Clinical Oncology News - May 2011 - Digital Edition by McMahon Group

Independent News for the Oncologist and Hematologist/Oncologist clinicaloncology.com • May 2011 • Vol. 6, No. 5

CLINICAL TRIALS

M aurie Markman, MD, discusses the future of the Clinical Trials Cooperative Group Program.

SOLID TUMORS

6 9

Medicare Patients Receive Subpar Care For Ovarian Cancer

G enentech builds case for FDA hearing on Avastin. P ET response is prognostic indicator in esophagogastric cancer. SUPPORTIVE CARE

R eport helps doctors counsel cancer survivors.

reatment for ovarian cancer fell short of current standards more than 60% of the time in an analysis of 8,200 Medicare patients. Most patients had primary surgery, but roughly 25% received no chemotherapy. Of those who had surgery and chemotherapy, almost 50% did not receive the recommended six cycles of therapy. In patients receiving primary chemotherapy, three-fourths did not complete six cycles and two-thirds did not go on to have surgery. In 17% of cases, older patients with ovarian cancer had no primary therapy. These findings come from a study presented at the annual meeting of the Society of Gynecologic Oncologists (abstract 2). see MEDICARE, page 20 

PRN

A Q&A with new ACCC president Thomas Whittaker, MD.

HematOlogic DISEASE

24 25

New standard of care proposed for young MCL patients.

V TD beats VT regimen in multiple myeloma.

Tasigna® (nilotinib) as CML Therapy Following Resistance to Gleevec® (imatinib mesylate): A Case Discussion

See page 10

WWW.CMEZONE.COM

GUEST EDITORIAL

Vogl, New York …

Open Letter to David Koch: How to Spend on Prostate Research Dear Mr. Koch: I read with interest the article in the March 4, 2010, issue of The New York Times about your 19-year struggle with prostate cancer and your donations Steven Vogl, MD to cancer research. I suggest you focus your giving on a largely neglected issue that could markedly enhance the quality of life for large numbers of men with prostate cancer. It occurs to me that your contributions, large though they are, constitute only a tiny fraction of the amount see FUTURE, page 16 

BATTLE: A New Dawn for Personalized NSCLC Therapy Orlando, Fla.—Researchers have completed and published EGFR the first trial in non-small cell lung cancer to prospectively biopsy patients, and based on KRAS/BRAF tumor markers, use an adaptive randomization to select one of four drug therapies. VEGF/VEGFR-2 Researchers say the trial, called BATTLE, opens up the field for personalizing therapy for lung RXRs/Cyclin D1 cancer. Adjuvant therapy and even preventive lung cancer care could be impacted. In the study, led by Edward CCND1 S. Kim, chief of the Section of Head and Neck Medical Oncology and associate professor at A lung biopsy guided by computed tomography the University of Texas MD Anderson Cancer Center, in Houston, This represented a 50% improvement patients with chemorefractory non-small over observed results in historical patient cell lung cancer (NSCLC) had a 46% over- cohorts. The study was published in see BATTLE, page 28  all disease control at eight weeks (Figure).

POLICY & MANAGEMENT

ACOs: The Promise and the Peril Found Money: Part 3 of a Four-Part Series

n late March, the Centers for Medicare & Medicaid Services (CMS) unveiled its long-awaited proposed rule governing accountable care organizations (ACOs), a model that federal health officials hope will improve the quality of care given to Medicare patients while helping to lower costs.

Reimbursement Benefits Under the proposal, ACOs would have

to meet quality standards in certain key areas, including care coordination, patient–caregiver care experiences, patient safety, preventive health and care for at-risk populations such as the frail elderly. ACO participants would share the savings generated by reducing adverse events and avoiding costly hospitalizations and emergency room visits. The CMS would determine the amount see FOUND MONEY, page 26 

FDA News Yervoy approved for melanoma.

Zytiga approved for prostate cancer.

See page 8.

In Advanced Renal Cell Carcinoma...

Indication VOTRIENT is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

Important Safety Information WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical studies. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See “Warnings and Precautions,” Section 5.1, in complete Prescribing Information. Hepatic Effects: Patients with pre-existing hepatic impairment should use VOTRIENT with caution. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. Increases in serum transaminase levels (ALT, AST) and bilirubin were observed. Severe and fatal hepatotoxicity has occurred. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the ﬁrst 18 weeks). Before the initiation of treatment and regularly during treatment, monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. QT Prolongation and Torsades de Pointes: Prolonged QT intervals and arrhythmias, including torsades de pointes, have been observed with VOTRIENT. Use with caution in patients at higher risk of developing QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval,

and those with relevant pre-existing cardiac disease. Baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes within the normal range should be performed. Hemorrhagic Events: Fatal hemorrhagic events have been reported (all grades [16%] and Grades 3 to 5 [2%]). VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. Arterial Thrombotic Events: Arterial thrombotic events have been observed and can be fatal. In clinical RCC studies of VOTRIENT, myocardial infarction, angina, ischemic stroke, and transient ischemic attack (all grades [3%] and Grades 3 to 5 [2%]) were observed. Use with caution in patients who are at increased risk for these events. Gastrointestinal Perforation and Fistula: Gastrointestinal perforation or fistula has occurred. Fatal perforation events have occurred. Use with caution in patients at risk for gastrointestinal perforation or fistula. Monitor for symptoms of gastrointestinal perforation or fistula. Hypertension: Hypertension has been observed. Hypertension was observed in 47% of patients with RCC treated with VOTRIENT. Hypertension occurs early in the course of treatment (88% occurred in the first 18 weeks). Blood pressure should be well-controlled prior to initiating VOTRIENT. Monitor for hypertension and treat as needed. If hypertension persists despite antihypertensive therapy, the dose of VOTRIENT may be reduced or discontinued as appropriate.

Move Forward With VOTRIENT In a phase 3, randomized, double-blind, placebo-controlled trial, VOTRIENT provided signiﬁcant improvement in progression-free survival (PFS) in both treatment-naïve and cytokine-pretreated patients with advanced RCC1,2

All patients

Treatment-naïve patients

Cytokine-pretreated patients

11.1 months (95% CI, 7.4-14.8)

7.4 months (95% CI, 5.6-12.9)

overall median PFS with VOTRIENT (n=290) vs 4.2 months (95% CI, 2.8-4.2) with placebo (n=145) (P<0.001) 2,3

median PFS with VOTRIENT (n=155) vs 2.8 months (95% CI, 1.9-5.6) with placebo (n=78) (P<0.001) 2,3

median PFS with VOTRIENT (n=135) vs 4.2 months (95% CI, 2.8-5.6) with placebo (n=67) (P<0.001) 2,3

9.2 months (95% CI, 7.4-12.9)

NCCN Guidelines Category 1 recommendation4 • First-line therapy for relapsed or Stage IV unresectable RCC of predominant clear cell histology

Proven safety proﬁle1,2 • Most common adverse events observed with VOTRIENT (>20%) were diarrhea, hypertension, hair color changes (depigmentation), nausea, anorexia, and vomiting — Grade 3/4 fatigue occurred in 2% of patients; all grades, 19% — Grade 3/4 asthenia occurred in 3% of patients; all grades, 14%

Most common laboratory abnormalities were ALT and AST increases1 • Grade 3 ALT increases occurred in 10% of patients; grade 4, 2% • In clinical trials, 92.5% of all transaminase elevations of any grade occurred in the ﬁrst 18 weeks of treatment with VOTRIENT • Monitor serum liver tests before initiation of treatment with VOTRIENT and at least once every 4 weeks for at least the ﬁrst 4 months of treatment or as clinically indicated. Periodic monitoring should then continue after this time period

Once-daily oral dosing1 • The recommended dosage of VOTRIENT is 800 mg once daily without food (at least 1 hour before or 2 hours after a meal) • Dose modiﬁcations, interruptions, and discontinuations may be required in patients with hepatic impairment, drug interactions, and following adverse events • Forty-two percent of patients on VOTRIENT required a dose interruption; 36% of patients on VOTRIENT were dose-reduced VOTRIENT is a multitargeted tyrosine kinase inhibitor that is indicated for the treatment of patients with advanced RCC.

Wound Healing: VOTRIENT may impair wound healing. Temporary interruption of therapy with VOTRIENT is recommended in patients undergoing surgical procedures. VOTRIENT should be discontinued in patients with wound dehiscence. Hypothyroidism: Hypothyroidism was reported as an adverse reaction in 26/586 (4%). Monitoring of thyroid function tests is recommended. Proteinuria: Monitor urine protein. Proteinuria was reported in 44/586 (8%) (Grade 3, 5/586 [<1%] and Grade 4, 1/586 [<1%]). Baseline and periodic urinalysis during treatment is recommended. Discontinue for Grade 4 proteinuria. Pregnancy Category D: VOTRIENT can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while taking VOTRIENT. Drug Interactions: CYP3A4 Inhibitors (eg, ketoconazole, ritonavir, clarithromycin): Avoid use of strong inhibitors. Consider dose reduction of VOTRIENT when administered with strong CYP3A4 inhibitors. CYP3A4 Inducers (such as rifampin): Consider an alternate concomitant medication with no or minimal enzyme induction potential or avoid VOTRIENT. CYP Substrates: Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended.

Adverse Reactions: The most common adverse reactions (>20%) for VOTRIENT versus placebo were diarrhea (52% vs. 9%), hypertension (40% vs. 10%), hair color changes (depigmentation) (38% vs. 3%), nausea (26% vs. 9%), anorexia (22% vs. 10%), and vomiting (21% vs. 8%). Laboratory abnormalities occurring in >10% of patients and more commonly (*5%) in the VOTRIENT arm versus placebo included increases in ALT (53% vs. 22%), AST (53% vs. 19%), glucose (41% vs. 33%), and total bilirubin (36% vs. 10%); decreases in phosphorus (34% vs. 11%), sodium (31% vs. 24%), magnesium (26% vs. 14%), and glucose (17% vs. 3%); leukopenia (37% vs. 6%), neutropenia (34% vs. 6%), thrombocytopenia (32% vs. 5%), and lymphocytopenia (31% vs. 24%). VOTRIENT has been associated with cardiac dysfunction (such as a decrease in ejection fraction and congestive heart failure) in patients with various cancer types, including RCC. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 4/586 patients (<1%). Please see Brief Summary of Prescribing Information on adjacent pages. References: 1. VOTRIENT Prescribing Information. Research Triangle Park, NC: GlaxoSmithKline; 2010. 2. Sternberg CN, et al. J Clin Oncol. 2010;28(6):1061–1068. 3. Data on ﬁle, GlaxoSmithKline. 4. Referenced with permission from ©National Comprehensive Cancer Network, Inc 2010. All Rights Reserved. NCCN Guidelines™: Kidney Cancer, V.1.2011. NCCN. org Accessed January 12, 2011. NCCN® and NCCN GUIDELINES™ are trademarks owned by the National Comprehensive Cancer Network, Inc.

www.VOTRIENT.com

CLINICAL ONCOLOGY NEWS

Clinical Oncology News • May 2011

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BRIEF SUMMARY VOTRIENT™ (pazopanib) tablets The following is a brief summary only; see full prescribing information for complete product information. WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical studies. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. [See Warnings and Precautions (5.1).] 1 INDICATIONS AND USAGE VOTRIENT™ is indicated for the treatment of patients with advanced renal cell carcinoma (RCC). 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing: The recommended dose of VOTRIENT is 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3) of full prescribing information]. The dose of VOTRIENT should not exceed 800 mg. Do not crush tablets due to the potential for increased rate of absorption which may affect systemic exposure. [See Clinical Pharmacology (12.3) of full prescribing information.] If a dose is missed, it should not be taken if it is less than 12 hours until the next dose. 2.2 Dose Modification Guidelines: Initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200 mg steps based on individual tolerability. The dose of VOTRIENT should not exceed 800 mg. Hepatic Impairment: The dosage of VOTRIENT in patients with moderate hepatic impairment should be reduced to 200 mg per day. There are no data in patients with severe hepatic impairment; therefore, use of VOTRIENT is not recommended in these patients. [See Use in Specific Populations (8.6).] Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) may increase pazopanib concentrations and should be avoided. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg. Further dose reductions may be needed if adverse effects occur during therapy. This dose is predicted to adjust the pazopanib AUC to the range observed without inhibitors. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. [See Drug Interactions (7.1).] Concomitant Strong CYP3A4 Inducer: The concomitant use of strong CYP3A4 inducers (e.g., rifampin) may decrease pazopanib concentrations and should be avoided. VOTRIENT should not be used in patients who can not avoid chronic use of strong CYP3A4 inducers. [See Drug Interactions (7.1).] 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatic Effects: In clinical trials with VOTRIENT, hepatotoxicity, manifested as increases in serum transaminases (ALT, AST) and bilirubin, was observed [see Adverse Reactions (6.1)]. This hepatotoxicity can be severe and fatal. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). Across all monotherapy studies with VOTRIENT, ALT >3 X upper limit of normal (ULN) was reported in 138/977 (14%) and ALT >8 X ULN was reported in 40/977 (4%) of patients who received VOTRIENT. Concurrent elevations in ALT >3 X ULN and bilirubin >2 X ULN regardless of alkaline phosphatase levels were detected in 13/977 (1%) of patients. Four of the 13 patients had no other explanation for these elevations. Two of 977 (0.2%) patients died with disease progression and hepatic failure. Monitor serum liver tests before initiation of treatment with VOTRIENT and at least once every 4 weeks for at least the first 4 months of treatment or as clinically indicated. Periodic monitoring should then continue after this time period. Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT with weekly monitoring of liver function until ALT return to Grade 1 or baseline. Patients with isolated ALT elevations of >8 X ULN should have VOTRIENT interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks [see Dosage and Administration (2.2)]. Following reintroduction of VOTRIENT, if ALT elevations >3 X ULN recur, then VOTRIENT should be permanently discontinued. If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X ULN, VOTRIENT should be permanently discontinued. Patients should be monitored until resolution. VOTRIENT is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome [see Clinical Pharmacology (12.5) of full prescribing information]. Patients with only a mild indirect hyperbilirubinemia, known Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations. The safety of VOTRIENT in patients with pre-existing severe hepatic impairment, defined as total bilirubin >3 X ULN with any level of ALT, is unknown. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. [See Dosage and Administration (2.2) and Use in Specific Populations (8.6).]

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5.2 QT Prolongation and Torsades de Pointes: In clinical RCC studies of VOTRIENT, QT prolongation (≥500 msec) was identified on routine electrocardiogram monitoring in 11/558 (<2%) of patients. Torsades de pointes occurred in 2/977 (<1%) of patients who received VOTRIENT in the monotherapy studies. In the randomized clinical trial, 3 of the 290 patients receiving VOTRIENT had post-baseline values between 500 to 549 msec. None of the 145 patients receiving placebo had post-baseline QTc values ≥500 msec. VOTRIENT should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed. 5.3 Hemorrhagic Events: In clinical RCC studies of VOTRIENT, hemorrhagic events have been reported [all Grades (16%) and Grades 3 to 5 (2%)]. Fatal hemorrhage has occurred in 5/586 (0.9%) [see Adverse Reactions (6.1)]. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. 5.4 Arterial Thrombotic Events: In clinical RCC studies of VOTRIENT, myocardial infarction, angina, ischemic stroke, and transient ischemic attack [all Grades (3%) and Grades 3 to 5 (2%)] were observed. Fatal events have been observed in 2/586 (0.3%). In the randomized study, these events were observed more frequently with VOTRIENT compared to placebo [see Adverse Reactions (6.1)]. VOTRIENT should be used with caution in patients who are at increased risk for these events or who have had a history of these events. VOTRIENT has not been studied in patients who have had an event within the previous 6 months and should not be used in those patients. 5.5 Gastrointestinal Perforation and Fistula: In clinical RCC studies of VOTRIENT, gastrointestinal perforation or fistula has been reported in 5 patients (0.9%). Fatal perforation events have occurred in 2/586 (0.3%). Monitor for symptoms of gastrointestinal perforation or fistula. 5.6 Hypertension: Blood pressure should be well-controlled prior to initiating VOTRIENT. Patients should be monitored for hypertension and treated as needed with anti-hypertensive therapy. Hypertension (systolic blood pressure ≥150 or diastolic blood pressure ≥100 mm Hg) was observed in 47% of patients with RCC treated with VOTRIENT. Hypertension occurs early in the course of treatment (88% occurred in the first 18 weeks). [See Adverse Reactions (6.1).] In the case of persistent hypertension despite anti-hypertensive therapy, the dose of VOTRIENT may be reduced [see Dosage and Administration (2.2)]. VOTRIENT should be discontinued if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of VOTRIENT. 5.7 Wound Healing: No formal studies on the effect of VOTRIENT on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as pazopanib may impair wound healing, treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. The decision to resume VOTRIENT after surgery should be based on clinical judgment of adequate wound healing. VOTRIENT should be discontinued in patients with wound dehiscence. 5.8 Hypothyroidism: In clinical RCC studies of VOTRIENT, hypothyroidism reported as an adverse reaction in 26/586 (4%) [see Adverse Reactions (6.1)]. Proactive monitoring of thyroid function tests is recommended. 5.9 Proteinuria: In clinical RCC studies with VOTRIENT, proteinuria has been reported in 44/586 (8%) [Grade 3, 5/586 (<1%) and Grade 4, 1/586 (<1%)] [see Adverse Reactions (6.1)]. Baseline and periodic urinalysis during treatment is recommended. VOTRIENT should be discontinued if the patient develops Grade 4 proteinuria. 5.10 Pregnancy: VOTRIENT can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, VOTRIENT is expected to result in adverse reproductive effects. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. There are no adequate and wellcontrolled studies of VOTRIENT in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking 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 taking VOTRIENT. [See Use in Specific Populations (8.1).] 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience: 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 safety of VOTRIENT has been evaluated in 977 patients in the monotherapy studies which included 586 patients with RCC. With a median duration of treatment of 7.4 months (range 0.1 to 27.6), the most commonly observed adverse reactions (≥20%) in the 586 patients were diarrhea, hypertension, hair color change, nausea, fatigue, anorexia, and vomiting. The data described below reflect the safety profile of VOTRIENT in 290 RCC patients who participated in a randomized, double-blind, placebo-controlled study [see Clinical Studies (14) of full prescribing information]. The median duration of treatment was 7.4 months (range 0 to 23) for patients who received VOTRIENT and 3.8 months (range 0 to 22) for the placebo arm. Forty-two percent (42%) of patients on VOTRIENT required a dose interruption. Thirty-six percent (36%) of patients on VOTRIENT were dose reduced.

