I T I O N 2 0 0 9 â&#x20AC;˘ N O. 1

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Table 1. Large Nonrandomized Single-Arm Studies With Cetuximab or Panitumumab

Study

Treatment

Total Patients Included in Analysis (K-ras Mutants, %)

Di Fiore16

C±I

281 (37)

P value De Rook17

C±I

113 (41)

WT

MT

WT

MT

WT

MT

27.4

0

24 wk

12 wk

44 wk

36 wk

25

P+I

109 (41)

22

0

114 (27)

P value

40 P<0.001

24 wk

P<0.0001 12 wk

P=0.074 19

NR C±I

OS

P<0.0001

NR

P value Lievre19

PFS/TTP

NR

P value Cohn18

Objective Responses, %

26 wk

31.4 wk P=0.0001

27.3 wk

P=0.02 19 wk

NR 0

43 wk

20 wk

15 wk

NR 10.1 wk

14.3 mo

10.1 mo

P=0.026

C, cetuximab; I, irinotecan-based chemotherapy; MT, mutant type; NR, not reported; NS, not significant; OS, overall survival; P, panitumumab; PFS, progression-free survival; TTP, time to progression; WT, wild type

predict for clinical benefit.10-12 It seems that factors other than EGFR expression would better dictate efficacy or lack thereof.

The Biology of K-ras K-ras, the human homolog of the Kirsten rat sarcoma-2 virus oncogene, can harbor oncogenic mutations that yield a constitutively active protein in nearly 50% of patients with CRC.13,14 In more than 90% of tumors, these mutations mostly are located in codons 12 and 13.15 Because ras is downstream from EGFR, aberrant signaling in K-ras mutant-type (MT) mCRC may lead to dysregulation of the ras-dependent signaling pathway whether or not the upstream receptor is silenced by anti-EGFR monoclonal antibodies.14

K-ras as a Predictive Marker A number of recent, nonrandomized studies have failed to demonstrate a benefit with anti-EGFR therapies in patients with MT K-ras (Table 1).16-19 In fact, the cumulative results of various randomized trials of cetuximab or panitumumab confirm that the presence of K-ras mutation in tumors is highly predictive of resistance to anti-EGFR therapy (Table 2).20-23 The CRYSTAL (Cetuximab combined with irinotecan in first line therapy for metastatic colorectal cancer) study was a Phase III randomized trial of irinotecan (Camptosar, Pfizer Oncology) with fluorouracil (5-FU) and leucovorin (FOLFIRI) with or without cetuximab in the first-line treatment of mCRC. The study showed that patients with wild-type (WT) K-ras exhibited a statistically significant improvement in progression-free survival (PFS; the primary end point of

26

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

the study), with the combination of cetuximab and FOLFIRI versus FOLFIRI alone, whereas those with MT K-ras did not.20,21 Two recent Phase III studies have assessed the role of panitumumab or cetuximab as single agents compared with best supportive care (BSC) alone in patients with refractory mCRC.22,23 When compared with BSC, patients in the WT K-ras group receiving panitumumab showed improved PFS (primary end point), whereas the MT K-ras group did not. Similarly, the results of another randomized trial (CO.17) that evaluated the role of K-ras mutations in defining benefit from cetuximab in mCRC (69% of all patients had tissue available for analysis), found that patients with WT K-ras treated with cetuximab and BSC experienced a significant improvement in overall survival (primary end point) compared with BSC alone, whereas the MT K-ras group did not.23

K-ras Testing Reproducible, relatively inexpensive, and highly sensitive assays for K-ras testing are available through many diagnostic laboratories in the United States. Two commonly used methods to evaluate samples for K-ras mutations include real-time polymerase chain reaction, which uses fluorescent probes specific for the most common mutations in codons 12 and 13; and directsequencing analysis of exon 2 in the K-ras gene, which can be used to identify K-ras mutations.24 An assay is typically performed on paraffin-embedded tissue.24 K-ras mutations are early events in the development of CRC, and there is strong concordance in mutation status between primary and metastatic sites.25 Therefore, K-ras genotyping can be done on

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Table 2. Phase III Randomized Studies With Panitumumab And Cetuximab

Study

Total Patients Included in Analysis (K-ras Mutants, %)

Van Cutsem

540 (36)

(CRYSTAL)20,21

Objective Responses, %

PFS

Treatment

WT

MT

WT

MT

WT

MT

FOLFIRI

40

43

8.7 mo

8.1 mo

21

17.5

FOLFIRI+C

59.3

43.2

9.9 mo

7.6 mo

24.9

17.7

P=0.025

P=0.46

P=0.017

P=0.47

P=0.22

P=0.85

P+BSC

17

0

12.3 wk

7.4 wk

8.1

4.9

BSC

0

0

7.3 wk

7.3 wk

7.6

4.4

NR

NR

P<0.0001

NS

NS

NS

C+BSC

12.8

1.2

3.7 mo

1.8 mo

9.5

4.5

BSC

0

0

1.9 mo

1.8 mo

4.8

4.6

NR

NR

P<0.001

NS

P<0.001

NS

P value Amado22

427 (43)

P value Karapetis23 (CO.17)

394 (42.3)

P value

OS, mo

BSC, best supportive care; C, cetuximab; FOLFRI, irinotecan with fluorouracil (5FU) and leucovorin; MT, mutant type; NR, not reported; NS, not significant; OS, overall survival; P, panitumumab; PFS, progression-free survival; WT, wild type

archival tissue of either the primary or the metastatic site without the need for fresh biopsy.

Implications for EGFR Inhibitors in mCRC The consistency of results across various studies mandates the routine testing of K-ras status before initiating anti-EGFR therapies in patients with mCRC. If K-ras mutation is detected, anti-EGFR therapy should be withheld. As a group, patients with WT K-ras are likely to have improved efficacy, although a significant percentage of individual patients will not benefit from therapy. The improvement of the selection process with EGFR inhibitors has multiple benefits, including preventing unnecessary toxicities in patients who are unlikely to benefit from those agents, cost containment, and more efficient use of available resources.

The European Medicines Agency has approved the use of panitumumab and cetuximab only in patients with WT K-ras mCRC. In the United States, the FDA is expected to address the issue in the near future. K-ras testing for the selection of patients who may not be candidates for anti-EFGR therapies is already part of the National Comprehensive Cancer Network guidelines (www.nccn. org). On January 13, 2009, the American Society of Clinical Oncology (ASCO) released its first provisional clinical opinion recommending that all patients with mCRC who are candidates for anti-EGFR therapy have their tumors tested for K-ras gene mutations. If a patient has a mutated form of the K-ras gene, ASCO recommends against the use of anti-EGFR therapy.24

Conclusion In the refractory setting, the presence of K-ras mutations will prevent unnecessary use of anti-EGFR therapies in about 40% to 50% of all patients. For patients with MT K-ras outside of clinical studies and if BSC is not considered acceptable, then mitomycin C, a relatively inexpensive drug with documented activity in refractory mCRC would be a reasonable alternative.26,27 For refractory patients with WT K-ras, EGFR inhibitors should be used, preferably in combination with irinotecan, but also possibly with oxaliplatin (Eloxatin, SanofiAventis). Finally, it is unlikely that the choice of therapy in the first-line setting will be affected by the current data, until the question is addressed in prospective randomized studies. Bevacizumab (Avastin, Genentech) therapy appears to provide similar benefit in patients with mCRC regardless of K-ras status.28,29 However, emerging data validating a potential role for EGFR inhibitors in selected patients with mCRC could challenge the current standard.21,30

References 1.

Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin. 2008;58(2):71-96, PMID: 19110912.

2. Cohen DJ, Hochster HS. Update on clinical data with regimens inhibiting angiogenesis and epidermal growth factor receptor for patients with newly diagnosed metastatic colorectal cancer. Clin Colorectal Cancer. 2007;7(suppl 1):S21-S27, PMID: 18361803.

3. Reidy D, Saltz L. Targeted strategies in the treatment of metastatic colon cancer. J Natl Compr Canc Netw. 2007;5(9):983-990, PMID: 17977504.

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27

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4. Díaz-Rubio E. Vascular endothelial growth factor inhibitors in colon cancer. Adv Exp Med Biol. 2006;587:251-275, PMID: 17163170.

5. Mendelsohn J, Baselga J. Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol. 2003;21(14):2787-2799, PMID: 12860957.

6. Arteaga C. Targeting HER1/EGFR: a molecular approach to cancer therapy. Semin Oncol. 2003;30(3 suppl 7):3-14, PMID: 12840796.

7. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004; 351(4):337-345, PMID: 15269313.

8. Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007; 25(13):1658-1664, PMID: 17470858.

9. Van Cutsem E, Nowacki M, Lang I, et al. Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer (mCRC): The CRYSTAL trial. J Clin Oncol. 2007;25(18S):4000.

10. Adams R, Maughan T. Predicting response to epidermal growth factor receptor-targeted therapy in colorectal cancer. Expert Rev Anticancer Ther. 2007;7(4):503-518, PMID: 17428171.

11. Chung KY, Shia J, Kemeny NE, et al. Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol. 2005;23(9):1803-1810, PMID: 15677699.

12. Mitchell EP, Hecht JR, Baranda J, et al. Panitumumab activity in metastatic colorectal cancer (mCRC) patients (pts) with low or negative tumor epidermal growth factor receptor (EGFr) levels: an updated analysis. J Clin Oncol. 2007;25(suppl):184s.

13. Schubbert S, Shannon K, Bollag G. Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer. 2007;7:295-308, PMID: 17384584.

14. Bos JL. Ras oncogenes in human cancer: a review. Cancer Res. 1989;49(17):4682-4689, PMID: 2547513.

15. Russo A, Bazan V, Agnese V, et al. Prognostic and predictive factors in colorectal cancer: Kirsten Ras in CRC (RASCAL) and TP53CRC collaborative studies. Ann Oncol. 2005;16(suppl 4): 44-49, PMID: 15923428.

16. Di Fiore F, Van Cutsem E, Laurent-Puig P, et al. Role of KRAS mutation in predicting response, progression-free survival, and overall survival in irinotecan-refractory patients treated with cetuximab plus irinotecan for a metastatic colorectal cancer: analysis of 281 individual data from published series. J Clin Oncol. 2008;26 (May 20 suppl). Abstract 403.

17. De Roock W, Piessevaux H, De Schutter J, et al. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab.

Ann Oncol. 2008;19(3):508-515, PMID: 17998284.

18. Cohn AL, Smith DA, Neubauer MA, et al. Panitumumab (pmab)

28

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regimen evaluation in colorectal cancer to estimate primary response to treatment (PRECEPT): Effect of KRAS mutation status on second-line treatment (tx) with pmab and FOLFIRI. J Clin Oncol. 2008;26(May 20 suppl). Abstract 4127.

19. Lièvre A, Bachet JB, Boige V, et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol. 2008;26(3):374-379, PMID: 18202412.

20. Van Cutsem E, Lang I, D’haens G, et al. KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: The CRYSTAL experience. J Clin Oncol. 2008;26(May 20 suppl).

Abstract 2.

21. Van Cutsem I, Lang G, D’Haens V, et al. KRAS status and efficacy in the CRYSTAL study: 1st-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab 71O E. Ann Oncol. 2008;19(suppl 8):44-46.

22. Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26(10):1626-1634, PMID: 18316791.

23. Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359(17):1757-1765, PMID: 18946061.

24. Allegra CJ, Jessup JM, Somerfield MR, et al. American Society of Clinical Oncology Provisional Clinical Opinion: Testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol. 2009 Feb 2 [Epub ahead of print], PMID: 19188670.

25. Artale S, Sartore-Bianchi A, Veronese SM, et al. Mutations of KRAS and BRAF in primary and matched metastatic sites of colorectal cancer. J Clin Oncol. 2008;26(25):4217-4219, PMID: 18757341.

26. Scartozzi M, Falcone A, Pucci F, et al. Capecitabine and mitomycin C may be an effective treatment option for third-line chemotherapy in advanced colorectal cancer. Tumori. 2006;92(5):384-388, PMID: 17168429.

27. Chong G, Dickson JL, Cunningham D, et al. Capecitabine and mitomycin C as third-line therapy for patients with metastatic colorectal cancer resistant to fluorouracil and irinotecan. Br J Cancer.

2005;93(5):510-514, PMID: 16091760.

28. Hurwitz H, Rosen O, Yi J, Ince W, Novotny W, Holmgren E. Clinical benefit of bevacizumab (BV) in metastatic colorectal cancer (MCRC) is independent of K-RAS mutation status: Exploratory analyses in a large placebo-controlled phase III study of previously untreated patients. Ann Oncol. 2008;19(S6). Abstract O-035.

29. Ince WL, Jubb AM, Holden SN, et al. Association of k-ras, b-raf, and p53 status with the treatment effect of bevacizumab. J Natl Cancer Inst. 2005;97:981-989, PMID: 15998951.

30. Folprecht G, Gruenberger T, Hartmann JT, et al. Randomized multicenter study of cetuximab plus FOLFOX or plus FOLFIRI in neoadjuvant treatment of non-resectable colorectal liver metastases (CELIM-STUDY). Ann Oncol. 2008;19(suppl 8):166-186.

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For more information, visit www.ALIMTA.com

Focus on histology ALIMTA for 1st-line advanced nonsquamous NSCLC (ALIMTA is not indicated in squamous cell)

CHANGE COURSE ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer. ALIMTA is not indicated for treatment of patients with squamous cell non-small cell lung cancer.

Important Safety Information for ALIMTA Myelosuppression is usually the dose-limiting toxicity with ALIMTA therapy.

Contraindication ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed or to any other ingredient used in the formulation.

hazard to the fetus and should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA.

The effect of third space fluid, such as pleural effusion and ascites, on ALIMTA is unknown. In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to ALIMTA administration.

Drug Interactions Concomitant administration of nephrotoxic drugs or substances that are tubularly secreted could result in delayed clearance of ALIMTA. See Warnings and Precautions above for specific information regarding ibuprofen administration.

Warnings and Precautions Patients must be instructed to take folic acid and vitamin B12 with ALIMTA as a prophylaxis to reduce treatment-related hematologic and GI toxicities.

Use in Specific Patient Populations It is recommended that nursing be discontinued if the mother is being treated with ALIMTA or discontinue the drug, taking into account the importance of the drug for the mother.

Pretreatment with dexamethasone or its equivalent has been reported to reduce the incidence and severity of skin rash.

The safety and effectiveness of ALIMTA in pediatric patients have not been established.

ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia).

Reduce doses for subsequent cycles based on hematologic and nonhematologic toxicities.

ALIMTA should not be administered to patients with a creatinine clearance <45 mL/min. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.

Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration.

If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicities.

Dose adjustments may be necessary in patients with hepatic insufficiency.

Dosage and Administration Guidelines Complete blood cell counts, including platelet counts and periodic chemistry tests, should be performed on all patients receiving ALIMTA. Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Modify or suspend therapy according to the Dosage Reduction Guidelines in the full Prescribing Information.

Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3 and the platelet count is ≥100,000 cells/mm3 and creatinine clearance is ≥45 mL/min.

Abbreviated Adverse Reactions (% incidence) The most severe adverse reactions (Grades 3/4) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, for the 1st-line treatment of patients with advanced non-small cell lung cancer (NSCLC) were neutropenia (15 vs 27); leukopenia (5 vs 8); thrombocytopenia (4 vs 13); anemia (6 vs 10); fatigue (7 vs 5); nausea (7 vs 4); vomiting (6 vs 6); anorexia (2 vs 1); and creatinine elevation (1 vs 1). Common adverse reactions (all Grades) with ALIMTA in combination with cisplatin versus gemcitabine with cisplatin, respectively, were nausea (56 vs 53); fatigue (43 vs 45); vomiting (40 vs 36); anemia (33 vs 46); neutropenia (29 vs 38); anorexia (27 vs 24); constipation (21 vs 20); leukopenia (18 vs 21); stomatitis/pharyngitis (14 vs 12); alopecia (12 vs 21); diarrhea (12 vs 13); thrombocytopenia (10 vs 27); neuropathy/sensory (9 vs 12); taste disturbance (8 vs 9); rash/desquamation (7 vs 8); and dyspepsia/ heartburn (5 vs 6).

Pregnancy Category D—ALIMTA may cause fetal harm when administered to a pregnant woman. Women should be apprised of the potential

Please see brief summary of Prescribing Information on adjacent page for additional safety and dosing guidelines.

ALIMTA® is a registered trademark of Eli Lilly and Company.

PM56165 0309 PRINTED IN USA © 2009, Lilly USA, LLC. ALL RIGHTS RESERVED.

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Treatment of Advanced

Non-Small Cell Lung Cancer: First-Line Therapy and Future Directions PRASHANTH ADAPALA, MD Fellow University of Texas Medical Branch Galveston, Texas

TOMASZ P. SROKOWSKI, MD Clinical Associate Department of Cancer Medicine The University of Texas M.D. Anderson Cancer Center Houston, Texas

EDWARD S. KIM, MD Assistant Professor of Medicine Department of Thoracic/Head and Neck Medical Oncology The University of Texas M.D. Anderson Cancer Center Houston, Texas

L

ung cancer is the leading cause of cancer-related death worldwide.

In the United States, it is estimated

that in 2008 approximately 215,020 new cases of lung cancer were diagnosed and 161,840 people died of the disease.1

Non-small cell lung cancer (NSCLC) is the most common histologic type, accounting for nearly 85% of all lung cancers. When resectable, NSCLC can be cured with surgery or surgery and adjuvant chemotherapy, but roughly two-thirds of patients present with locally advanced, inoperable, or metastatic disease. Although patients with metastatic disease are incurable, chemotherapy can lessen symptoms and improve survival.

The primary goal of therapy in metastatic or locally advanced and unresectable NSCLC is palliation. Chemotherapy in these patients can provide symptomatic improvement and a modest survival advantage over best supportive care.2 Median survival with standard doublet chemotherapy regimens is approximately 8 to 10 months. This dismal prognosis has remained relatively unchanged for the past 25 years3,4; during the past several years, however, advances in molecular targeted therapies—the development of several epidermal growth factor receptor

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

(EGFR) tyrosine kinase inhibitors (TKIs) and vascular endothelial growth factor (VEGF) inhibitors—and the approval of a number of new chemotherapeutic agents for advanced NSCLC have raised hope for improved outcomes in patients with this disease.

First-Line Chemotherapy In patients with good performance status (PS; 0-1 on the Eastern Cooperative Oncology Group scale), platinum-based doublet regimens constitute the mainstay of chemotherapy for advanced NSCLC.3 In 1996, based on a meta-analysis showing a survival benefit in patients treated with cisplatin,2 the American Society of Clinical Oncology (ASCO) devised guidelines recommending the use of cisplatin-based chemotherapy for patients with advanced NSCLC and good PS. Clinicians should keep in mind, however, that for patients with an incurable disease, quality of life (QoL) is an important concern. The considerable

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toxicity of cisplatin-based regimens has prompted efforts to develop better-tolerated, equally efficacious treatments. To this end, trials have considered the use of newer agents, either as monotherapy or in combination regimens, and the use of carboplatin in lieu of cisplatin in doublet regimens.

COMPARISON

OF

PLATINUM-BASED DOUBLET REGIMENS

In comparisons of platinum-based doublets, 2 variables must be considered: the platinum agent used (ie, cisplatin or carboplatin) and the agent combined with the platinum. The principal drugs combined with a platinum agent in the third-generation doublets are gemcitabine (Gemzar, Lilly), vinorelbine, docetaxel (Taxotere, Sanofi-Aventis), paclitaxel and, more recently, pemetrexed (Alimta, Lilly).

The FDA recently approved pemetrexed for firstline treatment of locally advanced or metastatic nonsquamous NSCLC. The approval was based on a large Phase III randomized trial by Scagliotti et al that compared cisplatin and gemcitabine with cisplatin and pemetrexed in the first-line setting of locally advanced or metastatic NSCLC.5 The overall survival (OS) was similar between both arms (median survival, 10.3 vs 10.3 months, respectively; hazard ratio [HR], 0.94; 95% confidence interval, 0.84-1.05) but with less toxicity in the pemetrexed arm. Preplanned subgroup analysis of patients with nonsquamous histology, mostly adenocarcinoma and large cell carcinoma, showed that the cisplatin and pemetrexed combination was statistically superior in terms of OS. This is the first randomized Phase III trial that reported a survival difference based on histology.

Numerous Phase III trials comparing the various doublets have failed to demonstrate the superiority of any one specific combination regimen (Table 1).3,6-9 A meta-analysis by Le Chevalier et al has confirmed that gemcitabine and platinum-based doublets provide no survival advantage in comparison with other modern platinum-based doublets.10 On the other hand, a small number of trials have shown survival advantages for cisplatin-based regimens in comparison with carboplatin-based regimens.6,9 The superior regimens in those trials consisted of taxane and cisplatin combinations, and the results fueled controversy about whether or not carboplatin is truly equivalent to cisplatin in terms of efficacy. Ardizzoni et al reported a meta-analysis of randomized trials comparing cisplatin- and carboplatin-based chemotherapy in the first-line treatment of advanced NSCLC.11 They identified 9 randomized trials (N=2,968 patients) that investigated the substitution of carboplatin for cisplatin in combination with the same agent(s). Ardizzoni et al found that the response rate (RR) was higher with cisplatin-based regimens (30% vs 24%; P<0.001), however, this did not translate into a significant survival advantage. Patients receiving cisplatin-based regimens experienced more severe toxicities. Subgroup analyses suggested that cisplatin-based regimens may

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provide a survival benefit for some patientsâ&#x20AC;&#x201D;namely, those with nonsquamous tumors and those treated with modern doublet regimens.

A platinum-based doublet is an appropriate first-line treatment for patients with good PS. Although cisplatin may offer a small survival advantage over carboplatin for certain subgroups of patients, because of the greater toxicities associated with cisplatin and the importance of QoL for this population, it is reasonable to use carboplatin-based therapy. Patients also should be considered for combination therapy with chemotherapy and targeted therapy (discussed below).

PREDICTING BENEFIT FROM PLATINUM-BASED REGIMENS It may be possible to determine, before treatment, which patients will derive benefit from receiving a platinum-based doublet rather than a nonâ&#x20AC;&#x201C;platinumcontaining regimen. In recent years, researchers have discovered mechanisms contributing to platinum resistance. Because platinum compounds dysregulate cellular functions by binding DNA and forming platinum adducts, enhanced nucleotide excision repair by tumor cells may contribute to platinum resistance. Altaha et al showed that high levels of the excision repair crosscomplementing group 1 (ERCC1) gene protein may play a major role in platinum resistance.12 In a retrospective analysis of ERCC1 mRNA levels in tumors from 56 patients treated with cisplatin plus gemcitabine (GC), Lord et al found that patients with low levels of ERCC1 mRNA had a higher RR (52% vs 36%) and longer median survival (15 vs 5 months; P<0.001) than did patients with high levels.13 Based on their findings, this research group conducted a customized chemotherapy trial.14 More than 400 patients were randomly assigned to either the control arm of docetaxel plus cisplatin (DC) or the experimental arm, in which chemotherapy was assigned based on levels of ERCC1 mRNA. Patients received DC if their ERCC1 mRNA levels were low, and docetaxel plus gemcitabine (DG) if their levels were high. Preliminary results from the first 264 patients showed that the overall RR (ORR) in the control arm was 40%. When patients were subdivided according to low and high ERCC1 mRNA levels, the RRs were 47% and 26%, respectively. In the experimental arm, the RRs in patients with low and high ERCC1 mRNA levels were 57% and 38%, respectively. The logistic regression model for tumor progression showed a significant improvement for patients randomly assigned to DC based on low ERCC1 mRNA levels, but final survival data are awaited.

Another research group showed that ERCC1 negativity by immunohistochemistry was predictive of benefit from adjuvant cisplatin-based chemotherapy, whereas patients with ERCC1-positive tumors seemed to derive no benefit.15 These data suggest that tumor ERCC1 mRNA or protein levels may be useful predictive markers of benefit from cisplatin-based chemotherapy in both early-stage and advanced NSCLC.16 Emerging data indicate that single-nucleotide polymorphisms

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Table 1. Single Agents Versus Platinum and Modern Agent Doublets in NSCLC Clinical Trial Treatment Armsa

N

Hoosier Oncology Group (J Clin Oncol 2000;18:122-130) Gemcitabine (1,000 d 1+8+15)/cisplatin (100) q4wk x 6 Cisplatin (100) q4wk x 6

260 262

30b 11

9.1b 7.6

39b 28

Southwest Oncology Group (J Clin Oncol 1998;16:2459-2465) Vinorelbine (25) q1wk/cisplatin (100) q4wk Cisplatin (100) q4wk

206 209

26b 12

8b 6

36b 20

European21 (J Clin Oncol 2000;18:3390-3399) Paclitaxel (175)/cisplatin (80) q3wk Cisplatin (100) q3wk

207 207

26b 17

8.1 8.6

30 36

Paclitaxel (225)/carboplatin (AUC 6) q3wk x 6 Paclitaxel (225) q3wk x 6

284 277

30b 17

8.8 6.7

37 32

Greek Cooperative Group (J Clin Oncol 2004;22:2602-2609) Docetaxel (100)/cisplatin (80) q3wk x 6 Docetaxel (100)

167 152

37b 22

10.5 8

44 43

164 170

30b 11

10b 8.6

40b 32

RR, %

Median 1-Year Survival, mo Survival, %

Cancer and Leukemia Group B 9730 (J Clin Oncol 2005;23:190-196)

Swedish Lung Cancer Study Group24 (J Clin Oncol 2005;23:8380-8388)

Gemcitabine (1,250) d 1+8/carboplatin (AUC 5) q3wk x 6 Gemcitabine (1,250) d 1+8 q3w x 6 a

Doses are shown in parentheses and are in milligrams per square meter (mL/m2 unless stated otherwise.

b

Statistically significant difference.

AUC, area under the curve; N, number of patients per arm; NSCLC, non-small cell lung cancer; RR, response rate

in the ERCC1 gene are associated with outcome in patients treated with cisplatin-based chemotherapy.17,18 Other DNA repair pathways also have been linked to platinum drug resistance.19 Research to identify and validate markers of tumor resistance to platinum compounds continues. If such markers can be verified and introduced into clinical practice, physicians will be able to avoid exposing patients with platinum-resistant disease to unnecessary toxicities. Alternatively, the development of novel agents that target and inhibit DNA repair mechanisms that contribute to platinum resistance may prove beneficial in the treatment of NSCLC.

MAINTENANCE CHEMOTHERAPY

AS A

STRATEGY

Multiple trials have examined the role of maintenance chemotherapy after completion of initial chemotherapy in metastatic NSCLC.20-23 Maintenance chemotherapy could be either continuation of one or more of the initial chemotherapy agents or the addition of a new nonâ&#x20AC;&#x201C; cross-resistant chemotherapy agent. In a large multicenter Phase III trial, Fidias et al compared docetaxel given immediately for up to 6 cycles in patients without

disease progression after initial chemotherapy with docetaxel given upon disease progression.24 Maintenance docetaxel was associated with a statistically significant improvement in progression-free survival (PFS) and a trend toward improvement in OS. At ASCO 2008, Ciuleanu et al reported the results of a multicenter Phase III trial of maintenance pemetrexed in patients with stage IIIB/IV NSCLC who had not progressed after 4 cycles of platinum-based chemotherapy.25 Similar to the results of the Fidias trial, pemetrexed significantly prolonged PFS and showed a trend toward improvement in OS. However, preplanned subgroup analysis of patients with adenocarcinoma showed a significant improvement in PFS, as well as OS. Also at ASCO 2008, Hida et al presented a large Phase III trial comparing 6 cycles of platinum doublet chemotherapy with 3 cycles of platinum doublet chemotherapy followed by gefitinib (Iressa, AstraZeneca) until disease progression.26 Patients in the gefitinib arm had a statistically significant improvement in PFS but no difference in OS. However, preplanned subgroup analysis based on histology showed that patients with adenocarcinoma histology had a significant improvement in both PFS

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Table 2. Selected Trials of Various Platinum-Based Regimens in First-Line Therapy for NSCLC Clinical Trial ECOG E15943

c

Paclitaxel-carboplatin

290

Paclitaxel-cisplatin

288

Docetaxel-cisplatin

RR, %

Median 1-Year Survival, mo Survival, % 34

7.8

31

289

7.4

31

Gemcitabine-cisplatin

288

8.1

36

Rosell et al6

Paclitaxel-carboplatin

309

25

8.2b

33

Paclitaxel-cisplatin

309

28

9.8

38

ILCP8

Paclitaxel-carboplatin

204

32

9.9

43

Vinorelbine-cisplatin

203

30

9.5

37

Gemcitabine-cisplatin

205

30

9.8

37

Paclitaxel-carboplatin

206

25

8

38

Vinorelbine-cisplatin

202

28

8

36

Docetaxel-cisplatin

408

32b

11.3b

46

Docetaxel-carboplatin

406

2

9.4

38

Vinorelbine-cisplatin

404

25

9.9-10.1c

41

TAX 3269

b

N

8.1

SWOG 95097

a

Treatment Arms

19a

Comments No significant differences among the arms. ECOG chose paclitaxel-carboplatin as its reference for subsequent trials.

QoL similar in the 2 arms.

Equal efficacy but significantly different toxicities among the 3 arms.

Paclitaxel-carboplatin less toxic, better tolerated than vinorelbine-cisplatin.

QoL was significantly improved in both docetaxel-containing arms.

