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

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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

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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

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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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CLINICAL ONCOLOGY NEWS SPECIAL EDITION 2009 • NO. 1

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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%)

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)

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%)

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%)

(3%)

23 (5%) 30 (7%)

9 8

(2%) (2%)

19 (4%) 23 (5%)

(3%)

21 (5%)

(1%)

16 (4%)

2 (0.5%)

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

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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

10.3 12.3 months months vs

Chemotherapy*

Avastin + chemotherapy*

19%

MCRC

15.6 20.3 months months

10.8 13.0 months months

Chemotherapy*

Avastin + chemotherapy*

Chemotherapy*

30%

Avastin + chemotherapy*

20%

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.

9151100

Printed in USA.

www.avastin.com

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TABLE of CONTENTS

Are you receiving Clinical Oncology News Digital Exclusive? To receive Clinical Oncology News 12 times per year, please sign up to receive our Digital Edition. Clinical Oncology News will come out in print six times a year and Clinical Oncology News Digital Exclusive will be published the other six months. The print version will also be available in digital format, as Clinical Oncology 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 page. We hope you enjoy it.

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

Hematologic Disease

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

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

Myelodysplastic Syndromes: Pharmacologic Agents That Extend Overall Survival

Supportive Care

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

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

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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

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

DERMATOLOGIC Hand & foot syndrome Cutaneous signs d

0 2

0 0

0 1

5 3

RESPIRATORY e

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

CARDIOVASCULAR g

OTHER h

a b c d e f g h

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

120

�

120

�

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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PRINTER-FRIENDLY VERSION AT CLINICALONCOLOGY.COM

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

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

Treatment

Response Rate, %

Median Time to Progression, mo

Overall Survival, mo

Hoff et al7

605

Capecitabinea

25.8

4.3

12.5

5-FU/LV (Mayo Clinic) 11.6

4.7

13.3

5.2

13.2

4.7

12.1

Van Cutsem et al

602

Capecitabine

18.9

5-FU/LV (Mayo Clinic) 15 a

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

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

Febrile neutropenia

CapOx23

IROX21

FOLFIRI22

FOLFIRI11

Diarrhea

13.6

Vomiting

2.4

Mucositis

Paresthesias

CapIri23,a

CapIri11,b

mIFL11

30.7

3.6

13.9

12.7

47.5

8.8

3.8

15.6

7.3

6.2

1.3

MI/stroke

60-Day mortality

3.6

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

10.7

11.9

Dehydration

5.4

1.7

Neutropenia

53.6

28.8

Neurotoxicity

Hypertension

12.5

1.7

MI/stroke

60-Day mortality

1.8

6.8

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.

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

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

Response Rate, %

Progression-Free Survival

Wt KRAS

Mt KRAS

Wt KRAS

Mt KRAS

61 d

59 d

Khambata-Ford et al

Cetuximab

80 (62.5:37.5)

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

32 wk

9 wk

Amado et al59

Panitumumab vs BSC

208 (59.6:40.4)

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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35. Mendelson J. Targeting the epidermal growth factor receptor for cancer therapy. J Clin Oncol. 2002;20(18 suppl):1s-13s, PMID: 12235219. 36. 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(18 suppl):abstract 4000. 37. Bokemeyer C, Bondarenko I, Makhson A, et al. Cetuximab plus 5-FU/FA/oxaliplatin (FOLFOX-4) versus FOLFOX-4 in the firstline treatment of metastatic colorectal cancer (mCRC): OPUS, a randomized phase II study. J Clin Oncol. 2007;25(18 suppl): abstract 4035. 38. Hecht JR, Mitchell E, Chidiac T, et al. An updated analysis of safety and efficacy of oxaliplatin (Ox)/bevacizumab (bev) +/panitumumab (pmab) for first-line treatment (tx) of metastatic colorectal cancer (mCRC): results from a randomized, controlled trial (PACCE). Presented at: ASCO Gastrointestinal Cancers Symposium; January 25-27, 2008; Orlando, FL. Abstract 273. 39. Hecht JR, Mitchell T, Chidiac T, et al. Interim results from PACCE: irinotecan (Iri)/bevacizumab (bev) +/- panitumumab (pmab) as first-line treatment (tx) for metastatic colorectal cancer (mCRC). Presented at: ASCO Gastrointestinal Cancers Symposium. January 25-27, 2008, Orlando, FL. Abstract 279. 40. Tols J, Koopman M, Cats A, et al. Chemotherapy, bevacizumab and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009;360(6):563-572, PMID: 191966731. 41. Seymour MT, for the UK NCRI Colorectal Clinical Studies Group. Fluorouracil, oxaliplatin, and CPT-11 (irinotecan) use and sequencing (MRC FOCUS): a 2,135-patient randomized trial in advanced colorectal cancer (ACRC). J Clin Oncol. 2005;23(18 suppl):abstract 3518. 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. 2007;25(18 suppl):abstract 4012. 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

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

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

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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)

27.4

24 wk

12 wk

44 wk

36 wk

P+I

109 (41)

114 (27)

P value

40 P<0.001

24 wk

P<0.0001 12 wk

P=0.074 19

NR C±I

P<0.0001

P value Lievre19

PFS/TTP

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

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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

FOLFIRI

8.7 mo

8.1 mo

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

12.3 wk

7.4 wk

8.1

4.9

BSC

7.3 wk

7.6

4.4

P<0.0001

C+BSC

12.8

1.2

3.7 mo

1.8 mo

9.5

4.5

BSC

1.9 mo

1.8 mo

4.8

4.6

P<0.001

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.

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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.