CLINICAL ONCOLOGY NEWS

Clinical Oncology News • May 2011

Letter from the Editor

Dear Readers:

would like to introduce you to a new regular columnist for Clinical Oncology News: Steven Vogl, MD, a private medical oncologist in New York City. I have attended a variety of oncology meetings and noticed the frequent presence of this community oncologist, who asks hard-hitting questions of study presenters. He introduces himself as “Vogl, New York.” At this year’s San Antonio Breast Cancer Symposium (SABCS), when he asked

his first question, the symposium organizers surprised him with a plaque in appreciation of his queries, saying they added value to the meeting. Dr. Vogl has attended every annual American Society of Clinical Oncology meeting since 1975 and every SABCS meeting for the past 10 years. He has turned up at the European Society for Medical Oncology meeting as well as numerous other cancer conventions. And he is always at the microphone, questioning away.

Table 1. Adverse Reactions Occurring in ≥10% of Patients who Received VOTRIENT VOTRIENT

Adverse Reactions Diarrhea Hypertension Hair color changes Nausea Anorexia Vomiting Fatigue Asthenia Abdominal pain Headache a

Placebo

(N = 290) (N = 145) All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4 % % % % % % 52 3 <1 9 <1 0 40 4 0 10 <1 0 38 <1 0 3 0 0 26 <1 0 9 0 0 22 2 0 10 <1 0 21 2 <1 8 2 0 19 2 0 8 1 1 14 3 0 8 0 0 11 2 0 1 0 0 10 0 0 5 0 0

National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Other adverse reactions observed more commonly in patients treated with VOTRIENT than placebo and that occurred in <10% (any grade) were alopecia (8% versus <1%), chest pain (5% versus 1%), dysgeusia (altered taste) (8% versus <1%), dyspepsia (5% versus <1%), facial edema (1% versus 0%), palmar-plantar erythrodysesthesia (hand-foot syndrome) (6% versus <1%), proteinuria (9% versus 0%), rash (8% versus 3%), skin depigmentation (3% versus 0%), and weight decreased (9% versus 3%). Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients who Received VOTRIENT and More Commonly (≥5%) in Patients who Received VOTRIENT Versus Placebo VOTRIENT (N = 290) Parameters Hematologic Leukopenia Neutropenia Thrombocytopenia Lymphocytopenia Chemistry ALT increased AST increased Glucose increased Total bilirubin increased Phosphorus decreased Sodium decreased Magnesium decreased Glucose decreased a

Placebo (N = 145)

All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4 % % % % % % 37 34 32 31

0 1 <1 4

0 <1 <1 <1

6 6 5 24

0 0 0 1

0 0 <1 0

53 53

10 7

2 <1

22 19

1 <1

0 0

National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Hepatic Toxicity: In a controlled clinical study with VOTRIENT for the treatment of RCC, ALT >3 X ULN was reported in 18% and 3% of the VOTRIENT and placebo groups, respectively. ALT >10 X ULN was reported in 4% of patients who received VOTRIENT and in <1% of patients who received placebo. Concurrent elevation in ALT >3 X ULN and bilirubin >2 X ULN in the absence of significant alkaline phosphatase >3 X ULN occurred in 5/290 (2%) of patients on VOTRIENT and 2/145 (1%) on placebo. [See Dosage and Administration (2.2) and Warnings and Precautions (5.1).] Hypertension: In a controlled clinical study with VOTRIENT for the treatment of RCC, 115/290 patients (40%) receiving VOTRIENT compared with 15/145 patients (10%) on placebo experienced hypertension. Grade 3 hypertension was reported in 13/290 patients (4%) receiving VOTRIENT compared with 1/145 patients (<1%) on placebo. The majority of cases of hypertension

As an oncologist without ties to industry, Dr. Vogl enjoys a freedom of speech that some physicians might envy. Numerous physicians, including Andrew Seidman, MD, who is on this publication’s editorial advisory board, have pointed out that “he makes some good points and asks some good questions.” So, I asked Dr. Vogl to become a regular columnist, and I am delighted he has consented. I hope you enjoy his first column, which starts on the front page of this issue.

were manageable with anti-hypertensive agents or dose reductions with 2/290 patients (<1%) permanently discontinuing treatment with VOTRIENT because of hypertension. In the overall safety population for RCC (N = 586), one patient had hypertensive crisis on VOTRIENT. [See Warnings and Precautions (5.2).] QT Prolongation and Torsades de Pointes: In a controlled clinical study with VOTRIENT, QT prolongation (≥500 msec) was identified on routine electrocardiogram monitoring in 3/290 (1%) of patients treated with VOTRIENT compared with no patients on placebo. Torsades de pointes was reported in 2/586 (<1%) patients treated with VOTRIENT in the RCC studies. [See Warnings and Precautions (5.3).] Arterial Thrombotic Events: In a controlled clinical study with VOTRIENT, the incidences of arterial thrombotic events such as myocardial infarction/ischemia [5/290 (2%)], cerebral vascular accident [1/290 (<1%)], and transient ischemic attack [4/290 (1%)] were higher in patients treated with VOTRIENT compared to the placebo arm (0/145 for each event). [See Warnings and Precautions (5.4).] Hemorrhagic Events: In a controlled clinical study with VOTRIENT, 37/290 patients (13%) treated with VOTRIENT and 7/145 patients (5%) on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events in the patients treated with VOTRIENT were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). Nine (9/37) patients treated with VOTRIENT who had hemorrhagic events experienced serious events including pulmonary, gastrointestinal, and genitourinary hemorrhage. Four (4/290) (1%) patients treated with VOTRIENT died from hemorrhage compared with no (0/145) (0%) patients on placebo. [See Warnings and Precautions (5.5).] In the overall safety population in RCC (N = 586), cerebral/intracranial hemorrhage was observed in 2/586 (<1%) patients treated with VOTRIENT. Hypothyroidism: In a controlled clinical study with VOTRIENT, more patients had a shift from thyroid stimulating hormone (TSH) within the normal range at baseline to above the normal range at any postbaseline visit in VOTRIENT compared with the placebo arm (27% compared with 5%, respectively). Hypothyroidism was reported as an adverse reaction in 19 patients (7%) treated with VOTRIENT and no patients (0%) in the placebo arm. [See Warnings and Precautions (5.7).] Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. Proteinuria: In the controlled clinical study with VOTRIENT, proteinuria has been reported as an adverse reaction in 27 patients (9%) treated with VOTRIENT. In 2 patients, proteinuria led to discontinuation of treatment with VOTRIENT. Lipase Elevations: In a single-arm clinical study, increases in lipase values were observed for 48/181 patients (27%). Elevations in lipase as an adverse reaction were reported for 10 patients (4%) and were Grade 3 for 6 patients and Grade 4 for 1 patient. In clinical RCC studies of VOTRIENT, clinical pancreatitis was observed in 4/586 patients (<1%). Cardiac Dysfunction: Pazopanib has been associated with cardiac dysfunction (such as a decrease in ejection fraction and congestive heart failure) in patients with various cancer types, including RCC. In the overall safety population for RCC (N = 586), cardiac dysfunction was observed in 4/586 patients (<1%). 7 DRUG INTERACTIONS 7.1 Drugs That Inhibit or Induce Cytochrome P450 3A4 Enzymes: In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib. CYP3A4 Inhibitors: Coadministration of pazopanib with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) may increase pazopanib concentrations. A dose reduction for VOTRIENT should be considered when it must be coadministered with strong CYP3A4 inhibitors [see Dosage and Administration (2.2)]. Grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib. CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers can not be avoided [see Dosage and Administration (2.2)]. 7.2 Effects of Pazopanib on CYP Substrates: Results from drug-drug interaction studies conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19 [see Clinical Pharmacology (12.3) of full prescribing information]. Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended. Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events. [See Clinical Pharmacology (12.3) of full prescribing information.] 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D [see Warnings and Precautions (5.10)]. VOTRIENT can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of VOTRIENT in pregnant women. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib to pregnant rats during organogenesis at a dose level of ≥3 mg/ kg/day (approximately 0.1 times the human clinical exposure based on AUC) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch) and incomplete or absent ossification. In addition, there was

Thanks for reading this publication, and as always, please send feedback about any of the articles to korourke@ mcmahonmed.com. I’d love to hear from you. Regards, Kate O’Rourke Managing Editor Clinical Oncology News

Clinical Oncology News welcomes letters to the editor. Email your thoughts to korourke@mcmahonmed.com.

SOLID TUMORS

Clinical Oncology News • May 2011

Breast

Genentech Builds Case for FDA Hearing on Avastin On June 28-29, Genentech is scheduled to explain at an FDA hearing why its drug bevacizumab (Avastin) should remain an FDA-approved option for women with metastatic breast cancer (MBC). In a document submitted to the FDA, Genentech has outlined the data and analyses that will form the crux of its argument. Although oncologists have been inundated by the debate banter in recent months, some of the talking points are new. Perhaps the most pivotal point of Genentech’s argument is that it is inappropriate to grant accelerated approval for bevacizumab in combination with

paclitaxel—and not with other chemotherapy partners—and then revoke the approval because of subsequent data involving different chemotherapies.

reduced fetal body weight, and pre- and post-implantation embryolethality in rats administered pazopanib at doses ≥3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was observed at doses ≥30 mg/kg/day (approximately 0.007 times the human clinical exposure). In addition, severe maternal body weight loss and 100% litter loss were observed at doses ≥100 mg/kg/day (0.02 times the human clinical exposure), while fetal weight was reduced at doses ≥3 mg/kg/day (AUC not calculated). 8.3 Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VOTRIENT, 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. 8.4 Pediatric Use: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. In repeat-dose toxicology studies in rats including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses ≥3 mg/kg/day (approximately 0.07 times the human clinical exposure based on AUC). Doses of 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC) were not tolerated in 13- and 26-week studies with rats. Body weight loss and morbidity were observed at these doses. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks. 8.5 Geriatric Use: In clinical trials with VOTRIENT for the treatment of RCC, 196 subjects (33%) were aged ≥65 years, and 34 subjects (6%) were aged >75 years. No overall differences in safety or effectiveness of VOTRIENT were observed between these subjects and younger subjects. However, patients >60 years of age may be at greater risk for an ALT >3 X ULN. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment: The safety and pharmacokinetics of pazopanib in patients with hepatic impairment have not been fully established. In clinical studies for VOTRIENT, patients with total bilirubin ≤1.5 X ULN and AST and ALT ≤2 X ULN were included [see Warnings and Precautions (5.1)]. An interim analysis of data from 12 patients with normal hepatic function and 9 with moderate hepatic impairment showed that the maximum tolerated dose in patients with moderate hepatic impairment was 200 mg per day [see Clinical Pharmacology (12.3) of full prescribing information]. There are no data on patients with severe hepatic impairment [see Dosage and Administration (2.2)]. 8.7 Renal Impairment: Patients with renal cell cancer and mild/moderate renal impairment (creatinine clearance ≥30 mL/min) were included in clinical studies for VOTRIENT. There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to significantly affect the pharmacokinetics of pazopanib since <4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 subjects with various cancers, creatinine clearance (30-150 mL/min) did not influence clearance of pazopanib. Therefore, renal impairment is not expected to influence pazopanib exposure, and dose adjustment is not necessary. 10 OVERDOSAGE Pazopanib doses up to 2,000 mg have been evaluated in clinical trials. Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively. Treatment of overdose with VOTRIENT should consist of general supportive measures. There is no specific antidote for overdosage of VOTRIENT. Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not significantly renally excreted and is highly bound to plasma proteins. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with pazopanib have not been conducted. However, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci in 2 females and a single case of adenoma in another female was observed at doses of 1,000 mg/kg/day (approximately 2.5 times the human clinical exposure based on AUC). Pazopanib did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay. Pazopanib may impair fertility in humans. In female rats, reduced fertility including increased pre-implantation loss and early resorptions were noted at dosages ≥30 mg/kg/day (approximately 0.4 times the human clinical exposure based on AUC). Total litter resorption was seen at 300 mg/kg/ day (approximately 0.8 times the human clinical exposure based on AUC). Post-implantation loss, embryolethality, and decreased fetal body weight were noted in females administered doses ≥10 mg/kg/day (approximately 0.3 times the human clinical exposure based on AUC). Decreased corpora lutea and increased cysts were noted in mice given ≥100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given ≥300 mg/kg/day for

“This is especially true when the subsequent data show a consistent positive effect of Avastin, but at lesser magnitude of effect on median PFS

26 weeks (approximately 1.3 and 0.85 times the human clinical exposure based on AUC, respectively). Decreased corpora lutea was also noted in monkeys given 500 mg/kg/day for up to 34 weeks (approximately 0.4 times the human clinical exposure based on AUC). Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates and testicular sperm concentrations at doses ≥3 mg/kg/ day, epididymal sperm concentrations at doses ≥30 mg/kg/day, and sperm motility at ≥100 mg/kg/day following 15 weeks of dosing. Following 15 and 26 weeks of dosing, there were decreased testicular and epididymal weights at doses of ≥30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC); atrophy and degeneration of the testes with aspermia, hypospermia and cribiform change in the epididymis was also observed at this dose in the 6-month toxicity studies in male rats. 17 PATIENT COUNSELING INFORMATION See Medication Guide. The Medication Guide is contained in a separate leaflet that accompanies the product. However, inform patients of the following: • Therapy with VOTRIENT may result in hepatobiliary laboratory abnormalities. Monitor serum liver tests (ALT, AST, and bilirubin) prior to initiation of VOTRIENT and at least once every 4 weeks for the first 4 months of treatment or as clinically indicated. Inform patients that they should report any of the following signs and symptoms of liver problems to their healthcare provider right away. • yellowing of the skin or the whites of the eyes (jaundice), • unusual darkening of the urine, • unusual tiredness, • right upper stomach area pain. • Gastrointestinal adverse reactions such as diarrhea, nausea, and vomiting have been reported with VOTRIENT. Patients should be advised how to manage diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs. • Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. • Patients should be advised to inform their healthcare providers of all concomitant medications, vitamins, or dietary and herbal supplements. • Patients should be advised that depigmentation of the hair or skin may occur during treatment with VOTRIENT. • Patients should be advised to take VOTRIENT without food (at least 1 hour before or 2 hours after a meal). VOTRIENT is a trademark of GlaxoSmithKline.

[progression-free survival] with chemotherapies other than paclitaxel,” writes Sandra Horning, MD, Michael Labson, JD, and Paul Schmidt, JD, counsel for Genentech. The FDA granted accelerated approval for the bevacizumab-paclitaxel combination in MBC based on the E2100 study that showed a 5.5-month improvement in PFS. The FDA has said it will rescind this indication based on studies, including AVADO (AVastin And DOcetaxel) and RIBBON-1 (bevacizumab plus capecitabine, a taxane, or an anthracycline), that demonstrated the drug only modestly improved PFS and didn’t increase overall survival (OS). Genentech argues that AVADO and RIBBON-1 merely suggest that bevacizumab’s therapeutic impact may vary depending on its chemotherapy partner. The company points out that three Phase II trials of bevacizumab and paclitaxel in MBC show median PFS of 11.5, 12.9 and 13.9 months, which is in line with the 11.3 months seen in E2100. At the June hearing, Genentech also will present data previously not submitted to the FDA from the Phase IV, openlabel ATHENA study. The trial, which enrolled 2,296 patients with MBC, tested bevacizumab in combination with chemotherapies including paclitaxel or docetaxel. Median time to progression (TTP) in the 325 patients receiving the paclitaxel and bevacizumab combination was 10.6 months (Ann Oncol 2001 March 28 [Epub ahead of print], PMID: 21444356). Genentech argues that the Food, Drug, and Cosmetic Act states that once the accelerated approval standard is met, withdrawal is not appropriate unless data establish that there is no longer a reasonable likelihood of clinical benefit, and studies have not done this. The company proposes to launch a doubleblind, randomized trial that incorporates a biomarker component to identify patients more likely to derive benefit from the bevacizumab-paclitaxel combination. They ask that the MBC indication be maintained in the meantime. Many oncologists have pointed out that detecting improvements in OS in the first-line setting of MBC is difficult, because subsequent lines of therapy may obscure the effect of a treatment tested in a clinical trial. “The lack see FDA HEARING, page 19 

CLINICALONCOLOGY NEWS

Clinical Oncology News • May 2011

EDITORIAL BOARD

Solid Tumors Bone Metastases Allan Lipton, MD Milton S. Hershey Medical Center, Penn State University Hershey, PA

Breast Cancer Andrew Seidman, MD Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Maura N. Dickler, MD Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Gastrointestinal Cancer Edward Chu, MD University of Pittsburgh Cancer Institute, University of Pittsburgh Pittsburgh, PA

Cathy Eng, MD University of Texas, MD Anderson Cancer Center Houston, TX

Leonard Saltz, MD Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Gastrointestinal Cancer and Sarcoma Ephraim Casper, MD Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Genitourinary Cancer Ronald M. Bukowski, MD Taussig Cancer Center, Cleveland Clinic Foundation Cleveland, OH

Gynecologic Cancer

Lung Cancer, Emesis Richard J. Gralla, MD Hofstra North Shore-Long Island Jewish School of Medicine, Monter Cancer Center North Shore University Hospital and Long Island Jewish Medical Center Lake Success, NY

Prostate Cancer Michael A. Carducci, MD AEGON Professor in Prostate Cancer Research, Co-Director, Prostate/GU Cancer and Chemical Therapeutics Programs, Johns Hopkins Kimmel Cancer Center Baltimore, MD

Hematologic Malignancies Jennifer R. Brown, MD, PhD Dana-Farber Cancer Institute, Harvard Medical School Boston, MA

Harry Erba, MD, PhD University of Michigan Ann Arbor, MI

Infection Control

Bioethics

Susan K. Seo, MD

Joseph P. DeMarco, PhD

Memorial Sloan-Kettering Cancer Center New York, NY

Cleveland State University Cleveland, OH

Oncology Nursing

Paul J. Ford, PhD

Betty Ferrell, RN, PhD City of Hope National Medical Center Duarte, CA

Cleveland Clinic Foundation Lerner College of Medicine of Case Western Reserve University Cleveland, OH

Policy and Management

Pharmacy

Mary Lou Bowers, MBA Cindy O’Bryant, PharmD University of Colorado Cancer Center Denver, CO

The Pritchard Group Rockville, MD

Rhonda M. Gold, RN, MSN Sara S. Kim, PharmD The Mount Sinai Medical Center New York, NY

The Pritchard Group Rockville, MD

Shaji Kumar, MD Mayo Clinic Rochester, MN

Editorial Philosophy

Richard Stone, MD Dana-Farber Cancer Institute, Harvard Medical School Boston, MA

Community Oncology Michael J. Fisch, MD, MPH University of Texas MD Anderson Cancer Center Houston, TX

Symptom Control and Palliative Care William S. Breitbart, MD Memorial Sloan-Kettering Cancer Center New York, NY

The Editorial Board of Clinical Oncology News is instrumental in guiding the content that appears in the newsmagazine. A significant proportion of the news coverage comes from studies presented at cancer conventions and meetings. Prior to these meetings such as the ASCO annual meeting, board members are asked to identify abstracts that should be covered in their area of specialty. They then review the articles before they are published. Board members, in their area of specialty, are also consulted about review article topics, and whether or not to cover specific trends, studies that appear in peer-reviewed journals, reports from government agencies, etc., and review the articles before they go to print. Additionally, all news articles that appear in Clinical Oncology News are sent to the sources quoted in each article to review and verify the accuracy of the article’s content. Educational review articles, commentaries, and other clinician-authored pieces are written exclusively by the named authors.