The overall response rate for the 1,155 eligible patients was 19%, with no significant difference between the treatment arms.

Statistically significant difference.

Median survival times for comparison of vinorelbine/cisplatin with docetaxel/cisplatin are 10.1 and 11.3 months, and for comparison of vinorelbine/cisplatin with docetaxel/carboplatin are 9.9 and 9.4 months.

ECOG, Eastern Cooperative Oncology Group; ILCP, Italian Lung Cancer Project; N, number of patients per arm; NSCLC, non-small cell lung cancer; RR, response rate; QoL, quality of life; SWOG, Southwest Oncology Group

and OS, again highlighting the importance of histology in the treatment of NSCLC. The formal results of the SATURN (erlotinib vs placebo maintenance therapy) trial testing erlotinib (Tarceva, OSI Pharmaceuticals) maintenance after platinum-based doublet chemotherapy in stage IIIB/IV NSCLC are eagerly awaited.

The SATURN trial has met its primary end point of PFS, and the manufacturer has announced that it will submit an application to the FDA for approval in this setting.27

Molecular Targeted Therapies Even with the use of third-generation chemotherapy doublets, the prognosis of patients with advanced NSCLC remains bleak. As a result, much research effort has been invested in the development of molecular targeted therapies for use alone or in combination with chemotherapy to treat this disease. Therapeutic targets include the EGFR, VEGF, and insulin-like growth factor type I receptor (IGF-IR) pathways (Table 2).

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Anti-EGFR and anti-VEGF strategies are available for the treatment of advanced NSCLC.

AGENTS TARGETING EGFR EGFR (also known as HER-1 or erb-B1) is a member of the ErbB family of transmembrane glycoprotein receptors. EGFR consists of an extracellular ligandbinding domain, a transmembrane domain, and an intracellular domain with a tyrosine kinase (TK) region.

Known ligands for EGFR include the epidermal growth factor, transforming growth factor-Îą, and amhiregulin.

Upon ligand binding, EGFR forms homodimers or heterodimers with other family member receptors, resulting in activation of its TK and secondary signaling pathways.28 Activation of these downstream signaling events inhibits apoptosis and promotes tumor cell growth and proliferation, invasion, metastasis, and angiogenesis. Altered or increased expression of EGFR has been observed in up to 80% of cases of NSCLC and is associated with a worse prognosis.

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Overexpression of EGFR is most commonly found in squamous cell tumors (84%), followed by large cell tumors (68%), and adenocarcinomas (65%).29 Clearly, EGFR is a rational therapeutic target in NSCLC. EGFR can be inhibited by interfering with signal transduction through the use of small-molecule TKIs, such as erlotinib and gefitinib or by blocking the ligand-binding domain with monoclonal antibodies, such as cetuximab (Erbitux, Bristol-Myers Squibb) and panitumumab (Vectibix, Amgen), or gefitinib (Iressa, AstraZeneca).

Gefitinib. Gefitinib, an orally active, selective EGFR TKI that originally gained accelerated approval as monotherapy for the treatment of NSCLC refractory to platinum-based regimens and docetaxel, did not fulfill its promise in large, randomized Phase III trials.30-32 FDA approval for gefitinib has been modified to allow only patients already on this medication and benefiting from it to continue using it. It is no longer recommended as a treatment option for NSCLC outside a clinical trial.

Nevertheless, trials continue to evaluate gefitinib as first- and later-line therapy. Results from INTEREST (Iressa NSCLC Trial Evaluating Response and Survival Against Taxotere), a randomized Phase III trial comparing gefitinib with docetaxel in previously treated patients with metastatic or recurrent NSCLC in the United States, demonstrated statistically significant survival equivalence for gefitinib and docetaxel.33 Douillard et al presented an update of the INTEREST trial at ASCO 2008 and reported that the survival effects of gefitinib were equal in different molecular and clinical subgroups of patients, including tumor EGFR status or histology.34 Patients with NSCLC who are nonsmokers or of Asian ethnicity or those who have an adenocarcinoma histology have been reported to derive greater benefit from EGFR TKIs. Thus, IPASS (First-line Iressa Versus Carboplatin/ Paclitaxel in Asia), a randomized Phase III trial, evaluated gefitinib monotherapy or paclitaxel-carboplatin (PCb) as a first-line treatment for locally advanced stage IIIB/IV or metastatic NSCLC of adenocarcinoma subtype among nonsmokers or “light” former smokers. Reporting the preliminary results at the European Society for Medical Oncology (ESMO) 2008 Congress, Mok et al noted that although IPASS met its primary end point of PFS in favor of gefitinib, the PFS advantage was not constant overtime, initially favoring PCb and later gefitinib.35 PFS was statistically significant in the subgroup of patients with EGFR mutation-positive tumors. Objective response rates, QoL, and the tolerability profile were statistically significant in the gefitinib arm. OS was similar in both groups at the time of analyses, but final results are still awaited.

Erlotinib. Erlotinib, an orally active quinazoline, is a potent selective EGFR TKI. It is approved for the second- and third-line treatment of patients with

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advanced NSCLC based on the results of the BR-21 trial, in which the survival of patients treated with erlotinib was better than that of a placebo group.36 In view of its activity in the salvage setting, a number of trials have evaluated erlotinib in the first-line setting. Preclinical studies suggested that the effects of combinations of erlotinib and certain cytotoxic agents, including gemcitabine and cisplatin, were additive.37 This led to 2 large Phase III trials comparing the addition of erlotinib or placebo to standard first-line chemotherapy regimens in patients with advanced NSCLC. However, like gefitinib plus first-line chemotherapy, erlotinib plus standard chemotherapy did not improve survival when compared with chemotherapy alone in this setting.

Erlotinib in combination with chemotherapy did not improve OS or time to progression (TTP) in either the TRIBUTE (Tarceva Response in Conjugation With Paclitaxel and Carboplatin)38 or TALENT (Tarceva Lung Cancer Investigation) trials.39 However, on subgroup analysis of TRIBUTE data, the 72 patients in the erlotinib arm who reported never smoking exhibited significantly greater TTP and better OS than did the 44 “never-smokers” treated with PCb only (median survival, 23 vs 10 months; HR, 0.49; P=0.01). The results of this subgroup analysis may have important implications for the optimal use of EGFR inhibitors in the future, but evidence is insufficient at this point to recommend combination therapy with erlotinib and PCb for never-smokers with advanced NSCLC. A recently opened TORCH (Tarceva or Chemotherapy) Phase III trial in Italy is comparing firstline erlotinib followed at progression by second-line chemotherapy (GC for 6 cycles) versus the same chemotherapy on a first-line basis followed by erlotinib at progression for advanced NSCLC.40 The eligibility criteria for this trial do not discriminate based on ethnicity, histologic subtype, or smoking status. The planned accrual is 900 patients by September 2010, and the primary outcomes are the OS and PFS rates after 9 weeks of first-line treatment with erlotinib. Another very interesting approach under Phase III evaluation is the combination of erlotinib with bevacizumab (Avastin, Genentech), an anti-angiogenic agent, for the firstline treatment of advanced NSCLC (see “Combination Therapy With Anti-VEGF and Anti-EGFR Agents”).

Cetuximab. Cetuximab is an immunoglobulin G human/mouse chimeric monoclonal antibody targeting the extracellular domain of the EGFR. It is FDAapproved to treat selected patients with metastatic colorectal cancer and head and neck cancer. Although cetuximab is not indicated for use in patients with NSCLC outside clinical trials, its activity as monotherapy or in combination with chemotherapy in NSCLC is being assessed.

A Phase II study of single-agent cetuximab in 66 patients with heavily pretreated and mostly EGFR-

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positive (n=60) advanced NSCLC reported a disease control rate of 34.8% (including a partial RR of 4.5%), a median TTP of 2.3 months, and a median survival of 8.9 months. These results are comparable with outcomes reported for the FDA-approved secondline therapies for NSCLC: pemetrexed, docetaxel, and erlotinib.41 The combination of cetuximab (400 mg/ m2 IV at week 1, then 250 mg/m2 weekly thereafter) with docetaxel (75 mg/m2 IV every 3 weeks) has been assessed in the second-line setting in patients with EGFR-positive tumors. The results are encouraging, with an RR of approximately 25% in this population of patients with chemotherapy-refractory disease.42 A multicenter Phase III study in patients with advanced NSCLC after failure of initial platinum-based chemotherapy is under way in the United States and Canada.

The study randomizes patients to 1 of 4 treatment arms: cetuximab plus docetaxel, cetuximab plus pemetrexed, docetaxel alone, or pemetrexed alone.43 Cetuximab in combination with a number of platinum-based regimens, including paclitaxel plus cisplatin (PC) and gemcitabine plus carboplatin (GCb), has been assessed in Phase I/II trials as first-line treatment for EGFR-expressing advanced NSCLC, with encouraging results: RRs of 26% to 29%, median TTP of about 5 to 6 months, and median survival of approximately 10 to 11 months.44, 45 These results compare favorably with the outcomes of standard doublet chemotherapy. In a randomized Phase II study of first-line cisplatin plus vinorelbine with or without cetuximab among 86 patients with EGFR-positive advanced NSCLC, the disease control rate (response or stable disease, 84% vs 67%) and survival (median, 8.3 vs 7 months) favored the cetuximab-containing arm.46 These results led to a Phase III trial, FLEX (First-line Trial for Patients With EGFR-Expressing Advanced NSCLC) trial, which evaluated this regimen in patients with EGFR-positive stage IIIB/IV NSCLC of all histologies. The FLEX trial, the results of which were reported at ASCO 2008

by Pirker et al, met its primary end point of OS.47 Although PFS was the same in both arms (4.8 months; HR, 0.943), OS (11.3 months vs 10.1 months; HR, 0.871; P=0.044), time-to-treatment failure (4.2 months vs 3.7 months; HR, 0.86; P=0.015), and objective RR (36% vs 29%; P=0.012) were significantly prolonged in the cetuximab arm. Also, preplanned subgroup analysis showed survival benefit in all subgroups, including patients with squamous cell tumors. Results of a completed Phase III trial (BMS-099) of PC or docetaxel plus carboplatin (DCb) with or without cetuximab in a similar patient population were reported as not significantly different, with PFS as the primary end point.48 Additional data from this trial, especially OS rates, are eagerly awaited. There may be a role for cetuximab in combination with chemotherapy in the first-line treatment of NSCLC. Additionally, there is a Phase III second-line study (SELECT) of combination docetaxel or pemetrexed with or without cetuximab nearing completion.

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PREDICTORS

OF

RESPONSE

TO

EGFR INHIBITORS

Reported RRs to EGFR TKIs in patients with advanced NSCLC are approximately 10% to 20%.

Certain subgroups of patients have a higher likelihood of benefiting from these agents窶馬amely, female patients, never-smokers, patients with adenocarcinoma histology, and patients of Asian origin.

Researchers have identified somatic mutations in the kinase domain of the EGFR gene (in exons 18-21) in the majority of NSCLCs that demonstrated remarkable responses to EGFR TKIs.49-51 An ongoing single-arm Phase II study is assessing erlotinib as first-line treatment in patients with advanced NSCLC and sensitizing EGFR mutations. Preliminary data from the first 38 patients showed an RR of 82% and a projected 1-year survival rate of 82%, which far exceed the results expected with standard chemotherapy.52 A number of retrospective studies and an analysis of EGFR mutation status in the IDEAL (Iressa dose evaluation for advanced lung cancer ) trials of gefitinib monotherapy have reported that among patients treated with EGFR TKIs, those who have EGFR mutations exhibit significantly improved TTP and/or survival compared with patients who have wild-type EGFR.53,54 Not all studies, however, have reported an association between EGFR mutations and improved outcomes. Some researchers have suggested that EGFR gene copy number (as assessed by fluorescent in situ hybridization) or level of EGFR protein expression may be a better predictor of benefit from EGFR TKIs.55-58 This issue is unresolved and remains a focus of research.

Markers of resistance to EGFR inhibitors also have been identified. The K-ras gene encodes guanosine triphosphates that function downstream of EGFR in the mitogen-activated protein kinase signaling pathway. Mutations in K-ras in multiple tumor types have been noted, including NSCLC (15%-30% of cases), and they are associated with a worse outcome. Cigarette smoking has been strongly associated with K-ras gene mutations in patients with adenocarcinoma of the lung.59 In a recent analysis of tumor tissues from 274 patients who participated in TRIBUTE, a Phase III study,38 K-ras mutations were noted in 21% of tumors and were associated with significantly shorter survival and TTP in the group receiving erlotinib plus chemotherapy. In contrast, EGFR mutations were detected in 13% of tumors and were associated with significantly improved outcomes.60,61 Pao et al evaluated 60 lung adenocarcinomas from patients with a known response to either gefitinib or erlotinib for the presence of EGFR or K-ras mutations.61 They found that 17 tumors with identified EGFR mutations responded to gefitinib or erlotinib, whereas 9 tumors found to have K-ras mutations did not. This suggests that K-ras mutations are associated with primary resistance to gefitinib or erlotinib, and that a determination of the mutational status for both EGFR and K-ras may help determine which patients are most likely to benefit from treatment with an EGFR TKI.

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Table 3. Selected Targeted Agents Being Evaluated in NSCLC Agent

Mechanism

Phase of Development in Advanced NSCLCa

Epidermal growth factor receptor (EGFR) Erlotinib

TKI of EGFR

• Monotherapy approved for second-, third-line use • Phase III (first-line monotherapy) • Phase III (first-line with bevacizumab)

Gefitinib

TKI of EGFR

• Not to be commenced in a new patient outside a clinical trial (details in text) • Phase II/III (maintenance after first-line chemotherapy; first-line treatment in selected patient populations)

Cetuximab

Monoclonal Ab against extracellular domain

• Phase III (first- and second-line use with chemotherapy)

Panitumumab

Monoclonal Ab against extracellular domain

• Phase II (first-line use with PCb)

Lapatinib

EGFR and erb-B2 TKI

• Phase II

Canertinib

TKI of eGFR, erb-B2, erb-B3

• Phase II

Vascular endothelial growth factor (VEGF) signaling pathway Bevacizumab

Monoclonal Ab against VEGF

• Approved for first-line use with PCb for nonsquamous-predominant NSCLC • Phase III (first-line use in combination with other chemotherapeutics and targeted agents)

ZD6474 (vandetanib)

TKI of VEGFR-2, EGFR, RET

• Phase III (second-line use with docetaxel) • Phase II (first-line use with PCb)

AZD2171

TKI of VEGFR-1, -2, -3, PDGFR, c-Kit

• Phase II/III (first-line use alone or with PCb)

Sunitinib

TKI of VEGFR-1, -2, -3, PDGFR, c-Kit, Flt-3

• Phase II (second- and third-line use with erlotinib; first-line use in combination with PCb and bevacizumab planned)

AMG 706

TKI of VEGFR-1, -2, -3, PDGFR, c-Kit

• Phase II (first-line use with PCb)

Lonafarnib

Farnesyl transferase inhibitor

• Phase III trial of first-line combination with PCb stopped early with lack of survival benefit on interim analysis

Tipifarnib

Farnesyl transferase inhibitor

• Phase II trial of first-line monotherapy completed with no objective responses

Sorafenib

TKI of Raf-1, VEGFR-2 and -3, PDGFR • Phase III (first-line use with PCb)

Ras/Raf/MAPK

Mammalian target of rapamycin (mTOR) Temsirolimus

mTOR inhibitor

• Phase II (first-line monotherapy)

Everolimus

mTOR inhibitor

• Phase I/II (second- or third-line use with EGFR TKIs, docetaxel, or pemetrexed)

Src family of nonreceptor tyrosine kinases Dasatinib a

Src TKI

• Phase II (first-line monotherapy) • Phase I (combination with erlotinib)

See text for details and references.

Ab, antibody; Flt-3, FMS-like tyrosine kinase 3; MAPK, mitogen-activated protein kinase; NSCLC, non-small cell lung cancer; PCb, paclitaxel and carboplatin; PDGFR, platelet-derived growth factor receptor; RET, REarranged during Transfection; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor

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In addition to the mutations in EGFR that have been described to confer sensitivity to EGFR TKIs, EGFR mutations that confer resistance to these agents have been identified more recently. In tumors with sensitizing EGFR mutations and an initial response to EGFR TKI therapy, resistance ultimately develops. In approximately 50% of such cases, a single secondary mutation in the EGFR exon 20, T790M, has been identified.62-64 It is unclear whether this is an acquired mutation or whether it is present in a subset of tumor cells before EGFR TKI treatment, with the treatment then essentially selecting out these resistant cells for survival and tumor growth.65 Other tumor properties, such as the expression of markers of epithelial-tomesenchymal transition, also have been associated with resistance to EGFR TKIs.66 The identification of various markers of sensitivity and resistance to EGFR TKIs has strongly encouraged the movement toward personalized medicine for patients with cancer. It is hoped that personalized medicine will result in treatments being selected based on molecular markers in tumors. This emerging evidence also suggests, however, that a single marker predicting EGFR TKI sensitivity or resistance is unlikely to be sufficiently reliable. Therefore, researchers are attempting to develop more broad-based tools for predicting sensitivity or resistance to EGFR inhibitors, such as gene-expression profiling, but studies are at an early stage.67

AGENTS TARGETING

THE

VEGF SIGNALING PATHWAY

Angiogenesis is essential for the growth and metastatic spread of tumors. Several retrospective and prospective studies have shown that increased microvascular density in NSCLC tumors correlates with advanced disease and inferior patient outcome.68-71 Similarly, increased tumor expression of pro-angiogenic factors, such as VEGF, basic fibroblast growth factor, and interleukin (IL)-8, has been associated with inferior prognosis.71-76 VEGF signaling plays a central role in the regulation of tumor angiogenesis, and both the VEGF ligand and its receptors (VEGFR-1, -2, and -3) are the targets of intense preclinical and clinical research.77 Bevacizumab, a humanized monoclonal antibody that binds VEGF, is approved for use in combination with chemotherapy in advanced colorectal cancer and advanced nonsquamous-predominant NSCLC. Following promising results in a Phase II trial,78 878 patients were enrolled in E4599 to receive 6 cycles of paclitaxel (200 mg/m2) and carboplatin (area under the curve, 6) with or without bevacizumab (15 mg/kg) as first-line treatment for stage IIIB or IV NSCLC.79 Patients with squamous histology were excluded because an excessive risk for life-threatening hemoptysis in association with these tumor types had been observed in the preceding Phase II trial.78 In the E4599 study, the combination of PCb and bevacizumab improved RR (35% vs 15%), PFS, and median OS (12.3 vs 10.3 months; P=0.003) relative to chemotherapy alone.

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Fifteen treatment-related deaths occurred in the group given PCb plus bevacizumab, including 5 from pulmonary hemorrhage and 5 from complications of febrile neutropenia; 2 treatment-related deaths occurred in the group given chemotherapy alone.

Nevertheless, the OS advantage with the addition of bevacizumab to PCb in this patient population outweighed the risk for treatment-related death and led to the approval of bevacizumab in combination with first-line PCb for advanced nonsquamous NSCLC. Of note, an unplanned subset analysis of survival by sex in E4599 found that the survival benefit was confined to male participants, although female patients did benefit in terms of response and PFS.80 Bevacizumab is being assessed in combination with other first-line chemotherapy regimens for advanced nonsquamouspredominant NSCLC, and AVAIL (Avastin in Lung Cancer), a large Phase III trial of bevacizumab in combination with first-line GC, has reported positive results with PFS as the primary end point. In an update presented at ESMO 2008, the PFS was maintained at longer follow-up.81 However, OS did not reach statistical significance, although it may have been confounded because most patients received subsequent heterogeneous therapy following progressive disease, which was not specified in the initial protocol. Taken together with ECOG E4599, first-line bevacizumab with platinum-based doublet chemotherapy provides important clinical benefits to patients with stage IIIB/ IV nonsquamous NSCLC. An alternative anti-angiogenic strategy under evaluation in NSCLC is inhibition of VEGFR TKs. The moststudied VEGF TKI in NSCLC to date is ZD6474 (vandetanib; Zactima, AstraZeneca), an orally administered agent that also inhibits EGFR. A number of Phase II studies of vandetanib, alone or in combination with chemotherapy, for previously treated NSCLC have been reported. These studies did not exclude patients with squamous histology and have shown promising results and favorable toxicity profiles. In one randomized Phase II trial, patients with locally advanced or metastatic NSCLC previously treated with platinum were randomly assigned to receive monotherapy once daily with either vandetanib (300 mg) or gefitinib (250 mg).82 A statistically significant improvement in median PFS (primary end point) was noted for vandetanib compared with gefitinib. In another Phase II trial, 127 patients with advanced NSCLC previously treated with platinum were randomly assigned to receive docetaxel alone or docetaxel in combination with vandetanib (100 or 300 mg once daily).83 This study met its primary end point of prolonged median PFS for docetaxel plus vandetanib 100 mg compared with docetaxel alone (18.7 vs 12 weeks). These results led to ZODIAC (ZACTIMA in combination with Docetaxel in non-small cell lung cancer), an international, randomized Phase III trial of docetaxel combined with vandetanib 100 mg or placebo as second-line therapy for locally advanced or metastatic NSCLC.84 This trial has been reported

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positive for PFS and detailed results are expected soon. Vandetanib also is being tested with pemetrexed in the second-line setting of metastatic NSCLC. ZEAL (ZACTIMA Efficacy with Alimta in Lung cancer) is an international Phase III trial of approximately 500 patients comparing pemetrexed with or without vandetanib. It has completed accrual and clinicians are awaiting final results.85 Vandetanib also is under evaluation in the first-line treatment of NSCLC. A randomized, multicenter Phase II study of vandetanib alone or in combination with standard PCb as first-line treatment for locally advanced, metastatic, or recurrent NSCLC has completed accrual and has been reported.86 Sorafenib (Nexavar, Onyx Pharmaceuticals/Bayer) is another orally bioavailable, multitargeted receptor TKI with activity against VEGFR-2 and -3, plateletderived growth factor receptor (PDGFR), and Raf-1 that is approved as monotherapy in advanced renal cell carcinoma (RCC). In a recent single-arm Phase II trial, sorafenib 400 mg twice daily showed evidence of single-agent activity in the second- and third-line settings for advanced NSCLC.87 A randomized Phase III trial, ESCAPE (Evaluation of Sorafenib, Carboplatin, and Paclitaxel Efficacy), evaluated sorafenib in combination with 6 cycles of first-line PCb chemotherapy for stage IIIB or IV NSCLC. This trial did not meet its primary end point of OS, and subgroup analysis of the data showed an actual detrimental effect for patients with squamous histology.88 An ongoing Phase III NEXUS (NSCLC research Experience Utilizing Sorafenib) trial is therefore evaluating the combination of sorafenib with gemcitabine and cisplatin in the first-line setting of patients with stage IIIB/IV nonsquamous NSCLC.89 At ASCO 2008, Schiller et al presented data on a randomized Phase II study (E2501) of sorafenib versus placebo in patients with NSCLC who have failed at least 2 prior regimens. Preliminary results suggested that sorafenib prolonged PFS in heavily pretreated patients with slowgrowing tumors90 AZD2171, a TKI of VEGFR-1, -2, and -3, PDGFR, and c-Kit, is also being assessed in a Phase II/ III trial. Patients are being randomized to PCb with or without AZD2171 for the first-line treatment of stage IIIB or IV NSCLC following encouraging results in a Phase I trial.91 Other, similar agents at earlier stages of clinical development in NSCLC include AMG 706, sunitinib (Sutent, Pfizer), and axitinib (AG-013736, Pfizer).

COMBINATION THERAPY WITH ANTI-VEGF ANTI-EGFR AGENTS

AND

EGFR signaling plays a role in the regulation of angiogenesis that is at least partly mediated through control of the expression of pro-angiogenic factors, including VEGF and IL-8.92,93 Preclinical studies have shown that dual blockade of the EGFR and VEGF signaling pathways has additive or synergistic antitumor and antiangiogenic effects94-96 and Phase I/II clinical trials of this combination therapeutic strategy are showing promising results in solid tumors, including NSCLC.97-99 BeTa (Bevacizumab and Tarceva) is a Phase III trial

evaluating whether adding bevacizumab to secondline erlotinib versus erlotinib alone will improve OS.100 In a recent press release, Genentech Inc. announced that the study did not meet the primary end point of OS, but the combination improved the secondary end points of RR and PFS.101 In a Southwest Oncology Group Phase II trial (SWOG 0536), the combination of carboplatin, paclitaxel, bevacizumab, and cetuximab is being evaluated in the first-line setting.102 The study has completed accrual and was reported at the Multidisciplinary Symposium in Thoracic Oncology at Chicago in November 2008. The incidence of pulmonary hemorrhage was 2%. Additionally, the RR (53%), PFS (7 months), and OS (14 months) were the highest ever reported in a SWOG lung cancer study.

A number of ongoing studies should shed further light on combination therapy. ATLAS (A Study Comparing Bevacizumab Therapy With or Without Erlotinib for First-line Treatment of Non–Small Cell Lung Cancer), another ongoing multicenter Phase III trial in the United States, is assessing the efficacy of “maintenance” bevacizumab with or without erlotinib after completion of chemotherapy plus bevacizumab for the first-line treatment of stage IIIB or stage IV NSCLC. Several early-phase studies also are considering combinations of VEGFR and EGFR TKIs, such as sorafenib plus gefitinib and sunitinib plus erlotinib, for previously treated NSCLC. Such combinations of targeted agents may yield greater and more prolonged treatment benefits.

INSULIN-LIKE GROWTH FACTOR INHIBITORS Insulin-like growth factors also are showing promise in the treatment of NSCLC.103,104 Karp et al evaluated the anti-insulin-like growth factor I receptor (IGFIR) antibody CP-751871 (Pfizer) in combination with PCb in treatment-naïve advanced NSCLC.104 Updated results presented at ASCO 2008 showed a significant ORR of 51% in the CP-751871 arm.105 Of particular significance is the impressive 72% ORR seen in the subgroup of patients with squamous cell histology. In view of these results, a Phase III trial is being planned to study CP-751871 along with a platinum-based doublet in the first-line setting.

MAMMALIAN TARGET

OF

RAPAMYCIN INHIBITORS

Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that plays a critical role in tumorigenesis through its effects on transcriptional and translational proteins, which ultimately control cell growth and proliferation. mTOR inhibitors have shown promise in a variety of solid and hematologic malignancies.106 Temsirolimus (Torisel, Wyeth), an ester of the natural antibiotic rapamycin, is an mTOR inhibitor that has been investigated in a number of malignancies with promising results and is the first mTOR inhibitor approved by the FDA as a treatment for cancer. A Phase II study of first-line temsirolimus monotherapy in stage IIIB and IV NSCLC has been completed.

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Everolimus (Afinitor, Novartis) is another mTOR inhibitor under investigation in a number of malignancies, including NSCLC. It was approved in March 2009 for selected patients with renal cell carcinoma. Given the success achieved with mTOR inhibition in RCC, clinicians eagerly await the results of clinical trials of this agent in NSCLC.

SRC FAMILY

OF

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Scagliotti GV, De Marinis F, Rinaldi M, et al. Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer. J Clin Oncol. 2002;20(21):4285-4291, PMID: 12409326.

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NONRECEPTOR TYROSINE KINASES

The Src family of nonreceptor tyrosine kinases (SFKs) is another promising therapeutic target in NSCLC. SFKs regulate signals from multiple cellsurface molecules, including integrins, growth factors, and G protein-coupled receptors. Activation of c-Src mediates cell proliferation, differentiation, migration, adhesion, invasion, angiogenesis, and immune function. SFKs are commonly overexpressed and activated in NSCLC.107,108 Dasatinib (Sprycel, BristolMyers Squibb) is an SFK inhibitor that is approved for use in some hematologic malignancies. Cell-line and xenograft studies have shown antitumor activity of SFK inhibitors in NSCLC,109,110 and a US Phase II trial of dasatinib monotherapy for the first-line treatment of advanced NSCLC is ongoing. Preclinical studies also have shown additive or synergistic activity against NSCLC cell lines with the combination of SFK inhibitors and EGFR TKIs,111 and a US Phase I trial of the combination of erlotinib and dasatinib is ongoing.112

Conclusion The treatment of advanced NSCLC is an exciting and rapidly evolving field. With cytotoxic chemotherapy doublets yielding only a modest improvement in survival, it was feared that a plateau had been reached for treatment benefits in NSCLC. However, research is focusing on the development of molecular targeted therapies, and agents targeting EGFR and VEGF signaling are leading the way in this new era of NSCLC research and treatment. Bevacizumab and cetuximab (in combination with chemotherapy) and erlotinib are the first biologic agents that have demonstrated an ability to prolong survival in patients with advanced NSCLC. Pemetrexed with cisplatin has also demonstrated front-line activity. Numerous Phase II/III trials continue to assess these and other targeted agents, with many promising early results.

Other strategies are being evaluated, including earlier detection, chemoprevention, and predictive markers. It is imperative that research leading to identification and validation of markers that can predict, before treatment, which patients are most likely to benefit from specific therapeutic agents. The most exciting results in this area to date have been seen with markers of sensitivity to EGFR TKIs and cisplatin. As research on genomic and proteomic techniques continues, therapy tailored to specific tumors may offer an opportunity for improved efficacy and disease control with both cytotoxic and biologic compounds.

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62. Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 2005;352(8):786-792, PMID: 15728811.

63. Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005;2(3):e73, PMID: 15737014.

64. Kwak EL, Sordella R, Bell DW, et al. Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci U S A. 2005;102(21):7665-7670, PMID: 15897464.

65. Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Natl Rev Cancer.

2007;7(3):169-181, PMID: 17318210.

66. Yauch RL, Januario T, Eberhard DA, et al. Epithelial versus mesenchymal phenotype determines in vitro sensitivity and predicts clinical activity of erlotinib in lung cancer patients. Clin Cancer Res. 2005;11(24 pt 1):8686-8698, PMID: 16361555.

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78. Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer.

J Clin Oncol. 2004;22(11):2184-2191, PMID: 15169807.

79. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355(24):2542-2550, PMID: 17167137.

80. Brahmer JR, Gray R, Schiller JH, et al. ECOG 4599 phase III trial of carboplatin and paclitaxel ±bevacizumab: subset analysis of survival by gender. J Clin Oncol. 2006;24(18 suppl). Abstract 7063.

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Manegold C, von Pawel J, Zatloukal P, et al. BO17704 (AVAIL): A phase III randomised study of first-line bevacizumab combined with cisplatin/ gemcitabine (CG) in patients (pts) with advanced or recurrent non-squamous, non-small cell lung cancer (NSCLC) [abstract]. Ann Oncol. 2008;19(8):LBA1

82. Natale RB, Bodkin D, Govindan R, et al. A comparison of the antitumour efficacy of ZD6474 and gefitinib (Iressa) in patients with NSCLC: results of a randomized, double-blind phase II study. In: Proceedings of the 11th World Conference on Lung Cancer; July 3-6, 2005; Barcelona, Spain. Abstract O-104.

83. Heymach J, Johnson B, Prager D, et al. A phase II trial of ZD6474 plus docetaxel in patients with previously treated NSCLC: followup results. J Clin Oncol. 2006;24(18S). Abstract 7016.

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84. ZACTIMA (an anti-EGFR / anti-VEGF agent) combined with docetaxel compared to docetaxel in non-small cell lung cancer (ZODIAC). ClinicalTrials.gov. Accessed November 7, 2008.

85. Efficacy Study Comparing ZD6474 in Combination With Pemetrexed and Pemetrexed Alone in 2nd Line NSCLC Patients (ZEAL). Clinical Trials.gov. Accessed November 7, 2008.

86. Heymach J, West H, Kerr R, et al. ZD6474 in combination with carboplatin and paclitaxel as first-line treatment in patients with NSCLC: results of the run-in phase of a two-part randomized phase II study. In: Proceedings of the 11th World Conference on Lung Cancer; July 3-6, 2005; Barcelona, Spain. Lung Cancer.

2005;49(suppl 2):S247. Abstract P-497.

87. Gatzemeier U, Blumenschein G, Fosella F, et al. Phase II trial of single-agent sorafenib in patients with advanced non-small cell lung carcinoma. J Clin Oncol. 2006;24(18S). Abstract 7002.

88. Scagliotti G, von Pawel J, Reck M, et al. Phase III trial comparing carboplatin and paclitaxel with or without sorafenib in chemonaive patients with stage IIIB (with effusion) or IV non-small cell lung cancer. Presented at: IASLC-ESMO 1st European Lung Cancer Conference; April 23-26, 2008; Geneva, Switzerland. Late Breaking Abstract.

89. A Trial Comparing Gemcitabine, Cisplatin and Sorafenib to Gemcitabine, Cisplatin and Placebo in First-Line Treatment of Stage IIIb With Effusion and Stage IV Non-Small Cell Lung Cancer (NSCLC). Clinical Trials.gov. Accessed November 7, 2008.

90. Schiller JH, Lee JW, Hanna NH, et al. A randomized discontinuation phase II study of sorafenib versus placebo in patients with non-small cell lung cancer who have failed at least two prior chemotherapy regimens: E2501 (Abstract). J Clin Oncol 26: 2008 (May 20 suppl; abstr 8014).

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Laurie SA, Arnold A, Gauthier I, et al. Final results of a phase I study of daily oral AZD2171, an inhibitor of vascular endothelial growth factor receptors (VEGFR), in combination with carboplatin (C) + paclitaxel (T) in patients with advanced non-small cell lung cancer (NSCLC): a study of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG). J Clin Oncol.

2006;24(18S). Abstract 3054.

92. Ciardiello F, Caputo R, Bianco R, et al Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor. Clin Cancer Res. 2001;7(5):1459-1465, PMID: 11072252.

93. Hirata A, Ogawa S, Kometani T, et al. ZD1839 (Iressa) induces antiangiogenic effects through inhibition of epidermal growth factor receptor tyrosine kinase. Cancer Res. 2002;62(9):25542560, PMID: 11980649.

94. Shaheen RM, Tseng WW, Davis DW, et al. Tyrosine kinase inhibition of multiple angiogenic growth factor receptors improves survival in mice bearing colon cancer liver metastases by inhibition of endothelial cell survival mechanisms. Cancer Res. 2001;61(4):1464-1468, PMID: 11245452.

95. Jung YD, Mansfield PF, Akagi M, et al. Effects of combination anti-vascular endothelial growth factor receptor and anti-epidermal growth factor receptor therapies on the growth of gastric cancer in a nude mouse model. Eur J Cancer. 2002;38(8):11331140, PMID: 12008203.

96. Morelli MP, Cascone T, Troiani T, et al. Anti-tumor activity of the combination of cetuximab, an anti-EGFR blocking monoclonal antibody, and ZD6474, an inhibitor of VEGFR and EGFR tyrosine kinases. J Cell Physiol. 2006;208(2):344-353, PMID: 16688779.

97. Herbst RS, Johnson DH, Mininberg E, et al. Phase I/II trial evaluating the anti-vascular endothelial growth factor monoclonal antibody bevacizumab in combination with the HER-1/epidermal growth factor receptor tyrosine kinase inhibitor erlotinib for patients with recurrent non-small-cell lung cancer. J Clin Oncol.

2005;23(11):2544-2555, PMID: 15753462.

98. Fehrenbacher L, O’Neill VJ, Belani CP, et al. A phase II, multicenter, randomized clinical trial to evaluate the efficacy and safety of bevacizumab in combination with either chemotherapy (docetaxel or pemetrexed) or erlotinib hydrochloride compared with chemotherapy alone for treatment of recurrent or refractory non-small cell lung cancer. J Clin Oncol 2006;24(18S).

Abstract 7062.

99. Herbst R, O’Neill VJ, Fehrenbacher L. Phase II study of efficacy and safety of bevacizumab in combination with chemotherapy or erlotinib compared with chemotherapy alone for treatment of recurrent or refractory non–small-cell lung cancer. J Clin Oncol.

2007;25(30):4743-4750.

100. Avastin and Tarceva for Locally Advanced or Metastatic NonSquamous Non-Small-Cell Lung Cancer. Clinical Trials.gov.

Accessed November 7, 2008.

101. Genentech: Phase III Study Evaluating the Combination of Avastin and Tarceva as Second-Line Treatment for Advanced Non-Small Cell Lung Cancer [press release] October 5, 2008. http://www.gene.com/gene/news/press-releases/display. do?method=detail&id=11527.

102. Cetuximab, Paclitaxel, Carboplatin, and Bevacizumab in Treating Patients With Advanced Non-Small Cell Lung Cancer (SWOG 0536). Clinical Trials.gov. Accessed November 7, 2008.

103. Morgillo F, Kim WY, KIm ES, Ciardello F, Waun KH, Lee HY. Implication of the insulin-like growth factor-IR pathway in the resistance of non-small cell lung cancer cells to treatment with gefitinib. Clin Cancer Res. 2007;13(9):2795-2803, PMID: 17473213.

104. Karp DD, Paz-Ares, LG, Blakely LJ, et al. Efficacy of the antiinsulin like growth factor I receptor (IGF-IR) antibody CP-751871 in combination with paclitaxel and carboplatin as first-line treatment for advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2007;25;18S(suppl). Abstract 7506.

105. Karp DD, Paz-Ares LG, Novello S, et al. High activity of the antiIGF-IR antibody CP-751,871 in combination with paclitaxel and carboplatin in squamous NSCLC (Abstract). J Clin Oncol. 2008; 26(suppl). Abstract 8015.

106. Janus A, Robak, T, Smolewski P. The mammalian target of the rapamycin (mTOR) kinase pathway: its role in tumorigenesis and targeted antitumour therapy. Cell Mol Biol Lett. 2005;10(3):479498, PMID: 16217558.

107. Zhang J, Kalyankrishna S, Wislez M, et al. SRC-family kinases are activated in non-small cell lung cancer and promote the survival of epidermal growth factor receptor-dependent cell lines. Am J Pathol. 2007;170(1):366-376, PMID: 17200208.

108. Masaki T, Igarashi K, Tokuda M, et al. pp60c-src activation in lung adenocarcinoma. Eur J Cancer. 2003;39(10):1447-1455, PMID: 12826049.

109. Zheng R, Yano S, Matsumori Y, et al. SRC tyrosine kinase inhibitor, m475271, suppresses subcutaneous growth and production of lung metastasis via inhibition of proliferation, invasion, and vascularization of human lung adenocarcinoma cells. Clin Exp Metastasis. 2005;22(3):195-204, PMID: 16158247.

110. Johnson FM, Saigal B, Talpaz M, Donato NJ. Dasatinib (BMS354825) tyrosine kinase inhibitor suppresses invasion and induces cell cycle arrest and apoptosis of head and neck squamous cell carcinoma and non-small cell lung cancer cells. Clin Cancer Res. 2005;11(19 pt 1):6924-6932, PMID: 16203784.

111. Song L, Morris M, Bagui T, Lee FY, Jove R, Haura EB. Dasatinib (BMS-354825) selectively induces apoptosis in lung cancer cells dependent on epidermal growth factor receptor signaling for survival. Cancer Res. 2006;66(11):5542-5548, PMID: 16740687.

112. Phase I dasatinib/erlotinib in recurrent NSCLC. ClinicalTrials.gov.

Accessed May 12, 2008.

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HEMATOLOGIC DISEASE Chronic Myeloid Leukemia

New Lessons From the Imatinib IRIS Study in CML SAN FRANCISCO—A recent study suggests that clinicians should maintain patients with chronic myeloid leukemia (CML) on imatinib for at least two years, even in the absence of a complete cytogenetic response (CCR), before switching to an alternative therapy.

According to the study, the durability and quality of a late CCR to imatinib (Gleevec, Novartis) is not different from that of a CCR achieved more rapidly in patients with CML. This news is from the latest analysis of IRIS (International Randomized study of Interferon versus ST1571), the trial that established imatinib as the front-line choice for CML. Seven years after it was initiated, IRIS is still generating important clinical information.

“At seven years, the CCR rate in patients who continue to respond to imatinib is approximately 85%,” said Stephen G. O’Brien, MD, PhD, Department of Haematology, University of Newcastle, Newcastle, United Kingdom. The overall survival (OS) rate at seven years among those who were initially randomized to imatinib was 86%, and the event-free survival (EFS) was 81%. Freedom from progression to accelerated phase or blast crisis (AP/BC) was 93%. Of those patients who achieved a CCR on imatinib, 17% have lost the CCR but several regained it, often through dose intensification, and only 2% have died from their disease.

The updated results were presented at the most recent annual meeting of the American Society of Hematology (abstract 186). In IRIS, 1,106 patients with CML were randomized to 400 mg of imatinib or to the combination of interferon (IFN) and cytarabine (ARA-C), which was the standard when IRIS was initiated. The focus of the new analysis was on 332 of the 554 patients who were initially randomized to imatinib and who are still receiving this agent as a first-line treatment. Of 553 patients initially randomized to IFN/ARA-C, only nine (1.6%) remain on this combination.

One of the most encouraging findings from the long-term results is that AP/BC rates appear to diminish over time. The highest rates of progression were in the first three years, when 1.5%, 2.8% and 1.6% of the patients, respectively, experienced AP/BC. In the subsequent four years, the rates were 0.9%, 0.5%, 0% and 0.4%, respectively. Of the 15 patients who achieved a CCR and then progressed to AP/BC, only three did so after the second year.

Major molecular responses (MMR) and CCR continued to accrue over time, with a small but substantial proportion of patients taking up to two years to reach these milestones. A slow response, however, does not appear to represent a fragile response. In subsequent follow-up, the likelihood of remaining in MMR or CCR appeared to be similar in those with a late response and in those with an early response. These findings challenge the strategy of switching patients with CML to an alternative treatment strategy if a CCR is not achieved within six months.

“Patients with a late response do achieve sustained responses,” said Dr. O’Brien, suggesting that clinicians should be patient. Although the effort to demonstrate reduced survival in patients who discontinued therapy in the IRIS study appears to be complicated by the substantial rate of those

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These findings challenge the strategy of switching CML patients to an alternative treatment strategy if a CCR is not achieved within six months. who went on to receive imatinib off-label, Dr. O’Brien did report that survival at five years among those who discontinued therapy for a reason other than safety was 85%. In contrast, survival was only 50% among those who discontinued for safety and were therefore less likely to receive imatinib or another tyrosine kinase inhibitor subsequently.

No new safety-related issues have been raised regarding long-term exposure to imatinib, “confirming a favorable risk– benefit ratio,” said Dr. O’Brien. Only 5% of those from the initial randomization who discontinued therapy did so for reasons of safety or tolerability. The most common reason for discontinuation was lack of efficacy, but this was cited in only 15% of the total imatinib study group. Although Dr. O’Brien cautioned that no set of characteristics has been confirmed to provide absolute protection from relapse, the good news is that the risk of relapse does appear to diminish over time.

“Between years 6 and 7, only 17 patients [3% of the total who achieved CCR] discontinued imatinib,” Dr. O’Brien reported. The reasons for late discontinuation were adverse events in three patients, unrelated death in one and a cause unrelated to safety or efficacy in one. The remaining 12 discontinued because of disease progression; this included one death. Although these results are encouraging, Dr. O’Brien also noted that 40% of patients have discontinued imatinib, and 17% who had achieved CCR subsequently lost this degree of response. More research is needed to identify strategies that would consolidate the initial rates of response, he said.

Francois Xavier Mahon, MD, University Victor Ségalen, Bordeaux, France, agreed that these results are highly encouraging, but he believes that the focus should now be on increasing the rate of complete molecular response (CMR).

“Increasing CMR is the only way to contemplate the possibility for stopping the treatment,” said Dr. Mahon, who was involved in the STIM (Stopping Imatinib) study. “It is interesting to see the increasing of CMR rate over time in the IRIS study. We have shown that the CMR can be sustained after discontinuation of imatinib, particularly in patients pretreated with IFN.” Suggesting that this is the key outcome, Dr. Mahon concluded that “obviously we need more patients and longer follow-up to determine factors affecting the persistence of CMR.” —Ted Bosworth

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SUPPORTIVE CARE Anemia

Some Clinicians Losing Sleep Over REMS for ESAs As risk mitigation strategy for ESAs looms, impact of compliance triggers concern Any initiative aimed at increasing the appropriate use of potentially risky drugs should be welcomed, but not everyone is on board with the Risk Evaluation and Mitigation Strategy (REMS) program being advanced by the FDA for erythropoietin-stimulating agents (ESAs).

“Although we’re not yet sure what form the REMS will take, there may be very onerous compliance aspects to this, such as confirming patient and prescriber registration and providing detailed patient counseling sessions. This has major operational implications written all over it,” said Indu Lew, PharmD, corporate director of education and research, Saint Barnabas Health Care System, in West Orange, N.J. “I think this would pose a huge burden on offices,” said John Finnie, MD, staff hematologist and medical oncologist at the David C. Pratt Cancer Center at St. John’s Mercy Medical Center, in St. Louis, Missouri.

According to FDA statements, the point of a REMS is “to ensure that the benefits of the drug or biological product outweigh the risks of the product.” As of early March 2009, 14 drugs had a REMS approved by the FDA—most have not been met with much resistance and affect only small patient populations. The REMS currently being developed for ESAs, in contrast, will be applied to “a tremendous volume of patients,” said Dr. Lew. She stressed that she is not averse to measures that promote the safe use of ESAs “or any other medication, for that matter. But mapping out criteria and responsibilities for adherence to the REMs may well be quite arduous.”

Phil Johnson, RPh, director of pharmacy at H. Lee Moffitt Cancer Center, in Tampa, Fla., stressed that “the basic concept of [the] REMS is not bad. But it has the potential to create a logistical nightmare, particularly if a REMS is created not only for ESAs but also for every medication that carries a black box warning.” Mr. Johnson added that the “REMS appears to pass the liability from any adverse drug consequences away from the manufacturer and the FDA, and on to those of us saddled with compliance—which means the prescriber and the pharmacist.”

One Size Does Not Fit All The FDA was given authority to require risk mitigation strategies by Section 909 of the FDA Amendments Act of 2007.

There is no single set of components. Instead, a unique REMS is developed by the manufacturer and approved by the FDA for each agent. Typically, a REMS will include plans for training and certifying clinicians in the use of the drug, developing consent forms so that patients are aware of the risks, and monitoring experience with the drug in the clinical setting.

The biologic agent certolizumab (Cimzia, UCB Pharma) is

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one example of a drug that has a REMS and was given one because the drug inhibits patients’ immune responses, causing up to 3% of patients to develop serious infections. The REMS for certolizumab includes a detailed account of the infections that caregivers and patients can use to balance risks versus benefits, along with training and consent requirements. Other agents carry simpler REMs. For example, the risk mitigation materials for Advair, an asthma inhaler from GlaxoSmithKline, consists simply of a “medication guide” that might best be characterized as an easy-to-read package insert. The guide does mention the fact that the drug may increase the risk for asthma-related death, but does not go into a detailed account of how to lessen that risk.

The fact that every REMS is different is one of the greatest potential problems cited by critics of the drug management strategy.

If variable criteria are used to certify that an agent has been administered within the confines of its REMS, the workload could be untenable. “So far, each process is different, and I think this is causing some distress,” said Tim Franson, MD, a health care consultant who participated in early discussions of the REMS. “There is also some confusion about who is responsible for assuring physician and pharmacist compliance and what the liabilities are for practitioners failing to comply.”

Restricted Access?

For those who are less enthusiastic about the REMS for ESAs, one of the key issues is a potential restriction on access to the drugs, at least partly created by the hassle factor of complying with the new regulations. The anemia drugs currently carry a black box warning against treating hemoglobin levels of 12 g/dL or higher in several types of cancer, such as breast and cervical, because of evidence that this therapy may increase the risk for tumor progression and reduce overall survival. However, clinicians are already expected to know this information.

“In the practice of medicine, we are responsible for employing a variety of drugs with significant toxicities,” Mr. Johnson said. “It seems obvious that [the] REMS will stand in the way of using ESAs either because of reluctance from clinicians to prescribe a drug that requires extra effort or from patients who are concerned about drugs that require a REMS.” Although risk mitigation strategies are typically specific for individual drugs, the REMS being developed for ESAs is expected to be valid for the entire drug class. Trish Hawkins, a spokeswoman for Amgen, said that the company, along with Centocor/Ortho Biotech, are working together with the FDA for a uniform REMS to be applied to both darbepoetin alfa (Aranesp) and erythropoietin alfa (Procrit/Epogen). In the initial proposal discussed at a March 2008 FDA Oncologic Drugs Advisory Committee meeting, components of the REMS included a

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see REMS, page 59 �

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SOLID TUMORS Breast

Breast Cancer Approach: Same for Young and Old PHOENIX—Women older than 70 years have equivalent outcomes after surgery for breast cancer as younger women and should not be viewed as high risk, according to two studies presented at the recent annual meeting of the Society for Surgical Oncology (SSO).

“More and more, we’re seeing evidence that shows clearly we should treat older patients in the same way that we would treat younger patients,” said Elizabeth A. Mittendorf, MD, an assistant professor of surgical oncology at the University of Texas M.D. Anderson Cancer Center in Houston, and a study author.

In the first of the studies from the SSO meeting, women with an average age of 76 had short- and long-term survival rates similar to those of much younger women. A second study examining sentinel lymph node biopsy among women over age 70 found that age did not affect identification or false-negative rates. Investigators hope that the reports will encourage more aggressive treatment for older women than has historically been the case.

“[Older patients] should not be denied treatment based on age alone.”

—Nazanin Khakpour, MD

Until recently, older women were excluded from all major breast cancer trials. This left physicians unsure about the merits and risks involved in treating older women, resulting in undertreatment of this population. Studies have shown that older women who develop breast cancer often do not receive the same care offered to younger women (J Clin Oncol 2006;24:4369-4370, PMID: 16983104).

This is problematic in itself, but experts warn that elderly women represent a large and growing population of breast cancer patients. “Women age 65 years or older constitute half of new breast cancer patients each year and this population is growing. These women should not be denied treatment based on age alone,” said Nazanin Khakpour, MD, a surgeon and an assistant member of the Don and Erika Wallace Comprehensive Breast Program at H. Lee Moffitt Cancer Center and Research Institute in Tampa, Fla., who co-authored one of the studies.

Dr. Khakpour and colleagues examined the postoperative outcomes for 736 women with an average age of 76 years who underwent surgery for breast cancer. The operations included 294 mastectomies, 468 lumpectomies and three procedures on the chest wall.

The 30-day mortality was 0.3% and the 10-year mortality was 26%, not different from published rates in studies involving younger women. The study revealed that patients with comorbidities appear to be at higher risk for complications than patients of older age.

In another study presented at the SSO meeting, researchers from M.D. Anderson reviewed the results of 4,146 women who underwent sentinel lymph node biopsy between 1993 and 2006. Compared with the 3,548 women younger than 70

50

years, sentinel lymph node biopsy in the 598 women older than 70 years was associated with a similar identification rate (96.2% vs. 97.1%; P=0.15) and similar false-negative rate (4.9% vs. 5.3%; P=0.81).

The study also showed older women tended to have less advanced tumors by stage (P=0.0003) and tumor grade (P<0.0001), with more estrogen receptor-positive tumors (83.8% vs. 75.0%; P<0.0001) and HER2-negative tumors (86.8% vs. 82.3%; P=0.013).

“Older breast cancer patients with a clinically negative axilla should be offered sentinel lymph node biopsy as part of their surgical treatment,” said Dr. Mittendorf.

In 2007, the International Society of Geriatric Oncology published evidence-based recommendations for the diagnosis and treatment of breast cancer in older women (Lancet Oncol 2007;8:1101-1115, PMID: 18054880). The report includes specifics for screening, surgery, radiotherapy, adjuvant and neoadjuvant hormone treatment and chemotherapy, and treatment of metastatic disease.

It concludes: “Surgery should not be denied to patients with breast cancer who are older than 70 years of age and should not differ from procedures offered to younger patients, unless patient preference dictates.”

—Christina Frangou

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SOLID TUMORS CLINICAL ONCOLOGY NEWS SPECIAL EDITION 2009 • NO. 1 DIGITAL EDITION • JUNE 2009

Colon

Does Bevacizumab Have a Future In Early-Stage Colon Cancer?

Orlando, Fla.—A trial investigating whether adding bevacizumab (Avastin, Genentech) to modified FOLFOX-6 benefits patients with stage II or III colon cancer has concluded that the drug did not improve disease-free survival (DFS) ... or did it?

When initial results of this trial were revealed in April, the Wall Street Journal labeled the drug a failure in this setting. An analysis of the data, however, shows that the issue may not be so cut and dry. The study, the first to report results on the use of bevacizumab in early-stage colon cancer, was presented at the 2009 annual meeting of the American Society of Clinical Oncology (ASCO; LBA4).

Analyzing the Data The study set out to measure three-year DFS for a hazard ratio (HR) of 0.75 in 2,710 patients who were randomized to receive six months of mFOLFOX-6 (5-fluorouracil, leucovorin and oxaliplatin) or six months of mFOLFOX-6 combined with bevacizumab (5 mg/kg every two weeks) plus an additional six months of bevacizumab after completion of chemotherapy. The median duration of bevacizumab administration was 11.5 months, with less than 2% of patients lost to follow-up in both arms. Demographics were equivalent in both arms.

After a median follow-up of three years, 77.4% of patients receiving bevacizumab were still alive compared with 75.5% who had not received the drug, a difference that was not statistically significant (P=0.15; HR, 0.89). Increased grade 3/4 toxicities were greater in the investigational arm, including hypertension (12% vs. 1.8%), pain (11.1% vs. 6.3%) and wound healing (1.7% vs. 0.3%).

Dr. Wolmark said there was a statistically significant benefit in DFS during the one year that patients received bevacizumab.

He suggested that future clinical trials should investigate the use of bevacizumab for longer than one year.

“Did we fail abominably or did we fail with distinction … with cum laude or with a hope of redemption?

We saw an absolute difference of [less than] 2% in favor of bevacizumab at three years and this was disappointing,” said Norman Wolmark, MD, chairman of the Department of Human Oncology at Allegheny General Hospital, Pittsburgh. He presented the data at ASCO. Pointing to the Kaplan-Meier curves associated with the study, however, Dr. Wolmark said “there is an interesting pattern to these curves in that they separate early in favor of bevacizumab and then they come together.” He said that this finding raises the question as to whether there ever was a beneficial effect of bevacizumab that was statistically significant. A

re-analysis of the data provided the answer.

“During the time that bevacizumab was given, six months during chemotherapy and six months beyond the chemotherapy, we saw a robust benefit associated with bevacizumab—a hazard ratio of 0.60 or a 40% reduction in event rate, with a highly statistically significant P value [P=0.0004],” said Dr. Wolmark. “At one year, there was an absolute difference of 3.6% in favor of bevacizumab. This magnitude was similar to that which we saw in the Herceptin trial in breast cancer, NSABP protocol B31.”

Although Dr. Wolmark conceded that the trial did not meet the prespecified end point, he said it was clear that there was a statistically significant transient benefit in DFS during the 12 months that patients received the vascular endothelial growth factor (VEGF) inhibitor. He suggested that strong consideration should be given to future clinical trials investigating the use of bevacizumab for longer than one year.

Experts Weigh In In his discussion of the C-08 trial at the ASCO meeting, Lee Ellis, MD, professor of surgical oncology and interim chair of the Department of Cancer Biology at the University of Texas M.D. Anderson Cancer Center, Houston, provided insight and perspective on the findings. He said it was unfortunate that the C-08 trial as designed was negative.

“In patients with metastatic disease, we are more tolerant of toxicity, costs and any inconvenience because our backs and our patients’ backs are against the wall.

But, in the adjuvant setting, only 3% to 5% of patients at best will benefit from the addition of bevacizumab to FOLFOX,” Dr. Ellis said. “There is no increase in the cure rate with bevacizumab, so we have to assume that bevacizumab must be continued indefinitely in order to provide some benefit. We should not administer a potent drug like bevacizumab forever in a population where most of the patients will not benefit.” Dr. Ellis was emphatic that the drug should not be provided in the adjuvant setting. He also pointed out that VEGF receptors are present on central nervous system cells and researchers do not know what the long-term impact of a drug that targets these cells would be.

Cathy Eng, MD, an associate professor in the Department of Gastrointestinal Medical Oncology at M.D. Anderson, pointed out that Dr. Wolmark did not indicate the origin of the increase in pain and that any costeffectiveness analysis would have to take side effects into consideration. “The cost-effectiveness of this is unknown, but should include the toxicities that are commonly associated with bevacizumab therapy—15% to 25% of patients develop hypertension due to bev,” she said. “Is it worth it for the adjuvant setting in which there is no gross evidence of the disease? If we were to believe Dr. Wolmark, how long would you continue bevacizumab for—indefinitely? How much is enough?”

Dr. Eng also pointed out that there was no indication

Micrograph of an invasive adenocarcinoma.

‘If we were to believe Dr. Wolmark, how long would you continue bevacizumab for—indefinitely? How much is enough? There is no data in CRC to support the use of singleagent bevacizumab as a maintenance regimen.’

—Cathy Eng, MD

when the follow-up surveillance, including imaging, was conducted in patients, and this could have impacted the outcome of the Kaplan-Meier curves. “There is no data in CRC [colorectal cancer] to support the use of single-agent bevacizumab as a maintenance regimen,” she said.

Ed Chu, MD, chief of the Section of Medical Oncology and deputy director of clinical research at the Yale Cancer Center, Yale University School of Medicine, New Haven, Conn., agreed with Drs. Ellis and Eng. “The bottom line of C-08 is that it is a negative study, and that there is no role for using bevacizumab, at least for now, in the adjuvant setting in combination with FOLFOX chemotherapy,” said Dr. Chu. “Even if [bevacizumab] were to be continued, the added toxicity and costs are not justified. Moreover, only at most two or three patients out of 100 would benefit from its use, which again is extremely difficult to justify. It would be impossible to design and conduct [the] study that Dr. Wolmark is suggesting.”

The AVANT trial, which is similar in design to the C-08 trial presented at ASCO, should provide further information. This trial, involving more than 3,500 patients, has completed enrollment and randomizes patients to one of three arms: FOLFOX-4, FOLFOX-4 with bevacizumab (5 mg/kg), or XELOX (capecitabine and oxaliplatin) with bevacizumab (7.5 mg/kg). Patients receive therapy for six months and, in the latter two arms, bevacizumab is continued for an additional six months (7.5 mg/kg for both arms).

“At this point, everyone is eagerly awaiting the results of the AVANT study, which should report sometime next year,” Dr. Chu said. “If that study is negative, that will close the door on bev in the adjuvant setting. However, if it is positive, then that should open up a few more wrinkles.”