Steven D. Passik, PhD Vanderbilt University Medical Center Nashville, TN

Maurie Markman, MD Cancer Treatment Centers of America Philadelphia, PA

Joseph V. Pergolizzi Jr., MD Johns Hopkins University School of Medicine Baltimore, MD

Lung, and Head and Neck Cancers Edward S. Kim, MD University of Texas, MD Anderson Cancer Center Houston, TX

Russell K. Portenoy, MD Beth Israel Medical Center New York, NY

McMahon Publishing is a 38-year-old, family-owned medical publishing and medical education company. McMahon publishes seven clinical newspapers, seven special editions, and continuing medical education and custom publications.

Charles F. von Gunten, MD

University of California, San Diego, CA

POSTMASTER: Please send address changes to Clinical Oncology News, 545 W. 45th St., 8th Floor, New York, NY 10036. www.mcmahonmed.com

CLINICAL TRIALS

Clinical Oncology News • May 2011

The Clinical Trials Cooperative Group Program: Time for a Painful Reality Check EDITORIAL BOARD COMMENTARY Maurie Markman, MD Vice President of Patient Oncology Services and National Director for Medical Oncology, Cancer Treatment Centers of America, Philadelphia

t a time of revolutionary changes in our understanding of the fundamental molecular biology of cancer and of increasingly rapid development of exciting novel therapeutic agents whose design and preclinical activity is based on this knowledge, it is still a fact that fewer than 3% of U.S. cancer patients actually participate in clinical trials.1 As a result, the pace of testing drugs that have the potential to rather dramatically impact the survival and quality of life of cancer patients has been slowed substantially. It is far more than a theoretical concern that many genuinely beneficial agents will never be tested in human studies. At this most inopportune time, it has

been widely acknowledged and extensively discussed that the once-magnificent National Cancer Institute (NCI) Cooperative Group clinical trials apparatus, arguably for the past 40-plus years the absolute true jewel in our entire national government’s anticancer efforts, is in very serious trouble. Dysfunction exists on multiple levels and for many reasons, and swift and truly bold action is essential if there is any realistic hope it can be saved.2 Anyone who doubts the validity of this statement, written by one who has actively participated in the clinical trials system for more than two decades, should seriously consider the following: Per capita payment/reimbursement from the NCI to investigators and institutions to support research nurses, data management and other efforts essential to conducting outstanding clinical research and protecting the interests of participants in such research has not increased for many years. This rather unbelievable state of affairs is all the more distressing when one considers the objectively factual statement that the complexity, regulatory requirements,

‘Where studies fail to produce any reportable data, one must raise the difficult ethical issue of the research community’s failure to fulfill its contract with study participants.’

and length of follow-up (due to improved survival outcomes of research participants!) have increased substantially over this time period. Remarkably, it appears to have simply been assumed that investigators and institutions that have agreed to participate in NCI-sponsored trials would somehow “find the funds” required to safely and efficiently conduct such research. It is more than a little unclear if there is any reality to such assumptions, considering the current and future economic and health care environment in this country. Recently reported data clearly demonstrate the impact of multiple factors on the time to initiation and completion of NCI-sponsored clinical studies. These include inadequate funding of research infrastructure; third-party payer denial of care associated with cancer patients

participating in clinical trials; contracting issues; and dramatically increased complexity, regulatory oversight and bureaucracy associated with clinical trials.3,4 Actual activation of cooperative group trials from the initial submission of a “concept” frequently takes far longer than two years.2,3,5 Furthermore, the rate of study accrual is commonly woefully inadequate, with a large proportion of NCI trials having to close before any useful information is generated.6 In this highly problematic situation, where studies fail to produce any reportable data, one must raise the difficult ethical issue of the research community’s failure to fulfill its contract with study participants to “generate information that will be of benefit to future patients” in a particular clinical setting. In an effort to improve the current

drug. Additionally, patients will receive an FDA-approved medication guide informing them of the potential risks. The drug’s approval is based on results of the Phase III, double-blind ZETA (Zactima Efficacy in Thyroid Cancer Assessment) trial that randomized 331 patients with unresectable locally advanced or metastatic medullary thyroid cancer to vandetanib 300 mg (n=231) or placebo (n=100). Patients randomized to vandetanib had a significant improvement in progression-free survival (PFS) compared with those randomized to placebo, with a median PFS of at least 22.6 versus 16.4 months (hazard ratio, 0.35; 95% confidence interval, 0.24-0.53; P<0.0001). At the primary PFS analysis, no significant overall survival difference between groups was noted. The most common

adverse reactions to vandetanib were diarrhea (57%), rash (53%), acne (35%), nausea (33%), hypertension (33%), headache (26%), fatigue (24%), decreased appetite (21%) and abdominal pain (21%).

see REALITY CHECK, page 21 

FDA NEWS

Zytiga Approved for Prostate Cancer

he FDA has approved the oral agent abiraterone acetate (Zytiga, Centocor Ortho Biotech) in combination with prednisone for the treatment of men with metastatic castrationresistant prostate cancer who have received prior chemotherapy containing docetaxel. Approval was based on a Phase III, randomized placebo-controlled study of 1,195 patients who had received prior chemotherapy containing a taxane. Patients were randomized in a 2:1 fashion to receive either abiraterone 1 g daily in combination with prednisone 5 mg twice daily or a placebo in combination with prednisone 5 mg twice daily. In an interim analysis of the multicenter trial, patients who received the abiraterone acetate and prednisone combination had a median overall survival of 14.8 months compared with 10.9 months for patients in the control arm (hazard ratio [HR], 0.646; 95% confidence interval, 0.543-0.768; P<0.0001). In an updated analysis, results were consistent with those from the interim analysis, with a

4.6-month difference between the two arms in median survival (15.8 vs. 11.2 months; HR, 0.74). The most common adverse reactions (≥5%) were joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia and upper respiratory tract infection.

Vandetanib for Metastatic Medullary Thyroid Cancer

he FDA has approved the oral drug vandetanib (AstraZeneca) for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable, locally advanced or metastatic disease. Prior to this action, no FDA-approved treatments for this type of cancer existed. Approval for vandetanib, a tyrosine kinase inhibitor, is accompanied by a Risk Evaluation and Mitigation Strategy (REMS) aimed at informing health care professionals about serious side effects of the drug: QT prolongation, torsades de pointes and sudden death. Only health care professionals and pharmacies certified through the vandetanib REMS program, a restricted distribution program, will be able to prescribe and dispense the

Ipilimumab Approved for Melanoma

he FDA has approved ipilimumab (Yervoy, Bristol-Myers Squibb) for patients with metastatic melanoma based on results from a multinational trial. In the study, 676 patients with previously treated, unresectable stage III/ IV melanoma were randomized in a 3:1:1 ratio to ipilimumab (3 mg/kg every three weeks for four cycles) plus the glycoprotein (gp)100 peptide vaccine in a conventional dose, the same regimen see FDA NEWS, page 29 

2-D Bar Codes in ClinOnc 1. Get the FREE Microsoft Tag Reader application through your smartphone browser by going to http://gettag.mobi and follow the steps to download. (There may be a charge from your wireless provider for the data services.) 2. Open the Tag Reader and find the ClinOnc bar-code image in this publication. 3. Let the Tag Reader focus on the bar-code image to instantly access related materials and/or Web sites.

SOLID TUMORS

Clinical Oncology News • May 2011

Esophagogastric

In Esophagogastric Cancer Study ...

Radiation Fails, PET Response Shown To Be Prognostic San Francisco—A recent German study shows that radiation therapy failed to improve outcomes in patients with cancer of the esophagogastric junction who responded poorly to preoperative chemotherapy. The study also bolstered the idea that positron emission tomography (PET) response is a prognostic indicator. Progression-free survival (PFS) was less than 40% at 38 weeks among patients who were given radiation therapy after they exhibited a poor early response to chemotherapy based on PET scans. That contrasted with a PFS of 60% among patients whose tumors responded to chemotherapy, defined as at least a 35% reduction in tracer uptake on PET, and who therefore did not receive radiation. The study was reported at the Gastrointestinal Cancers Symposium (abstract 3). “Consistent with data from our previous study, early PET response during chemotherapy is prognostic, as time to progression is better in PET responders,” said investigator Florian Lordick, MD, PhD, an oncologist at Klinikum Braunschweig and Hannover Medical School in Germany. “Survival is poor in nonresponders, despite the addition of radiation therapy. Early metabolic response assessment by FDG [fluorodeoxyglucose]-PET permits the identification of tumors with a very dismal biology.” In general, esophageal cancer has a poor prognosis. For patients with resectable disease, neoadjuvant treatment may prove beneficial. Dr. Lordick and his colleagues previously showed that patients with a PET-documented response to preoperative chemotherapy had a twofold improvement in event-free survival (Lancet Oncol 2007;8:797-805, PMID: 17693134). The team wanted to see if they could improve outcomes in those who did not show an early response to preoperative chemotherapy by adding radiation therapy, said Dr. Lordick. To address this question, the investigators enrolled 56 patients with locally advanced adenocarcinoma of the esophagogastric junction (stage T3-4, no distant metastasis). All but two patients had T3 disease, and all 56 had nodal involvement. After baseline FDG-PET imaging, all patients received cisplatin-5-fluorouracil– based chemotherapy, and response was assessed by PET on day 14. Patients who had at least a 35% reduction from baseline in tracer uptake continued chemotherapy for three months. Nonresponders continued chemotherapy but also received a 32-Gy dose of hyperfractionated radiation therapy (1.6 Gy twice per day). Patients in

both groups underwent surgical resection upon completion of therapy. The primary end point was surgical resection with

clear margins (R0). Secondary end points included histologic response, time to progression and overall survival. PET results showed that 33 patients responded to chemotherapy and 23 did not. One patient in each group did not have surgery because of tumor progression. Of the remaining 54 patients, 49 had subtotal esophagectomy and five had extended transhiatal gastrectomy (three

responders and two nonresponders). Dr. Lordick reported that 27 chemotherapy responders (82%) had no residual disease after surgery, versus 16 (70%) of the nonresponders. Histopathologic examination showed that four responders had complete remissions and eight had subtotal remission, resulting in a major remission rate of

TRIAL CURRENTLY RECRUITING

A Randomized Phase II Trial for Newly Diagnosed Glioblastoma Patients: Cilengitide in subjects with newly diagnOsed glioblastoma multifoRme and unmethylated MGMT genE promoter A randomized, multicenter, open-label, controlled, phase II study investigating two cilengitide regimens in combination with standard treatment (TMZ with concomitant RT, followed by TMZ) versus standard therapy alone MAIN INCLUSION CRITERIA Newly diagnosed supratentorial glioblastoma (WHO grade IV) Unmethylated MGMT gene promoter status ECOG PS 0-1 Baseline Gd-MRI Stable or decreasing dose of steroids (for 5 days)

MAIN EXCLUSION CRITERIA Prior anti-angiogenic therapy Investigational agents within 30 days Chemotherapy within 5 years Prior cranial radiotherapy Placement of Gliadel® wafer Significant hepatic or renal impairment Coagulation disorder, myocardial insufficiency, peptic ulcer or another malignancy

MGMT: O6-methylguanine–DNA methyltransferase; RT: radiotherapy; TMZ: temozolomide Cilengitide (EMD 121974) currently is under clinical investigation and has not been approved for use in the United States, Canada, Europe, or elsewhere. The product has not been proved to be safe or effective and any claims of safety and effectiveness can be made only after regulatory review of the data and approval of the labeled claims.

Learn More About the CORE trial Please call 1-800-507-5284 or refer to ClinicalTrials.gov for more information (http://www.clinicaltrials.gov/ct2/show/NCT00813943) The CORE study is in collaboration with the Canadian Brain Tumour Consortium (CBTC).

101108 - 115024

see RADIATION, page 20 

Sponsored by Novartis Pharmaceuticals Corporation

Tasigna® (nilotinib) as CML Therapy Following Resistance to Gleevec® (imatinib mesylate): A Case Discussion Stuart L. Goldberg, MD Chief, Division of Leukemia John Theurer Cancer Center Hackensack University Medical Center Hackensack, New Jersey

Introduction ®

Gleevec (imatinib mesylate) is a targeted therapy for chronic myelogenous leukemia (CML), a myeloproliferative neoplasm arising from a clonal expansion of a myeloid stem cell containing a genetic translocation between chromosomes 9 and 22—also known as the Philadelphia chromosome (Ph).1 This translocation produces a fusion gene, BCRABL, which generates the constitutively active tyrosine kinase Bcr-Abl.1 Tasigna® (nilotinib) binds to the ATP-binding region of Bcr-Abl, inhibiting downstream growth-promoting pathways.1 Detection of Ph+ cells has become part of the standard workup for CML. The International Randomized Study of Interferon vs STI571 (IRIS) trial, which compared imatinib with interferon-alfa plus cytarabine, reported a 7-year progression-

100

Percent

80 60 40

free survival rate of 81.2% and an overall survival rate of 86.4%.2 Despite this, there remains an unmet need for additional treatments because clinical trials have demonstrated that after a median of 7 years, 16.8% of Ph+ CML patients receiving imatinib had experienced progression events.2 The tyrosine kinase inhibitor (TKI) Tasigna is indicated for the treatment of chronic phase (CP) and accelerated phase Ph+ CML in adult patients resistant or intolerant to prior therapy that included imatinib, and for the treatment of patients with newly diagnosed Ph+ CML in CP. Tasigna is structurally related to imatinib and is a Bcr-Abl inhibitor.3 Tasigna was evaluated previously in an open-label, noncomparative trial enrolling adult patients with imatinib resistance or intolerance. The median time of prior imatinib therapy was 32 months, at a median maximum dose of 600 mg.4 After 24 months of Tasigna treatment, 51% of patients had achieved a major cytogenetic response (0%-35% Ph+ dividing cell metaphases) (Figure 1).4 Of these patients, 37% had a complete cytogenetic response (CCyR; no observed Ph+ metaphases).4 Patients harboring a variety of BCR-ABL mutations associated with imatinib resistance responded to Tasigna therapy. The major exception was BCR-ABL with the T315I mutation.4

Tasigna helps achieve responses in adult patients with Ph+ CML-CP Overall Responder Rate (n=321) 51 95% CI: 46%-57% 37 95% CI: 32%-42% 15 95% CI: 11%-19%

20 0

MCyR

CCyR

PCyR

Figure 1. Cytogenetic response observed in adult patients switched to Tasigna after failing imatinib first-line treatment. At the time of data cutoff, 321 patients with Ph+ CmL in CP with a minimum follow-up of 24 months were enrolled. The efficacy end point in Ph+ CmL in CP was unconfirmed mCyR, which included CCyR and PCyR. An unconfirmed mCyR was defined as a CyR determined by one bone marrow sample. mCyR includes CCyR and PCyR. CCyR, complete cytogenetic response; CI, confidence interval; CML, chronic myelogenous leukemia; CP, chronic phase; CyR, cytogenetic response; MCyR, major cytogenetic response; PCyR, partial cytogenetic response; Ph+, Philadelphia chromosome-positive. Based on reference 4.