Drs. Eng and Chu serve on the advisory board of Clinical Oncology News.

—Kate O’Rourke

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PEOPLE AND PLACES

CLINICAL ONCOLOGY NEWS SPECIAL EDITION 2009 • NO. 1 DIGITAL EDITION • JUNE 2009

Around the Water Cooler This new section will bring you news about people and places in the field of oncology. If you have news to share (new job, award, cancer center closure or expansion, etc.), please send information to korourke@mcmahonmed.com.

Joseph F. Fraumeni Jr., MD

J

oseph F. Fraumeni Jr., MD, director of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute, has received the American Association for Cancer Research (AACR) Award for Lifetime Achievement in Cancer Research.

Dr. Fraumeni is most well known for the syndrome that bears his name, along with that of his colleague Frederick P. Li, MD. Li-Fraumeni syndrome (LFS) is a rare, inherited disorder that predisposes people to certain cancers including breast cancer, sarcomas and a variety of other tumors. The search for genetic underpinnings of the familial syndrome eventually led to collaborative studies in the laboratory of Stephen Friend, MD, PhD, at Harvard Medical School, Boston, where the team discovered germline mutations in the p53 tumor suppressor gene.

The findings were especially dramatic because p53 mutations were previously found in the tumor tissue of a substantial number of patients with cancer.

Dr. Fraumeni also was involved in the Cancer Mortality Atlas project. “Perhaps as important to me as the discovery and characterization of LFS is the U.S. Cancer Mortality Atlas project,” said Dr. Fraumeni in a press statement.

By developing computer-generated and color-coded maps of cancer mortality at the county level, it was possible to visualize high-risk areas where Dr. Fraumeni and his colleagues conducted epidemiologic studies that identified a number of previously unrecognized carcinogenic hazards. These include smokeless tobacco, which has been linked to oral cancer; shipyard asbestos exposure and inhaled arsenic in smelter workers and residents of surrounding communities, which can cause lung cancer; agricultural herbicides, which can cause lymphoma; and high levels of arsenic in drinking water, which can cause bladder cancer.

Victor E. Velculescu, MD, PhD

V

ictor E. Velculescu, MD, PhD, associate professor of oncology at Johns Hopkins Kimmel Cancer Center,

Baltimore, has received the AACR Award for Outstanding Achievement in Cancer Research.

Dr. Velculescu pinpointed the PIK3CA gene as one of the most frequently m u tate d g e nes ever identified in human cancer. He also developed a method to rapidly identify diseaserelated genes and measure gene expression called SAGE (Serial Analysis of Gene Expression).

With his colleagues, he developed the first-draft genome sequence of four human cancer types: breast, colorectal, pancreatic and an aggressive form of brain cancer called glioblastoma multiforme.

Todd R. Golub, MD

T

odd R. Golub, MD, founding director of the cancer program at the Broad Institute and Charles A. Dana Investigator in human cancer genetics at the DanaFarber Cancer Institute, Boston, has received the 33rd annual AACR Richard and Hinda Rosenthal Memorial Award for his groundbreaking contributions to cancer research through the application of basic biology and genomics to cancer diagnostic and therapeutic target discovery.

His work led to the commercialization of genomic tests to aid patients in treatment decisions. His current work, using genomics to transform the drug discovery process, has led to potential new treatments for AML, prostate cancer and Ewing’s sarcoma.

Donald Small, MD, PhD

C

hildhood cancer specialist Donald Small, MD, PhD, received the Frank A. Oski Award from the American Society of Pediatric Hematology/ Oncology. The award honors clinicians and basic science investigators in pediatric hematology and oncology who have made significant research contributions to the field. Dr. Small and his team were the first to clone the human FLT3 receptor gene, which is the most

prevention of cancer, and who embodies the dedication of the princess to multinational collaborations.

Otis W. Brawley, MD

O

frequently mutated gene in acute myeloid leukemia (AML). The FLT3 mutation is a predictor of poor survival for patients with AML. After discovering that the gene contributes to turning normal hematopoietic blood cells into leukemic cells, Dr. Small identified small molecules capable of inhibiting the receptor and showed that these drugs would kill leukemia cells that contain the FLT3 mutation, while leaving normal blood cells unharmed.

This led to a new targeted therapy for acute leukemia. From there, Dr. Small led the design of clinical trials using one of these drugs, first as a monotherapy and later in combination with chemotherapy, for adults with AML. Most recently, the drug has entered clinical trials through the Children’s Oncology Group for children with FLT3-mutant AML and infants with acute lymphocytic leukemia.

tis W. Brawley, MD, chief medical officer at the American Cancer Society, is the recipient of the fourth annual AACR-Minorities in Cancer Research Jane Cooke Wright Lectureship for his contributions to the field of cancer in the area of health disparities.

Dr. Brawley is a strong advocate for providing state-ofthe-art treatment to disadvantaged groups, and has continued to challenge negative attitudes toward these populations. His commitment to health disparities has prompted many young scientists to conduct research in this field. Dr. Brawley’s research on prostate cancer has led to clinical trials of dietary agents, which may be used for prostate cancer chemoprevention. He also was instrumental in establishing the importance of hormonal prevention strategies for prostate cancer.

Curtis C. Harris, MD

W. Marston Linehan, MD

urtis C. Harris, MD, chief of the Laboratory of Human Carcinogenesis at the National Cancer Institute, has received the third annual AACR Princess Takamatsu Memorial Lectureship for his several decades of scientific collaborations with Japanese scientists and his early and continuing efforts to forge friendships between Japanese and U.S. scientific communities.

“Cancer is worldwide. However, etiology, incidence and mortality vary among populations,” Dr. Harris said. “An international collaborative effort is required to understand these differences as well as similarities.”

Dr. Harris’s research demonstrated how inheritable characteristics of DNA play a role in a person’s susceptibility to environmental carcinogens. The AACR Princess Takamatsu Memorial Lectureship is presented to a scientist whose novel and significant work has had or may have a far-reaching impact on the detection, diagnosis, treatment or

. Marston Linehan, MD, chief of the urological branch for the Center for Cancer Research at the National Cancer Institute, has received the 14th annual AACR Joseph H. Burchenal Memorial Award for Outstanding Achievement in Clinical Research for defining the genetic basis of clear cell kidney cancer, hereditary papillary renal carcinoma (HPRC and chromophobe kidney cancer, and providing the basis for the molecular therapeutic approaches to therapy for these diseases. Dr. Linehan’s research in kidney cancer has been far-reaching, including the establishment of a comprehensive hereditary kidney cancer program at the National Institutes of Health to study families with kidney cancer and to identify the genes involved, identifying the gene responsible for HPRC and helping to define the current approaches for HPRC clinical and surgical management.

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In Studies 1, 2 and 4 with SC administration of VIDAZA, adverse reactions of neutropenia, thrombocytopenia, anemia, nausea, vomiting, diarrhea, constipation, and injection site erythema/reaction tended to increase in incidence with higher doses of VIDAZA. Adverse reactions that tended to be more pronounced during the first 1 to 2 cycles of SC treatment compared with later cycles included thrombocytopenia, neutropenia, anemia, nausea, vomiting, injection site erythema/pain/bruising/reaction, constipation, petechiae, dizziness, anxiety, hypokalemia, and insomnia. There did not appear to be any adverse reactions that increased in frequency over the course of treatment.

Overall, adverse reactions were qualitatively similar between the IV and SC studies. Adverse reactions that appeared to be specifically associated with the IV route of administration included infusion site reactions (e.g., erythema or pain) and catheter site reactions (e.g., infection, erythema, or hemorrhage).

In clinical studies of either SC or IV VIDAZA, the following serious adverse reactions occurring at a rate of < 5% (and not described in Tables 1 or 2) were reported: Blood and lymphatic system disorders: agranulocytosis, bone marrow failure, pancytopenia, splenomegaly. Cardiac disorders: atrial fibrillation, cardiac failure, cardiac failure congestive, cardio-respiratory arrest, congestive cardiomyopathy. Eye disorders: eye hemorrhage. Gastrointestinal disorders: diverticulitis, gastrointestinal hemorrhage, melena, perirectal abscess. General disorders and administration site conditions: catheter site hemorrhage, general physical health deterioration, systemic inflammatory response syndrome. Hepatobiliary disorders: cholecystitis. Immune system disorders: anaphylactic shock, hypersensitivity. Infections and infestations: abscess limb, bacterial infection, cellulitis, blastomycosis, injection site infection, Klebsiella sepsis, neutropenic sepsis, pharyngitis streptococcal, pneumonia Klebsiella, sepsis, septic shock, Staphylococcal bacteremia, Staphylococcal infection, toxoplasmosis. Metabolism and nutrition disorders: dehydration. Musculoskeletal and connective tissue disorders: bone pain aggravated, muscle weakness, neck pain. Neoplasms benign, malignant and unspecified: leukemia cutis. Nervous system disorders: cerebral hemorrhage, convulsions, intracranial hemorrhage. Renal and urinary disorders: loin pain, renal failure. Respiratory, thoracic and mediastinal disorders: hemoptysis, lung infiltration, pneumonitis, respiratory distress. Skin and subcutaneous tissue disorders: pyoderma gangrenosum, rash pruritic, skin induration. Surgical and medical procedures: cholecystectomy. Vascular disorders: orthostatic hypotension.

6.3 Postmarketing Experience Adverse reactions identified from spontaneous reports have been similar to those reported during clinical trials with VIDAZA. 7 DRUG INTERACTIONS No formal assessments of drug-drug interactions between VIDAZA and other agents have been conducted [see Clinical Pharmacology (12.3) in the full prescribing information].

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D VIDAZA may cause fetal harm when administered to a pregnant woman.

Azacitidine was teratogenic in animals. Women of childbearing potential should be advised to avoid pregnancy during treatment with VIDAZA. If this drug is used during pregnancy or if a patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Female partners of male patients receiving VIDAZA should not become pregnant [see Nonclinical Toxicology (13)].

Early embryotoxicity studies in mice revealed a 44% frequency of intrauterine embryonal death (increased resorption) after a single IP (intraperitoneal) injection of 6 mg/m2 (approximately 8% of the recommended human daily dose on a mg/m2 basis) azacitidine on gestation day 10.

Developmental abnormalities in the brain have been detected in mice given azacitidine on or before gestation day 15 at doses of ~3-12 mg/m2 (approximately 4%-16% the recommended human daily dose on a mg/m2 basis). In rats, azacitidine was clearly embryotoxic when given IP on gestation days 4-8 (postimplantation) at a dose of 6 mg/m2 (approximately 8% of the recommended human daily dose on a mg/m2 basis), although treatment in the preimplantation period (on gestation days 1-3) had no adverse effect on the embryos. Azacitidine caused multiple fetal abnormalities in rats after a single IP dose of 3 to 12 mg/m2 (approximately 8% the recommended human daily dose on a mg/m2 basis) given on gestation day 9, 10, 11 or 12. In this study azacitidine caused fetal death when administered at 3-12 mg/m2 on gestation days 9 and 10; average live animals per litter was reduced to 9% of control at the highest dose on gestation day 9. Fetal anomalies included: CNS anomalies (exencephaly/encephalocele), limb anomalies (micromelia, club foot, syndactyly, oligodactyly), and others (micrognathia, gastroschisis, edema, and rib abnormalities).

8.3 Nursing Mothers It is not known whether azacitidine or its metabolites are excreted in human milk. Because of the potential for tumorigenicity shown for azacitidine in

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animal studies and the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into consideration the importance of the drug to the mother.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use Of the total number of patients in Studies 1, 2 and 3, 62% were 65 years and older and 21% were 75 years and older. No overall differences in effectiveness were observed between these patients and younger patients.

In addition there were no relevant differences in the frequency of adverse reactions observed in patients 65 years and older compared to younger patients. Of the 179 patients randomized to azacitidine in Study 4, 68% were 65 years and older and 21% were 75 years and older. Survival data for patients 65 years and older were consistent with overall survival results. The majority of adverse reactions occurred at similar frequencies in patients < 65 years of age and patients 65 years of age and older.

Azacitidine and its metabolites are known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function [see Dosage and Administration (2.5) in full prescribing information and Warnings and Precautions (5.3)].

8.6 Gender Differences There were no clinically relevant differences in safety and efficacy based on gender.

8.7 Race Greater than 90% of all patients in all trials were Caucasian. Therefore, no comparisons between Caucasians and non-Caucasians were possible.

13 NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility The potential carcinogenicity of azacitidine was evaluated in mice and rats.

Azacitidine induced tumors of the hematopoietic system in female mice at 2.2 mg/kg (6.6 mg/m2, approximately 8% the recommended human daily dose on a mg/m2 basis) administered IP three times per week for 52 weeks.

An increased incidence of tumors in the lymphoreticular system, lung, mammary gland, and skin was seen in mice treated with azacitidine IP at 2.0 mg/kg (6.0 mg/m2, approximately 8% the recommended human daily dose on a mg/m2 basis) once a week for 50 weeks. A tumorigenicity study in rats dosed twice weekly at 15 or 60 mg/m2 (approximately 20-80% the recommended human daily dose on a mg/m2 basis) revealed an increased incidence of testicular tumors compared with controls.

The mutagenic and clastogenic potential of azacitidine was tested in in vitro bacterial systems Salmonella typhimurium strains TA100 and several strains of trpE8, Escherichia coli strains WP14 Pro, WP3103P, WP3104P, and CC103; in in vitro forward gene mutation assay in mouse lymphoma cells and human lymphoblast cells; and in an in vitro micronucleus assay in mouse L5178Y lymphoma cells and Syrian hamster embryo cells.

Azacitidine was mutagenic in bacterial and mammalian cell systems. The clastogenic effect of azacitidine was shown by the induction of micronuclei in L5178Y mouse cells and Syrian hamster embryo cells.

Administration of azacitidine to male mice at 9.9 mg/m2 (approximately 9% the recommended human daily dose on a mg/m2 basis) daily for 3 days prior to mating with untreated female mice resulted in decreased fertility and loss of offspring during subsequent embryonic and postnatal development.

Treatment of male rats 3 times per week for 11 or 16 weeks at doses of 15-30 mg/m2 (approximately 20-40%, the recommended human daily dose on a mg/m2 basis) resulted in decreased weight of the testes and epididymides, and decreased sperm counts accompanied by decreased pregnancy rates and increased loss of embryos in mated females. In a related study, male rats treated for 16 weeks at 24 mg/m2 resulted in an increase in abnormal embryos in mated females when examined on day 2 of gestation.

17 PATIENT COUNSELING INFORMATION Instruct patients to inform their physician about any underlying liver or renal disease.

Advise women of childbearing potential to avoid becoming pregnant while receiving treatment with VIDAZA. For nursing mothers, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into consideration the importance of the drug to the mother. Advise men not to father a child while receiving treatment with VIDAZA. Manufactured for: Celgene Corporation Summit, NJ 07901 Manufactured by: Ben Venue Laboratories, Inc. Or Baxter Oncology GmbH Bedford, OH 44146 33790 Halle/Westfalen Germany VidPlyPI.001 BS 08/08

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Myelodysplastic Syndromes: Pharmacologic Agents That Extend Overall Survival STEVEN D. GORE, MD Professor of Oncology Sidney Kimmel Comprehensive Cancer Center Johns Hopkins University School of Medicine Baltimore, Maryland

T

he myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic cancers characterized by a hyperproliferative bone marrow, dysplastic cellular elements, and ineffective hematopoiesis.1

As a result, patients with MDS are at risk for symptomatic anemia, infection, and bleeding, as well as progression to acute myelogenous leukemia, which is often refractory to standard treatment.1 Approximately 2.7 to 4.5 per 100,000 people in the United States are affected with MDS each year. This translates to more than 10,000 new diagnoses per year and a prevalence of up to 60,000 people in the United States.2 Although supportive care with blood transfusions and administration of hematopoietic growth factors historically has been the standard of care for patients with MDS, the advent of drugs with novel mechanisms of action has resulted in

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a new era of more effective treatment for these syndromes.1 Previous clinical trials of therapies for MDS have focused on surrogate end points for clinical outcomes, including response rates and decreased transfusion needs, which may not necessarily translate into improved survival. This review summarizes recent data highlighting actual prolongation in overall survival (OS) in response to the newer pharmacologic agents for the management of MDS.

Best Supportive Care Best supportive care (BSC) for patients with MDS consists of periodic transfusions as well as

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

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Probability of Survival

1.0

0.8

0.6

0.4

0.2

0 0

2

4

6

8

10

12

14

16

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Figure 1. Probability of overall survival in myelodysplastic syndromes treated with erythropoietin plus granulocyte colony-stimulating factor (EPO + G-CSF).

P=0.002 Adapted from reference 4.

the use of growth factors (eg, erythropoietin [EPO] and granulocyte colony-stimulating factor [G-CSF]).

According to National Comprehensive Cancer Network guidelines, BSC alone can be used for patients with MDS that falls into the International Prognostic Scoring System (IPSS)-defined low or intermediate-1 risk categories.1 Although no randomized prospective study has shown improvement in survival for patients with MDS treated with EPO or G-CSF, 2 retrospective studies compared contemporary or historical control groups treated with transfusions alone with those treated with EPO plus G-CSF. In both studies, the use of this combination was associated with a benefit in survival.3,4 For example, Park and colleagues reported that 5-year OS was significantly higher in patients treated with growth factors (64%) relative to those who were treated with transfusion alone (39%; P<0.0001), corresponding to a hazard ratio (HR) for death in the growth-factor group of 0.43 (95% confidence interval [CI], 0.25-0.72).3 Similarly, Jadersten and colleagues performed a retrospective analysis of the long-term outcome of 121 patients with MDS treated with EPO plus G-CSF and 237 patients with MDS who did not receive treatment. Even when adjusting for all major prognostic variables (World Health Organization classification, karyotype, cytopenias, level of transfusion need, age,

and sex), treatment was associated with improved OS (HR, 0.61; 95% CI, 0.44-0.83; P=0.002; Figure 1). However, the survival benefit was limited to those individuals with a transfusion requirement of more than 2 units per month.4 Iron overload, which can result in end-organ damage and reduced survival, is related to serial transfusions for patients with MDS receiving BSC.1 Although not strictly a direct treatment for MDS, iron chelation therapy with deferasirox (Exjade, Novartis) is increasingly offered to patients receiving chronic transfusions for MDS. In a prospective analysis of the impact of a variety of iron chelation therapies on survival in large MDS cohorts, Rose and colleagues reported that median OS was 115 months in chelated and 51 months in nonchelated patients (P<0.0001; Figure 2), even after adjustment for other prognostic parameters (eg, sex, age, IPSS classification, transfusion requirements).5 This analysis was limited because patients were not randomly assigned to receive chelation or not; physicians may have selected patients with better prognosis for chelation.

Methyltransferase Inhibitors Epigenetic silencing of genes involved in the control of normal cell growth and differentiation may be mediated by hypermethylation of cytosine residues on DNA in the context of MDS.6 The methyltransferase

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150

Median Overall Survival (mo)

With chelation therapy Without chelation therapy 120

90

60

30

0

Total a

IPSS Int I b

IPSS low c,d

Figure 2. Median overall survival with and without chelation therapy. a

P<0.0001; b P=0.003; c P=0.003

d

Median overall survival was not reached.

IPSS, International Prognostic Scoring System Adapted from reference 5.

inhibitors are a class of antineoplastics that deplete nuclear DNA methyltransferase, the enzyme responsible for the methylation of DNA, thereby promoting demethylation of newly synthesized DNA. Two methyltransferase inhibitors have been approved for the treatment of MDS: azacitidine (AZA; Vidaza, Pharmion) and decitabine (Dacogen, MGI Pharma).6 In 2002, Silverman and colleagues reported the results of a Phase III study that randomized 191 patients with MDS to receive either AZA (75 mg/m2 per day subcutaneously for 7 consecutive days every 28 days) or supportive care. The time to acute myelogenous leukemia (AML) transformation or death was significantly greater for those who received AZA than for those who received supportive care alone (21 vs 12 months).

Furthermore, patients treated with AZA trended toward longer OS than did those who received supportive care alone (20 vs 14 months; P=0.1).7 The prospective randomized Phase III AZA-001 study compared OS following treatment with AZA plus BSC versus three conventional care regimens (CCR; BSC alone, low-dose chemotherapy, and high-dose chemotherapy) in 358 patients with high-risk MDS.8 At a median follow-up of 21 months, treatment with AZA resulted in superior median OS compared with treatment with CCR (24 vs 15 months; HR, 0.58; 95% CI, 0.43-0.77; Figure 3). Two-year estimated OS was improved following treatment with AZA (51% vs 26%) and was relatively stable when stratifying according to IPSS subgroup.

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Interestingly, the effect on survival was observed despite the fact that response rates to AZA were low (complete remission [CR], 17%; partial response [PR], 12%).

Another important issue associated with the AZA001 study is the discovery that patients with changes to chromosome 7 derived significant benefit from AZA. Specifically, in patients with â&#x20AC;&#x201C;7/del(7q), median OS was 13.1 months in the AZA group (n=30) and 4.6 months in the CCR group (n=27), corresponding to an HR of 0.34 (95% CI, 0.17-0.67; P=0.0017).8 These data raise the possibility that AZA could be targeted to this subset of patients, who otherwise have a relatively poor prognosis.

In a separate subgroup analysis of 78 patients aged 75 or older with high-risk MDS, Seymour and colleagues reported that median OS was 10.8 months in the CCR group, whereas median OS was not reached at 17.7 months of follow-up in the AZA group (HR, 0.48; 95% CI, 0.26-0.89; P=0.0193). Furthermore, OS rates at 2 years were significantly higher in the AZA group when compared with the BSC group (55% vs 15%; P=0.0003).9 Clinical trials of the other methyltransferase inhibitor, decitabine, have shown clinical benefit but have not demonstrated an increase in OS in patients with MDS. For example, in a Phase II multicenter trial of 66 patients with MDS (median age, 68 years; age range, 38-84 years), IV decitabine was administered over 4 hours at a dose of 15 mg/m2 every 8 hours for 3 consecutive days; cycles were repeated every 6 weeks. The actuarial

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Proportion Surviving

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Time from randomization, mo

Figure 3. Overall survival for patients with myelodysplastic syndromes on treatment with azacitidine.

P=0.0001 Adapted from reference 8.

median survival time from diagnosis was 22 months and from start of therapy 15 months. For the IPSS high-risk group, the median survival was 14 months.10 A subsequent Phase III trial randomized patients to receive either IV decitabine (15 mg/m2 administered over 3 hours every 8 hours for 3 consecutive days, repeated every 6 weeks for up to 6 cycles) or BSC alone.11 Patients treated with decitabine did not experience a statistically significant increase in time to AML progression or death than did patients who received BSC alone (12.1 vs 7.8 months; P=0.16). In an unplanned post-hoc analysis, patients in the decitabine arm with de novo disease had a statistically significant increment in median time to AML transformation or death compared with those who received supportive care (12.6 vs 9.4 months; P=0.04). This end point also was significantly superior for the decitabine arms in high-risk disease (9.3 vs 2.8 months; P=0.01) and treatment-naĂŻve patients (12.3 vs 7.3 months; P=0.08) in post-hoc analyses.11 Study of a 5-day dosing regimen for decitabine also produced promising results. Kantarjian and colleagues studied 54 patients with high- or intermediate-risk MDS treated with IV decitabine (administered 20 mg/m2 over a 1-hour period once daily for 5 days and repeated at 4-week intervals) and reported a median survival time of 20 months, with 1- and 2-year survival rates of 61% and 41%, respectively in a Phase II trial.12 In a retrospective study, decitabine treatment appeared to be associated with greater survival than

intensive chemotherapy in patients with high-risk MDS (mean survival, 22 vs 12 months; P<0.001).13 Furthermore, after accounting for all pretreatment factors, a multivariate analysis of survival in the 491 patients who received decitabine or intensive chemotherapy determined that decitabine treatment was an independent, favorable prognostic factor for survival (HR, 0.74; P=0.006). The same group of investigators also reported that independent adverse prognostic factors in terms of survival in response to decitabine therapy included chromosome 5 and/or 7 abnormalities, older age, and prior MDS therapy (excluding growth factors), suggesting that pretreatment factors can be used to predict a response to decitabine.14 A recent study by Wijermans and colleagues showed no survival benefit of decitabine in patients with highrisk MDS treated with the FDA-approved dose schedule. The investigators randomized 233 patients (median age, 70 years; age range, 60-90 years) with primarily IPSS intermediate-2 (55%) or high-risk (38%) MDS, to supportive care or decitabine (15 mg/m2 administered intravenously over 4 hours every 8 hours for the first 3 consecutive days, of every 6-week cycle, for a maximum of 8 cycles). Median OS was 0.84 years in the decitabine group and 0.71 years in the supportive-care group (HR, 0.88; 95% CI, 0.66-1.17; P=0.38). The investigators speculated that the less robust effect of decitabine on OS in the study population might be the result of shorter treatment duration (â&#x2030;¤8 cycles) compared with other

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trials or the use of subsequent treatments after disease progression.15

Lenalidomide Therapy Lenalidomide (Revlimid, Celgene) is an orally active thalidomide derivative that modulates the bone marrow microenvironment by inhibiting angiogenesis and by modulating ligand-induced responses, including those stimulated by the pro-inflammatory cytokines, tumor necrosis factor-α, interleukin-1β, and transforming growth factor-β.16 The pivotal MDS-003 study demonstrated that the use of lenalidomide resulted in transfusion independence in 67% of patients with low-risk MDS with the 5q deletion abnormality.17 However, the drug was much less effective in patients without this abnormality.18 Long-term outcomes in response to lenalidomide treatment in patients with MDS and the 5q deletion abnormality were studied in an analysis of 168 patients participating in 4 clinical trials with follow-up of more than 5 years.19 Investigators reported that the transfusion-independence response to lenalidomide was durable, with a median duration of 2.2 years, with some patients exceeding 5-year response rates. Furthermore, a multivariate analysis demonstrated that cytogenetic response had a greater predictive power for extended survival and freedom from disease progression (HR, 5.295; P<0.001). These data suggest that lenalidomide may alter the natural history of disease and perhaps extend survival in responding patients, with 10-year OS predicted at 84% for those with cytogenetic response versus 4% for those without. Regardless, prospective studies to specifically investigate the effect of lenalidomide on OS are required.

Conclusion Although BSC and iron chelation therapy can result in modest prolongation in OS, there are now 3 FDAapproved pharmacologic therapies—AZA, decitabine, and lenalidomide—indicated for the treatment of MDS. However, AZA is the first and only FDA-approved drug to demonstrate a significant extension of OS compared to conventional care regimens, for patients with intermediate-2 and high-risk MDS. The effectiveness of these therapies may vary depending on pretreatment variables, including IPSS classification and cytogenetic abnormalities.

References 1.

Greenberg PL, Attar E, Battiwalla M, et al. Myelodysplastic syndromes. J Natl Compr Canc Netw. 2008;6(9):902-926.

2. Ma X, Does M, Raza A, Mayne ST. Myelodysplastic syndromes: incidence and survival in the United States. Cancer.

2007;109(8):1536-1542.

3. Park S, Grabar S, Kelaidi C, et al. Predictive factors of response and

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survival in myelodysplastic syndrome treated with erythropoietin and G-CSF: the GFM experience. Blood. 2008;111(2):574-582.

4. Jadersten M, Malcovati L, Dybedal I, et al. Erythropoietin and granulocyte-colony stimulating factor treatment associated with improved survival in myelodysplastic syndrome. J Clin Oncol.

2008;26(21):3607-3613.

5. Rose C, Brechignac S, Vassilief D, et al. Positive impact of iron chelation therapy on survival in regularly transfused MDS patients.

Blood. 2007;110(11). Abstract 249.

6. Warlick ED, Smith BD. Myelodysplastic syndromes: review of pathophysiology and current novel treatment approaches. Curr Cancer Drug Targets. 2007;7(6):541-558.

7. Silverman LR, Demakos EP, Peterson BL, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol. 2002;20(10):2429-2440.

8. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol.

2009;10(3):223-232.

9. Seymour J, Fenaux P, Silverman L, et al. Effects of azacitidine (AZA) versus conventional care regimens (CCR) in elderly (≥75 years) patients (pts) with myelodysplastic syndromes (MDS) from the AZA-001 survival trial. Blood. 2008;112(11). Abstract 3629.

10. Wijermans P, Lubbert M, Verhoef G, et al. Low-dose 5-aza2’-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: a multicenter phase II study in elderly patients. J Clin Oncol. 2000;18(5):956-962.

11. Kantarjian H, Issa JP, Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer. 2006;106(8):1794-1803.

12. Kantarjian H, Garcia-Manero G, O’Brien S, et al. Survival and efficacy of decitabine in myelodysplastic syndromes (MDS), analysis of the 5-day IV dosing regimen. Blood. 2007;110(11). Abstract 115.

13. Kantarjian HM, O’Brien S, Huang X, et al. Survival advantage with decitabine versus intensive chemotherapy in patients with higher risk myelodysplastic syndrome: comparison with historical experience. Cancer. 2007;109(6):1133-1137.

14. Kantarjian HM, O’Brien S, Shan J, et al. Update of the decitabine experience in higher risk myelodysplastic syndrome and analysis of prognostic factors associated with outcome. Cancer.

2007;109(2):265-273.

15. Wijermans P, Suciu S, Baila L, et al. Low dose decitabine versus best supportive care in elderly patients with intermediate or high risk MDS not eligible for intensive chemotherapy: final results of the randomized phase III study (06011) of the EORTC leukemia and German MDS study groups. Blood. 2008;112(11). Abstract 226.

16. Maier SK, Hammond JM. Role of lenalidomide in the treatment of multiple myeloma and myelodysplastic syndrome. Ann Pharmacother. 2006;40(2):286-289.

17. List A, Dewald G, Bennett J, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med. 2006;355(14):1456-1465.

18. Raza A, Reeves JA, Feldman EJ, et al. Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1 risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood. 2008;111(1):86-93.

19. List A, Wride K, Dewald G, et al. Cytogenetic response to lenalidomide is associated with improved survival in patients with chromosome 5q deletion. Leuk Res. 2007;31(suppl 1):S38.

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SOLID TUMORS Genitourinary

Value of Genitourinary Cancer Markers Questioned ORLANDO, FLA.—A number of new molecular markers for genitourinary cancers have received considerable hype, but are they ready for prime time?

At the recent Genitourinary Cancers Symposium , researchers pointed out that a large number of markers are under investigation, and some markers, such as single-nucleotide polymorphisms for prostate cancer, have received considerable attention. However, data as to whether the markers will improve patient outcomes in the clinic are sparse.

“People seem to be extremely ready to make clinical recommendations on what is really very early-stage research,” said Andrew Vickers, PhD, an associate attending research methodologist at Memorial Sloan-Kettering Cancer Center, in New York City. Dr. Vickers discussed pitfalls in the development and use of prognostic markers at the recent symposium. He said that clinicians have been barraged with information about a slew of new markers that have been identified for renal cell carcinoma, bladder cancer and other genitourinary cancers, but the search for these prognostic markers has been wider than it has been deep.

Dr. Vickers and his colleagues conducted a systemic review of tumor markers and found that more than 100 different markers were reported in 67 papers. “In other words, there were more markers than papers,” said Dr. Vickers. “This is problematic.” According to him, it is better to know a lot about a few markers than to know a little about each of a large number of markers. Dr. Vickers said that similar to research on anticancer agents, research on molecular markers progresses through a series of stages from preclinical testing to definitive evaluation of clinical value. He said many clinicians may not be aware of it, but the concept of “phases” for marker researchers, like Phase I, II and III for drugs, has been proposed but has not yet gained widespread adoption.

Nonetheless, he said some markers are being aggressively promoted after showing only differences between convenience samples or statistical associations with outcomes. “For example, the prostate cancer marker, early prostate cancer antigen (EPCA), has yet to be evaluated in men at elevated risk for prostate cancer undergoing biopsy,” said Dr. Vickers. Yet, EPCA has been described as a “highly specific serum marker” and has generated considerable media attention. As such, he said EPCA is like most other genitourinary cancer markers—its predictive accuracy is unproven and its true clinical value is unknown.

Interestingly, Dr. Vickers and his colleagues found that among the 67 papers they reviewed, about 40% made clinical recommendations. “I think some of these markers have been oversold,” Dr. Vickers said. “Biomarker development is a much younger field than drug development. In biomarker development, people know less about the rules, and it is easier to be taken in by the sales message.”

Molecular biomarker research is a relatively new field and most clinicians are not aware of the stages that a marker has to go through and that early-stage results cannot be directly translated into clinical recommendations. “The takehome message is that a prognostic molecular marker has to be shown to have a specific clinical benefit,” said Dr. Vickers. “That has to be demonstrated in a published paper. This doesn’t mean that we have to go away and conduct new randomized trials, it just means we have to analyze the data we have in a different way. Having a P value or a measure of predictive accuracy is not enough—we need to know the clinical implications.”

Robert Nam, MD, an associate professor of surgery at Sunnybrook Health Sciences Centre at the University of Toronto, Toronto, Ontario, Canada, said he agrees with Dr. Vickers.

He said, however, that prognostic markers for prostate cancer may be harder to assess than markers for other tumor types.

“Prostate cancer is a unique malignancy in that it takes several years [>10] to obtain meaningful clinical end points.

Thus, it is very difficult to evaluate prognostic markers to the standards he proposes and, often, earlier surrogate end points are needed,” said Dr. Nam. “This is in contrast to other cancers such as breast cancer where the natural course of the disease requires less time, and so it is easier to evaluate new markers for breast cancer for which there are many well-established ones.”

—John Schieszer

SUPPORTIVE CARE Anemia REMS, page 48 �

medication guide, a methodology for communicating risks to patients and a variety of educational initiatives. However, the FDA’s own literature calls for health care providers who prescribe a REMS-mandated drug to “have particular training or experience, or are specially certified,” and this is what is worrisome to many of those following this new mandate.

“Who is responsible for confirming that the provider is qualified for involvement in which REMS?” Dr. Franson said.

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“Currently, there is no explicit infrastructure or oversight across all REMS programs beyond the responsibility of the pharmaceutical company to create an individual REMS.” Although Dr. Franson anticipates some type of monitoring to evaluate compliance with the REMS and even in evaluating its success in reducing medication errors, “it is not yet clear who is responsible for making this work. I think we just have to stay tuned.”

—Ted Bosworth

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Patient Support Coordinator Program A dedicated, central point of contact helping providers and patients who rely on Celgene products

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To contact a PSC: Call 1-800-931-8691 Email patientsupport@celgene.com Fax 1-800-822-2496 www.CelgenePSC.com Available to answer questions Monday – Friday from 8:00 AM to 7:00 PM ET RevAssist® S.T.E.P.S.®, Patient Support Coordinator®, and PSC® are registered trademarks of Celgene Corporation. © 2008 Celgene Corporation

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Treatment of

Multiple Myeloma SHAJI KUMAR, MD Associate Professor of Medicine Division of Hematology Mayo Clinic Rochester, Minnesota

S. VINCENT RAJKUMAR, MD Professor of Medicine Division of Hematology Mayo Clinic Rochester, Minnesota

KENNETH C. ANDERSON, MD Kraft Family Professor of Medicine Harvard Medical School Jerome Lipper Myeloma Center Dana-Farber Cancer Institute Boston, Massachusetts

M

ultiple myeloma (MM) is a neoplasm of terminally differentiated plasma cells.

It is characterized by the accumulation of clonal plasma cells predominantly

in the bone marrow, with malignant cells appearing in the blood in significant numbers only late in the evolution of the disease.1

The malignant plasma cells secrete a monoclonal protein (M protein), either in the form of an intact immunoglobulin (Ig) or unbound free κ or λ light chain, which can be detected in the serum or urine of most patients. The clonal plasma cells and the secreted M protein are the hallmarks of a spectrum of plasma cell proliferative disorders that involve multistep progression from monoclonal gammopathy of undetermined significance (MGUS) to early-stage asymptomatic (smoldering) myeloma (SMM), and finally to symptomatic MM requiring therapy. Recent epidemiologic studies have shown that an MGUS stage precedes development of active myeloma in all patients.2 This review will describe the epidemiology, diagnosis, and pathophysiology of MM and discuss the treatment options for the disease.

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1.0

0.8

1971-1976 1977-1982

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disposition is not evident, family clusters have been reported. More recently, studies have shown increased incidence of MM and MGUS among first-degree relatives of patients with MM.11 Some researchers have hypothesized an infectious etiology, given the normal plasma cell function,12 but no definite evidence exists.

Survival Rate

1983-1988 0.6

1989-1994 1995-2000 2001-2006

0.4

0.2

0 0

20

40

60

80

100

120

Time, mo

Figure 1. Kaplan-Meier curves.

Overall survival from the time of diagnosis grouped into 6-year intervals based on the date of diagnosis.

This research was originally published in reference 6. © American Society of Hematology.

Epidemiology The annual incidence of MM in the general population is approximately 4 cases per 100,000 individuals.

It is estimated that each year in the United States, nearly 20,000 individuals are newly diagnosed with MM and nearly 11,000 patients die as a result of the disease.3 MM constitutes 1% of all malignancies and 10% of all hematologic malignancies, making it second only to lymphoma in terms of incidence. The median age of patients at diagnosis is 66 years, with a slight male predominance.4 MM is twice as common in blacks than in whites, whereas Asians are believed to have the lowest incidence. The overall survival (OS) of patients with MM has improved over the past decade and likely is a reflection of the increased use of autologous stem cell transplantation (ASCT) and the introduction of novel therapies (Figure 1).5,6

Etiology and Risk Factors Although various factors—including environmental, genetic, and infectious—have been implicated, the etiology of MM remains unknown. Radiation has been implicated, based in part on an increased incidence among survivors of the atomic bomb and individuals with occupational exposure.7 Chemicals such as benzene, petroleum products, and pesticides have been associated with MM.8-10 Although a clear genetic pre-

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Pathophysiology Malignant plasma cells arise from postgerminal center B lymphocytes that have undergone switch recombination. The seminal event that initiates the malignant transformation is not known, and it is likely that a series of events eventually leads to the myeloma phenotype. Translocations involving the immunoglobulin heavy chain (IgH) locus on chromosome 14 lead to activation of various oncogenes, such as cyclin D1, cyclin D2, fibroblast growth factor receptor 3, c-maf, and mafB, depending on the specific partner chromosome involved.13 These translocations, termed primary IgH translocations, are seen in nearly 50% of patients with MM. Most of the remaining patients typically have trisomies of one or more odd-numbered chromosomes (with the exception of chromosome 13), a group referred to as hyperdiploid myeloma. IgH translocations and hyperdiploidy appear to be early events, occurring during the MGUS stage. It is not known whether the risk for progression of MGUS to MM occurs with differing rates based on specific underlying cytogenetic abnormalities. Genetic deletions involving chromosome 13 frequently are seen in MM and usually are associated with IgH translocations. Chromosome 13 abnormalities originally were detected in 50% of patients with abnormal karyotypes, and thus were detectable in 10% to 20% of all patients.13,14 Various other cytogenetic abnormalities, thought to be secondary events, also can be seen, especially in the later stages of the disease; these include mutations involving the p53 and retinoblastoma genes, and deletions or gains on chromosome 1. Despite the apparent morphologic homogeneity of this disease, it is becoming increasingly clear that myeloma is a very heterogeneous disease with significant genetic diversity that, to a large extent, drives the clinical presentation and outcome.

Another important aspect of the disease is the role of other cells in the bone marrow microenvironment— such as endothelial cells, stromal cells, osteoblasts, and osteoclasts—that promote myeloma cell proliferation and survival.15 Some have suggested that there may be abnormalities in these cells as well, but strong evidence is lacking. There is, however, a close interaction between myeloma cells and the surrounding cells, mediated through a multitude of cytokines and adhesion molecules. Increased bone marrow angiogenesis has been associated with disease progression, and is a powerful prognostic factor.16 Although some myeloma symptoms are a result of the replacement of normal marrow by plasma cell accumulation, most

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A

B

C

D

Figure 2.

Panel A: Skull radiograph showing diffuse lytic lesions. Panel B: Radiograph of left humerus demonstrating a pathologic fracture associated with a lytic lesion. Panel C: Serum electrophoresis demonstrating a monoclonal peak in the gamma region, representing the monoclonal protein and the densitometry tracing above.

Panel D: Bone marrow micrograph demonstrating increased numbers of plasma cells in a patient with myeloma.

are the result of direct action by tumor cells. This includes anemia induced by apoptosis of erythroblasts caused by the interaction between Fas molecules on the erythroblast and the Fas ligand expressed by the myeloma cell. Another example is bone lesions caused by an imbalance between osteoblastic and osteoclastic activity secondary to changes in various cytokines.

Clinical Features The majority of patients with active MM present with symptoms secondary to anemia, bone lesions, hypercalcemia, or renal failure, whereas diagnosis in asymptomatic patients may follow incidental discovery of an M protein in serum or urine. Clinical examination may reveal pallor resulting from anemia; tenderness along the spine or other bones secondary to bony involvement; evidence of cord compression on neurologic examination due to vertebral collapse or compression resulting from plasmacytoma; peripheral neuropathy; subcutaneous masses caused by extramedullary plasmacytomas; altered mental status related to uremia; hyperviscosity or hypercalcemia; and ophthalmic changes secondary to hyperviscosity. Laboratory evaluation typically demonstrates the presence of M protein on serum and/or urine protein electrophoresis or immunofixation (Figure 2); anemia and thrombocytopenia; or elevated calcium, creatinine, or uric acid. Radiologic evaluation can identify the presence of lytic lesions or evidence of vertebral body compression fractures (Figure 2). Bone marrow examination can reveal increased numbers of monoclonal plasma cells (Figure 2), which at times may demonstrate a plasmablastic morphology.

Diagnosis Patients with suspected MM should complete an evaluation, as detailed in Table 1. An M protein in the

Table 1. Required Laboratory Evaluation for MM Complete blood count and differential peripheral blood smear Chemistry screen including calcium and creatinine Serum protein electrophoresis, immunofixation Nephelometric quantification of immunoglobulins Routine urinalysis, 24-h urine collection for electrophoresis and immunofixation Measurement of free monoclonal light chains Bone marrow aspirate and trephine biopsy (conventional cytogenetics, immunophenotyping, plasma cell labeling index, and FISH studies) Radiologic skeletal bone survey including spine, pelvis, skull, humeri, and femurs (an MRI or a PET scan may be helpful in selected circumstances) β2-microglobulin, C-reactive protein, and lactate dehydrogenase Optional: Dental evaluation/dental x-rays should be considered at the time of diagnosis, given the risk of ONJ with subsequent bisphosphonate therapy FISH, fluorescence in situ hybridization; MM, multiple myeloma; MRI, magnetic resonance imaging; ONJ, osteonecrosis of the jaw; PET, positron emission tomography

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Table 2. Diagnostic Criteria for MGUS, SMM, Symptomatic MM, and PCL MGUS Serum M protein <3.0 g/dL and Clonal plasma cells in the bone marrow <10% (when biopsy is performed) and No evidence of other lymphoproliferative disorder and No ROTI (see below)

SMM Serum M protein 竕･3.0 g/dL or Clonal plasma cells in the bone marrow 竕･10% and No ROTI (see below)

Symptomatic MM M protein detectable in serum and/or urine and Clonal plasma cells in bone marrow or presence of plasmacytoma and ROTI (often referred to as CRAB) Calcium levels increased: serum calcium >0.25 mmol/L above the upper limit of normal or >2.75 mmol/L Renal insufficiency: creatinine >173 mmol/L Anemia: hemoglobin 2 g/dL below the lower limit of normal or hemoglobin <10 g/dL Bone lesions: lytic lesions or osteoporosis with compression fractures (on x-ray, MRI, or CT) Other: symptomatic hyperviscosity, amyloidosis, recurrent bacterial infections (>2 episodes in 12 mo)

PCL Clonal plasma cell proliferation Absolute plasma cell count >2,000/mcL

CT, computed tomography; MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma; MRI, magnetic resonance imaging; ROTI, related organ or tissue impairment; SMM, smoldering myeloma; PCL, plasma cell leukemia Adapted from reference 17.

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serum or urine is the most common laboratory finding that prompts a diagnostic workup for myeloma. The most important initial step in making the diagnosis is distinguishing symptomatic myeloma from MGUS and asymptomatic or early-stage myeloma (SMM), conditions that do not require immediate treatment (Table 2).17 Patients with MGUS have a fixed annual risk of approximately 1% for progressing to MM or a related plasma cell disorder.18 Those with a non窶的gG M protein greater than 1.5 g/dL and an abnormal free light chain (FLC) ratio have the maximum risk for progression, with the risk increasing with a greater number of abnormal features. Other factors associated with increased risk include the presence of urinary M protein, circulating plasma cells, and increased marrow plasmacytosis. In contrast, patients with SMM have an estimated 5% to 10% risk for progression each year for the first 5 years, with the risk decreasing in subsequent years.19 The presence of an abnormal serum FLC ratio identifies patients with SMM at a higher risk for progression to myeloma.20 Several variants have been described based on clinical and laboratory features. Some patients with clinical features compatible with SMM at times have few small lytic lesions and have a slow clinical course, often referred to as indolent myeloma. Occasionally, patients may present with osteosclerotic bone lesions in the absence of any of the symptoms of POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes) syndrome; this is called osteosclerotic myeloma.21 Although the presence of an M protein is the hallmark of myeloma, 1% to 2% of patients will have no M protein detectable on serum or urine electrophoresis. This group of patients, diagnosed with nonsecretory myeloma, has become rarer with the introduction of the serum FLC assay. However, other disorders associated with M proteins should be kept in the differential diagnosis while a patient with suspected myeloma is evaluated (Table 3).

Staging and Prognosis For 2 decades, clinicians have used the DurieSalmon staging system (Table 4), which is based on an indirect estimate of tumor burden.22 To a large extent, this tool has been replaced by the simpler, but powerful International Staging System, which provides a better prognostic assessment (Table 4).23 Additionally, several prognostic factors have been described; the most important have been the presence of certain genetic abnormalities, the performance status of the patient, and estimates of plasma cell proliferative rate.

A system of identifying high-risk patients also has been developed and can be used to help make treatment decisions (Table 5).24

Treatment of Newly Diagnosed Myeloma Once the decision to initiate treatment has been made, clinicians should make every effort to enroll patients in clinical trials. The suggested treatment

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Table 3. Differential Diagnosis of Monoclonal Gammopathies Diagnosis Solitary plasmacytoma

Description • Presence of a plasmacytoma in the absence of multiple osteolytic lesions, no bone marrow evidence of monoclonal plasma cells, or other features of myeloma • Half of patients eventually develop myeloma, especially patients with persistent monoclonal protein after treatment of the solitary plasmacytoma

Primary systemic amyloidosis

• Tissue deposition of light chain-derived amyloid fibrils (β-pleated sheets), apple green birefringence on polarizing microscopy, and tissue deposits stain for κ or λ light chain • Presents as cardiomyopathy, nephrotic syndrome, malabsorption, hepatic failure, peripheral neuropathy, or other symptoms, based on organ involvement • Typically, lytic lesions and hypercalcemia not seen, low level of marrow plasmacytosis • Rarely, co-exists with myeloma, or myeloma may develop subsequently

POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes)

• Major criteria: polyneuropathy, monoclonal plasma cell disorder • Sclerotic bone lesions, Castleman’s disease, organomegaly (spleen, liver, or lymph nodes), volume overload (peripheral edema, pleural effusion, ascites), endocrinopathy (adrenal, thyroid, pituitary, gonadal, parathyroid, pancreatic), skin changes (hyperpigmentation, hypertrichosis, plethora, hemangiomata, white nails), papilledema • 2 major criteria plus at least 1 minor criterion required for diagnosis

Waldenström’s macroglobulinemiaa

• IgM monoclonal gammopathy regardless of the size of the monoclonal protein • 10% or greater bone marrow infiltration by lymphoplasmacytic cells • Typical immunophenotype (surface IgM+, CD5±, CD10–, CD19+, CD20+, CD22+, CD23–)

Cryoglobulinemia

• Cryoglobulins are either Igs or a mixture of Igs and complement components that precipitate out of blood at temperatures lower than 37°C • Type I: (5%-25%); isolated monoclonal Ig (typically IgG or IgM, less commonly IgA or free Ig light chains), typically Waldenström’s macroglobulinemia or multiple myeloma • Type II: (essential mixed cryoglobulinemia, 40%-60%); mixture of polyclonal Ig along with a monoclonal Ig, typically IgM or IgA, with rheumatoid factor activity, often related to infections • Type III: (40%-50%); mixed cryoglobulins consisting of polyclonal Igs, often secondary to connective tissue diseases

Light-chain deposition disease

• Granular deposits of monoclonal light chains, lacks the fibrillar ultrastructure of amyloid deposits that can affect kidneys, heart, or liver • Associated with elevated free light chains, κ is more common than λ (compared with amyloidosis, in which λ is more common)

Heavy-chain deposition disease

• Rare condition associated with non-amyloid deposits arising from Ig light chains as well as fragments of heavy chains

a

Patients with serum IgM concentration <3.0 g/dL, in the absence of anemia, hepatosplenomegaly, lymphadenopathy, and systemic symptoms, and minimal or no lymphoplasmacytic infiltration of the bone marrow (<10 %) are considered to have an IgM MGUS rather than Waldenström’s macroglobulinemia.

Ig, immunoglobulin; MGUS, monoclonal gammopathy of undetermined significance

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Table 4. Staging Systems in Myeloma Durie-Salmon Staging Stage Stage I

Criteria All of the following: Hemoglobin value >10 g/dL Serum calcium value normal or ≤12 mg/dL Normal bone X-rays, solitary bone plasmacytoma only Low M-component production rate IgG value <5 g/dL; IgA value <3 g/dL Bence Jones protein <4 g/24 h

Stage II

Neither stage I nor stage III

Stage III

One or more of the following: Hemoglobin value <8.5 g/dL Serum calcium value >12 mg/dL Advanced lytic bone lesions (scale 3) High M-component production rate IgG value >7 g/dL; IgA value >5 g/dL Bence Jones protein >12 g/24 h

International Staging System for MM Stage I

Serum β2-microglobulin <3.5 mg/L; serum albumin ≥3.5 g/dL; median survival 62 mo

Stage II

Not stage I or III; median survival 44 mo

Stage III

Serum β2-microglobulin ≥5.5 mg/L; median survival 29 mo

Ig, immunoglobulin; MM, multiple myeloma Based on references 22 and 23.

for patients not enrolled in a clinical trial is described in Figure 3.24 The first critical step is to determine whether a patient is eligible for ASCT and is willing to undergo the procedure. Traditionally, eligibility has been based on age, reflecting the results of randomized clinical trials (RCTs); however, some evidence suggests that selected older patients can derive similar benefit.25 Thus, the decision to undergo ASCT must be based on a patient’s physiologic age and preference. The criteria used for assessing response to treatment and likelihood for relapse after successful therapy has been revised to incorporate recent advances, such as the FLC assay (Table 6).26

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INITIAL TREATMENT If a patient is considered a potential candidate for ASCT, initial therapy is aimed at maximizing disease control with the least toxicity. Traditionally, this has included 4 to 6 months of therapy with one or more commonly used regimens, followed by stem cell collection and high-dose therapy.27-30 The long-term impact of the initial therapy on the outcome of ASCT remains undefined, with individuals refractory to initial therapy obtaining as much benefit from ASCT as those who have responded to initial therapy.31 In this scenario, the 5 important attributes for initial therapy are as follow: 1. effectively controlling disease and minimizing early mortality, thereby providing the maximum possibility of reaching an ASCT; 2. minimizing possible toxicity; 3. administering therapy with the least negative impact on quality of life; 4. minimizing impact on the ability to collect stem cells; and 5. continuing administration with minimal modification—given the lack of a survival advantage for early ASCT—if a decision is made to delay ASCT. Until recently, the most commonly used initial regimen has been either single-agent dexamethasone or a combination of vincristine, doxorubicin, and dexamethasone (VAD). With the introduction of newer agents, however, this paradigm has changed and the current approach to initial therapy in the absence of a clinical trial is 1 of 3 regimens: the combination of lenalidomide (Revlimid, Celgene) and low-dose dexamethasone; thalidomide and dexamethasone (TD); or bortezomib (Velcade, Millennium Pharmaceuticals) and dexamethasone.

Various clinical trials in patients newly diagnosed with MM provide support for this approach. In 2 Phase III trials, TD compared with dexamethasone alone was associated with increased response rates and longer time to progression (TTP), but toxicities, especially thrombotic events, were higher with the combination.29,32 The combination also has been compared with the VAD regimen and has been found to have a superior response rate.33 Lenalidomide-dexamethasone was studied in Phase II and III trials, and long-term followup demonstrates a 2-year survival rate greater than 90%. In comparison with dexamethasone alone, the combination imparts a higher response rate and longer progression-free survival (PFS). Another Phase III trial compared lenalidomide and high-dose (standard) dexamethasone with lenalidomide and low-dose (weekly) dexamethasone. This study demonstrated improved survival, despite a lower response rate, for patients treated with lower-dose dexamethasone, effectively eliminating high-dose dexamethasone treatment from the setting of newly diagnosed disease.34 The bortezomib-dexamethasone combination has been examined in the setting of newly diagnosed MM in several clinical trials, with high response rates and excellent safety.35 This combination has been compared with

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VAD as induction therapy prior to SCT in a Phase III trial, with deeper responses and reduced need for tandem ASCT as well as improved PFS after SCT.36 The exciting results seen with the novel agents raised the question of whether these agents in combination can further enhance the upfront treatment of myeloma. The combination of bortezomib, thalidomide, and dexamethasone (VTD) was compared with TD in a Phase III trial.

VTD resulted in significantly higher response rates and deeper responses, which translated into an improved PFS following SCT.37 Subsequently, lenalidomide has been combined with bortezomib and dexamethasone (VRD), resulting in a 100% response rate with very good partial response (VGPR) or better in nearly two-thirds of the patients.38 To maximize the initial treatment, the EVOLUTION trial added cyclophosphamide to the VRD combination and reported a 100% response rate with high VGPR rates after a median of 4 cycles of therapy.39 The long-term impact of these highly active regimens is not clear and longer follow-up will be required to delineate their effect on the natural history of the disease.

ROLE

OF

ASCT

Several RCTs have indicated that ASCT improves the outcome of patients with MM, whereas others have suggested no benefit for ASCT, especially in patients responsive to initial therapy.40-42 In the IFM94 and Myeloma VII trials, previously untreated patients younger than age 65, were randomly assigned to receive either conventional chemotherapy (CCT) or ASCT. Patients receiving ASCT had a superior response rate, event-free survival (EFS), and OS compared with those receiving CCT.40,41 In contrast, MAG91 demonstrated improved EFS and time without symptoms, treatment, and toxicity (TWiSTT) with ASCT, but no improvement in OS, in patients younger than age 65.43 Similarly, the Intergroup study S9321 showed that patients with untreated MM randomly assigned to either ASCT or CCT, with further randomization of responding patients to interferon maintenance or no maintenance, did not reveal any OS benefit.44 The Spanish cooperative group PETHEMA conducted a randomized trial comparing ASCT with CCT in patients who responded to initial therapy and demonstrated higher complete response (CR) rates with ASCT but no differences in PFS or OS.42 In the MAG90 trial, patients were randomly assigned to receive ASCT after 3 to 4 cycles of initial therapy, or to continue CCT, with ASCT done at time of first relapse or if the patient became refractory to initial therapy.45 Although the OS was similar in this study, TWiSTT was significantly better for the early ASCT group.

SCT in myeloma involves collection of peripheral blood stem cells, using either granulocyte colonystimulating factor or granulocyte-macrophage colonystimulating factor alone or following initial priming with cyclophosphamide and collection during recovery.

Purging of tumor cells from the stem cell collection, using various selection methods, has not translated

into any improvement, likely a reflection of the disease biology and the inability of the conditioning therapy to completely eradicate the tumor clone. The most widely used conditioning regimen is that of melphalan 200 mg/m2, based on results of the IFM95-02 trial, in which patients were randomly assigned to receive either 8 Gy total body irradiation (TBI) plus 140 mg/m2 melphalan, or 200 mg/m2 melphalan alone.46 Patients receiving only melphalan had a faster recovery of neutrophils and platelets, and milder mucositis, without any effect on EFS or OS. Ongoing trials are attempting to improve melphalan conditioning by increasing the melphalan dose (alone or in combination with cytoprotectants such as amifostine), adding skeletal targeted radioisotopes such as samarium or holmium, using skeletal targeted TBI, or adding novel agents such as bortezomib.

The role of ASCT in the treatment of MM continues to evolve in the era of novel agents. The high response rates seen with the new combination regimens incorporating novel agents have brought the role of SCT into question once again. Recent studies have shown that even with the high response rates obtained with the novel agent combinations, SCT provides additional tumor reduction. Whether this can be replaced by additional cycles of novel agent combinations remains to be studied. However, MM remains an incurable disease and in the absence of randomized trials demonstrating lack of benefit with SCT, it still should be considered a part of the therapeutic armamentarium for MM. Ongoing trials are examining the best way to integrate these treatment modalities to provide maximum benefit to patients.

ROLE

OF

SECOND ASCT

The concept of a second transplant was introduced to examine if further consolidation can be achieved with additional cycles of ASCT. Three RCTs have assigned previously untreated patients to a single or double transplant. The IFM94 trial showed a slight improvement in the combined CR and VGPR rate with double transplant (50% vs 42%), but at 7 years, EFS (20% vs 10%) and OS (42% vs 21%) doubled with the second ASCT.47 The benefit of a second transplant was, for the most part, restricted to individuals failing to achieve a VGPR after first transplant (OS at 7 years of 43%, vs 11%). This is particularly relevant, given that a significant proportion of patients undergoing induction therapy with novel agents achieve a VGPR state after the initial ASCT, thus negating the need for a second ASCT. In the Bologna 96 trial, the addition of a second ASCT prolonged EFS by 12 months and TTP by 17 months, with a projected OS at 6 years of 44% for single transplant and 63% for double transplant.48 Again, patients who failed to achieve a CR or near CR after the first ASCT obtained the maximum benefit from the second cycle of ASCT. In the MAG95 clinical trial, patients were randomly assigned to receive single or double ASCTs and then further randomized to selected or unselected CD34-positive cells.49 The study

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Table 5. Prognostic Factors in MM Prognostic Factors International Staging System stage III Older age Performance status Metaphase cytogenetics Chromosome 13 monosomy or deletions Hypodiploidy FISH tests Translocations t(4;14), t(14;16) Deletion 17p (p53 abnormalities) PCLI ≥1% High LDH Circulating plasma cells Abnormal free light chain ratio

High-risk Myeloma Del 17p, t(4;14), or t(14;16) on FISH Deletion 13 or hypodiploidy on cytogenetics PCLI >3% B2M >5.5 mcg/dL (in the absence of renal failure) B2M, β2-microglobulin; FISH, fluorescence in situ hybridization; LDH, lactate dehydrogenase; MM, multiple myeloma; PCLI, plasma cell labeling index Based on reference 24.

again confirmed an OS advantage for this approach.