CLINICAL ONCOLOGY NEWS • mAY 2011

The most frequently reported nonhematologic adverse events (AEs) in adult patients with Ph+ CML-CP are listed in Table 1.4 The most common grade 3/4 hematologic AEs associated with Tasigna were anemia, neutropenia, and thrombocytopenia (Figure 2).4 The most frequent grade 3/4 laboratory abnormalities were elevated lipase (18%), hypophosphatemia (17%), hyperglycemia (12%), and elevated bilirubin (7%).4 The Tasigna prescribing information carries a boxed warning related to possible prolongation of the cardiac QT interval. According to the Tasigna prescribing information, electrocardiograms (ECGs) should be performed at baseline, 7 days after initiation, periodically as clinically indicated, and following dose adjustments. In addition, hypokalemia or hypomagnesemia must be corrected prior to initiating Tasigna therapy.4 The concomitant use of strong CYP3A4 inhibitors or anti-arrhythmic drugs and other drugs that may prolong the QT interval should also be avoided. Patients should avoid food 2 hours before and 1 hour after taking dose. A dose reduction is recommended in patients with hepatic impairment as Tasigna exposure is increased in patients with impaired hepatic function. Caution is also recommended in patients with a history of pancreatitis. Furthermore, the use of Tasigna may result in elevations in bilirubin, aspartate aminotransferase/alanine aminotransferase ratio, and alkaline phosphatase.4

Case Presentation A 68-year-old man arrives at the hematology clinic for evaluation. He was referred by his pulmonologist, who diagnosed him with leukocytosis. The patient has a long-standing history of moderate to severe chronic obstructive pulmonary disease (COPD) related to pack-per-day smoking. He also has a history of hypertension and cholecystectomy. During a routine examination 1 year earlier, he had a white blood cell (WBC) count of 14,000/µL with normal differential. This high count was attributed to recent steroid inhaler treatment for COPD exacerbation. Six months later, the patient’s WBC had risen to 22,000/µL, which was attributed to febrile bronchitis. One week later, he presented with mild upper-left quadrant discomfort. He currently uses an ipratropium/salbutamol combination inhaler for COPD and enalapril for hypertension. The patient presents as afebrile. He has a blood pressure of 157/88 mm Hg and a heart rate of 82 beats per minute. Physical examination of head, ears, eyes, nose, and throat

Table 1. Tasigna Safety Profile Adverse Reactions

All Grades, %

Grade 3/4, %

Nausea

Rash

Headache

Pruritus

Fatigue

Vomiting

Diarrhea

Cough

Constipation

Arthralgia

Nasopharyngitis

Pyrexia

Pain in extremity

Myalgia

Back pain

Asthenia

Abdominal pain

Dyspnea

Edema, peripheral

Based on reference 4.

is unremarkable. His chest has diminished breath sounds due to COPD. Heart examination shows regular rate and rhythms with no murmurs. There is no peripheral edema. A neurologic examination shows nonfocal deficit. The patient’s abdomen is soft and nontender, and his spleen is felt 7 cm below the left costal margin. Renal and hepatic functions are normal. Eastern Cooperative Oncology Group and Karnofsky performance statuses are 1 and 80%, respectively. A complete blood count reveals a WBC of 63,000/µL, hemoglobin (Hb) level of 14.2 g/dL, and platelet count of 534,000/µL. The differential finds 73% neutrophils, 10% myelocytes, 5% metamyelocytes, 2% blasts, 1% eosinophils, and 1% basophils. A bone

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the Science Behind PoSitive Patient outcomeS

100

Hematologic (Grade 3/4) Adverse Events (N=321)

20 0

Thrombocytopenia

Neutropenia

11 Anemia

Figure 2. Tasigna grade 3/4 hematologic adverse events. Based on reference 4.

marrow aspiration is ordered. The findings are nearly 100% cellularity and an elevated myeloid to erythroid (M:E) precursor ratio of 10:1. There are 3% myeloblasts and 2% basophils. Bone marrow cytogenetic analysis reveals 70% (14/20) Ph+ metaphases. Peripheral blood real-time quantitative polymerase chain reaction (RQ-PCR) shows the presence of BCR-ABL RNA transcripts at a level equivalent to 87% of the International Scale (IS) normalized CML baseline. The patient is given a diagnosis of Ph+ CMLCP with a high-risk Sokal score.

Treatment Response and Subsequent Therapy In this patient, treatment with imatinib 400 mg daily is initiated and is well tolerated with some muscle cramping during the first month. Oral calcium supplementation alleviates this reaction. The patient has increased dyspnea secondary to COPD exacerbation after 4 weeks, and mild anemia (Hb, 10.8 g/dL). By 3 months, the patient exhibits a complete hematologic response (CHR). The patient has a partial cytogenetic response (PCyR) at month 6, with 30% (6/20) Ph+ metaphases. Peripheral blood RQ-PCR at month 6 detects BCR-ABL transcripts at 7% IS. Initial treatment is continued with no further tolerability issues. At the 12-month examination, the patient continues to have a CHR. Bone marrow cytogenetics show mild granulocyte hyperplasia (M:E ratio of 5:1), but no evidence of excess blasts or dysplasia. Cytogenetic analysis continues to report only a PCyR. There are 15% (3/20) Ph+ metaphases. The molecular response is slightly improved to 4% IS. This is still too high to constitute a major molecular response (MMR, which is <0.1% IS). The patient’s partial treatment response is concerning. Patient compliance is verified; the patient and clinician decide to continue with imatinib 400 mg daily. One month later, at month 13, the patient experiences muscle cramps, especially at night, and begins taking calcium supplements with tonic water. The patient returns for cytogenetic analysis at month 14. There is no evidence

of excess blasts in the bone marrow, but the patient continues to have 15% Ph+ metaphases. RQ-PCR displays a BCR-ABL RNA transcript level of 3% IS. Mutational analysis finds no evidence of BCR-ABL gene mutations. The guidelines do not define this as treatment failure until month 18, at which point they recommend a treatment switch. If this at-risk patient does not demonstrate a CCyR at 18 months, then current guidelines recommend changing to another TKI.

Discussion Both the National Comprehensive Cancer Network (NCCN) and the European LeukemiaNet (ELN) have issued guidelines for treating patients with Ph+ CML. These guidelines provide monitoring schedules and criteria for deciding when to change therapy. The NCCN guidelines advise that Ph+ CML patients who have achieved only a PCyR after 12 months of imatinib therapy may continue at the same dosage or increase it to as high as 800 mg per day, if tolerated.1 The ELN guidelines define an optimal response at 12 months as achievement of CCyR (Table 2).5 The physician in the present case study followed the guidelines by maintaining the imatinib dose when the patient continued to have only a PCyR after month 12. Similarly, it will be important to change treatment if the

exposure of Tasigna is reduced in patients with total gastrectomy. More frequent followup with these patients should be considered, and dose increase may be considered, if necessary. Since the capsules contain lactose, Tasigna is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactose-containing products, or of glucose-galactose malabsorption. Women of childbearing potential should avoid becoming pregnant while taking Tasigna, and should be advised of the potential hazard to the fetus if they do.4

References 1. National Comprehensive Cancer Network. NCCN clinical practice guideline in oncology. Chronic myelogenous Leukemia. Version (V.2.2011). 2. GLEEVEC® (imatinib mesylate) tablets. Prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2010. 3. Weisberg E, manley PW, Breitenstein W, et al. Characterization of AmN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell. 2005; 7(2): 129-141. 4. TasigNa® (nilotinib) capsules. Prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2011. 5. Baccarani m, Cortes J, Pane F, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009;27(35):6041-6051. 6. Quintás-Cardama a, Kantarjian H, Jones D, et al. Delayed achievement of cytogenetic and molecular response is associated with increased risk of progression among patients with chronic myeloid leukemia in early chronic phase receiving high-dose or standard-dose imatinib therapy. Blood. 2009; 113(25): 6315-6321. 7. Hughes TP, Hochhaus A, Branford S, et al. Longterm prognostic significance of early molecular response to imatinib in newly diagnosed chronic leukemia: an analysis from the international randomized study of interferon versus STI571 (IRIS). Blood. 2010;116(19):3758-3765. 8. Kantarjian Hm, Giles F, Gattermann N, et al. Nilotinib (formerly AmN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood. 2007; 110(10): 3540-3546.

Table 2. ELN Rating of First-Line Treatment Response Response Definition and Criteria From the ELN Milestone

Optimal

Suboptimal

Failure

3 months

CHR + minor CyR

No CyR

<CHR

6 months

PCyR

<PCyR

No CyR

12 months

CCyR

PCyR

<PCyR

18 months

MMR

<MMR

<CCyR

Any time

Stable or improving MMR

Loss of MMR, mutations

Loss of CyR or CHR

AM7-1014904

current imatinib dose fails to elicit a CCyR at 18 months. There is growing awareness that patients such as this one who do not respond rapidly to initial therapy are at risk for poor ultimate response and disease progression. Data from the University of Texas MD Anderson Cancer Center indicate that imatinib recipients without a CCyR by month 12 only have a 42% chance of ever achieving a CCyR and a 31% chance of achieving an MMR. Their chance of disease progression is 38%.6 By comparison, patients without a CCyR at month 3 still have a 75% likelihood of eventually achieving one and a 62% probability of an MMR.6 As well, imatinib recipients in the IRIS trial with a month 12 MMR had a significantly better 7-year event-free survival than other patients (91% vs 79%, respectively).7 Improvements in RQ-PCR techniques may enhance our predictive power and allow for more rapid and efficient therapy adjustments. Tasigna is an appropriate choice if the patient fails treatment with imatinib, based on results from clinical trials in patients resistant or intolerant to imatinib treatment and its toxicity profile. The patient’s history of hypertension and prior pulmonary disease (COPD) placed him at an increased risk for pleural effusions. Pleural effusions are uncommon with Tasigna, being observed in 1% of patients in clinical trials.4 Sudden deaths have been reported in CML patients treated with Tasigna in clinical studies (n=5,661; 0.3%). The occurrence of some of these deaths early after initiating Tasigna suggests the possibility that ventricular repolarization abnormalities may have contributed to their occurrences.4 Tasigna is known to cause prolonged cardiac QTc intervals in patients with resistant or intolerant Ph+ CML, requiring ECGs at baseline, 7 days after initiation, and periodically thereafter, and electrolyte monitoring at treatment initiation and periodically thereafter.4 Occurrence of clinically meaningful prolongation occurred in 1% of the patients in the Tasigna second-line Ph+ CML-CP trial.8 The present patient did not encounter this problem. Physicians should also be aware that the

CCyR, complete cytogenetic response; CHR, complete hematologic response; CyR, cytogenetic response; ELN, European LeukemiaNet; MMR, major molecular response; PCyR, partial cytogenetic response Based on reference 5.

CLINICAL ONCOLOGY NEWS • mAY 2011

BB109

Percent

Boxed WARNING and Additional Important Safety Information TASIGNA prolongs the QT interval. ECGs should be obtained to monitor the QTc at baseline, 7 days after initiation, and periodically thereafter, as well as following any dose adjustments. Sudden deaths have been reported in patients receiving TASIGNA. TASIGNA should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Hypokalemia or hypomagnesemia must be corrected prior to TASIGNA administration and should be periodically monitored. The concomitant use of strong CYP3A4 inhibitors or anti-arrhythmic drugs (including, but not limited to, amiodarone, disopyramide, procainamide, quinidine, and sotalol) and other drugs that may prolong the QT interval (including, but not limited to, chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin, and pimozide) should be avoided. The concomitant use of strong CYP3A4 inducers should be avoided (including, but not limited to, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, and phenobarbital). Patients should avoid food 2 hours before and 1 hour after taking dose. A dose reduction is recommended in patients with hepatic impairment as nilotinib exposure is increased in patients with impaired hepatic function. Treatment with TASIGNA can cause Grade 3/4 thrombocytopenia, neutropenia, and anemia. Caution is recommended in patients with a history of pancreatitis. The use of TASIGNA may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase.

TASIGNA can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia (see Boxed WARNING). The exposure of nilotinib is reduced in patients with total gastrectomy. Since the capsules contain lactose, TASIGNA is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactose-containing products, or of glucose-galactose malabsorption. Complete blood counts should be performed every 2 weeks for the first 2 months and then monthly thereafter. Women of childbearing potential should avoid becoming pregnant while taking TASIGNA and should be advised of the potential hazard to the fetus if they do. In newly diagnosed Ph+ CML-chronic phase, the most commonly reported non-hematologic adverse drug reactions (>10%) were rash, pruritus, headache, nausea, fatigue, and myalgia. In resistant or intolerant Ph+ CML-chronic phase, the most commonly reported non-hematologic adverse drug reactions (>10%) were rash, pruritus, nausea, fatigue, headache, constipation, diarrhea, vomiting, and myalgia. In resistant or intolerant Ph+ CML-accelerated phase, the most commonly reported nonhematologic adverse drug reactions (>10%) were rash, pruritus, and fatigue. Please see brief summary of Prescribing Information on the following pages.

Tasigna® (nilotinib) Capsules Initial U.S. Approval: 2007 BRIEF SUMMARY: Please see package insert for full prescribing information. WARNING: QT PROLONGATION AND SUDDEN DEATHS Tasigna prolongs the QT interval (5.2). Sudden deaths have been reported in patients receiving nilotinib (5.3). Tasigna should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome (4). Hypokalemia or hypomagnesemia must be corrected prior to Tasigna administration and should be periodically monitored (5.2). Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided (5.7). Patients should avoid food 2 hours before and 1 hour after taking dose (5.8). A dose reduction is recommended in patients with hepatic impairment (5.9). ECGs should be obtained to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, as well as following any dose adjustments. (5.2, 5.3, 5.6, 5.12) 1 INDICATIONS AND USAGE 1.1 Newly Diagnosed Ph+ CML-CP Tasigna (nilotinib) is indicated for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The effectiveness of Tasigna is based on major molecular response and cytogenetic response rates [see Clinical Studies (14.1) in the full prescribing information]. The study is ongoing and further data will be required to determine long-term outcome. 1.2 Resistant or Intolerant Ph+ CML-CP and CML-AP Tasigna is indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (Ph+ CML) in adult patients resistant or intolerant to prior therapy that included imatinib. The effectiveness of Tasigna is based on hematologic and cytogenetic response rates [see Clinical Studies (14.2) in the full prescribing information]. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing Tasigna should be taken twice daily at approximately 12 hour intervals and must not be taken with food. The capsules should be swallowed whole with water. No food should be consumed for at least 2 hours before the dose is taken and no food should be consumed for at least one hour after the dose is taken [see Boxed Warning, Warnings and Precautions (5.8), Clinical Pharmacology (12.3) in the full prescribing information]. For patients who are unable to swallow capsules, the contents of each capsule may be dispersed in one teaspoon of applesauce (puréed apple). The mixture should be taken immediately (within 15 minutes) and should not be stored for future use [see Clinical Pharmacology (12.3) in the full prescribing information]. Tasigna may be given in combination with hematopoietic growth factors such as erythropoietin or G-CSF if clinically indicated. Tasigna may be given with hydroxyurea or anagrelide if clinically indicated. Newly Diagnosed Ph+ CML-CP The recommended dose of Tasigna is 300 mg orally twice daily [see Clinical Pharmacology (12.3) in the full prescribing information]. Resistant or Intolerant Ph+ CML-CP and CML-AP The recommended dose of Tasigna (nilotinib) is 400 mg orally twice daily [see Clinical Pharmacology (12.3) in the full prescribing information]. 2.2 Dose Adjustments or Modifications QT interval prolongation: Table 1: Dose Adjustments for QT Prolongation ECGs with a QTc >480 msec

1. Withhold Tasigna, and perform an analysis of serum potassium and magnesium, and if below lower limit of normal, correct with supplements to within normal limits. Concomitant medication usage must be reviewed. 2. Resume within 2 weeks at prior dose if QTcF returns to <450 msec and to within 20 msec of baseline. 3. If QTcF is between 450 msec and 480 msec after 2 weeks, reduce the dose to 400 mg once daily. 4. If, following dose-reduction to 400 mg once daily, QTcF returns to >480 msec, Tasigna should be discontinued. 5. An ECG should be repeated approximately 7 days after any dose adjustment.

Myelosuppression Tasigna may need to be withheld and/or dose reduced for hematological toxicities (neutropenia, thrombocytopenia) that are not related to underlying leukemia (Table 2). Table 2: Dose Adjustments for Neutropenia and Thrombocytopenia Newly diagnosed Ph+ CML in chronic phase at 300 mg twice daily Resistant or intolerant Ph+ CML in chronic phase or accelerated phase at 400 mg twice daily

ANC* <1.0 x 109/L and/or platelet counts <50 x 109/L

1. Stop Tasigna, and monitor blood counts 2. Resume within 2 weeks at prior dose if ANC >1.0 x 109/L and platelets >50 x 109/L 3. If blood counts remain low for >2 weeks, reduce the dose to 400 mg once daily

*ANC = absolute neutrophil count See Table 3 for dose adjustments for elevations of lipase, amylase, bilirubin, and/or hepatic transaminases [see Adverse Reactions (6.1)]. Table 3: Dose Adjustments for Selected Non-hematologic Laboratory Abnormalities Elevated serum lipase or amylase ≥Grade 3

1. Withhold Tasigna, and monitor serum lipase or amylase 2. Resume treatment at 400 mg once daily if serum lipase or amylase return to ≤Grade 1

Elevated bilirubin ≥Grade 3

1. Withhold Tasigna, and monitor bilirubin 2. Resume treatment at 400 mg once daily if bilirubin return to ≤Grade 1

Elevated hepatic transaminases ≥Grade 3

1. Withhold Tasigna, and monitor hepatic transaminases 2. Resume treatment at 400 mg once daily if hepatic transaminases return to ≤Grade 1

Other Non-hematologic Toxicities If other clinically significant moderate or severe non-hematologic toxicity develops, withhold dosing, and resume at 400 mg once daily when the toxicity has resolved. If clinically appropriate, escalation of the dose back to 300 mg (newly diagnosed Ph+ CML-CP) or 400 mg (resistant or intolerant Ph+ CML-CP and CML-AP) twice daily should be considered. For Grade 3 to 4 lipase elevations, dosing should be withheld, and may be resumed at 400 mg once daily. Test serum lipase levels monthly or as clinically indicated. For Grade 3 to 4 bilirubin or hepatic transaminase elevations, dosing should be withheld, and may be resumed at 400 mg once daily. Test bilirubin and hepatic transaminases levels monthly or as clinically indicated [see Warnings and Precautions (5.4, 5.5), Use in Specific Populations (8.7) in the full prescribing information]. Hepatic Impairment If possible, consider alternative therapies. If Tasigna must be administered to patients with hepatic impairment, consider the following dose reduction: Table 4: Dose Adjustments for Hepatic Impairment (At Baseline) Newly diagnosed Ph+ CML in chronic phase at 300 mg twice daily

Mild, Moderate or Severe*

An initial dosing regimen of 200 mg twice daily followed by dose escalation to 300 mg twice daily based on tolerability

Resistant or intolerant Ph+ CML in chronic phase or accelerated phase at 400 mg twice daily

Mild or Moderate*

An initial dosing regimen of 300 mg twice daily followed by dose escalation to 400 mg twice daily based on tolerability

Severe*

A starting dose of 200 mg twice daily followed by a sequential dose escalation to 300 mg twice daily and then to 400 mg twice daily based on tolerability

*Mild = mild hepatic impairment (Child-Pugh Class A); Moderate = moderate hepatic impairment (Child-Pugh Class B); Severe = severe hepatic impairment (Child-Pugh Class C) [see Boxed Warning, Warnings and Precautions (5.9), Use in Specific Populations (8.7) in the full prescribing information]. Concomitant Strong CYP3A4 Inhibitors Avoid the concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). Grapefruit products may also increase serum concentrations of nilotinib and should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with Tasigna be interrupted. If patients must be co-administered a strong CYP3A4 inhibitor, based on pharmacokinetic studies, consider a dose reduction to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML-CP. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. If the strong inhibitor is discontinued, a washout period should be allowed before the Tasigna dose is adjusted upward to the indicated dose. Close monitoring for prolongation of the QT interval is indicated for patients who cannot avoid strong CYP3A4 inhibitors [see Boxed Warning, Warnings and Precautions (5.2, 5.7), Drug Interactions (7.2) in the full prescribing information]. Concomitant Strong CYP3A4 Inducers Avoid the concomitant use of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital). Patients should also refrain from taking St. John’s Wort. Based on the nonlinear pharmacokinetic profile of nilotinib, increasing the dose of Tasigna when co-administered with such agents is unlikely to compensate for the loss of exposure [see Drug Interactions (7.2) in the full prescribing information]. 3 DOSAGE FORMS AND STRENGTHS 150 mg red opaque hard gelatin capsules with black axial imprint “NVR/BCR”. 200 mg light yellow opaque hard gelatin capsules with a red axial imprint “NVR/TKI”. 4 CONTRAINDICATIONS Do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome [see Boxed Warning]. 5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression Treatment with Tasigna can cause Grade 3/4 thrombocytopenia, neutropenia and anemia. Perform complete blood counts every two weeks for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding Tasigna temporarily or dose reduction [see Dosage and Administration (2.2)]. 5.2 QT Prolongation Tasigna has been shown to prolong cardiac ventricular repolarization as measured by the QT interval on the surface ECG in a concentration-dependent manner [see Adverse Reactions (6.1), Clinical Pharmacology (12.4) in the full prescribing information]. Prolongation of the QT interval can result in a type of ventricular tachycardia called torsade de pointes, which may result in syncope, seizure, and/or death. ECGs should be performed at baseline, seven days after initiation, periodically as clinically indicated and following dose adjustments [see Warnings and Precautions (5.12)]. Tasigna should not be used in patients who have hypokalemia, hypomagnesemia or long QT syndrome. Hypokalemia or hypomagnesemia must be corrected prior to initiating Tasigna and these electrolytes should be monitored periodically during therapy [see Warnings and Precautions (5.12)]. Significant prolongation of the QT interval may occur when Tasigna is inappropriately taken with food and/or strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT. Therefore, co-administration with food must be avoided and concomitant use with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT should be avoided [see Warnings and Precautions (5.7, 5.8)]. The presence of hypokalemia and hypomagnesemia may further enhance this effect [see Warnings and Precautions (5.6, 5.12)]. 5.3 Sudden Deaths Sudden deaths have been reported in patients with CML treated with nilotinib in clinical studies (n= 5,661; 0.3%). The relative early occurrence of some of these deaths relative to the initiation of nilotinib suggests the possibility that ventricular repolarization abnormalities may have contributed to their occurrence. 5.4 Elevated Serum Lipase The use of Tasigna can cause increases in serum lipase. Caution is recommended in patients with a previous history of pancreatitis. If lipase elevations are accompanied by abdominal symptoms, interrupt dosing and consider appropriate diagnostics to exclude pancreatitis. Test serum lipase levels monthly or as clinically indicated. 5.5 Hepatotoxicity The use of Tasigna may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase. Hepatic function tests should be checked monthly or as clinically indicated [see Warnings and Precautions (5.12)].

5.6 Electrolyte Abnormalities The use of Tasigna can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Electrolyte abnormalities must be corrected prior to initiating Tasigna and these electrolytes should be monitored periodically during therapy [see Warnings and Precautions (5.12)]. 5.7 Drug Interactions The administration of Tasigna with agents that are strong CYP3A4 inhibitors or anti-arrhythmic drugs (including, but not limited to amiodarone, disopyramide, procainamide, quinidine and sotalol) and other drugs that may prolong QT interval (including, but not limited to chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin and pimozide) should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with Tasigna be interrupted. If interruption of treatment with Tasigna is not possible, patients who require treatment with a drug that prolongs QT or strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval [see Boxed Warning, Dosage and Administration (2.2), Drug Interactions (7.2) in the full prescribing information]. 5.8 Food Effects The bioavailability of nilotinib is increased with food. Tasigna must not be taken with food. No food should be taken at least 2 hours before and at least one hour after the dose is taken. Grapefruit products and other foods that are known to inhibit CYP3A4 should be avoided [see Boxed Warning, Drug Interactions (7.2) and Clinical Pharmacology (12.3) in the full prescribing information].

In patients with CML-CP, the most commonly reported non-hematologic adverse drug reactions (>10%) were rash, pruritus, nausea, fatigue, headache, constipation, diarrhea, vomiting and myalgia. The common serious drug-related adverse reactions (>1%) were thrombocytopenia, neutropenia and anemia. In patients with CML-AP, the most commonly reported non-hematologic adverse drug reactions (>10%) were rash, pruritus and fatigue. The common serious adverse drug reactions (>1%) were thrombocytopenia, neutropenia, febrile neutropenia, pneumonia, leukopenia, intracranial hemorrhage, elevated lipase and pyrexia. Sudden deaths and QT prolongation were reported. The maximum mean QTcF change from baseline at steadystate was 10 msec. Increase in QTcF >60 msec from baseline was observed in 4.1% of the patients and QTcF of >500 msec was observed in 4 patients (<1%) [see Boxed Warning, Warnings and Precautions (5.2, 5.3), Clinical Pharmacology (12.4) in the full prescribing information]. Discontinuation due to drug-related adverse reactions was observed in 16% of CML-CP and 10% of CML-AP patients. Most Frequently Reported Adverse Reactions Tables 5 and 6 show the percentage of patients experiencing treatment-emergent adverse reactions (excluding laboratory abnormalities) regardless of relationship to study drug. Adverse reactions reported in greater than 10% of patients who received at least one dose of Tasigna are listed. Table 5: Most Frequently Reported Non-hematologic Adverse Reactions (Regardless of Relationship to Study Drug) in Patients with Newly Diagnosed Ph+ CML-CP (≥10% in Tasigna 300 mg twice daily or Gleevec 400 mg once daily groups)a

5.9 Hepatic Impairment Nilotinib exposure is increased in patients with impaired hepatic function. A lower starting dose is recommended for patients with mild to severe hepatic impairment (at baseline) and QT interval should be monitored closely [see Boxed Warning, Dosage and Administration (2.2) and Use in Specific Populations (8.7) in the full prescribing information]. 5.10 Total Gastrectomy The exposure of nilotinib is reduced in patients with total gastrectomy. More frequent follow-up of these patients should be considered. Dose increase or alternative therapy may be considered in patients with total gastrectomy [see Clinical Pharmacology 12.3) in the full prescribing information]. 5.11 Lactose Since the capsules contain lactose, Tasigna is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactose-containing products or of glucose-galactose malabsorption. 5.12 Monitoring Laboratory Tests Complete blood counts should be performed every two weeks for the first two months and then monthly thereafter. Chemistry panels, including the lipid profile, should be checked periodically. ECGs should be obtained at baseline, seven days after initiation and periodically thereafter, as well as following dose adjustments [see Warnings and Precautions (5.2)]. Laboratory monitoring for patients receiving Tasigna may need to be performed more or less frequently at the physician’s discretion. 5.13 Use in Pregnancy There are no adequate and well controlled studies of Tasigna in pregnant women. However, Tasigna may cause fetal harm when administered to a pregnant woman. Nilotinib caused embryo-fetal toxicities in animals at maternal exposures that were lower than the expected human exposure at the recommended doses of nilotinib. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of child-bearing potential should avoid becoming pregnant while taking Tasigna [see Use in Specific Populations (8.1) in the full prescribing information]. 6 ADVERSE REACTIONS The following serious adverse reactions can occur with Tasigna and are discussed in greater detail in other sections of the package insert [see Boxed Warning, Warnings and Precautions (5)].

Patients with Newly Diagnosed Ph+ CML-CP

Sudden deaths [see Boxed Warning, Warnings and Precautions (5.3)] Elevated serum lipase [see Warnings and Precautions (5.4)] Hepatotoxicity [see Warnings and Precautions (5.5)] Electrolyte abnormalities [see Boxed Warning, Warnings and Precautions (5.6)] 6.1 Clinical Trials Experience 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. Newly diagnosed Ph+ CML-CP The data below reflect exposure to Tasigna from a randomized trial in newly diagnosed patients with Ph+ CML in chronic phase treated at the recommended dose of 300 mg twice daily (n=279). The median time on treatment in the nilotinib 300 mg twice daily group was 18.6 months. The median actual dose intensity was 593 mg/day in the nilotinib 300 mg twice daily group. The most common (>10%) non-hematologic adverse drug reactions were rash, pruritus, headache, nausea, fatigue and myalgia. Upper abdominal pain, alopecia, constipation, diarrhea, dry skin, muscle spasms, arthralgia, abdominal pain, peripheral edema and asthenia were observed less commonly (≤10% and >5%) and have been of mild to moderate severity, manageable and generally did not require dose reduction. Pleural and pericardial effusions occurred in 1% of patients. Gastrointestinal hemorrhage was reported in 0.4% of patients. Increase in QTcF >60 msec from baseline was observed in 1 patient (0.4%) in the 300 mg twice daily treatment group. No patient had an absolute QTcF of >500 msec. The most common hematologic adverse drug reactions (all grades) were myelosuppression including: thrombocytopenia (17%), neutropenia (15%) and anemia (7%) See Table 7 for Grade 3/4 laboratory abnormalities.

TASIGNA 300 mg twice daily

GLEEVEC 400 mg once daily

N=279

N=280

N=279

N=280

CTC Gradesb 3 / 4 (%)

All Grades

Skin and subcutaneous tissue disorders

Rash Pruritus Alopecia

36 19 10

16 7 5

<1 <1 0

1 0 0

Gastrointestinal disorders

Nausea Constipation Diarrhea Vomiting Abdominal pain upper Abdominal pain

19 15 14 9

38 4 37 22

1 0 <1 0

1 0 2 <1

15 12

10 9

<1 1

<1 <1

Nervous system disorders

Headache

General disorders and administration site conditions

Fatigue Pyrexia Asthenia Edema, peripheral

19 10 11 8

14 12 9 17

<1 0 <1 0

1 0 0 0

Musculoskeletal and connective tissue disorders

Myalgia Arthralgia Muscle spasms Pain in extremity Back pain

14 15 10 9 12

16 13 29 13 10

<1 <1 0 0 <1

0 0 <1 <1 1

Respiratory, thoracic Cough and mediastinal disorders

Infections and infestations

Nasopharyngitis Upper respiratory tract infection

Eye disorders

Eyelid edema

aExcluding bNCI

laboratory abnormalities Common Terminology Criteria for Adverse Events, Version 3.0 Table 6: Most Frequently Reported Non-hematologic Adverse Reactions in Patients with Resistant or Intolerant Ph+ CML Receiving Tasigna 400 mg Twice Daily (Regardless of Relationship to Study Drug) (≥10% in any Group)a CML-CP

CML-AP

N=321 Body System and Preferred Term

N=137

All Grades (%)

CTC Gradesb 3 / 4 (%)

All Grades (%)

CTC Gradesb 3 / 4 (%)

Skin and subcutaneous tissue disorders

Rash Pruritus Night sweat Alopecia

36 32 12 11

2 <1 <1 0

29 20 27 12

0 0 0 0

Gastrointestinal disorders

Nausea Constipation Diarrhea Vomiting Abdominal pain Abdominal pain upper Dyspepsia

37 26 28 29 15

1 <1 3 <1 2

22 19 24 13 16

<1 0 2 0 3

14 10

<1 <1

12 4

<1 0

Headache

Discontinuation due to adverse events regardless of causality was observed in 7% of patients. Resistant or intolerant Ph+ CML-CP and CML-AP In the single open-label multicenter clinical trial, a total of 458 patients with Ph+ CML-CP and CML-AP resistant to or intolerant to at least one prior therapy including imatinib were treated (CML-CP=321; CML-AP=137) at the recommended dose of 400 mg twice daily. The median duration of exposure in days for CML-CP and CML-AP patients is 561 (range 1-1096) and 264 (range 2-1160), respectively. The median dose intensity for patients with CML-CP and CML-AP is 789 mg/day (range 151–1110) and 780 mg/day (range 150-1149), respectively and corresponded to the planned 400 mg twice daily dosing. The median cumulative duration in days of dose interruptions for the CML-CP patients was 20 (range 1-345), and the median duration in days of dose interruptions for the CML-AP patients was 23 (range 1–234).

GLEEVEC 400 mg once daily

Body System and Preferred Term

Myelosuppression [see Warnings and Precautions (5.1)] QT prolongation [see Boxed Warning, Warnings and Precautions (5.2)]

TASIGNA 300 mg twice daily

Nervous system disorders

(continued)

Table 6: Most Frequently Reported Non-hematologic Adverse Reactions in Patients with Resistant or Intolerant Ph+ CML Receiving Tasigna 400 mg Twice Daily (Regardless of Relationship to Study Drug) (≥10% in any Group)a CML-CP

CML-AP

N=321 Body System and Preferred Term

Metabolism and Nutrition Disorders: Common: electrolyte imbalance (including hypomagnesemia, hyperkalemia, hypokalemia, hyponatremia, hypocalcemia, hypophosphatemia, hypercalcemia, hyperphosphatemia), diabetes mellitus, hyperglycemia, hypercholesterolemia, hyperlipidemia. Uncommon: dehydration, decreased appetite, increased appetite. Unknown frequency: hyperuricemia, gout, hypoglycemia, dyslipidemia.

N=137

All Grades (%)

CTC Gradesb 3 / 4 (%)

All Grades (%)

CTC Gradesb 3 / 4 (%)

General disorders and administration site

Fatigue Pyrexia Asthenia Edema, peripheral Myalgia

32 22 16 15 19

3 <1 0 <1 2

23 28 14 12 16

<1 2 1 0 <1

Musculoskeletal and connective tissue disorders

Arthralgia Muscle spasms Bone pain Pain in extremity Back pain Musculoskeletal pain

26 13 14 20 17

2 <1 <1 2 2

16 15 15 18 15

0 0 2 1 <1

Respiratory, thoracic Cough and mediastinal Dyspnea disorders Oropharyngeal pain

27 15 11

<1 2 0

18 9 7

0 2 0

Infections and infestations

Nasopharyngitis Upper respiratory tract infection

Metabolism and nutritional disorders

Anorexia

Psychiatric disorders Insomnia

Vascular disorders

Hypertension

aExcluding

laboratory abnormalities bNCI Common Terminology Criteria for Adverse Events, Version 3.0 Laboratory Abnormalities Table 7 shows the percentage of patients experiencing treatment-emergent Grade 3/4 laboratory abnormalities in patients who received at least one dose of Tasigna. Table 7: Percent Incidence of Clinically Relevant Grade 3/4* Laboratory Abnormalities Patient Population Resistant or Intolerant Ph+ Newly Diagnosed Ph+ CML-CP

CML-CP

CML-AP

TASIGNA 300 mg twice daily N=279 (%)

GLEEVEC 400 mg once daily N=280 (%)

TASIGNA 400 mg twice daily N=321 (%)

TASIGNA 400 mg twice daily N=137 (%)

Hematologic Parameters Thrombocytopenia Neutropenia Anemia Biochemistry Parameters Elevated lipase Hyperglycemia Hypophosphatemia Elevated bilirubin (total) Elevated SGPT (ALT) Hyperkalemia Hyponatremia Hypokalemia Elevated SGOT (AST) Decreased albumin

10 12 4

9 20 5

301 312 11

423 424 27

7 6 5 4 4 2 <1 <1 1 0

3 0 8 <1 3 1 <1 1 1 0

18 12 17 7 4 6 7 2 3 4

18 6 15 9 4 4 7 9 2 3

Biochemistry Parameters Hypocalcemia Elevated alkaline phosphatase Elevated creatinine

<1 0 0

0 <1 <1

2 <1 <1

5 1 <1

*NCI Common Terminology Criteria for Adverse Events, version 3.0 1 CML-CP: Thrombocytopenia: 12% were grade 3, 18% were grade 4 2CML-CP: Neutropenia: 16% were grade 3, 15% were grade 4 3CML-AP: Thrombocytopenia: 11% were grade 3, 32% were grade 4 4CML-AP: Neutropenia: 16% were grade 3, 26% were grade 4 6.2 Additional Data from Clinical Trials The following adverse drug reactions were reported in patients in the Tasigna clinical studies at the recommended doses. These adverse drug reactions are ranked under a heading of frequency, the most frequent first using the following convention: common (1%-10%), uncommon (0.1%-1%), and unknown frequency (single events). For adverse drug reactions listed under “Investigations”, very common events (≥10%), which were not included in Tables 5 and 6, are also reported. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category. Infections and Infestations: Common: folliculitis. Uncommon: upper respiratory tract infection (including sinusitis, nasopharyngitis, pharyngitis), bronchitis, herpes virus infection, candidiasis pneumonia, urinary tract infection, gastroenteritis. Unknown frequency: sepsis, subcutaneous abscess, anal abscess, furuncle, tinea pedis. Neoplasms Benign, Malignant and Unspecified: Common: Skin papilloma. Unknown frequency: papilloma. Blood and Lymphatic System Disorders: Common: febrile neutropenia, pancytopenia, lymphopenia. Unknown frequency: thrombocytosis, leukocytosis. Immune System Disorders: Unknown frequency: hypersensitivity. Endocrine Disorders: Uncommon: hyperthyroidism hypothyroidism. Unknown frequency: hyperparathyroidism secondary, thyroiditis.