However, results of a recent randomized trial suggest that the second ASCT may be replaced by a short course of maintenance thalidomide.50 In this study, patients who were newly diagnosed were treated with TD and subsequently randomly assigned to either tandem transplantation up front or single ASCT followed by maintenance therapy with thalidomide (100 mg/d for 6 months). Patients receiving maintenance thalidomide had superior PFS and OS at 3 years.

MAINTENANCE THERAPY AFTER ASCT ASCT clearly improves response rates in patients with newly diagnosed MM compared with conventional therapy, but patients invariably relapse. Various trials have attempted to maintain the ASCT response through maintenance approaches. A small RCT of interferon alfa 3 x 106 units/m2 subcutaneously 3 times weekly following initial ASCT suggested a modest improvement in EFS.51 In IFM99-02, patients with standard-risk MM

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(β2-microglobulin [B2M] <3 mg/L, and no chromosome 13 deletion) were randomly assigned to receive no maintenance, pamidronate, or pamidronate plus thalidomide 2 months after tandem ASCT.52 The response rates were significantly higher for the thalidomide arm; this translated into an improved EFS of 52%, compared with 36% with no maintenance and 37% with pamidronate alone.

The 4-year estimated survival from diagnosis was higher with thalidomide (87%) compared with no maintenance (77%). There have been additional studies examining the role of thalidomide maintenance; a PFS advantage has been noted for thalidomide following SCT in all studies, with survival advantage seen in 4 of 5 studies. An ongoing large study (Cancer and Leukemia Group B) is evaluating lenalidomide as maintenance after single ASCT. Other approaches for post-transplant maintenance have included immunotherapeutic strategies, such as dendritic cell vaccines. Long-term results of these trials should be evaluated before this is adopted into routine practice.

ALLOGENIC STEM CELL TRANSPLANT Although allogeneic stem cell transplant (alloSCT) has been shown to mediate a potentially curative graftversus-myeloma effect, it also is associated with a high level of toxicity.53 Most of the initial reports on the use of allogeneic approaches have come from small studies or from transplant registries. In a retrospective case-matched analysis from the European Blood and Marrow Transplant Registry, patients treated with allogeneic bone marrow transplant (allo-BMT) were compared with a similar group of patients who received ASCT.54 The OS was significantly better for the ASCT arm than for the allo-BMT arm, with median survival of 34 and 18 months, respectively. The poorer survival in allo-BMT patients could be attributed mostly to the higher treatment–related mortality (41% vs 13%).

Among patients surviving the first year, there was a trend for better OS and EFS for allo-BMT. The use of nonmyeloablative SCT is intended to curb treatment–related mortality by depending more on the anti-tumor effect of the graft than on the initial cytoreduction achieved by the conditioning regimen.

The IFM99-03/99-04 trials included patients with highrisk myeloma (B2M level >3 mg/L and chromosome 13 deletion at diagnosis).55 In IFM99-03, 65 patients with an HLA-identical sibling donor were assigned to receive reduced-intensity conditioning (RIC) alloSCT; in IFM99-04, 219 patients without an HLA-identical sibling donor were assigned to undergo a second ASCT. The investigators found that RIC-alloSCT was associated with an inferior outcome compared with tandem ASCT. In an Italian trial, 108 patients younger than age 65 with newly diagnosed MM received standard ASCT, followed by low-dose TBI conditioning and HLA-matched sibling peripheral blood SCT (median of 2-4 months from ASCT), then mycophenolate mofetil– cyclosporine graft-versus-host disease prophylaxis,

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Transplant-Ineligible

Transplant-Eligible

MPT x 12 cycles or MPV

Induction Therapy a Lenalidomide-Low-dose Dexamethasone Bortezomib-Dexamethasone Thalidomide-Dexamethasone

Collect stem cells after 4 cycles of induction

Option 1

Option 2

Autologous stem cell transplant

Continue induction therapy

Second transplant or maintenance thalidomide if not in complete response or very good partial response after first transplant

Continue until maximum response or indefinite based on adverse effects

Figure 3. Approach to patient with newly diagnosed MM. a

Bortezomib-containing regimens preferred in patients with high-risk myeloma based on adverse cytogenetics and in patients with renal failure. Combination regimens such as VRD and VTD may be considered outside a clinical trial in patients in whom rapid response is required due to disease-related complications or aggressive disease.

MM, multiple myeloma; MPT, melphalan-prednisone-thalidomide; MPV, melphalan-prednisone-bortezomib; VRD, bortezomib-dexamethasone-lenalidomide; VTD, bortezomib-dexamethasone-thalidomide Based on reference 24.

and finally a second ASCT.56 At a median follow-up of 3 years, treatment-related mortality was 11% for the alloSCT group versus 4% for the double ASCT group; CR rate was 46% versus 16%; OS was 84% versus 62% (P=0.003); and PFS was 75% versus 41% (P=0.00008).

This trial had several shortcomings, however, and the results cannot be generalized.

PATIENTS NOT ELIGIBLE

FOR

TRANSPLANT

Patients not eligible to receive a transplant constitute a sizable proportion of patients, given that nearly two-thirds of individuals with MM are older than age 65 at diagnosis.1 For decades, melphalan and prednisone (MP) have been the mainstays of therapy for patients not eligible for SCT. A meta-analysis of multiple randomized trials failed to demonstrate any benefit for combination regimens compared with MP. In a Phase III clinical trial, Italian investigators examined the addi-

tion of thalidomide to MP.57 Patients older than 65 years with newly diagnosed MM, or younger than age 65 and ineligible for SCT, were randomly assigned to receive MP (melphalan 4 mg/m2, days 1-7, and prednisone 40 mg/m2, days 1-7) or MP plus thalidomide 100 mg daily (MPT) for 6 cycles. Patients in the MPT arm continued on maintenance thalidomide after the 6 cycles until relapse. At 6 months from initiation of therapy, 76% of patients in the MPT arm had a response (CR or partial), compared with 47.6% in the MP arm. With comparable follow-up, the EFS at 2 years doubled with the addition of thalidomide to MP (54% vs 27%), with those older than age 70 deriving similar benefit as the younger patients. Grade 3 and 4 adverse events (AEs), however, nearly doubled with the addition of thalidomide (48% for MPT vs 25% for MP) and 11 patients had toxicity-related deaths in the MPT group, compared with 6 patients in the MP group. Deep vein thrombosis

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was the most common grade 3/4 AE in the MPT group, with 13 of the first 65 patients developing the condition.

After introduction of enoxaparin prophylaxis, however, 2 of the remaining 64 patients developed thrombosis.

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A second clinical trial, conducted in France (IFM99-06) randomly assigned patients aged 65 to 75 to receive MP (12 cycles at 6-week intervals), MPT (maximum tolerated thalidomide dose, up to 400 mg/d), or MEL100

Table 6. Response Criteria for MM Response Subcategory

Response Criteria

CR

• Negative immunofixation on the serum and urine and • Disappearance of any soft tissue plasmacytomas and • <5% plasma cells in bone marrow

Stringent CR

• Normal FLC ratio and

(CR as above plus)

• Absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence

VGPR

• Serum and urine M-component detectable by immunofixation but not on electrophoresis or • ≥90% reduction in serum M-component plus urine M-component <100 mg/24 h

PR

• ≥50% reduction of serum M protein and reduction in 24-h urinary M protein by ≥90% or to <200 mg per 24 h • If the serum and urine M protein are unmeasurable, a ≥50% decrease in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria • If serum and urine M protein are unmeasurable, and serum free light assay is also unmeasurable, ≥50% reduction in bone marrow plasma cells is required in place of M-protein, provided baseline percentage was ≥30% • In addition to the above criteria, if present at baseline, ≥50% reduction in the size of soft tissue plasmacytomas is also required

SD

• Not meeting criteria for CR, VGPR, PR, or PD

PD

Increase of 25% from baseline in • Serum M-component (absolute increase must be ≥0.5 g/dL) and/or • Urine M-component (absolute increase must be ≥200 mg/24 h) and/or • Only in patients without measurable serum and urine M-protein levels: the difference between involved and uninvolved FLC levels (absolute increase must be >10 mg/dL) • Bone marrow plasma cell percentage (absolute % must be 10%) • Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas • Development of hypercalcemia (corrected serum calcium >11.5 mg/dL) that can be attributed solely to the plasma cell proliferative disorder

Relapse from CR

• Reappearance of serum or urine M protein by immunofixation or electrophoresis or • Development of ≥5% plasma cells in the bone marrow or • Appearance of any other sign of progression (ie, new plasmacytoma, lytic bone lesion, or hypercalcemia)

CR, complete response; FLC, free light chain; MM, multiple myeloma; PD, progressive disease; PR, partial response; SD, stable disease; VGPR, very good partial response Based on reference 26.

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(induction therapy with VAD x 2, cyclophosphamide 3 g/m2-based mobilization, and 2 courses of melphalan 100 mg/m2 with stem cell support).58 A CR or VGPR was seen in 9%, 64%, and 58% of patients in the MP, MPT, and MEL100 groups, respectively; at a median follow-up of 32.2 months, the corresponding PFS rates were 17.2, 29.5, and 19 months. The median OS rates were 30.3 months, not reached at 56 months, and 38.6 months in the MP, MPT, and MEL100 groups, respectively. There have been 5 randomized studies comparing MPT with MP, including the 2 mentioned above. The trials have consistently demonstrated a PFS advantage for addition of thalidomide, with 2 of the 5 showing an improvement in OS as well. Based on these results, the recommendation is to add 100 mg per day of thalidomide to the MP regimen and limit the therapy to 12 months for patients ineligible for SCT. Patients should be given daily aspirin for thromboprophylaxis, and clinicians should limit the use of low–molecular-weight heparin to patients with higher risk for thrombosis.

The role of bortezomib in combination with MP was examined in the large Phase III VISTA trial, in which patients with previously untreated MM who were not candidates for ASCT were randomly assigned to receive bortezomib plus MP (VMP) or MP alone.59 Patients in the VMP arm received IV bortezomib 1.3 mg/m2 twice per week (weeks 1, 2, 4, 5) for 4 cycles of 6 weeks (8 doses per cycle), followed by once per week (weeks 1, 2, 4, 5) for 5 cycles of 6 weeks (4 doses per cycle) in combination with oral melphalan 9 mg/m2 and prednisone 60 mg/m2 once daily on days 1 to 4 of each cycle. Patients in the MP arm received MP once daily on days 1 through 4 for 9 cycles of 6 weeks. Both the median TTP and OS at 2 years were significantly better in the VMP group: TTP, 24 months with VMP versus 16.6 months with MP; OS at 2 years, 82.6% with VMP versus 69.5% with MP. MP also has been studied in combination with lenalidomide; Phase II results are promising, and a Phase III trial comparing this regimen with MPT is ongoing.60

Management of Relapsed MM The key determinants of the approach to the patient with relapsed disease depend on previous therapy, duration of response to previous therapy, and presence of high-risk cytogenetic features. Patients relapsing on initial therapy or within 12 months of ASCT, and those with the high-risk genetic abnormalities previously described should be considered at high risk for early mortality. Patients without any of these high-risk features have several options for treatment at first relapse. ASCT remains an option both for those with or without previous ASCT, as long as they are considered eligible for transplant. Retrospective studies support the use of a second ASCT in patients with relapsed disease. Nontransplant approaches can involve the use of a single active agent or combinations of active agents that have been studied in dif-

Table 7. Options for Relapsed MM Bortezomib ± dexamethasone Lenalidomide ± dexamethasone Melphalan, prednisone (± thalidomide, lenalidomide or bortezomib) Cyclophosphamide, prednisone Vincristine, adriamycin, dexamethasone Thalidomide ± dexamethasone Bortezomib, doxorubicin HCl liposome injection (± dexamethasone) Bortezomib, thalidomide, dexamethasone Cyclophosphamide, thalidomide, dexamethasone Dexamethasone (pulse dose) DT-PACE (± bortezomib) DT-PACE, dexamethasone, thalidomide, cisplatin, adriamycin, cyclophosphamide, etoposide; MM, multiple myeloma

ferent clinical trials. A compilation of the regimens that have been evaluated in different clinical trials is presented in Table 7.

As with newly diagnosed MM, inclusion of patients in clinical trials of new agents is recommended for patients with relapsed MM. Outside of a clinical trial, repeating the initial therapy is favored, as long it was tolerated without significant toxicity. Studies into the natural history of MM point toward decreasing response duration, with each relapse reflecting increasingly acquired drug resistance.61 Two of the most promising drugs undergoing clinical trials in this setting include the IMiD pomalidomide, in development by Celgene, and the proteosome inhibitor carfilzomib, in development by Proteolix. The Phase II trial of pomalidomide and dexamethasone enrolled 60 patients with relapsed MM who had received 1 to 3 prior regimens. The overall response rate was 58%, including a 25% VGPR, and the regimen was very well tolerated with manageable toxicity profile. The response rate among patients who were previously refractory to lenalidomide was 29%, demonstrating nonoverlapping mechanisms of action.62 The Phase II trial of carfilzomib, a proteasome inhibitor, enrolled 31 patients with relapsed MM, who have had 3 or fewer prior therapies. The responses were relatively rapid, occurring within 2 cycles; the overall response rate was 36%, and response was higher among those without previous exposure to bortezomib.63 Other agents being evaluated in ongoing clinical trials are listed in Table 8.

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Table 8. Novel Drugs Undergoing Clinical Trials in Myeloma IMiD—pomalidomide (Celgene) New proteasome inhibitor—carfilzomib (Proteolix) Histone deacetylase inhibitors—vorinostat (Zolinza, Merck); panabinostat (Novartis) Monoclonal antibodies—neural cell adhesion molecule (CD56), interleukin-6 Hsp-90 inhibitors—tanespimycin (Kosan); retaspimycin (Infinity Pharmaceuticals) PI3k/Akt pathway inhibitor—perifosine (Keryx Biopharmaceuticals) Farnesytransferase inhibitor—tipifarnib (Zarnestra, Johnson & Johnson) Bcl2 inhibitors—ABT737, obatoclax Anti-VEGF agents—sorafenib (Nexavar, Bayer); sunitinib (Sutent, Pfizer) mTOR inhibitors—everolimus (Afinitor, Novartis); temsirolimus (Toricel, Wyeth)

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reducing skeletal events in patients with MM. The duration of therapy with bisphosphonates and the frequency of administration have been revisited as a result of the increasing recognition of osteonecrosis of the jaw (ONJ) as a complication of the therapy. Although zoledronic acid has been associated with a higher risk for ONJ, pamidronate also can lead to this side effect, with the risk correlating to the duration of therapy. Mayo Clinic has developed a consensus statement regarding the use of bisphosphonates in MM, and the American Society of Clinical Oncology has revised its guidelines to reflect the concerns regarding ONJ.66,67

ANEMIA Anemia is common in patients with MM and is multifactorial in origin. Typically, effective therapy is associated with improvement in hemoglobin. Although clinicians have used erythropoietic agents in a limited manner, the most recent guidelines have placed increasing restrictions on their use. Concurrent use of erythropoietin in patients taking lenalidomide or thalidomide increases the risk for thrombosis. Mayo Clinic’s approach is to avoid using erythropoietin in patients with MM, unless hemoglobin does not improve with effective therapy. The target for hemoglobin is 10 to 11 g/dL.

HYPERCALCEMIA

Patients With High-Risk Features at Diagnosis Patients with cytogenetic deletions 13 and 17p and translocations (t) 4;14 or 14;16 on fluorescence in situ hybridization tests; cytogenetic hypodiploidy, plasma cell labeling index greater than 3%; and B2M greater than 5.5 tend to have very short response duration with ASCT and should be considered for clinical trials evaluating novel drug combinations.64 The outcome of these patients with newer induction therapy regimens, however, is not well studied; there are emerging data that bortezomib and lenalidomide may overcome some of these poor prognostic features. Patients with these abnormalities should consider novel approaches with lenalidomide and/or bortezomib–containing regimens, and should delay the use of ASCT until relapse.

However, recent data also have suggested that patients with t(4;14) with low B2M and normal hemoglobin may have a better than expected outcome, again highlighting the heterogeneity of the disease.65 Selected patients also may be candidates for clinical trials with nonmyeloablative SCT.

Usually seen in the setting of uncontrolled MM, hypercalcemia can be managed with conservative measures, including aggressive hydration and use of loop diuretics. Bisphosphonates can allow for the longterm stable control of hypercalcemia.

RENAL FAILURE

Supportive Care

Renal impairment of varying degrees is present in nearly 20% of patients diagnosed with MM. Renal insufficiency in MM is multifactorial in etiology and may be the result of one or more factors, including cast nephropathy, hypercalcemia, hyperuricemia, dehydration, hyperviscosity, medications such as nonsteroidal anti-inflammatory drugs and, rarely, coexistent amyloidosis or light chain deposition disease.

Renal insufficiency in MM should be managed aggressively because renal function can either completely recover or improve significantly in some patients.

Aggressive hydration as well as management of hypercalcemia and hyperuricemia is imperative. The role of plasmapheresis is controversial and likely to benefit patients with high levels of FLCs. Prompt institution of antimyeloma therapy is important to prevent further deterioration of, and possibly ensure improvement of, renal function. Patients with advanced renal failure will require dialysis support.

BISPHOSPHONATES

VERTEBRAL COMPRESSION FRACTURES

The widespread use of bisphosphonates stems from early trials demonstrating a benefit for pamidronate in

Vertebral compression fractures contribute to significant morbidity in patients with MM, and vertebroplasty

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and kyphoplasty have a definite role in its management.

These procedures decrease the pain and improve the spinal deformities associated with compression fractures. However, RCTs are required to define the precise role of these interventions.

References 1.

Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med. 2004;351(18):1860-1873, PMID: 15509819.

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35. Jagannath S, Durie BG, Wolf J, et al. Bortezomib therapy alone and in combination with dexamethasone for previously untreated symptomatic multiple myeloma. Br J Haematol. 2005;129(6):776783, PMID: 15953004.

36. Harousseau JL, Mathiot C, Attal M, et al. Bortezomib/dexamethasone versus VAD as induction prior to autologous stem cell transplantation (ASCT) in previously untreated multiple myeloma (MM): updated data from IFM 2005/01 Trial. J Clin Oncol. 2008;26(suppl): Abstract 8505.

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39. Kumar S, Flynn IW, Noga SJ, et al. Safety and efficacy of novel combination therapy with bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in newly diagnosed multiple myeloma: initial results from the Phase I/II multicenter EVOLUTION trial. ASH Annual Meeting Abstracts.

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43. Fermand JP, Katsahian S, Divine M, et al. High-dose therapy and autologous blood stem-cell transplantation compared with conventional treatment in myeloma patients aged 55 to 65 years: long-term results of a randomized control trial from the Group Myelome-Autogreffe. J Clin Oncol. 2005;23(36):9227-9233, PMID: 16275936.

44. Barlogie B, Kyle RA, Anderson KC, et al. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321.

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46. Moreau P, Facon T, Attal M, et al. Comparison of 200 mg/m2 melphalan and 8 Gy total body irradiation plus 140 mg/m2 melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Myelome 9502 randomized trial. Blood. 2002;99(3):731-735, PMID: 11806971.

47. Attal M, Harousseau JL, Facon T, et al. Single versus double autologous stem-cell transplantation for multiple myeloma.

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54. Bjorkstrand BB, Ljungman P, Svensson H, et al. Allogeneic bone marrow transplantation versus autologous stem cell transplantation in multiple myeloma: a retrospective case-matched study from the European Group for Blood and Marrow Transplantation.

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56. Bruno B, Rotta M, Patriarca F, et al. A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med; 2007;356(11):1110-1120, PMID: 17360989.

57. Palumbo A, Bringhen S, Caravita T, et al. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: a randomised conrolled trial. Lancet. 2006;367(9513):825-831, PMID: 16530576.

58. Facon T, Mary JY, Hulin C, et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06). Lancet.

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59. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359(9):906-917, PMID: 18753647.

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62. Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low-dose dexamethasone (pom/dex) is highly effective therapy in relapsed multiple myeloma. ASH Annual Meeting Abstracts.

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63. Jagannath S, Vij R, Stewart KA, et al. Initial results of PX-171-003, an open-label, single arm, Phase II study of carfilzomib (CFZ) in patients with relapsed and refractory multiple myeloma (MM). ASH Annual Meeting Abstracts. Blood. 2008; 112(11):319. Abstract 864.

64. Gertz MA, Lacy MQ, Dispenzieri A, et al. Clinical implications of t(11;14)(q13;q32), t(4;14)(p16.3;q32), and -17p13 in myeloma patients treated with high-dose therapy. Blood. 2005;106(8): 2837-2840, PMID: 15976175.

65. Moreau P, Attal M, Garban F, et al. Heterogeneity of t(4;14) in multiple myeloma. Long-term follow-up of 100 cases treated with tandem transplantation in IFM99 trials. Leukemia. 2007;21(9):20202024, PMID: 17625611.

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FIRST–Frontline Investigation of REVLIMID®/dex vs Standard Thal

CURRENTLY ENROLLING

A Randomized Phase III Study of Patients With Previously Untreated Multiple Myeloma (CC-5013-MM-020/IFM 07-01) Primary Objective To compare progression-free survival with lenalidomide (REVLIMID) plus low-dose dexamethasone (Rd) given until disease progression or for 18 four-week cycles versus combination of melphalan, prednisone, and thalidomide (MPT) given for 12 six-week cycles.

Key Eligibility Criteria • Previously untreated, symptomatic multiple myeloma • Not a candidate for or have declined stem cell transplantation • ECOG PS ≤2

Study Design Treatment Aa (Rd) • Lenalidomide po once daily, days 1-21 each cycle • Dexamethasone po once weekly, days 1, 8, 15, and 22 each cycle Treatment (28-day cycles) continues until disease progression

Treatment Ba (Rd) N=1590

• Lenalidomide po once daily, days 1-21 each cycle • Dexamethasone po once weekly, days 1, 8, 15, and 22 each cycle 18 cycles, 28 days each

Treatment Cb (MPT)

Progressionfree Survival Follow-up Phase Patients will be followed until disease progression

Long-term Follow-up Phase Patients followed for survival and subsequent antimyeloma therapies

• Melphalan po once daily, days 1-4 each cycle • Prednisone po once daily, days 1-4 each cycle • Thalidomide po once daily, continuously 12 cycles, 42 days each aDosage

bDosage

varies based on age and renal function. varies by age and baseline neutrophil and platelet counts.

For more information or to participate, please contact: www.clinicaltrials.gov (NCT00689936) Elvira Klissourska, PhD (eklissourska@celgene.com) Celgene Corporation www.celgene.com

REVLIMID® is a registered trademark of Celgene Corporation. Investigational use of REVLIMID® (lenalidomide). © 2008 Celgene Corporation 06/08

CELG08050

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U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research

B[V^bR 0baaV[T 2QTR <;0<9<4F <]]\_ab[VaVR` The Office of Oncology Drug Products is recruiting BC/BE (or equivalent) Medical Oncologists and Hematologists to serve as Clinical Reviewers at our beautiful new campus in Silver Spring, MD. Our work involves cutting-edge biotechnology-based therapies for malignant disease including: Signal Transduction Inhibitors

Immune Response Modifiers

Growth Factors

Monoclonal Antibodies

Anti-Sense Oligonucleotides

Cytokines

Anti-Angiogenic Agents

Immunoconjugates

Novel Cytotoxic Agents

Cell-Differentiating Agents

Proteasome Inhibitors

Chemoprevention Agents

Our physicians lead multidisciplinary scientific teams of highly skilled professionals on projects that provide intellectually-stimulating interactions with academic investigators, NCI/NIH, cooperative groups, and pharmaceutical and biotechnology companies.

Opportunities for scientific conferences, professional meetings and career advancement. Up to one day per week for academic clinical activities or research possible. Flexible and/or home-based working schedules available.

Salary & Benefits: An excellent benefits package (health insurance, life insurance, thrift savings plan, retirement) · Civil Service Salary at the GS-14 level of $83,445 plus an additional very generous supplemental allowance determined by relevant experience and medical specialty. · Recruitment Bonuses and Student Loan Repayments · Flexible and/or Home-based work schedules available · Opportunities to continue Professional Development GENERAL INFORMATION: Positions being filled as civil service or U.S. Commissioned Corps require U.S. citizenship. Permanent U.S. residents may apply for Staff Fellowship appointments in physician and scientist positions. Graduates of foreign colleges/universities must provide proof of U.S. education equivalency certification.

PHYSICIANS: (Medical Oncology and/or Hematology): Basic Requirements: Degree: Doctor of Medicine or Doctor of Osteopathy from a school in the United States or Canada approved by a recognized accrediting body in the year of the applicant’s graduation. [A Doctor of Medicine or equivalent degree from a foreign medical school that provided education and medical knowledge substantially equivalent to accredited schools in the United States may be demonstrated by permanent certification by the Educational Commission for Foreign Medical Graduates (ECFMG) (or a fifth pathway certificate for Americans who completed premedical education in the United States and graduate education in a foreign country).] Board Certified or Board Eligible in Medical Oncology and/or Hematology.

FOR CONSIDERATION: Submit electronic curriculum vitae with a cover letter to Recruitment Team via e-mail at: OND-Employment@fda.hhs.gov Please indicate that you are applying to source code #09-038.

For more information, please contact Joseph E. Gootenberg, M.D. at joseph.gootenberg@fda.hhs.gov or at 301-796-1362.

FDA IS AN EQUAL OPPORTUNITY EMPLOYER AND HAS A SMOKE FREE ENVIRONMENT. MINORITIES, WOMEN, INDIVIDUALS WITH DISABILITIES AND VETERANS ARE ENCOURAGED TO APPLY.

ASCO Career Fair, booth 3664

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ALOXI® (palonosetron HCl) injection BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE Chemotherapy-Induced Nausea and Vomiting ALOXI is indicated for: • Moderately emetogenic cancer chemotherapy – prevention of acute and delayed nausea and vomiting associated with initial and repeat courses • Highly emetogenic cancer chemotherapy – prevention of acute nausea and vomiting associated with initial and repeat courses DOSAGE AND ADMINISTRATION Recommended Dosing Chemotherapy-Induced Nausea and Vomiting Dosage for Adults - a single 0.25 mg I.V. dose administered over 30 seconds. Dosing should occur approximately 30 minutes before the start of chemotherapy.

Instructions for I.V. Administration ALOXI is supplied ready for intravenous injection.

ALOXI should not be mixed with other drugs. Flush the infusion line with normal saline before and after administration of ALOXI. Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit.

CONTRAINDICATIONS ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components. [see Adverse Reactions (6) in full prescribing information ] WARNINGS AND PRECAUTIONS Hypersensitivity Hypersensitivity reactions may occur in patients who have exhibited hypersensitivity to other 5-HT3 receptor antagonists.

ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates reported in practice.

In clinical trials for the prevention of nausea and vomiting induced by moderately or highly emetogenic chemotherapy, 1374 adult patients received palonosetron.

Adverse reactions were similar in frequency and severity with ALOXI and ondansetron or dolasetron. Following is a listing of all adverse reactions reported by ≥ 2% of patients in these trials (Table 1).

Table 1: Adverse Reactions from ChemotherapyInduced Nausea and Vomiting Studies ≥ 2% in any Treatment Group ALOXI Ondansetron Dolasetron Event 0.25 mg 32 mg I.V. 100 mg I.V. (N=410) (N=633) (N=194) Headache 60 (9%) 34 (8%) 32 (16%) Constipation 29 (5%) 8 (2%) 12 (6%) Diarrhea 8 (1%) 7 (2%) 4 (2%) Dizziness 8 (1%) 9 (2%) 4 (2%) Fatigue 3 (< 1%) 4 (1%) 4 (2%) Abdominal Pain 1 (< 1%) 2 (< 1%) 3 (2%) Insomnia 1 (< 1%) 3 (1%) 3 (2%) In other studies, 2 subjects experienced severe constipation following a single palonosetron dose of approximately 0.75 mg, three times the recommended dose. One patient received a 10 mcg/kg oral dose in a postoperative nausea and vomiting study and one healthy subject received a 0.75 mg I.V. dose in a pharmacokinetic study.

In clinical trials, the following infrequently reported adverse reactions, assessed by investigators as treatment-related or causality unknown, occurred following administration of ALOXI to adult patients receiving concomitant cancer chemotherapy: Cardiovascular: 1%: non-sustained tachycardia, bradycardia, hypotension, < 1%: hypertension, myocardial ischemia, extrasystoles, sinus tachycardia, sinus arrhythmia, supraventricular extrasystoles and QT prolongation. In many cases, the relationship to ALOXI was unclear.

Dermatological: < 1%: allergic dermatitis, rash.

Hearing and Vision: < 1%: motion sickness, tinnitus, eye irritation and amblyopia.

Gastrointestinal System: 1%: diarrhea, < 1%: dyspepsia, abdominal pain, dry mouth, hiccups and flatulence.