Psychiatric Disorders: Common: depression, insomnia. Uncommon: anxiety. Unknown frequency: disorientation, confusional state, amnesia, dysphoria. Nervous System Disorders: Common: dizziness, hypoesthesia, paresthesia. Uncommon: intracranial hemorrhage, migraine, loss of consciousness (including syncope), tremor, disturbance in attention, hyperesthesia. Unknown frequency: brain edema, optic neuritis, peripheral neuropathy, lethargy, dysesthesia. Eye Disorders: Common: eye hemorrhage, periorbital edema, eye pruritus, conjunctivitis, dry eye. Uncommon: vision impairment, vision blurred, visual acuity reduced, photopsia, eye irritation. Unknown frequency: papilloedema, diplopia, photophobia, eye swelling, blepharitis, eye pain, chorioretinopathy, conjunctival hemorrhage, conjunctivitis allergic, conjunctival hyperemia, ocular hyperemia, ocular surface disease, scleral hyperemia. Ear and Labyrinth Disorders: Common: vertigo. Unknown frequency: hearing impaired, ear pain, tinnitus. Cardiac Disorders: Common: angina pectoris, arrhythmia (including atrioventricular block, cardiac flutter, extrasystoles, atrial fibrillation, bradycardia), palpitations, electrocardiogram QT prolonged. Uncommon: cardiac failure, pericardial effusion, coronary artery disease, cyanosis, cardiac murmur. Unknown frequency: myocardial infarction, ventricular dysfunction, pericarditis, ejection fraction decrease. Vascular Disorders: Common: hypertension, flushing. Uncommon: hypertensive crisis, hematoma. Unknown frequency: shock hemorrhagic, hypotension, thrombosis. Respiratory, Thoracic and Mediastinal Disorders: Common: dyspnea, dyspnea exertional, epistaxis, cough, dysphonia. Uncommon: pulmonary edema, pleural effusion, interstitial lung disease, pleuritic pain, pleurisy, pharyngolaryngeal pain, throat irritation. Unknown frequency: pulmonary hypertension, wheezing. Gastrointestinal Disorders: Common: pancreatitis, abdominal discomfort, abdominal distension, dyspepsia, flatulence. Uncommon: gastrointestinal hemorrhage, melena, mouth ulceration, gastroesophageal reflux, stomatitis, esophageal pain, dysgeusia, dry mouth. Unknown frequency: gastrointestinal ulcer perforation, retroperitoneal hemorrhage, hematemesis, gastric ulcer, esophagitis ulcerative, subileus, gastritis, hemorrhoids, hiatus hernia, rectal hemorrhage, sensitivity of teeth, gingivitis. Hepatobiliary Disorders: Common: hepatic function abnormal. Uncommon: hepatitis, jaundice. Unknown frequency: cholestasis, hepatotoxicity, hepatomegaly. Skin and Subcutaneous Tissue Disorders: Common: night sweats, eczema, urticaria, erythema, hyperhidrosis, contusion, acne, dermatitis, dry skin. Uncommon: exfoliative rash, drug eruption, pain of skin, ecchymosis, swelling of face. Unknown frequency: erythema nodosum, skin ulcer, palmar-plantar erythrodysesthesia syndrome, petechiae, photosensitivity, blister, dermal cyst, sebaceous hyperplasia, skin atrophy, skin discoloration, skin exfoliation, skin hyperpigmentation, skin hypertrophy. Musculoskeletal and Connective Tissue Disorders: Common: bone pain, musculoskeletal chest pain, musculoskeletal pain, flank pain. Uncommon: musculoskeletal stiffness, muscular weakness, joint swelling. Unknown frequency: arthritis. Renal and Urinary Disorders: Common: pollakiuria. Uncommon: dysuria, micturition urgency, nocturia. Unknown frequency: renal failure, hematuria, urinary incontinence, chromaturia. Reproductive System and Breast Disorders: Uncommon: breast pain, gynecomastia, erectile dysfunction. Unknown frequency: breast induration, menorrhagia, nipple swelling. General Disorders and Administration Site Conditions: Common: pyrexia, chest pain, pain (including neck pain and back pain), chest discomfort, malaise. Uncommon: face edema, gravitational edema, influenza-like illness, chills. Unknown frequency: feeling hot, localized edema. Investigations: Common: blood amylase increased, gamma-glutamyltransferase increased, blood creatinine phosphokinase increased, weight decreased, weight increased. Uncommon: hemoglobin decreased, blood lactate dehydrogenase increased, blood urea increased. Unknown frequency: blood insulin increased, very low density lipoprotein increased, blood parathyroid hormone increased, blood pressure increased. 6.3 Postmarketing Experience The following additional adverse reactions have been reported during post approval use of Tasigna. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cases of tumor lysis syndrome have been reported in Tasigna treated patients with resistant or intolerant CML. Malignant disease progression, high WBC counts and/or dehydration were present in the majority of these cases. 10 OVERDOSAGE Overdose with nilotinib has been reported, where an unspecified number of Tasigna capsules were ingested in combination with alcohol and other drugs. Events included neutropenia, vomiting, and drowsiness. In the event of overdose, the patient should be observed and appropriate supportive treatment given. 16 HOW SUPPLIED/STORAGE AND HANDLING Tasigna (nilotinib) 150 mg capsules are red opaque hard gelatin capsules, size 1 with black axial imprint “NVR/BCR”. Tasigna (nilotinib) 200 mg capsules are light yellow opaque hard gelatin capsules, size 0 with the red axial imprint “NVR/TKI.” Tasigna capsules are supplied in blister packs. 150 mg Carton of 4 blister packs of (4x28) ........................................................................................NDC 0078-0592-87 Blisters of 28 capsules............................................................................................................NDC 0078-0592-51 200 mg Carton of 4 blister packs of (4x28) ........................................................................................NDC 0078-0526-87 Blisters of 28 capsules............................................................................................................NDC 0078-0526-51 Each blister pack contains one folded blister card of 28 capsules each, for dosing two in the morning and two in the evening at 12 hour intervals over a 7 day period. Tasigna (nilotinib) capsules should be stored at 25°C (77°F); excursions permitted between 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. T2010-104 Manufactured by: Novartis Pharma Stein AG Stein, Switzerland © Novartis

Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936

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Clinical Oncology News • May 2011

Prostate

Guest Editorial

Reaching Out to David Koch

FUTURE continued from page 1 

of money being spent on cancer research and drug development. The institutes to which you have contributed (I know only about the ones mentioned in the Times article) are very well funded already. Their volume of work may increase by virtue of your gifts, but the fundamental nature and course of their research probably will not change much. On the other hand, very little money is going toward identifying patients with cancer who may safely avoid treatment, and so can be spared its major deleterious effects. For men with prostate cancer, these effects are urinary incontinence, sexual impotence, urinary burning and frequent voiding. I suggest you make a major long-term commitment to investigating the biology of early prostate cancer with this goal in mind. As a man who has undergone all the major types of therapy used against prostate cancer, you are sure to understand the major toxicities involved. I fear that you had to experience some of these side effects. The major and prolonged toxicities of prostate cancer treatment probably are much more frequent than most urologists admit. For instance, in a recent Spanish prospective trial, men treated for prostate cancer were asked how bad their problems were three years post-treatment. Among men with no relevant problems at baseline, 64% of those who had undergone nerve-sparing prostatectomy and 83% of those who had undergone prostatectomy without effort to spare the nerves said they had severe sexual problems. External beam radiation resulted in 35% with severe sexual problems, and brachytherapy (seed implant) was also high at 30%. All of these treatments result in many men being severely impaired in sexual function (J Clin Oncol 2010;28:4687-4696, PMID: 20921463). Similar questions regarding urinary incontinence among those who had minimal initial problems in this area showed severe problems in 31% of patients after non–nerve-sparing radical prostatectomy, 27% after nerve-sparing radical prostatectomy, 11% after external radiation and 13% after brachytherapy. If we could help decide that half these men did not need treatment, then the incidence of these problems would be halved—a major advance. There are four kinds of men who present with early prostate cancer without symptoms—the biggest group consists of those who will never be bothered by it throughout their lives. A small group contains the unfortunate few who already have undetectable metastatic cancer that will kill them, even if all cancer in the prostate is destroyed by cutting it

n March 4, 2011, The New York Times published an article by Michael Cooper about the charity of David H. Koch, a billionaire oilman who donated $100 million to open a new cancer center at the Massachusetts Institute of Technology. According to Mr. Cooper, Mr. Koch has given money (in major quantities, so far $200 million) for cancer research on the same principle he uses to bet on horses—he gave money to major centers like Memorial-Sloan Kettering in New York City and the University of Texas MD Anderson Cancer Center in Houston so that he would be “betting on every horse in the race.” The article states that Mr. Koch was found to have advanced prostate cancer in 1992 and told he would not live long. He has been on the investigational agent abiraterone (Johnson & Johnson) for the past year, after being treated with surgery, radiation and other hormone therapies. It occurred to me that if I were advising a very rich man with prostate cancer about what he could accomplish to help cancer patients, I would have different goals in mind that could only be achieved with a lot of money focused on a single neglected problem—that of deciding with improved accuracy which men with prostate cancer could either defer or forever escape toxic treatments. I then faced the issue of how to get my suggestion to Mr. Koch. The very rich do not list their email addresses on Google. I was at loss for six weeks as to how to communicate with him. After the editor of Clinical Oncology News invited me to contribute an opinion column to this newsmagazine (see page 5), it occurred to me that publishing an open letter to Mr. Koch might get his attention—perhaps from a friend forwarding a copy to him, from his staff noting that he was mentioned in a favorable light, from a mention by his physicians (who may read this newsmagazine) or from the mysterious ways information seems to reverberate around the Internet and somehow find its way to those interested in it. My hope is that the following letter finds its way to Mr. Koch. —Steven Vogl, MD

out or by other means (such as radiation or freezing). In these first two groups, local treatment will not help the patient, and the side effects can impair significantly their quality of life. Remaining are two groups of men with aggressive cancers that have not yet spread but would cause mischief if left alone. These patients are the ones who should benefit from a local intervention such as surgery to destroy the primary tumor before it spreads. The first of these latter two groups contains those likely to live long enough for the prostate cancer to spread and kill them if allowed to do so. This can be quite a long time—in the best study of surgery versus observation for early prostate cancer, treated patients did not realize a reduction in distant metastases until after five years (N Engl J Med 2005;352:1977-1984, PMID: 15888698). In contrast, the second group with aggressive cancers that have not yet spread consists of men, many of whom are elderly, who have other illnesses (heart, lung, kidney disease, etc) that have a high likelihood of killing them before metastatic prostate cancer bothers them. The major thrust of my proposal is to develop much more sophisticated and elegant ways to separate out the first of the four groups, and to apply modern statistical methods to isolate the last group, and spare both these groups toxic interventions near their expected deaths.

However, I believe it is not enough to identify men at very low-risk for developing metastatic disease in their lifetimes. The decision not to treat involves ongoing follow-up and invites revision. We need to define and verify techniques

to follow such men over time to decide which of them needs local treatment after all. Especially in the United States, but also in parts of Western Europe, there is a tremendous emotional and financial push to treat, with many physicians and institutions having large financial rewards from treating prostate cancer, even in very low-risk individuals. Furthermore, individuals who have undergone treatment for localized prostate cancer, often with great difficulty, have a huge emotional investment in the decision to treat, and will apply community pressure in favor of aggressive treatment, based solely on the diagnosis of cancer. These groups will feel threatened by this undertaking, and will resist it at its outset and repeatedly during the course of each patient and with each publication. I suggest that you initially use a small amount of money to convene a small working group to help decide if these undertakings are worthy of your investment. Obvious candidates for a working group include Laurence Klotz, MD, of Toronto, who devised a program of “watchful waiting” without intervention for prostate cancer and published the results of a series of 450 patients followed for a median of nearly seven years (J Clin Oncol 2010;28:126-131, PMID: 19917860). The criteria he used to enroll patients were arbitrary, and he modified the criteria he used to offer treatment to those whose PSA [prostate-specific antigen] increased during the course of the study. His work is a starting point to what I am proposing.

Steven Vogl, MD, medical oncologist, New York City

Dr. Klotz based eligibility for his study on microscopic appearance of the tumor (Gleason score) and PSA; after initially allowing entry to older patients with higher Gleason scores and PSAs, he stopped doing this. There is a lot of room to look at much more sophisticated characteristics of tumor biology to identify low- and high-risk tumors, as well as characteristics of the host, including immune competence and general health. Recent small studies have suggested that the volume of cancer measured by the number of involved biopsy cores or by MRI [magnetic resonance imaging] (Br J Radiol 2005;78:S103-S111, PMID: 16306632) and tumor characteristics on MRI (apparent diffusion coefficients) may be helpful in selecting patients initially for “watchful waiting” (Br J Radiol 2011;84:31-37, PMID: 21172965). Serial MRI with serial measurement of diffusion coefficients also may be helpful in following patients to choose those in whom the decision not to treat needs to be changed. Another candidate for the initial working group is Peter Albertsen, MD, a urologist from Farmington, Conn., who seems to publish an article every few years about how few old men with prostate cancer really die from the disease. These analyses are based on patient age, differentiation of the tumor based on Gleason score and tumor stage by palpation. PSA levels (at baseline and over time) were not included in his models because PSA was not measured in the era when these patients presented. He just published a paper on the influence of a crude measure of comorbidity such as diabetes, stroke, heart or kidney disease (the Charlson score), on outcome (J Clin Oncol 2011; 29:1335-1341, PMID: 21357791). The effect was expected—the higher the comorbidity, the more likely the man is to die of something other than prostate cancer and the less likely to die of prostate cancer. In another article, he documents that the death rate from prostate cancer among men not treated for the cancer decreased in the 1990s compared with the 1980s (JAMA 2009;302:1202-1209, PMID: 19755699). This is not surprising, since screening increased in the second period, and just detecting a cancer five years earlier automatically prolongs survival from diagnosis by five years!

SOLID TUMORS

Clinical Oncology News • May 2011

Prostate

In Metastatic Castration-Resistant Prostate Cancer …

Study Shows Cabozantinib Shrinks Bone Metastases Orlando, Fla.—Treatment with the investigational wide-spectrum tyrosine kinase inhibitor cabozantinib (XL184, Exelixis) resulted in strong resolution of bone metastases and associated bone pain in men with metastatic castration-resistant prostate cancer (mCRPC) during the open-label lead-in phase of a company supported Phase II trial. The overall rate of disease control was 75% among 100 patients with mCRPC treated with cabozantinib during the lead-in phase of the trial, said investigator David C. Smith, MD, in a presentation of the results during the Genitourinary Cancers Symposium (abstract 127). Noting that the findings reinforce earlier data reported in November 2010, Dr. Smith, professor in the Departments of Internal Medicine and Urology at the University of Michigan, Ann Arbor, observed that of the 62 patients with at least one available bone scan, 53 patients (85%) had either complete or partial resolution of bone metastasis and eight additional patients (13%) exhibited stable disease. Thus, among those evaluable by bone scan, 61 of 62 patients (98%) exhibited control At least one expert from the new specialty of geriatric oncology should be recruited for the working group—these are physicians who are expert in balancing the benefits and toxicities of antitumor treatment with the severity of chronic conditions measured quantitatively. The study that tries to develop and validate a set of criteria to decide when to stop “watchful waiting” will be long and difficult. Death from prostate cancer, when it occurs, comes long after the initial intervention (N Engl J Med 2005;352:1977-1984, PMID: 15888698), so such criteria will take more than a decade to validate. This requires a long-term research and financial commitment recognizing that the study, and many of the participants, will outlive the investigators who start the study. Indeed, Dr. Klotz’ follow-up of almost seven years is too short. The only randomized study to prospectively compare radical prostatectomy and initial observation for palpable prostate cancer saw no difference in the incidence of distant metastases until after five years from diagnosis (Bill-Axelson, et al, PMID: 15888698). Even by 10 years, the difference was only 10%. Dr. Klotz projects that only 2.8% of men in his study have died of prostate cancer at 10 years. This represents only five deaths among 450 men entered. Although this is encouraging, I believe we need data well beyond 10 years of follow-up, especially in younger,

of disease (Figure). Originally, the study was designed to have a 12-week lead-in phase followed by a randomization phase, Dr. Smith explained, but because of the observed clinical activity of cabozantinib, the randomization phase was halted and data were unblinded. After discontinuation of active treatment with cabozantinib, rapid disease progression was observed. Based on those results, the investigators are accruing patients for a non-randomization expansion cohort, and are planning additional Phase II and III studies of the drug. At baseline, median age was 68 years and all patients had measurable metastatic disease. Slightly less than 50% of study participants had progressed on docetaxel, 88% had lymph node

Peter Albertsen, MD

Laurence Klotz, MD

healthier men. A recent report from Johns Hopkins gives the results of their “watchful waiting” policy with a median follow-up of only 2.7 years—they entered 769 men over about 15 years (J Clin Oncol, Epub April 4, 2011). The Web site of the Hopkins urology department states that their surgeons performed more than 1,000 radical prostatectomies annually. The criteria used, which were very strict, selected only about 5% of men for watchful waiting, and of these, 33% were switched to radical therapy because of more extensive involvement of the prostate with cancer on repeat biopsies or because of worsening Gleason scores on repeat biopsy. Very few men will be spared local therapy employing such strict policies favoring intervention—not surprising from a major surgical center. This kind of long-term study and follow-up requires stable, long-term funding and will require many years before it truly answers the questions posed. If well done, however, it should continue to

involvement, 78% had bone metastasis, 50% had significant pain and 37% required narcotics for pain. Twent y- s i x p a t i e n t s Scan for a Web dropped out before exclusive prostate c o m p l e t i n g 1 2 article; instructions page 8. weeks of treatment. Of 43 evaluable patients with bone metastases and bone pain, 60% reported improvement in pain at six and 12 weeks of treatment with cabozantinib. Of 33 evaluable patients who required narcotics for bone pain, 21 (64%) reported improvement in pain at six or 12 weeks, and 13 (46%) decreased or discontinued use of narcotics. Although adverse events were yield information of critical importance for many years. It will need stable leadership in terms of biologic studies, pathology, statistics, outcome assessment and ongoing patient evaluation—none of this comes cheaply or is easy to accomplish. Just conducting the study and properly presenting it to the media could make it easier for conscientious physicians to convince patients of the viability of a watchful-waiting policy. This benefit would begin as soon as the study was started. Using the prominent example of the ongoing study of watchful waiting, physicians could convince low-risk patients that the mere presence of prostate cancer does not require treatment and that many men will live long and comfortable lives with small amounts of cancer in their prostate glands, a chronic condition that probably will not require intervention. Refining criteria for toxic treatments is a more immediately rewarding place to invest philanthropic funds than basic research. Investments in basic and therapy research will take years, even decades, to bear fruit. It is unlikely that any men who have prostate cancer now will be alive if and when nanoparticles being developed at MIT become commercially available. In contrast, refining and disseminating criteria for “watchful waiting,” publicizing their availability and utility, and broadening the experience with and application of such criteria, can immediately improve the quality of life of many men who

common, few patients reported adverse events of grade 3 or higher. The most common adverse events of all grades included fatigue (71%), decreased appetite (62%), diarrhea (46%), nausea (40%), constipation (34%), dyspepsia (33%) and vomiting (29%). Prostate cancer experts not involved with the study were enthusiastic about the results. Oliver Sartor, MD, professor of medicine at Tulane University School of Medicine, in New Orleans, called the bone scan results “unprecedented,” noting that cabozantinib “appears to act by a whole new mechanism. Something remarkable appears to be going on. Pain is also decreased.” He added, however, that more information was needed. Celestia Higano, MD, professor of medicine and urology at the University of Washington, in Seattle, commented, “The drug looks very promising. I’ve never seen [bone] changes like this with any agent. It is a fascinating drug, but it does have some toxicity. It see BONE, page 18 

currently are being treated for prostate cancers that will never bother them in their lifetimes. I am not an expert in prostate cancer, nor have I ever done any prostate cancer research, but I know what issues matter to my patients. I am neither looking for a job nor seeking any funding. If this letter piques your interest, feel free to take my ideas anywhere you like. If you want my advice or participation in planning, I would be pleased to offer it without compensation in pursuit of this important line of study that could do so much to help so many. This kind of research does not have the “sex appeal” of therapeutic research. It does not emphasize cure so much as quality of life, symptom control, and careful consideration of risks and toxicities along with possible long-term benefits. It takes a generous, determined and independent donor to invest in a program of research in this direction. Although the investment will not result in the naming of a building or campus after the donor (you), the study (or studies, because the identification of those who need alternative intervention is probably separate from the initial decision not to intervene) could be named for you. If the results are as I expect, then the “Koch studies of watchful waiting” will be cited in medical literature and textbooks for decades, if not centuries. Sincerely, Steven E. Vogl, MD

SOLID TUMORS

Clinical Oncology News • May 2011

Prostate

BONE

‘As a clinician, [I think] the reported findings of improvement on bone scan are exciting, as improvements in bone scans are rarely observed; however, as a scientist, [I think] this optimism needs to be tempered with caution.’

continued from page 17 

is too early to tell what the role will be for this agent, but ongoing clinical trials will give us more information over the next several years.” Glenn Liu, MD, associate professor of medicine, University of Wisconsin Carbone Cancer Center, Madison, offered a perspective on the meaning of the bone scans. “As a clinician, [I think] the reported findings of improvement on bone scan are exciting, as improvements in bone scans are rarely observed; however, as a scientist, [I think] this optimism needs to be tempered with caution. Bone scans use the tracer technicium-99m-MDP, which locates to active areas of bone turnover, osteoblastic activity. Thus, while one explanation for

—Glenn Liu, MD

the bone scan improvement is improvement in tumor lesions, an alternative explanation is that the improvements seen on the bone scan might be the result of the effects of cabozantinib on tracer uptake in bone,” commented Dr. Liu.

“Nevertheless, these changes on bone scan are suggestive that cabozantinib is having a pharmacodynamic effect in this disease. Whether this pharmacodynamic effect will translate to clinical benefit will need to be addressed in the context of a randomized clinical trial.” Cabozantinib inhibits both MET and VEGFR2, which is thought to block progression of bone lesions. Preclinical studies showed that cabozantinib

inhibited progression of prostate cancer xenografts in bone. Dr. Smith disclosed a financial relationship with Exelixis. Dr. Sartor disclosed financial relationships with Amgen, Bristol-Myers Squibb, Celgene, Dendreon, GlaxoSmithKline, GPC Biotech, Medivation and Oncogenex. Dr. Higano and Dr. Liu had no relevant disclosures. —Bonnie Gillis

SUPPORTIVE CARE Nutrition

Report Helps Doctors Counsel Cancer Survivors on Nutrition The American Dietetic Association (ADA) has issued an overview of evidence-based nutritional guidelines for cancer survivors. The overview discusses nutritional interventions that can help prevent and manage chronic diseases that are common among survivors of malignancies. “With over 12 million American cancer survivors (about 4% of the population), it is time to concentrate on guidelines to help patients avoid the other complications that lead to death,” said lead author Kim Robien, PhD, RD, assistant professor of epidemiology and community health at the University of Minnesota in Minneapolis, in a statement. The ADA report comes at a time when more and more patients are asking their physicians about the role of food in cancer recurrence and prevention, said Mark Schattner, MD, PhD, an attending physician and director of the nutrition fellowship program at Memorial Sloan-Kettering Cancer Center, in New York City. “Nutritional therapies are such a hot topic nowadays,” said Dr. Schattner. “You hear questions from patients and family members. They want to know how they recover after treatment, how they recover after surgery, how they can tolerate chemotherapy and how family members can prevent cancer.” Studies indicate that cancer survivors improve their lifestyle behaviors after diagnosis but don’t maintain those new habits in the long term, Dr. Schattner said. The ADA report can be used to help counsel patients. “Preventing recurrence is the most important thing on a patient’s mind,” Dr. Schattner said.

“Telling them their risk of recurrence is lower [at a healthy weight] can sometimes motivate people.” Cancer survivors die of noncancer causes at significantly higher rates than the general population. Almost half of these deaths are due to cardiovascular disease. Other frequent causes of death include diabetes, endocrine disorders, osteopenia and osteoporosis—all of

specific nutrition interventions in managing these cancer- and treatment-specific effects will allow nutrition services and resources to be better allocated,” the authors said. For many years, the importance of nutrition has been overlooked as an integral part of cancer recovery and prevention, said Steven Clinton, MD, PhD, professor of internal medicine in the Division of Medical Oncology at Ohio State University, in Columbus. Only two other organizations—the American Cancer Society and the World Cancer Research Fund/American Insti-

time and incentive to focus on food and fitness, he said. According to the ADA report, cancer survivors should be encouraged to exercise regularly. Excess body weight is a well-known risk factor for cancer, and weight gain after diagnosis has been linked to higher mortality rates in breast cancer. Physical activity plays a “crucial” role in keeping weight under control, and “increasing evidence suggests that it exerts an important independent effect on survival after a breast or colorectal cancer diagnosis,” the report found.

‘With over 12 million American cancer survivors (about 4% of the population), it is time to concentrate on guidelines to help patients avoid the other complications that lead to death.’

—Kim Robien, PhD, RD

which can be affected by nutrition, the authors note. Oncologists can find the report in the March edition of the Journal of the American Dietetic Association (2011;111:368-375, PMID: 21338735). “Given the higher rates of comorbidity among [cancer] survivors and the importance of diet and exercise for promoting overall health, these data support a need for lifestyle interventions that target this vulnerable population,” the authors said in their paper. The investigators added that research in nutritional interventions for cancer survivors is still in its infancy and additional work is needed to develop more specific recommendations for this growing segment of the population. “Better information about the relative effectiveness of

tute for Cancer Research—have issued nutritional guidelines for cancer survivors, but the recommendations are broad. They emphasize achieving and maintaining a healthy weight; encourage regular physical activity and a diet rich in vegetables, fruit and whole grains; and support limiting meat and alcohol consumption. Both advocate food, rather than supplements, as the source of nutrients. Additionally, medical oncologists and other physicians who treat cancer patients receive little to no training in nutrition and physical fitness. Moreover, their reimbursements are based on technology and pharmaceutical interventions, with less emphasis on counseling patients, leaving providers with little

The report also noted that not much is known about diet composition and cancer survival. Findings from observational studies suggest that diets high in fruits, vegetables, whole grains and fish are associated with reduced mortality compared with a diet high in refined grains, processed and red meats, desserts and high-fat dairy products. Reports like the ADA study can improve clinicians’ understanding of an important area in cancer survivorship, said Dr. Clinton. “This ADA document provides a starting point for physicians, nurses and other caregivers of cancer patients and survivors with regard to dietary and lifestyle guidelines,” he said. —Christina Frangou

SOLID TUMORS

Clinical Oncology News • May 2011

Breast

FDA HEARING continued from page 6 

of statistically significant effect on OS is not surprising, as the [E2100] trial was not powered for OS and therefore had only limited power, at 25%, to detect an increase of three months at the median,” writes Genentech’s counsel. The company argues that drugs that have been approved in MBC do not meet the standard that the FDA is using for bevacizumab. The agency has accepted PFS and TTP end points as the basis for drug approvals in MBC without requiring a demonstration of OS benefit. Gemcitabine, argues Genentech, in particular does not meet the criteria that the FDA is now setting forth. Gemcitabine was approved based on TTP data, and mature data show that the drug’s effect on OS was not statistically significant. The company also says that the FDA has been unclear about the magnitude of PFS benefit that would be needed to justify clinical benefit, and this may discourage companies from developing drugs in the future. The company points out that bevacizumab’s withdrawal is significantly different from other withdrawals of accelerated approval. In the case of three agents for which the FDA has sought to rescind accelerated approval—gemtuzumab ozogamicin (Mylotarg, Pfizer), amifostine (Ethyol, MedImmune) and gefitinib (Iressa, AstraZeneca)—postmarketing studies clearly failed to meet their end points and, in Mylotarg’s case, identified fatal risks. At the June hearing, Genentech will present new information that the FDA Oncologic Drugs Advisory Committee (ODAC) did not consider when reviewing the MBC indication in July. This includes a statistical evaluation rebutting the FDA’s hypothesis that the results from E2100 are not meaningful because they reflect a “random high” and an assessment regarding why chemotherapy choice influences the magnitude of bevacizumab’s effect. They also will present an additional drug safety analysis that will demonstrate that the potential risks associated with bevacizumab are not greater than those of other agents added to chemotherapy in the first-line MBC setting. Since the FDA announced its decision, the European Medicines Agency’s Committee for Medicinal Products for Human Use and the National Comprehensive Cancer Network have come out in support of using the bevacizumab-paclitaxel combination in MBC, and the therapy continues to be endorsed by many well-respected oncologists. According to data gathered by Genentech, there has been a roughly 24% drop in prescriptions for bevacizumab for MBC since the July ODAC

The company argues that drugs that have been approved in metastatic breast cancer do not meet the standard that the FDA is using for bevacizumab.

decision. “This use pattern indicates that clinicians and patients continue to view Avastin as an important option for certain patients,” according to Genentech’s counsel. “This divergence of views demonstrates that the balance of benefits and risks falls within a zone

where physicians and patients should be allowed to make informed treatment choices based on individualized treatment determinations and clear disclosure of the available data in the approved labeling.” Oncologists will have to wait until June

to hear how the FDA will respond to Genentech’s argument. In the end, it may just come down to who is on the FDA ODAC at the time. Genentech has argued that only two members who voted to rescind the MBC indication were breast cancer oncologists and has requested that a new objective advisory committee oversee the hearing. At press time, the FDA had indicated that any changes to the committee would occur from organic agency procedures and that they would not add temporary voting members for the hearing. —Kate O’Rourke

SOLID TUMORS

Clinical Oncology News • May 2011

Ovarian

100 80

continued from page 1 

The data showed that patient demographics played a role in the care patients received, according to Melissa Thrall, MD, an oncologist at the University of Washington in Seattle, who presented the study. Non-whites, unmarried women and poorer patients were more likely to receive less-than-standard care. “Demographic factors are associated with the receipt of suboptimal care and may represent areas where quality improvement efforts can be focused,” Dr. Thrall said. She acknowledged, however, that more advanced age and medical frailty might have influenced clinical decision making that led to suboptimal care. “There is a need to increase efforts to identify and minimize treatment-limiting toxicity to improve completion of therapy in the population,” Dr. Thrall added. Given the general consensus surrounding optimal care for ovarian cancer, the results are surprising, said Michael Carney, MD, associate professor of obstetrics, gynecology and women’s health at the University of Hawaii in Honolulu. He was the invited discussant at the meeting. The findings are especially disappointing in light of the growing emphasis on quality of care as an outcome measure. “Similar to all ages, the Medicare population should receive the best we have to offer,” Dr. Carney asserted. “It is truly disappointing, shocking and sad to hear that [only] one out of three of the patients in this study received the standard of care.” The findings came from a retrospective review of the National Cancer

67.5

52.8

40 20 0

1995

2005

Figure 1. Ovarian cancer patients undergoing surgical debulking.

‘Demographic factors are associated with the receipt of suboptimal care and may represent areas where quality improvement efforts can be focused.’ —Melissa Thrall, MD

Institute’s (NCI) Surveillance, Epidemiology, and End Results (SEER) database, linked to Medicare claims data. Dr. Thrall and colleagues analyzed data on 8,211 Medicare patients who were diagnosed with ovarian cancer between 1995 and 2005. They identified women older than age 65 who had newly diagnosed stage III or IV ovarian cancer. The NCI and National Comprehensive Cancer Network recommend surgical debulking, whenever feasible, and systemic chemotherapy for advanced ovarian cancer. Few studies have examined adherence to the

recommendations in clinical practice, particularly in women older than age 65, who account for half of patients with the disease. Dr. Thrall set out to fill the knowledge gap using SEER. The data revealed that 59% of patients received primary surgery, and 24% were treated with primary chemotherapy. In the remaining 17% of cases, Dr. Thrall and colleagues found no evidence that patients received any treatment. Moreover, the proportion of patients undergoing surgical debulking declined by more than 20% during the study period, from 67.5% in 1995 to 52.8% in 2005 (Figure 1). Patients treated with primary chemotherapy tended to be older (>70 years), had more comorbidities and were more likely to have stage IV disease or “advanced, not otherwise specified.” Of the 4,827 patients who had primary surgery, 76% had some adjuvant chemotherapy, but only 55% completed the recommended six courses (Figure 2). Among 2,017 women treated with primary chemotherapy, 24% received six cycles and 32% had some cancer-directed surgery. “Of all the women, only 39% had both surgery and at least six cycles of chemotherapy,” Dr. Thrall reported. Patients who received optimal care tended to be better off socioeconomically, better educated, and were more likely to live in the South or West. Older women, blacks, sicker or frailer patients and those who lived in the Midwest were less likely to have surgery and six cycles of chemotherapy. Dr. Carney said that four of these findings “don’t make sense.” These findings were lower rates of primary surgery and higher rates of primary chemotherapy among blacks, marital status as a significant treatment factor, the influence of geographic location on treatment and a

Received some chemotherapy Received recommended six cycles of chemotherapy

100 80

Patients, %

MEDICARE Patients, %

76 55

40 20 0

Figure 2. Chemotherapy trends in patients receiving primary surgery.

decline in the rate of surgical debulking. “This is an important report as it raises serious questions regarding the adequacy of treatment of an older population of women with epithelial ovarian cancer,” said Maurie Markman, MD, vice president of patient oncology services and national director for medical oncology at the Cancer Treatment Centers of America, in Philadelphia. “While the study does not explain why patients did not receive the recommended treatment, the data strongly suggest the need for a more detailed analysis of the reasons for the clinical decisions in this patient population. Based on the results of such a review, it is possible educational efforts will be suggested that could lead to improved quality of care for women presenting with this difficult malignancy.” —Charles Bankhead

Esophagogastric

RADIATION continued from page 9 

36%. Among early nonresponders, the addition of radiation led to one complete histopathologic remission and five subtotal remissions, for a total major remission rate of 26% among the early nonresponders, who received radiation (P=0.56). During a median follow-up of 38 months, 13 chemotherapy responders had relapses, which were distant in 10 cases. That compared with 16 relapses among nonresponders, 11 of which were distant recurrences (P=0.102). As in their previous study, the investigators found that nonresponders had a much-shortened PFS compared with chemotherapy responders, a median of about 14 to 15 months versus about 30 months (P=0.035). Median overall survival was 18 months among

nonresponders but had not been reached in the patients who had early responses to chemotherapy. Another trial investigating PET-guided treatment of esophageal cancer is planned, with a design similar to the one reported by Dr. Lordick. In the upcoming trial, nonresponders by PET will receive an intensified regimen in an effort to overcome treatment resistance. The regimen consists of taxane-cisplatin combination chemotherapy, followed by intensity-modulated radiation therapy to a target dose of 45 to 50 Gy, followed by surgical resection. “If this study shows some benefit of the experimental arm, the next step would be to embark on a multicenter trial,” said Dr. Lordick. “The aim would be to randomize nonresponders to discontinue all therapy or to an intensification of preoperative treatment.” Although the German trial failed to meet the primary end point, the strategy

of using PET to guide treatment has potential as an aid to tailored therapy, noted Jennifer Obel, MD, an oncologist at North Shore University Medical Center in Chicago, during a news conference held at the symposium. “Hopefully, in the future we can use this technology to quickly move to other therapies and evaluate whether they’re helping the patient or not,” she said. Commenting on the study for Clincal Oncology News, Bruce Minsky, MD,

associate dean and professor of radiation oncology at The University of Chicago, and chief quality officer at The University of Chicago Medical Center, said, “Although the number of patients is limited, the trial was well designed and performed. The results are impressive; however, they need to be confirmed in a larger trial before this approach should be adopted in general practice.” —Charles Bankhead

Web Exclusives Available! Advocates Push To Raise Awareness of Esophageal Cancer

To scan, see instructions on page 8.

Endoscopic Therapy Favored for Early Esophageal Cancer

CLINICAL TRIALS

Clinical Oncology News • May 2011

REALITY CHECK continued from page 8 

state of affairs related to this highly clinically relevant national effort, it has recently been proposed that the NCI Cooperative Groups “consolidate” into fewer individual entities.2 It is not at all clear, however, how such an effort will improve the multiple bureaucratic steps inherent in the processes of study approval, activation, data reporting, and follow-up; evaluation of conflicts of interest; contracting with company sponsors; the multistep scientific review of trials; and the individual institutional (plus central) regulatory oversight. Furthermore, it should be noted that it is apparently the goal for future NCIsponsored trials to increasingly focus on research involving biological markers. This is unquestionably a scientifically rational aim, but one that will surely substantially increase the complexity, data management, regulatory requirements, and costs of study-specific evaluations and treatment (e.g., biopsies or imaging studies performed solely for research purposes that will not under current rules be able to be billed to third-party health insurers). Finally, despite understandably optimistic statements coming from certain quarters regarding the well-recognized relevance of cancer research to the general health, welfare and economic prosperity of our country, the reality of our nation’s fiscal situation also will certainly result in reduced financial support (perhaps substantially less) for such efforts in the near and potentially distant future. It is likely that some people will disagree, perhaps strongly, with this negative and admittedly quite distressing present and future view of federally sponsored cooperative group clinical cancer research in the United States. Many suggestions for improving the current unsustainable status quo have been and surely will continue to be proposed. Currently, however, the absolute absence of a powerfully comprehensive, objectively workable and financially viable plan designed to move the cooperative group process from its current fiscal and bureaucratic mess to a scientifically rigorous and highly efficient clinical trials enterprise remains

a terrible void. We need a clinical trial system totally focused on the rapid development, initiation and completion of genuinely exciting, innovative and patient-friendly studies that are specifically designed as rational steps along the continuum of a well-conceived plan whose goal is revolutionizing the management of malignant disease. Is it realistically possible that such a plan can be developed, and quickly? Comments and feedback on this article can be sent to maurie.markman@ctca-hope. com or korourke@mcmahonmed.com.

review of a topic but no longer have a hard copy?