General: 1%: weakness, < 1%: fatigue, fever, hot flash, flu-like syndrome.

Liver: < 1%: transient, asymptomatic increases in AST and/or ALT and bilirubin. These changes occurred predominantly in patients receiving highly emetogenic chemotherapy.

Metabolic: 1%: hyperkalemia, < 1%: electrolyte fluctuations, hyperglycemia, metabolic acidosis, glycosuria, appetite decrease, anorexia.

Musculoskeletal: < 1%: arthralgia.

Nervous System: 1%: dizziness, < 1%: somnolence, insomnia, hypersomnia, paresthesia.

Psychiatric: 1%: anxiety, < 1%: euphoric mood.

Urinary System: < 1%: urinary retention.

Vascular: < 1%: vein discoloration, vein distention.

Postmarketing Experience The following adverse reactions have been identified during postapproval use of ALOXI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Very rare cases (<1/10,000) of hypersensitivity reactions and injection site reactions (burning, induration, discomfort and pain) were reported from postmarketing experience of ALOXI 0.25 mg in the prevention of chemotherapy-induced nausea and vomiting.

DRUG INTERACTIONS Palonosetron is eliminated from the body through both renal excretion and metabolic pathways with the latter mediated via multiple CYP enzymes. Further in vitro studies indicated that palonosetron is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1 and CYP3A4/5 (CYP2C19 was not investigated) nor does it induce the activity of CYP1A2, CYP2D6, or CYP3A4/5. Therefore, the potential for clinically significant drug interactions with palonosetron appears to be low.

Coadministration of 0.25 mg I.V. palonosetron and 20 mg I.V. dexamethasone in healthy subjects revealed no pharmacokinetic drug-interactions between palonosetron and dexamethasone.

In an interaction study in healthy subjects where palonosetron 0.25 mg (I.V. bolus) was administered on day 1 and oral aprepitant for 3 days (125 mg/80 mg/80 mg), the pharmacokinetics of palonosetron were not significantly altered (AUC: no change, Cmax: 15% increase).

A study in healthy volunteers involving single-dose I.V. palonosetron (0.75 mg) and steady state oral metoclopramide (10 mg four times daily) demonstrated no significant pharmacokinetic interaction.

In controlled clinical trials, ALOXI injection has been safely administered with corticosteroids, analgesics, antiemetics/antinauseants, antispasmodics and anticholinergic agents.

Palonosetron did not inhibit the antitumor activity of the five chemotherapeutic agents tested (cisplatin, cyclophosphamide, cytarabine, doxorubicin and mitomycin C) in murine tumor models.

USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects: Category B Teratology studies have been performed in rats at oral doses up to 60 mg/kg/day (1894 times the recommended human intravenous dose based on body surface area) and rabbits at oral doses up to 60 mg/ kg/day (3789 times the recommended human intravenous dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to palonosetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, palonosetron should be used during pregnancy only if clearly needed.

Labor and Delivery Palonosetron has not been administered to patients undergoing labor and delivery, so its effects on the mother or child are unknown.

Nursing Mothers It is not known whether palonosetron is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants and the potential for tumorigenicity shown for palonosetron in the rat carcinogenicity study, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

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Pediatric Use Safety and effectiveness in patients below the age of 18 years have not been established.

Geriatric Use Population pharmacokinetics analysis did not reveal any differences in palonosetron pharmacokinetics between cancer patients ≥ 65 years of age and younger patients (18 to 64 years). Of the 1374 adult cancer patients in clinical studies of palonosetron, 316 (23%) were ≥ 65 years old, while 71 (5%) were ≥ 75 years old. No overall differences in safety or effectiveness were observed between these subjects and the younger subjects, but greater sensitivity in some older individuals cannot be ruled out. No dose adjustment or special monitoring are required for geriatric patients.

Of the 1520 adult patients in ALOXI PONV clinical studies, 73 (5%) were ≥65 years old. No overall differences in safety were observed between older and younger subjects in these studies, though the possibility of heightened sensitivity in some older individuals cannot be excluded. No differences in efficacy were observed in geriatric patients for the CINV indication and none are expected for geriatric PONV patients. However, ALOXI efficacy in geriatric patients has not been adequately evaluated.

Renal Impairment Mild to moderate renal impairment does not significantly affect palonosetron pharmacokinetic parameters. Total systemic exposure increased by approximately 28% in severe renal impairment relative to healthy subjects.

Dosage adjustment is not necessary in patients with any degree of renal impairment.

Hepatic Impairment Hepatic impairment does not significantly affect total body clearance of palonosetron compared to the healthy subjects. Dosage adjustment is not necessary in patients with any degree of hepatic impairment.

Race Intravenous palonosetron pharmacokinetics was characterized in twenty-four healthy Japanese subjects over the dose range of 3 – 90 mcg/kg. Total body clearance was 25% higher in Japanese subjects compared to Whites, however, no dose adjustment is required. The pharmacokinetics of palonosetron in Blacks has not been adequately characterized.

OVERDOSAGE There is no known antidote to ALOXI. Overdose should be managed with supportive care.

Fifty adult cancer patients were administered palonosetron at a dose of 90 mcg/kg (equivalent to 6 mg fixed dose) as part of a dose ranging study. This is approximately 25 times the recommended dose of 0.25 mg. This dose group had a similar incidence of adverse events compared to the other dose groups and no dose response effects were observed.

Dialysis studies have not been performed, however, due to the large volume of distribution, dialysis is unlikely to be an effective treatment for palonosetron overdose. A single intravenous dose of palonosetron at 30 mg/kg (947 and 474 times the human dose for rats and mice, respectively, based on body surface area) was lethal to rats and mice. The major signs of toxicity were convulsions, gasping, pallor, cyanosis and collapse.

PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (17.2) in full prescribing information Instructions for Patients • Patients should be advised to report to their physician all of their medical conditions, any pain, redness, or swelling in and around the infusion site [see Adverse Reactions (6) in full prescribing information].

• Patients should be instructed to read the patient insert.

Rx Only Mfd by OSO Biopharmaceuticals, LLC, Albuquerque, NM, USA or Pierre Fabre, Médicament Production, Idron, Aquitaine, France and Helsinn Birex Pharmaceuticals, Dublin, Ireland.

ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license.

Distributed and marketed by Eisai Inc., Woodcliff Lake, NJ 07677. © 2008 Eisai Inc. All rights reserved. Printed in USA. AL350 10/08

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STRONG. FROM THE START.

HELP ESTABLISH A SUCCESSFUL CINV PREVENTION STRATEGY FROM THE FIRST CYCLE When your patients experience acute chemotherapy-induced nausea and vomiting (CINV) during their first cycle of chemotherapy, they may have an increased risk of CINV on subsequent days and in subsequent cycles.1-3

ALOXI®: Starts strong to prevent CINV4 A single IV dose lasts up to 5 days after MEC4,5* Can be used with multiple-day chemotherapy regimens6† * Moderately emetogenic chemotherapy. † Based on sNDA approval in August 2007, the restriction on repeated dosing of ALOXI (palonosetron HCl) injection within a 7-day interval was removed.

ALOXI® (palonosetron HCl) injection 0.25 mg is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy, and acute nausea and vomiting associated with initial and repeat courses of highly emetogenic chemotherapy.

Important Safety Information ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components. Most commonly reported adverse reactions include headache (9%) and constipation (5%).

Please see the following brief summary of prescribing information.

REFERENCES: 1. The Italian Group for Antiemetic Research. Dexamethasone alone or in combination with ondansetron for the prevention of delayed nausea and vomiting induced by chemotherapy. N Engl J Med. 2000;342:1554-1559. 2. Hickok JT, Roscoe JA, Morrow GR, et al.

5-Hydroxytryptamine-receptor antagonists versus prochlorperazine for control of delayed nausea caused by doxorubicin: a URCC CCOP randomised controlled trial. Lancet Oncol. 2005;6:765-772. Epub September 13, 2005. 3. Cohen L, de Moor CA, Eisenburg P, Ming EE, Hu H. Chemotherapyinduced nausea and vomiting: incidence and impact on patient quality of life at community oncology settings. Support Care Cancer. 2007;15:497503. Epub November 14, 2006. 4. Gralla R, Lichinitser M, Van der Vegt S, et al. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol. 2003;14:1570-1577. 5. Eisenberg P, Figueroa-Vadillo J, Zamora R, et al. Improved Prevention of Moderately Emetogenic Chemotherapy-induced Nausea and Vomiting with Palonosetron, a Pharmacologically Novel 5-HT3 Receptor Antagonist: Results of a Phase III, Single-Dose Trial Versus Dolasetron. Cancer. 2003;98:2473-2482. 6. ALOXI® (palonosetron HCl) injection full prescribing information.

ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license.

Distributed and marketed by Eisai Inc. © 2008 Eisai Inc. All rights reserved. Printed in USA. AL348 10/08

www.ALOXI.com

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SUPPORTIVE CARE CLINICAL ONCOLOGY NEWS SPECIAL EDITION 2009 • NO. 1 DIGITAL EDITION • JUNE 2009

Rash

Tools in Works for Managing EGFR Inhibitor Skin Reactions Hollywood, Fla.—A task force of clinicians convened by the National Comprehensive Cancer Network (NCCN) is developing recommendations for treating the dermatologic toxicities associated with epidermal growth factor receptor (EGFR) inhibitors.

Skin rashes associated with the targeted agents are a dual-edged sword: Although they usually signal that the drugs are working, managing the persistent side effects can be difficult, and side effects are not uncommon. Experts say that some degree of skin toxicity and nail alterations affect up to threefourths of patients undergoing EGFR therapy.

“We see these patients in the clinic and even in retail pharmacies quite frequently,” said Margaret McGuinness, PharmD, pharmacy manager of Northwest Cancer Specialists in Portland, Ore. “So it’s important to have practical solutions to suggest to them.”

At the 13th annual NCCN conference, Barbara Burtness, MD, a medical oncologist at Fox Chase Cancer Center, in Philadelphia, offered details on the group’s recommendations for keeping EGFR inhibitor-induced skin conditions in check. Dr. Burtness focused specifically on the EGFR inhibitors cetuximab (Erbitux, Bristol-Myers Squibb), panitumumab (Vectibix, Amgen), erlotinib (Tarceva, Genentech), gefitinib (Iressa, AstraZeneca) and lapatinib (Tykerb, GlaxoSmithKline). These drugs are currently used in non-small cell lung cancer (NSCLC), head and neck cancer, HER2-positive breast cancer and colon cancer, she noted.

The link between the rashes and response to EGFR inhibitor therapy has been well documented, Dr. Burtness said. In fact, treatment with these agents has been associated with significant survival benefits across multiple tumor types—especially in patients who develop skin toxicity. For example, in a study by Wacker et al that analyzed data from two Phase III studies of erlotinib in NSCLC, median survival was just 3.3 months for patients not developing rash, compared with 11.1 months for patients with skin toxicity of grade 2 or higher (Clin Cancer Res 2007;132:3913-3921, PMID: 17606725), Dr. Burtness noted.

Dermatologic Manifestations About 10 days after starting EGFR inhibitor treatment, patients may develop an acne-like rash (often pruritic) that peaks by week 2, she said. In the majority of patients (45%-100%), the rash appears as a papulopustular eruption on the face and upper body,

sometimes followed by crusting. By week 4, post-inflammatory effects start to emerge, and many patients develop xerosis and fissures (12%-58%), pruritus (10%-52%), periungual and nail alterations (12%-16%), early alopecia (uncommon), late alopecia developing after two to three months (4%-11%), and changes in hair texture, eyelids and eyelashes. The disrupted skin barrier can lead to bacterial, viral and fungal superinfection (impetigo, dissecting cellulitis, herpes, tinea, etc.).

Recent evidence shows that concomitant radiation therapy may compound skin toxicities.

“Since the presence of rash is associated with improved outcomes, we recommended that you consider treating the rash before you reduce the dose because of the rash,” Dr. Burtness said.

That approach dovetails with the Wacker et al study of erlotinib. The authors emphasized that the appearance of a rash should be seen as a sign that an EGFR inhibitor is having an effect on tumor growth. Conversely, the lack of a rash may signal that EGFRs are not exhibiting their maximum effect and dose escalation should be considered, the authors noted.

(The link between EGFR inhibitors and skin rash is thought to be the result of the drugs’ expression in the epidermis and sebaceous glands, among other skin structures.)

There is no standard treatment regimen, Dr. Burtness noted. But a number of approaches have been successful— primarily topical steroids, topical metronidazole gel, systemic antibiotics (minocycline) and systemic retinoids such as acitretin (Soriatane, Stiefel) and isotretinoin. Topical retinoids, in contrast, have not proven effective. Cultures may be helpful when there are frank signs of infection, such as treatment refractoriness, pain, purulent discharge and induration, the task force stated.

Preemptive Regimen Mario Lacouture, MD, director of the Skin and Eye Reactions to Inhibitors of EGFR and Kinases Clinic at Northwestern University, Chicago, has been instrumental in studying skin toxicities that occur with EGFR inhibitors and the tyrosine kinase inhibitors sorafenib (Nexavar, Bayer) and sunitinib (Sutent, Pfizer). Dr. Lacouture also is a member

Table. NCCN Task Force Recommendations On Selected EGFR-Induced Skin Reactions Desquamation

Petroleum jelly or other thick emollients Mild (neutral pH) soap Ammonium lactate 12%, salicylic acid 6%, urea 20%

Fissuring

Protective coverings; Monsel’s solution, silver nitrate, zinc oxide cream Liquid cyanoacrylate preparations to fissures to relieve pain and to promote healing

Paronychia

Bacterial and fungal culture; appropriate oral antibiotics Monsel’s (ferric subsulfate) solution or silver nitrate 4% thymol in alcohol, aluminum acetate soaks, dilute acetic acid (vinegar) soaks Nail clipping or possible removal of nail plate

Pruritus

Cool compresses, sedating antihistamines at evening/bedtime, topical steroids Gabapentin or pregabalin

of the NCCN Task Force.

A prophylactic regimen developed

by Dr. Lacouture was recently shown to reduce the risk for skin toxicity in a major study of panitumumab. The preemptive regimen consists of a daily moisturizer, a para-aminobenzoic acidfree sunscreen rated an SPF of 15 or higher, a topical steroid cream (hydrocortisone 1%) and oral doxycycline 100 mg twice daily.

the importance of prevention in an interview. “Some patients refuse to be treated with these agents because they don’t want to develop the rash they have seen on other patients,” said Dr. Mitchell, a gastrointestinal cancer specialist at Thomas Jefferson University, in Philadelphia.

The NCCN Task Force, however, felt that although there may be benefit to prophylaxis, reactive treatment should

‘Since the presence of rash is associated with improved outcomes, we recommended that you consider treating the rash before you reduce the dose because of the rash.’

—Barbara Burtness, MD

Use of this preemptive regimen reduced the occurrence of skin toxicity by 50% in a study of 95 colorectal cancer patients. In the study, patients were randomized to one of two regimens: irinotecan or FOLFIRI (fluorouracil [5-FU], irinotecan and folinic acid) started 24 hours before the first dose of panitumumab and continued for six weeks, or reactive therapy administered after toxicity occurred (Lacouture M et al. 2009 Gastrointestinal Cancers Symposium, abstract 291).

At six weeks, preemptively treated patients had a 29% incidence of grade 2 or higher skin toxicity, compared with 62% receiving reactive treatment. Specifically, grade 2 skin toxicity occurred in 23% and 40% of patients, respectively, and grade 3 toxicity in 6% and 21%.

Median time to first grade 2 or higher skin rash was 2.1 weeks in the reactive treatment arm, but has not been reached in the preemptive arm.

Edith Mitchell, MD, a key investigator in the panitumumab trials, underscored

be sufficient in most cases. “Since only a minority of patients develops a severe rash and the condition is self-limited, it was hard to come down in favor of prophylaxis,” Dr. Burtness said.

The task force also made recommendations for the treatment of other dermatologic manifestations (Table).

Ocular side effects have also been reported in association with EGFR inhibitors, including conjunctivitis, blepharitis, trichomegaly, corneal erosion and dry eye. Blepharitis can be treated with warm moist compresses and sterile eyelid cleanser. Symptomatic cases may respond within a week to a short course of topical neomycin, polymyxin B and dexamethasone ophthalmic eye ointment. For trichomegaly, eyelashes can be trimmed or removed, and even permanently removed with diathermy if necessary. Dry eye is treated with artificial tears or topical antiinflammatory agents.

—Caroline Helwick

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D

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CLINICAL ONCOLOGY NEWS SPECIAL EDITION 2009 • NO. 1 DIGITAL EDITION • JUNE 2009

Pain Management

Opioid Ban That Limited Pain Control Options Reversed Manufacturing and distribution of high-concentrate morphine sulfate solutions will be allowed under a temporary amendment to the FDA’s decision in March to halt the sale of unapproved opioid pain products.

T

he “enforcement discretion” on behalf of the agency came in response to concern from patients, physicians and health care organizations—particularly those in the palliative care community— over a potential shortage of 20 mg/mL morphine sulfate oral solution if the ban was put into effect. Many cancer patients have difficulty taking anything other than this easy-to-swallow 20 mg/mL morphine liquid.

“While the FDA remains committed to ultimately ensuring that all prescription drugs on the market are FDA-approved, we have to balance that goal with flexibility and compassion for patients who have few alternatives for the alleviation of their pain,” said Douglas Throckmorton, MD, deputy director of the FDA’s Center for Drug Evaluation and Research.

“In light of the concerns raised by these patients and their health care providers, we have adjusted our actions with regard to these particular products.”

The FDA will allow the continued manufacturing and distribution of 20 mg/mL morphine sulfate oral solution but only until an FDA-approved version “or another acceptable alternative therapy” is available, according to a revised statement by the agency on April 9.

On March 31, as part of its ongoing Unapproved Drugs Initiative, the FDA sent warning letters to the makers of 14 unapproved opioid products, citing possible enforcement action if manufacturing and distribution of unapproved prescription pain products were not halted within 60 and 90 days, respectively.

The FDA stated at the time of the initial

letters that “removal of the unapproved narcotic products will not create a shortage for consumers.”

Among the drugs targeted by the FDA were high-concentrate morphine sulfate oral solutions and immediaterelease tablets containing morphine sulfate, hydromorphone or oxycodone (not including oxycodone capsules). The companies receiving the letters were Boehringer Ingelheim Roxane, Cody Laboratories, Glenmark Pharmaceuticals, Lannett Company, Lehigh Valley Technologies, Mallinckrodt, Physicians Total Care, Roxane Pharmaceuticals and Xanodyne Pharmaceuticals.

“Doctors and patients often are unaware that not all drugs on the market are backed by FDA approval,” said Janet Woodcock, MD, director of the Center for Drug Evaluation and Research, at the time of the announcement.

A Quick Outcry The initial FDA action met with immediate criticism. Groups such as the Institute for Safe Medication Practices (ISMP) acknowledged the need for an improved safety review process for opioid products, stating that dosing errors and fatalities have occurred because of confusing or inappropriate labeling. Still, the ISMP worried that the FDA action, especially the removal of morphine concentrate oral liquid from the marketplace, would have “unintended safety consequences”—specifically, making pain control for patients receiving endof-life care more difficult by removing the easy-to-swallow 20 mg/mL mor-

The temporary amendment is good news for cancer patients, many of whom have difficulty taking anything other than the easy-to-swallow 20 mg/mL morphine liquid that would have been removed from the market if the ban had gone into effect. phine liquid from the market.

“Many cancer patients, especially those near the end of life with decreased level of consciousness but who can still be treated adequately with large doses of oral morphine to control pain, will have much more difficulty swallowing 10 mg/5 mL or 20 mg/5 mL morphine liquid than the 20 mg/mL liquid currently available,” the ISMP said in a statement following the announcement.

Heeding those concerns, the FDA acknowledged on April 9 that the 20 mg/mL morphine liquid is widely used by terminally ill patients. “The agency has determined that this dosage form is medically necessary, and should remain on the market until an approved alternative becomes available to the patients that need it,” the agency said in a statement.

Groups that had initially been critical of the FDA’s decision, such as the American

Free Guide to the Prevention of Chemotherapy Medication Errors 2009 Now Available

T

his pocket guide is intended to help clinicians develop practical strategies to prevent chemotherapy medication errors. It includes information on selected publicized chemotherapy errors and their outcomes; examples of potential causes of errors, such as look-alike/sound-alike drug names and the use of handwritten orders; examples of optimal requirements and prohibitions for chemotherapy orders; and how to assess the risk for medication errors at one’s own institution or practice site. Because nearly all authorities recommend implementation of an electronic order entry system, this guide discusses the use of technology and computerization (eg, computerized prescriber order-entry [CPOE] and bar coding) in medication error prevention, including the advantages of and caveats to these technologies.

To order a free copy of this pocket guide, send an e-mail with your full name, mailing address and institution to clinicaloncologynews@mcmahonmed.com.

Pain Foundation, praised its reversal.

“We would like to acknowledge them for their swift action in this case as they became aware of the impact this disruption was having on the community,” the foundation said in a statement. “In order to help remedy this, they would like to hear from providers if there are critical shortages in medications to help manage patients optimally.”

“The FDA appreciates the help we received from the palliative care community about how this drug is being used today to help patients,” said Theresa Toigo, director of the FDA’s Office of Special Health Issues. “We want to continue to talk to them as we move forward on this difficult issue.”

More information can be found at www.fda.gov/cder/drug/unapproved_ drugs/morphine_extension.htm.

—Donald M. Pizzi

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Treatment of

Nausea and Vomiting In the Oncology Setting DAVID G. FRAME, PHARMD Clinical Assistant Professor of Pharmacy The University of Michigan College of Pharmacy Ann Arbor, Michigan

WILLIAM LESLIE, MD Assistant Professor of Medicine Rush University Medical Center Chicago, Illinois

T

he American Society of Clinical Oncology,1 the European Society of Medical Oncology,2 the Multinational Association of

Supportive Care in Cancer,3 and the National Comprehensive

Cancer Network4 have all recently published antiemetic guidelines.

This review will focus on the most updated versions of the guidelines, all of which are very similar. By summarizing the guideline recommendations for the prevention and treatment of chemotherapy-induced nausea and vomiting (CINV) and radiation-induced nausea and vomiting (RINV), this review will assist physicians, pharmacists, and nurses in the selection of the most appropriate antiemetic regimens for individuals receiving chemotherapy or radiation therapy. The guidelines are described below and are outlined in Tables 1 and 2.

Additionally, the Figure is a useful algorithm describing the recommended course of antiemetic care.

Prevention of Anticipatory Nausea and Vomiting Each of the guidelines recommended the use of psychological techniques to prevent anticipatory nau-

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sea and vomiting; benzodiazepines can be used as an alternative or in addition to psychological techniques, if necessary. Because it is a learned response, the best prevention for anticipatory nausea and vomiting is aggressive prevention of acute and delayed nausea and vomiting with each course of chemotherapy or radiation.

Prevention of Acute-Onset CINV HIGHLY EMETOGENIC CHEMOTHERAPY For prevention of acute-onset CINV in patients treated with highly emetogenic agents, a 3-drug regimen that includes a single dose of a serotonin (5-HT3)–receptor antagonist, dexamethasone, and aprepitant (Emend, Merck) or its prodrug, fosaprepitant (Emend, Merck) is recommended. The 5-HT3– receptor antagonists include dolasetron (Anzemet,

CLINICAL ONCOLOGY NEWS SPECIAL EDITION 2009 • NO. 1

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Sanofi-Aventis/Organon), granisetron, ondansetron, and palonosetron (Aloxi, Eisai). Additional therapy with lorazepam and/or an H2 antagonist or proton pump inhibitor (PPI) may be considered.

MODERATELY EMETOGENIC CHEMOTHERAPY For patients treated with moderately emetogenic chemotherapeutic agents, recommended therapy is a 5-HT3–receptor antagonist plus dexamethasone.

Aprepitant or fosaprepitant should be added for patients receiving additional agents of moderate risk such as carboplatin, cisplatin, doxorubicin, epirubicin, ifosfamide, irinotecan, or methotrexate. Additional therapy with lorazepam and/or an H2 antagonist or PPI may be considered.

LOW EMETOGENIC CHEMOTHERAPY For patients treated with agents that have low emetogenic potential, a low dose of a single agent such as a dexamethasone or a dopamine antagonist is the recommended therapy.

MINIMALLY EMETOGENIC CHEMOTHERAPY Routine antiemetic prophylaxis is not recommended in patients without a history of nausea and vomiting who are treated with minimally emetogenic chemotherapy.

MULTIDAY CHEMOTHERAPY WITH HIGHLY EMETOGENIC AGENT

A

MODERATE

OR

To prevent acute-onset CINV, a daily regimen of a 5-HT3–receptor antagonist (or palonosetron 0.25 mg IV on days 1, 3, and 5) and dexamethasone is recommended. Aprepitant or fosaprepitant may be added (for up to 5 days) if a regimen is likely to be associated with significant delayed CINV. Additional therapy with lorazepam and/or an H2 antagonist or PPI may be considered.

Prevention of Delayed-Onset CINV HIGHLY EMETOGENIC CHEMOTHERAPY To prevent delayed-onset CINV in patients treated with highly emetogenic regimens, a combination of dexamethasone and aprepitant or fosaprepitant is recommended. Additional therapy with lorazepam and/or an H2 antagonist or PPI may be considered.

MODERATELY EMETOGENIC CHEMOTHERAPY Antiemetic prophylaxis should only be used for moderately emetogenic chemotherapy known to be associated with a significant incidence of delayed nausea and vomiting. In this circumstance, if aprepitant or fosaprepitant was not used in the prevention of acute nausea and vomiting, it is recommended that oral dexamethasone be used. A 5-HT3–receptor antagonist could be used as an alternative to dexamethasone.

Table 1. Treatment Recommendations for CINV Type of N/V

Recommended Therapy

Anticipatory N/V

• Psychological techniques • Alternative: benzodiazepines (alone or in combination with psychological techniques)

Acute-onset N/V with highly emetogenic chemotherapy Acute-onset N/V with moderately emetogenic chemotherapy

• 5-HT3–receptor antagonist, dexamethasone, and aprepitant or fosaprepitant • 5-HT3–receptor antagonist plus dexamethasone • 5-HT3–receptor antagonist, dexamethasone, and aprepitant or fosaprepitant if ≥2 moderate-risk chemotherapeutic agents

Acute-onset N/V with low emetogenic chemotherapy

• Single agent such as a dopamine antagonist or a low-dose corticosteroid

Acute-onset N/V with minimally emetogenic chemotherapy

• No routine use of antiemetics unless patient has a history of N/V

Delayed-onset N/V with highly emetogenic • Dexamethasone and aprepitant chemotherapy Delayed-onset N/V with moderately emetogenic chemotherapy

• Oral dexamethasone (plus aprepitant if used for acute) • Alternative: 5-HT3–receptor antagonist

CINV, chemotherapy-induced nausea and vomiting; 5-HT3, 5-hydroxytryptamine type 3 (serotonin type 3); N/V, nausea and vomiting

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Table 2. Treatment Recommendations for RINV Level of Radiation Emetogenicity

Recommended Therapy

Highly emetogenic

• 5-HT3–receptor antagonist plus dexamethasone

Moderately emetogenic irradiation of upper abdomen

• 5-HT3–receptor antagonist

Low emetogenic

• Rescue with a 5-HT3–receptor antagonist if patient experiences N/V • Prophylaxis with a 5-HT3–receptor antagonist before future radiation therapy

Minimally emetogenic

• Rescue with a dopamine antagonist or 5-HT3–receptor antagonist

5-HT3, 5-hydroxytryptamine type 3 (serotonin type 3); N/V, nausea and vomiting; RINV, radiation-induced nausea and vomiting

For patients treated with aprepitant or fosaprepitant, dexamethasone, and a 5-HT3–receptor antagonist for the prevention of acute nausea and vomiting, it is recommended that aprepitant or fosaprepitant with or without dexamethasone be given for delayed CINV. Additional therapy with lorazepam and/or an H2 antagonist or PPI may be considered.

MULTIDAY CHEMOTHERAPY To prevent delayed-onset CINV, the use of dexamethasone is recommended, however, aprepitant or fosaprepitant may be added if patients are considered at significant risk. The granisetron transdermal patch (Sancuso, ProStrakan) is approved for use in chemotherapy regimens of up to 5 days duration.

Prevention of RINV HIGHLY EMETOGENIC RADIATION THERAPY To prevent RINV in patients treated with highly emetogenic radiation therapy, the use of a 5-HT3– receptor antagonist combined with dexamethasone is recommended.

MODERATELY EMETOGENIC RADIATION THERAPY For patients treated with moderately emetogenic radiation therapy to the upper abdomen, a 5-HT3– receptor antagonist is recommended.

MILDLY EMETOGENIC RADIATION THERAPY If a patient experiences nausea and vomiting after mildly emetogenic radiation therapy, routine prophylaxis is not recommended, however rescue and subsequent prophylaxis with a 5-HT3–receptor antagonist is suggested.

MINIMALLY EMETOGENIC RADIATION THERAPY For patients who experience nausea and vomiting after minimally emetogenic radiation therapy, routine

prophylaxis is not recommended, but rescue and subsequent prophylaxis with a dopamine antagonist or a 5-HT3–receptor antagonist is considered standard of care.

Dosing of Antiemetic Agents The consensus is that there are no proven clinically relevant differences in the effectiveness of the available 5-HT3–receptor antagonists for preventing acute nausea and vomiting when they are given as recommended. The dosing guidelines for these agents are shown in Table 3. The recommended dosing of dexamethasone, aprepitant, and fosaprepitant is shown in Table 4. Because of a drug interaction, the dose of dexamethasone should be reduced by approximately 50% when it is used with aprepitant or fosaprepitant.5 Aprepitant and fosaprepitant are inhibitors of cytochrome P-450 (CYP) 3A4.5 They should not be used concurrently with agents that are metabolized

by CYP3A4 because this could cause elevated plasma concentrations of these drugs and potentially serious or life-threatening reactions. Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, etoposide, ifosfamide, imatinib (Gleevec, Novartis), irinotecan, paclitaxel, vinblastine, vincristine, and vinorelbine. Caution should be used when aprepitant or fosaprepitant is administered with these chemotherapy agents.5 Aprepitant and fosaprepitant also have been shown to partially inhibit cyclophosphamide bioactivation and thiotepa metabolism.

Coadministration of aprepitant or fosaprepitant with warfarin also may result in a clinically significant decrease in the international normalized ratio (INR).5 In patients receiving long-term warfarin therapy, the INR should be closely monitored in the 2-week period (particularly the first 7-10 days) following initiation of the 3-day regimen of aprepitant or fosaprepitant with each chemotherapy cycle.

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Individual Patient Risk Assessment • History of N/V • Age • Anxiety • History of motion sickness • Gender • Hydration status

Anticipatory N/V or high anxiety level

• Psychological techniques • ± Benzodiazepines

Chemotherapy

Single dose of 5-HT3 – receptor antagonist IV or PO + dexamethasone 10 mg IV + aprepitant 125 mg Highly emetogenic

Moderately emetogenic

Mildly emetogenic

Prophylactic prechemotherapy antiemetic regimen for acute-onset N/V

Minimally emetogenic

Single dose of 5-HT3 –receptor antagonist IV or PO + dexamethasone 8 mg IV + aprepitant 125 mg if ≥2 moderately emetogenic agents

Prophylactic postchemotherapy antiemetic regimen for chemotherapy associated with delayed-onset N/V

Dexamethasone 8 mg daily x 2-3 days + aprepitant 80 mg PO x 2 days if used for acute

Dexamethasone 4-8 mg IV

None recommended unless patient has a history of N/V

Dexamethasone 8 mg daily x 3-4 days + aprepitant 80 mg PO x 2 days

Treatment of breakthrough N/V

Adjunctive therapy: benzodiazepines, cannabinoids

Second-line therapy: use agent of different class (eg, phenothiazine or butyrophenone)

Figure. Treatment algorithm for chemotherapy-induced nausea and vomiting.

5-HT3, 5-hydroxytryptamine type 3 (serotonin type 3); N/V, nausea and vomiting

The coadministration of aprepitant or fosaprepitant may reduce the efficacy of hormonal contraceptives during and for 28 days after administration of the last dose of aprepitant or fosaprepitant.6,7 Alternative or backup methods of contraception should be used during treatment and for 1 month following the last dose of aprepitant or fosaprepitant.

Breakthrough Nausea and Vomiting When the primary antiemetic regimen fails to appropriately control nausea and vomiting, another agent with a different mechanism of action should be added.

Phenothiazines, substituted benzamides, and butyrophenones have antidopaminergic and anticholinergic properties and are often effective when a 5-HT3– receptor antagonist has failed. Most chemotherapy agents, except for carboplatin and cyclophosphamide, generally cause an early release of serotonin, which is why 5-HT3–receptor antagonists have the greatest

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efficacy against acute-onset nausea and vomiting.8 Dopaminergic pathways and substance P may be more involved in delayed-onset nausea and vomiting.

Although the butyrophenones are effective, the recent warning of QT prolongation and potential torsades de pointes with droperidol has required an electrocardiographic evaluation before its use.9 Standard doses of metoclopramide may be effective in combination but not alone.10 Thus, the phenothiazines often are used as primary agents for second-line therapy.

Also approved for use as second-line therapy are the cannabinoids dronabinol (Marinol, Solvay) and nabilone (Cesamet, Valeant). These agents have complex effects on the central nervous system (CNS), and it is thought that the antiemetic effect is caused by an interaction with the cannabinoid receptors (CB1), which are present throughout the central and peripheral nervous system. Both of these agents were studied in the 1980s, before the availability of the

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Table 3. Recommended Doses of 5-HT3–Receptor Antagonists for Acute Emesis Agent

Route

Dose

Dolasetron IV (Anzemet, Sanofi-Aventis/Organon) Oral

100 mg or 1.8 mg/kg

Granisetron

IV

1 mg or 0.01 mg/kg

Oral

2 mg (or 1 mga)

(Sancuso, ProStrakan)

Transdermal patch

52 cm2 containing 34.3 mg

Ondansetron

IV

8 mg or 0.15 mg/kg

Oral

16 mgb

IV

0.25 mg

Oral

0.5 mg

Palonosetron (Aloxi, MGI Pharma)

100 mg

a

The 1-mg dose is preferred by some panelists; it has been evaluated in a small randomized study of moderately emetogenic chemotherapy and in a Phase II study of highly emetogenic chemotherapy.

b

Randomized studies have tested an 8-mg twice-daily schedule.

5-HT3, 5-hydroxytryptamine type 3 (serotonin type 3)

5-HT3–receptor antagonists. In randomized trials, both cannabinoids were more effective than prochlorperazine. In one study, the combination of dronabinol and prochlorperazine was more effective than either agent alone.11 A meta-analysis also concluded that the cannabinoids were more effective than many conventional antiemetics, including prochlorperazine and metoclopramide.12 Adverse effects, particularly related to the CNS, occurred significantly more often with cannabinoids. Some were considered potentially beneficial (sedation and euphoria), whereas others were considered harmful (dizziness and dysphoria). Withdrawals resulting from adverse effects also were more common with cannabinoids. In contrast to dronabinol, nabilone has a longer duration of action, less frequent dosing, and an apparent lack of P450 enzyme inhibition, which may make it more convenient to use.13 Adjunctive therapy with benzodiazepines also may be considered, although these agents have never been proven to be effective as single agents. They may be more effective when used as adjunctive anxiolytic agents. Antihistamines also are generally ineffective as single agents, but may provide value in combination with other antiemetic agents, especially in patients

with a history of motion sickness.14 Some patients also may benefit from nonpharmacologic approaches such as relaxation techniques, biofeedback, acupressure, and music therapy.

New Directions In a Phase II trial, treatment with the atypical antipsychotic olanzapine (Zyprexa, Lilly) resulted in a 100% complete response rate (no emesis, no rescue) in the acute phase in 30 patients receiving cyclophosphamide, doxorubicin, and/or cisplatin.15 Olanzapine was begun 2 days before chemotherapy, was combined with granisetron and dexamethasone on day 1 of chemotherapy, and was added to dexamethasone on days 2 to 4 after chemotherapy. The complete response rate for the delayed period was 80%.

Although this was a small study, the high response rates are encouraging and may be the result of the olanzapine’s effects on multiple neurotransmitters, including dopamine at D1, D2, D3, and D4 brain receptors; serotonin at 5-HT2a, 5-HT2c, 5-HT3, and 5-HT6 receptors; catecholamines at α1-adrenergic receptors; acetylcholine at muscarinic receptors; and histamine at H1 receptors.15

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Table 4. Recommended Dosing of Dexamethasone, Aprepitant, And Fosaprepitant Dexamethasonea

Type of Emesis

Dosing and Schedule

High risk

Acute

20 mg once

Delayed

8 mg/d for 3-4 d

Acute

8 mg once

Delayed

8 mg/d for 2-3 db

Low risk

Acute

4-8 mg once

Aprepitant/Fosaprepitant

Type of Emesis

Dosing and Schedule

Acute

125 mg orally or IV, once

Delayed

80 mg/d orally, for 2 d

Moderate risk

a

Because of a drug interaction, the dose of dexamethasone should be reduced by 50% when it is given with aprepitant.

b

Many consensus panelists give the dosage as 4 mg twice daily.

Economics

Conclusion

When agents within a class have similar efficacy, as with the 5-HT3–receptor antagonists, part of the decision of which agent to use involves cost. In December 2006, generic ondansetron became available, substantially decreasing the cost of this agent. When evaluating cost to the health care system as well as the patient portion of payment for these agents, this generic option must be considered. However, this should not change decisions about when 5-HT3–receptor antagonists should be administered or the dose. Based on the pharmacology of this agent, it does not mean that a higher dose or more days would be appropriate just because of the reduced cost. It also does not mean that it is necessarily appropriate to use a 5-HT3–receptor antagonist in place of dexamethasone or dexamethasone plus aprepitant or fosaprepitant for delayed nausea and vomiting because there are few data evaluating the efficacy differences.

Studies that have evaluated 5-HT3–receptor antagonists alone in the delayed phase have not shown significant overall efficacy.

The recommendations in the major antiemetic consensus guidelines are very similar and are represented in this review of the prevention and treatment of CINV and RINV. Because of individual variations in response, neurotransmitter release, and drug metabolism, the efficacy of a certain antiemetic may be decreased, or its toxicity increased. These guidelines should be considered general recommendations, but one must remember that treatment should always be individualized, especially when nausea and vomiting have not been completely controlled. The 5-HT3– receptor antagonists plus dexamethasone have significantly improved the control of acute nausea and vomiting. The control of delayed nausea and vomiting continues to be more difficult. Recent studies have shown that aprepitant or fosaprepitant may improve results with several types of chemotherapy regimens.

However, there is still much work to be done to continue to improve outcomes for many patients receiving chemotherapy or radiation therapy.

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References

Suggested Readings

1.

Chawla SP, Grunberg SM, Gralla RJ, et al. Establishing the dose of the oral NK1 antagonist aprepitant or fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting. Cancer.

2003;97(9):2290-2300.

Kris MG, Hesketh PJ, Somerfield MR, et al. American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol. 2006;24(18):2932-2947, PMID: 167117289.

2. ESMO Guidelines Working Group, Herrstedt J. Chemotherapyinduced nausea and vomiting: ESMO clinical recommendations for prophylaxis. Ann Oncol. 2007;18(suppl 2):ii83-ii85, PMID: 17491061.

3. Roila F, Hesketh PJ, Herrstedt J, et al. Prevention of chemotherapy- and radiotherapy-induced emesis: results of the 2004 Perugia International Antiemetic Consensus Conference. Ann Oncol.

2006;17(1):20-28. Recommendation and slides updated March 2008: http://www.mascc.org. Accessed April 23, 2009.

4. Ettinger DS, Bierman PJ, Bradbury B, et al. Antiemesis. J Natl Compr Canc Netw. 2007;5(1):12-33, PMID: 17239323.

5. Shadle CR, Lee Y, Majumdar AK, et al. Evaluation of potential inductive effects of aprepitant on cytochrome P450 3A4 and 2C9 activity. J Clin Pharmacol. 2004;44(3):215-223, PMID: 14973304.

6. Emend (aprepitant) [prescribing information]. Whitehouse Station, NJ: Merck & Company; April 2008.

7. Emend (fosaprepitant dimeglumine) [prescribing information].

Whitehouse Station, NJ: Merck & Company; February 2009.

8. Minami M, Endo T, Hirafuji M, et al. Pharmacological aspects of anticancer drug-induced emesis with emphasis on serotonin release and vagal nerve activity. Pharmacol Ther. 2003;99(2): 149-165, PMID: 12888110.

9. Keefe DL. The cardiotoxic potential of the 5-HT(3) receptor antagonist antiemetics: is there cause for concern? Oncologist.

2002;7(1):65-72, PMID: 11854548.

10. Gralla RJ. Metoclopramide. A review of antiemetic trials. Drugs.

1983;25(suppl 1):63-73, PMID: 6682376.

11. Slatkin NE. Cannabinoids in the treatment of chemotherapyinduced nausea and vomiting: beyond prevention of acute emesis.

J Support Oncol. 2007;5(5 suppl 3):1-9, PMID: 17566383.

12. Tramer MR, Carroll D, Campbell FA, et al. Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. BMJ. 2001;323(7303):16-21, PMID: 11440936.

13. Ware MA, Daeninck P, Maida V. A review of nabilone in the treatment of chemotherapy-induced nausea and vomiting. Ther Clin Risk Manag. 2008:4(1):99-107, PMID: 18728826.

14. Morrow GR. Susceptibility to motion sickness and the development of anticipatory nausea and vomiting in cancer patients undergoing chemotherapy. Cancer Treat Rep. 1984;68(9):11771178, PMID: 6332674.

15. Navari RM, Einhorn LH, Loehrer PJ Sr. A phase II trial of olanzapine, dexamethasone, and palonosetron for the prevention of chemotherapy-induced nausea and vomiting: a Hoosier oncology group study. Support Care Ca. 2007;15(11):1285-1291, 17375339.

Dando TM, Perry CM. Aprepitant or fosaprepitant : a review of its use in the prevention of chemotherapy-induced nausea and vomiting.

Drugs. 2004;64(7):777-794.

De Wit R, Herrstedt J, Rapoport B, et al. Addition of the oral NK1 antagonist aprepitant or fosaprepitant to standard antiemetics provides protection against nausea and vomiting during multiple cycles of cisplatin-based chemotherapy. J Clin Oncol. 2003;21(22):4105-4111.

Eisenberg P, Figueroa-Vadillo J, Zamora R, et al; 99-04 Palonosetron Study Group. Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a Phase III, single-dose trial versus dolasetron. Cancer. 2003;98(11):2473-2482.

Grunberg SM. Antiemetic activity of corticosteroids in patients receiving cancer chemotherapy: dosing, efficacy, and tolerability analysis. Ann Oncol. 2007;18(2):233-240.

Hesketh PJ, Grunberg SM, Gralla RJ, et al. The oral neurokinin-1 antagonist aprepitant or fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatinâ&#x20AC;&#x201D;the Aprepitant or fosaprepitant Protocol 052 Study Group.

J Clin Oncol. 2003;21(22):4112-4119.

Ioannidis JP, Hesketh PJ, Lau J. Contribution of dexamethasone to control of chemotherapy-induced nausea and vomiting: a meta-analysis of randomized evidence. J Clin Oncol. 2000;18(19):3409-3422.

Martin CG, Rubenstein EB, Elting LS, Kim YJ, Osoba D. Measuring chemotherapy-induced nausea and emesis. Cancer. 2003;98:645-655.

McCrea JB, Majumdar AK, Goldberg MR, et al. Effects of the neurokinin-1 receptor antagonist aprepitant or fosaprepitant on the pharmacokinetics of dexamethasone and methylprednisolone. Clin Pharmacol Ther. 2003;74(1):17-24.

Mertens WC, Higby DJ, Brown D, et al. Improving the care of patients with regard to chemotherapy-induced nausea and emesis: the effect of feedback to clinicians on adherence to antiemetic prescribing guidelines. J Clin Oncol. 2003;21(7):1373-1378.

Navari RM. Role of neurokinin-1 receptor antagonists in chemotherapy-induced emesis: summary of clinical trials. Cancer Invest.

2004;22(4):569-576.

Schnell FM. Chemotherapy-induced nausea and vomiting: the importance of acute antiemetic control. Oncologist. 2003;8(2):187-198.

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Intrathecal Therapy For the Management of Cancer Pain OSCAR DE LEON-CASASOLA, MD Professor and Vice-chair for Clinical Affairs Department of Anesthesiology University at Buffalo School of Medicine and Biomedical Sciences Chief, Pain Medicine and Professor of Oncology Roswell Park Cancer Institute Buffalo, New York

C

ancer pain results from the growth of cancer in human tissues, as well as the therapies implemented to treat a malignancy. Adequate pain control can be achieved in the great majority of patients by implementing an aggressive pharmacologic treatment strategy using opioids and adjuvants.1,2 The implementation of such a strategy may achieve adequate pain control in 90% to 95% of patients.3 Consequently, 5% to 10% of patients will require some form of invasive therapy.

When specific guidelines are followed, the great majority of patients with cancer-related pain can expect adequate pain control. Control of pain and its related symptoms is a cornerstone of cancer treatment because it enhances quality of life by improving function and promoting compliance with treatment. Control of pain allows patients to focus on the joys of life.4 In addition to its salutary effects on quality of life, mounting evidence suggests that good pain control may positively influence survival.5,6 To implement optimal analgesic therapy, a thorough history and physical examination are essential, as is the judicious use of diagnostic testing to try to define the pathophysiologic components involved in the expression of pain. Intrathecal (IT) opioids are very effective for the treatment of somatic and visceral pain, but IT bupivacaine and/or clonidine is necessary for the treatment of neuropathic pain. Thus, a definition of the specific pathophysiologic components of a patient’s pain is critical for successful management of it.

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CLINICAL ONCOLOGY NEWS SPECIAL EDITION 2009 • NO. 1

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Intraspinal Analgesia Neuraxial analgesia is achieved by the epidural or IT administration of an opioid alone—very rarely—or in combination with another agent, such as bupivacaine, clonidine, or ziconotide (Prialt, Elan). When neuraxial analgesia is used, pain relief is obtained in a highly selective fashion, without motor and sympathetic blockade, so these modalities are highly adaptable to the home care environment.

When it was first introduced, the rationale behind neuraxial opioid therapy was that administration of small quantities of opioids in close proximity to their receptors in the substantia gelatinosa of the spinal cord would achieve high concentrations at these sites.7,8 As a result, this type of analgesia would be superior to that obtained with opioids administered by other routes because the total amount of drug is reduced and side effects are minimized. The biggest advantage of neuraxial analgesia is the ability to use multiple agents to target multiple receptors, resulting in better control of neuropathic, somatic, and visceral pain while minimizing side effects.

In general, patients with expected survival longer than 3 months are candidates for IT therapy with a permanent intraspinal catheter and an implanted subcutaneous pump. Those with expected survival less than 3 months require epidural therapy with an implanted system, such as the DuPen (Bard Access Systems) epidural catheter or the Port-a-Cath (Smiths Medical), which are connected to an external pump and allow for patient-controlled analgesia.9

Clinical Studies A multicenter prospective randomized clinical trial (RCT) compared IT therapy with comprehensive medical management after 1 month in 202 patients with refractory pain due to cancer.10 The primary outcome measure was a 20% improvement in analgesia, as measured on a visual analog scale (VAS) of 0 to 10. Additionally, changes in side effects based on the National Cancer Institute common toxicity criteria were monitored. Patients in the IT group showed a slight trend toward better analgesia, but the difference did not achieve statistical significance. However, a statistically significant improvement in the side-effect profile of patients randomized to the IT group was observed.

The 2 side effects that were most noticeably less severe with IT therapy were constipation and impaired consciousness. After 6 months, a trend toward increased survival was also noted in the IT group (54% vs 37%).

Although the total number of patients alive at the end of the analysis was small, approximately 25% more patients randomized to the IT group had survived.

A prospective longitudinal analysis of 30 crossover patients who received IT therapy found significant decreases in pain scores and drug toxicity (27% and 51%, respectively).11 Median survival was 103 days after crossover to an implantable drug delivery system, which was similar to that of patients in the RCT.

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The implementation of IT therapy is initially expensive because of the cost of equipment. In contrast, the cost of implementing long-term epidural therapy is low.

Two studies compared the cost of implementing therapy with these 2 modalities and showed a “break-even” point at approximately 3 months.12,13 Epidural therapy, therefore, becomes more expensive than IT therapy after 3 months, one reason to limit it to use in patients whose survival is anticipated to be shorter.

Clinical Guidelines A consensus panel recently published updated recommendations for the use of IT medications in patients with chronic noncancer pain.14 Although the consensus conclusions are limited to the noncancer population, 4 issues are important to discuss in this review: 1. equianalgesic doses of hydromorphone; 2. maximum doses of hydromorphone; 3. spinal cord lesions associated with bupivacaine; and 4. ziconotide as a first-line agent.

EQUIANALGESIC DOSES

OF

HYDROMORPHONE

The consensus authors concluded IT morphine and IT hydromorphone “in a dose 20% of that of morphine, induce an equianalgesic response.” However, they based this, in part, on a study in which the researchers administered hydromorphone at “a dose equivalent to the minimum intrathecal morphine dose shown to produce inflammatory masses in our sheep model (12 mg/d).”15 The researchers state that the morphine-to-hydromorphone conversion rate is 5:1 to 6:1 and that “no masses were observed at hydromorphone doses (3 and 6 mg/d) that were equianalgesic to morphine doses (18 and 36 mg/d, respectively).”15 Although this is the conversion rate that we have used in our clinical practice, its validity has not been confirmed.

MAXIMUM DOSES

OF

HYDROMORPHONE

The consensus panel recommends a maximum hydromorphone concentration of 10 mg/cm3 and a maximum dose of 4 mg per day for IT use to prevent granuloma formation. No reference supports this recommendation, however, and the panelists acknowledge that “physicians are advised to titrate doses of these 2 opioids (morphine and hydromorphone) not beyond an a priori upper limit that has been determined from clinical practice.”14 To date, we have treated approximately 60 patients with IT hydromorphone in combination with bupivacaine and/or clonidine at concentrations and doses well beyond those recommended by the panel, without any cases of granuloma. We use yearly magnetic resonance imaging to facilitate early diagnosis of this condition. We also ask patients at their monthly refill visits about symptoms that may be associated with the development of granulomas.

SPINAL CORD LESIONS ASSOCIATED WITH BUPIVACAINE The consensus document states that “transient neurologic syndrome (TNS), defined as radicular irritation

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after spinal anesthesia with local anesthetics, is hypothesized to fall on the lower end of a spectrum of toxic effects caused by local anesthetics.”14 However, no report on TNS after bupivacaine spinal anesthesia exists in the medical literature, although the complication has been associated with the use of lidocaine and mepivacaine.16 Additionally, the guidelines suggest that the combination of bupivacaine and clonidine can result in spinal cord lesions. This is based on a case report cited in a footnote to the guidelines.17 It is important to recognize that in the case in question, the neurologic deficit appeared 2 years after therapy with bupivacaine and clonidine at doses of 20 mg and 200 mcg per day, respectively. It is unclear if the spinal cord changes were related to neurotoxic effects of the drug, particularly because the rate of administration was 0.5 mL per hour and the edema in the spinal cord extended from the conus medullaris to the T5 level. The spread in cerebrospinal fluid of IT solutions administered at a rate of 0.5 mL per hour has been shown to be limited both in animal models and in humans.18,19 Thus, it is difficult to understand how the edema in the patient’s spinal cord was so extensive. Also, the tip of the catheter had migrated from the T12 to the T10 level, where the lesion was found, raising the possibility that the catheter migration could have resulted from injury to the spinal cord.

ZICONOTIDE

AS A

FIRST-LINE AGENT

The last polyanalgesic consensus recommended the use of ziconotide for patients in chronic pain when all other options had been exhausted.20 At that time, the drug had not been approved by the FDA, and only one RCT was available, by Staats et al.21 There are 2 issues with the study by Staats et al. First, patients were treated without a clear description of the source of nociception (somatic, visceral, or neuropathic), which could be a problem in the absence of targeted therapies. Second, the 2-week follow-up might result in other problems. Ziconotide requires a significant titration window to reach a therapeutic effect, and this is not normally achieved within a 2-week period. Thus, it is possible that the investigators were evaluating a placebo effect at that time. The therapeutic responses beyond that time might have decreased, and the success rate might have been lower if the follow-up had been longer. Consequently, the results of this study do not clearly support the use of ziconotide as a first-line agent.

In contrast, the panelists of the new recommendations have upgraded ziconotide to a first-line agent, at the same level as morphine and hydromorphone.14 The question is whether enough new data on therapeutic efficacy and safety are available to support that recommendation.14 The consensus supporting ziconotide as a first-line agent is based largely on 2 RCTs. In the first trial, 169 patients were randomized to ziconotide and 86 to placebo for the treatment of severe, chronic noncancer pain over a 6-day period in an inpatient hospital setting.22 Doses were started at 2.4 mcg per day and

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titrated up to 57.6 mcg per day. The mean percentage reduction in pain scores from baseline was 31% for the ziconotide group and 6% for the placebo group. This difference was statistically significant. Moreover, a significantly greater percentage of patients treated with ziconotide (34%) than of those given placebo (13%) responded to treatment (P<0.001). Despite this significant reduction in pain, however, of the 169 patients initially treated with ziconotide, 54 (32%) were considered responders and were eligible for 5 days of treatment as outpatients. A response to treatment was defined as a 30% or greater reduction in pain scale scores from baseline, stable or decreased concomitant opioid analgesic use, and no changes in type of opioid used during the study period.

The incidence of side effects was high during the titration period, with 95% of the patients treated with ziconotide experiencing at least 1 adverse event (AE), compared with 72% in the placebo group (P=0.001).

These side effects included abnormal gait, amblyopia, dizziness, nausea, and nystagmus.

The second trial randomized 112 patients to receive ziconotide, started at 2.4 mcg per day and titrated to a mean dose of 6.96 mcg per day over 3 weeks, and 112 patients to placebo.23 The mean percentage reduction in pain in the ziconotide group was 15% versus 7% in the placebo group (P=0.0336). This difference, although statistically significant, was not clinically meaningful. Moreover, the planned sample size of 110 patients in each group provided 80% power to detect an intergroup difference of at least 15 points in the mean percentage change as measured with the VAS. Because the intergroup difference was 8%, the results of the study are underpowered. Additionally, 60% of the patients rated their pain control as poor or fair, and 49% of those in the ziconotide group reported no or little satisfaction with the treatment. The incidence of side effects in the treatment group also was high in this study.

Since the publication of the guidelines, 3 other studies addressing the use of ziconotide in severe, chronic noncancer pain have been published.24-26 In the first study, 644 patients with severe, chronic pain were treated with ziconotide in an open-label, multicenter trial.24 Median duration of therapy was 2 months, with a range of 1 to 1,215 days; 119 patients were treated for at least 1 year. The mean dose was 8.4 mcg per day (range, 0.048-240 mcg/d). Pain scores decreased from 76 to 68 mm after 1 month of therapy and to 73 mm after 2 months of therapy. Virtually all patients experienced AEs (99.7%), of which 43.5% were mild, 42.3% moderate, and 14.2% severe. Half of those AEs were considered unrelated to therapy. The authors concluded that “longterm intrathecal ziconotide is an option for patients with severe, refractory pain.” However, the high incidence of side effects and the clinically insignificant reduction in pain do not support therapeutic efficacy under the present protocol design.

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receiving a stable dose of IT morphine.25 The mean percentage improvement in pain scores on the VAS was 14.5% (95% confidence interval, –9% to 38%) from baseline to week 5. The mean percentage decrease in oral opioid doses from baseline was 14%. The investigators concluded that the concomitant administration of IT ziconotide and morphine may reduce pain and decrease systemic opioid use in patients receiving treatment with IT morphine alone.25 Again, however, both the mean decrease in pain intensity and the reduction in systemic opioid use are clinically insignificant.

The third study generated similarly ambiguous findings.

Taken together, these 3 trials suggest that concomitantly administering ziconotide and morphine does not lead to clinically significant improvement for patients.

Moreover, evidence indicates that ziconotide loses stability when administered with either morphine or hydromorphone.14 Thus, the usefulness of administering ziconotide with morphine is not clear.

Conclusion The implementation of aggressive analgesic protocols is important in patients with cancer, independently of the stage of their disease, and it is a special priority in patients with advanced disease who are no longer candidates for potentially curative therapy.

Although rarely eliminated, pain can be controlled in the vast majority of patients with the implementation of aggressive comprehensive medical management and/or invasive techniques. In the small but significant proportion of patients whose pain is not readily controlled with pharmacologic therapy, IT therapy with multiple agents is associated with a high degree of success in well-selected patients. To this end, it is very reassuring to be able to conclude that at this point, we have the appropriate tools to adequately treat cancer-related pain in nearly every patient.

References 1.

American Pain Society. Principles of Analgesic Use in the Treatment of Acute Pain and Chronic Cancer Pain. 3rd ed. Skokie, IL: American Pain Society; 1992.

2. Jacox A, Carr DB, Payne R, et al. Management of Cancer Pain: Clinical Practice Guideline 9. Rockville, MD: Agency for Health Care Policy and Research; 1994. Research publication 94-0592.

3. Zech DF, Grond S, Lynch J, Hertel D, Lehmann KA. Validation of World Health Organization guidelines for cancer pain relief: a 10-year prospective study. Pain. 1995;63(1):65-76, PMID: 8577492.

4. Ferrell BR, Wisdom C, Wenzl C. Quality of life as an outcome variable in management of cancer pain. Cancer. 1989; 63(11 suppl):2321-2327, PMID: 2720579.

5. Liebeskind JC. Pain can kill. Pain. 1991;44(1):3-4, PMID: 2038486.

6. Lillemoe KD, Cameron JL, Kaufman HS, Yeo CJ, Pitt HA, Sauter PK. Chemical splanchnicectomy in patients with unresectable pancreatic cancer. A prospective randomized trial. Ann Surg.

1993;217(5):447-457, PMID: 7683868.

7. Cousins MJ, Mather LE. Intrathecal and epidural administration of opioids. Anesthesiology. 1984;61(3):276-310, PMID: 6206753.

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8. Yaksh TL. Spinal opiates: a review of their effect on spinal function with an emphasis on pain processing. Acta Anaesthesiol Scand Suppl. 1987;85:25-37, PMID: 2821725.

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