1. Lara PN, Paterniti DA, Chiechi C, et al. Evaluation of factors affecting awareness of and willingness to participate in cancer clinical trials. J Clin Oncol. 2005;23:92829289, PMID: 16361626. 2. Kuehn BM. National Cancer Institute begins revamp of clinical trials cooperative program. JAMA. 2011;305:767-768, PMID: 21343570. 3. Dilts DM, Sandler AB, Baker M, et al. Processes to activate phase III clinical trials in a cooperative oncology group: the case of Cancer and Leukemia Group B. J Clin Oncol. 2006;24:4553-4557, PMID: 17008694.

Novel Clinical Approaches May 21, 2011

Rescheduled

Ballroom • The Rittenhouse Hotel 210 West Rittenhouse Square Philadelphia, PA 9:00 am – 11:30 am Target Audience This activity is designed for oncologists, physicians, physician assistants, and other health care professionals involved in the treatment of patients with breast cancer or metastatic breast cancer. There are no prerequisites for attendees.

This activity is jointly sponsored by Global Education Group and Applied Clinical Education.

Program Agenda For information about the accreditation of this program, please contact Global at (303) 395-1782 or inquire@globaleducationgroup.com.

This activity is supported by an educational grant from Genentech, Inc.

9:00 am – 10:00 am 10:00 am – 11:20 am 11:20 am – 11:30 am

Registration and Breakfast Educational Session Q&A Session

Continuing Education Credit This activity has been approved for 1.5 AMA PRA Category 1 CreditsTM

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6. Cheng SK, Dietrich MS, Dilts DM. A sense of urgency: evaluating the link between clinical trial development time and the accrual performance of cancer therapy evaluation program (NCI-CTEP) sponsored studies. Clin Cancer Res. 2010;16:5557-5563, PMID: 21062929.

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multipart series but wish to see the other parts?

5. Dilts DM, Cheng SK, Crites JS, et al. Phase III clinical trial development: a process of chutes and ladders. Clin Cancer Res. 2010;16:5381-5389, PMID: 2106298.

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4. Klabunde CN, Keating NL, Potosky AL, et al. A population-based assessment of specialty physician involvement in cancer clinical trials. J Natl Cancer Inst. 2011; 103:1-14, PMID: 21317382.

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Clinical Oncology News • May 2011

Community Oncology

Q&A With the New ACCC President In March, Thomas Whittaker, MD, assumed the role of president of the Association of Community Cancer Centers (ACCC). Dr. Whittaker is a medical oncologist and physician partner at Central Indiana Cancer Centers in Indianapolis, where he has had a community practice for 17 years. In an interview with Clinical Oncology News managing editor Kate O’Rourke, Dr. Whittaker discusses some of the issues that he hopes to focus on during his presidency. Q: I hear that you are a champion of the oncology medical home. Can you describe briefly what this is and why you are a fan? A: The goal of the oncology medical home and the upcoming accountable care organizations [ACOs] are better care, better health and lower costs. The oncology medical home will mirror the patient-centered medical home that is currently being created and piloted in primary care across the country. These initiatives seek to transform the mission of practices and institutions, so that they can assume ownership of all of a patient’s needs in a highly personalized way. The concept fits very well into the realm of cancer care, where evolving therapies and successes have created practices that can focus on chronic care and not just the acute care that we used to do. We have so many more survivors who we work with for years and years—patients who look to us frequently for primary care, having been through the crisis of cancer. [The medical home looks at] how you leverage technology and enhance the entire care team to actively monitor and streamline treatment and how you optimize outcomes … All of those pieces are part of the oncology medical home. The ACCC will play a very valuable role in that, and I would like to see that as our mission in the next year. Q: Many centers have survivorship care programs. What does the oncology medical home offer that is different? A: It connects the dots. We have a lot of silos where we have preventive care, survivorship and active treatment. The medical home [coordinates those efforts, so that] everyone is working together from start to finish. [It involves] measuring your successes across the entire continuum of care for the patient. The biggest hurdle for some of these [medical home programs] is the reimbursement. The system hasn’t caught up with those kinds of payment schemes. We are still practicing in our current setting where we each do a function and job and want that to be reimbursed. There are going to have to be different payment methods for a medical home and ultimately things like accountable care organizations. Q: The Centers for Medicare & Medicaid Services just released a

proposed rule on ACOs. Is the rule what the ACCC was hoping for in terms of reimbursement? A: Matt Farber, the ACCC director of provider economics and public policy, has issued a response, in which he points out that several issues still need to be reviewed before we can determine whether the proposed rule provides favorable reimbursement for the oncology community. For example, is the shared savings of 50% to 60%, which is lower than some had expected, adequate? Is the risk-sharing aspect of the ACO rule problematic? Also, why no mention of specialty-specific ACOs, such as the oncology-centered ACO?

where they can go for their resources. So, those are the kinds of educational programs that I am anxious to see continue and improve.

Q: Besides championing the cause of oncology medical homes, what other goals do you have as ACCC president? A: The reason that I have so loved being part of this organization for the past 15 years is the association’s mission of education and advocacy. I would like to see that continue and grow. We have some fabulous programs ongoing that [try to reach] all of our membership: physicians, pharmacists, nurses, social workers and hospital administrators. We are working on a dispensing pharmacy initiative, an educational program that looks at metrics for opening a dispensing pharmacy and improving patient care alternatives for that clinic and pharmacy. A dispensing pharmacy is targeted at the community cancer center level. With the advent of so many oral chemotherapeutic agents, this will allow clinics or practices with pharmacists to dispense those agents and supportive care agents. This is a tremendous service for the patient with “one-stop shopping,” but more importantly it will help monitor, educate, validate and coordinate the oral chemotherapeutic care similar to what we have with infusional drugs. We are also looking to continue education on guidelines in community cancer centers and outpatient care settings. We recently completed a survey and study on transitions of care, moving from the hospital to the outpatient setting and how you pass the baton. We also have a really good educational program looking at small-population cancers in the community setting, how they are treated, how members can stay up to date on the latest information and

Q: What rare cancers have you concentrated on? A: We have focused on CML [chronic myeloid leukemia]. We are trying to identify effective practices in the treatment of CML for members. We are establishing designated community resource centers on CML that will serve as enduring sources of information for members. We have done surveys [to find out] how CML is treated at the local level, looking for gaps in knowledge. We are setting up a panel of referral centers that have said, “yes, we treat a lot of CML, and please use us as that easy phone referral source for your members [where members can call with questions].”

The workforce shortage is our biggest crisis.

Q: What types of advocacy efforts do you have ongoing? A: Certainly there is a lot with all the health care changes and regulations that we are going to continue to work on, commenting on LCDs [local coverage decisions] and NCDs [national coverage decisions] and medically unlikely edits. Legislatively, we try to comment and help where we can. We just had 50 of our members on Capitol Hill at last week’s meeting [the ACCC annual meeting]. Q: Is the ACCC involved with the drug shortage issue? A: We are. It is a concern for all of us. We put out a white paper in support of Senate Bill 296. [This bill] tries to get the manufacturers to take a little more responsibility in predicting upcoming shortages. So many of our patients are treated on clinical trials and [the shortages] certainly interrupt

and disrupt those studies. How do you interpret the data if you have not been able to Thomas use all the drugs Whittaker, MD as outlined in the protocols? [It also interferes with] trying to do evidence-based medicine and treating people on pathways. What I don’t understand and what certainly the ACCC doesn’t understand is how, in the past two years, manufacturers can without warning stop manufacture of drugs for a variety of reasons. When only two or three companies make the drug but all come offline at the same time, the timing is suspect. It certainly is frustrating and concerning when they all go down at the same time. Q: At the ACCC meeting, I learned that some oncology practices are using Web portals where patients can gain access to their health information and medical records. What do you think of these portals? A: From a provider standpoint, you decrease phone time and you have 24/7 availability for patients as well as providers. I think it will be a great tool for all of us to use in the future. I do have some concerns, though, because it really takes some of the interpretation out of the loop and that is a huge part of medicine. What is that lump or nodule or why is the potassium high or low? There is just no interpretation [of the data on the Web], whereas if I am sitting with patients in my clinic or talking with them on the phone personally, I can [explain] what it means. We are going to have huge problems with our oncology workforce shortage. Access gets harder and harder as there are fewer and fewer people to treat the increasing number of patients. I think [the portals will] help to address some of the issues of access that are going to be so tough for us. Q: Are there other tools that community practices are starting to use that you see taking off? A: Using electronic medical records [EMRs] in a meaningful useful way will help us standardize care. [Use of EMRs] makes it very easy to use pathways, it helps us to [provide] better evidencebased medicine, and it will help quality across the board. It is an exciting tool that will make our practices better, not that it is without pain. I still remember [when we first implemented EMRs in our clinic], they said, for three months you will hate it, for three months you will tolerate it and then you might appreciate it after six months. I started to appreciate

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Clinical Oncology News • May 2011

Community Oncology

it after month 18, but it really has helped our practice use pathways and improve our quality and quality measures. Q: What do you see as the biggest challenges for oncology practices? A: The access issues that go with the oncologist workplace shortage. Schedules are full and sometimes it is hard to get people in. [The shortage] is in all disciplines, that is the social workers, pharmacists, nurses and physicians. That is probably our biggest crisis. Obviously, the finances and how everything gets paid for is a problem, but truly having

the workforce in place to meet the need, as we see people getting older and we see the incidence of cancer increased, is going to be the huge challenge facing our practices. Q: Have we made any progress on the workplace shortage? A: The ACCC did a great job at getting the word out to our members, but I can’t say that a lot has been done yet to fix the problem. We need more oncologists, we need more mid-level providers and we need more nurses. There are certainly some nursing programs that are

increasing in number. We have not seen an increase yet in oncology fellowships, and there is a problem still with a decrease in some programs because of the lack of funding. Unfortunately, it is quite expensive to train fellows, so those positions are not well funded everywhere. Until we recognize that we need to educate more people and pay for it, it is going to be the continuing stumbling block. Q: Do you have anything else you would like to add? A: I am truly excited to be the ACCC

Senate Bill Addresses Drug Shortages

PHA

SE I

wo Democratic lawmakers have introduced a bill in the U.S. Senate that aims to improve the FDA’s capability to prevent drug shortages. In the past year, these shortages have become a national crisis, threatening patient safety and disrupting clinical trials. If the Preserving Access to Life-Saving Medications Act (S. 296) is signed into law, manufacturers will be required to notify the FDA of any discontinuation, interruption or other adjustment in the manufacture of a drug that “will likely result in a drug shortage.” Companies will be required to provide at least six months notice prior to the date of a manufacturing stoppage or other action affecting a drug’s availability. This covers adjustments related to the supply of raw materials, including active pharmaceutical ingredients; adjustments to production capabilities; and business decisions that may affect the manufacture of the drug, such as mergers, discontinuations and changes in production output. Penalties for failing to notify the FDA will be worked out if or when the bill is enacted, according to the legislative language. The bill also will require the FDA to take several actions. These include publishing information on existing drug shortages on the agency’s Web site and “to the maximum extent practicable, distribute such information to appropriate health care provider and patient organizations.” The FDA also will be responsible for implementing evidence-based criteria for identifying drugs that may be vulnerable to shortages and collaborating with manufacturers to establish and improve continuity of operations plans with regard to medically necessary drugs. The Association of Community Cancer Centers, the American Society of Clinical Oncology and other health care organizations are lobbying in support of the bill. Sens. Amy Klobuchar (D-Minn.) and Robert P. Casey Jr. (D-Pa.) introduced the bill in February, and at press time, the bill had been referred to the Committee on Health, Education, Labor, & Pensions. —Kate O’Rourke

president. It is a great organization. I was born an optimist but one of my partners is really a black belt in optimism. When I told him I was going to do this interview, he said that each year in oncology, there is a new fire drill and the amazing thing is—and he has been doing this 32 years —we have always been able to work through it and keep delivering better care and better therapies. I think that is going to continue to happen. We have new challenges, but the obstacles create innovation and change. I’m thrilled to be part of the leadership of ACCC and to have the opportunity to make an impact.

II TR

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An Investigational Therapeutic Cancer Vaccine for Unresectable Stage III NSCLC START (Stimulating Targeted Antigenic Responses To NSCLC) is a multi-center, Phase III clinical trial assessing the efficacy and safety of BLP25 liposome vaccine, an investigational therapeutic cancer vaccine, in patients with unresectable stage III non-small cell lung cancer (NSCLC), after chemoradiation. Based on experimental models, L-BLP25 may induce an immune response to MUC1, a tumor-associated antigen widely expressed on common cancers, that could potentially harness the body’s natural immune system to target cancer cells directly.1 MAIN INCLUSION CRITERIA Documented stable disease or response within 4 weeks after primary chemoradiotherapy for unresectable stage III disease Receipt of concomitant or sequential chemoradiotherapy: at least two cycles of platinum-based chemotherapy and 50 Gy radiation therapy Completed primary thoracic chemoradiotherapy between 4 and 12 weeks before randomization ECOG PS 0-1 Platelet count 140 x 109/L, WBC 2.5 x 109/L, and hemoglobin 90 g/L

MAIN EXCLUSION CRITERIA Any other lung cancer therapy including surgery Any history of metastatic cancer, malignant pleural effusion, another neoplasm, autoimmune disease, hepatitis B or C, immunodeficiency, or conditions requiring steroid therapy Received investigational systemic drugs (including off-label use of approved products) within 4 weeks prior to randomization

1. Butts C, Anderson H, Maksymiuk A, et al. Long-term safety of BLP25 liposome vaccine (L-BLP25) in patients with stage III/IV non-small cell lung cancer (NSCLC). ASCO Congress 2009; Abstract No. 3055. BLP25 liposome vaccine is currently under clinical investigation and has not been approved for use in the United States, Canada, Europe, or elsewhere. The product has not been proven to be safe or effective and any claims of safety and effectiveness can be made only after regulatory review of the data and approval of the labeled claims.

Learn More About the START Trial

Please call 1-800-507-5284 or refer to www.nsclcstudy.com or www.clinicaltrials.gov (NCT00409188)

101108 - 115622

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HEMATOLOGIC DISEASE

Clinical Oncology News • May 2011

Mantle Cell Lymphoma

New Standard Proposed for Young MCL Patients Orlando, Fla.—Researchers are advocating for a new standard of care in patients with mantle cell lymphoma (MCL) who are younger than 65 years. On the basis of results from a Phase III randomized trial, European researchers recommend alternating courses of R-CHOP and R-DHAP followed by highdose ARA-C (cytarabine) for this segment of the patient population with MCL. They say this regimen is superior to R-CHOP alone followed by autologous stem cell transplant (ASCT) because it increases the proportion of patients who achieve a complete response (CR) prior to ASCT. This outcome, in turn, is associated with a significant advantage in terms of time to treatment failure (TTF) after ASCT. In the multicenter trial, the molecular response to induction therapy, as assessed with real-time quantitative polymerase chain reaction (RQ-PCR), correlated with TTF, the trial’s primary end point, regardless of therapy. According to the lead author of the study, Olivier Hermine, MD, PhD, Necker Hospital, in Paris, this finding reinforces evidence that the quality of the CR before ASCT may be critical to long-term outcome. The experimental protocol “increased significantly the complete response rates and the TTF rates without a major increase in toxicity,” said Dr. Hermine, who presented the study at the annual meeting of the American Society of Hematology (abstract 110). Therefore, the alternating regimen with high-dose ARA-C and ASCT “should become the new standard of care in mantle cell lymphoma patients up to 65 years.” Experts not involved with the study took a more tempered view. “The results of this study are intriguing and promising, but it remains unclear whether the improved time to treatment failure is primarily related to the different induction therapy, improved rate of CR after induction therapy or different conditioning regimen for autologous stem cell transplant. Additional studies will be required to sort that out, and longer follow-up will be needed to determine whether an overall survival benefit emerges,” said Jennifer Brown, MD, PhD, attending physician with the Chronic Lymphocytic Leukemia & Lymphoma Program, Dana-Farber Cancer Institute, and assistant professor of

Complete response, %

100 Six cycles of R-CHOP Experimental arma

80 60 40

36 26

20 0

Figure. Comparison of confirmed complete response prior to ASCT. a

Experimental arm is six alternating cycles of R-CHOP and R-DHAP (rituximab plus dexamethasone, high-dose ARA-C and cisplatinum).

was 36% in the experimental-regimen patients and 26% (P=0.032) in patients on the R-CHOP arm (Figure). A similar advantage for the regimen that included ARA-C in induction and additional myeloablation was observed when the confirmed and unconfirmed CR rates were totaled. Although similar proportions of patients in the experimental and R-CHOP-alone arms (77% and 79%, respectively) went on to ASCT, and the CR rates (63% and 65%) and objective response rates (both arms, 97%) were similar in the two arms following ASCT, the median TTF has not been reached in the experimental arm but was 49 months in patients receiving R-CHOP alone. This difference produced a TTF hazard ratio (HR) of 0.68 (P=0.0352) favoring the experimental regimen. The RQ-PCR analysis showed far better responses with the more aggressive induction regimen. Specifically,

‘This study provides important Phase III data that the addition of high-dose cytarabine to induction therapy and the pretransplant conditioning regimen can improve TTF in younger MCL patients, although longer follow-up is needed to assess any impact on overall survival.’ —Michael E. Williams, MD

medicine at Harvard Medical School, both in Boston. In the trial, conducted by the European Mantle Cell Lymphoma Network (MCL net), 497 patients were randomized to either CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) plus rituximab (R-CHOP) for six cycles followed by ASCT with cyclophosphamide and total body irradiation (TBI) conditioning, or the experimental regimen of six alternating cycles of R-CHOP and R-DHAP (rituximab plus dexamethasone, high-dose ARA-C and cisplatinum) followed by the high-dose myeloablative regimen of melphalan, high-dose ARA-C (cytarabine) and TBI. There were 420 evaluable patients. Almost 80% were male; the median age was approximately 55 years; and 84% had stage IV disease at the beginning of the study. The overall objective response rate exceeded 90% in both groups and did not differ significantly, but the confirmed CR

a complete molecular response (MR) was achieved in 73% of patients in the experimental arm compared with 32% (P<0.0001) of those in the R-CHOP-alone arm. Bone marrow clearance of lymphoma cells was achieved in 68% of patients receiving the experimental regimen compared with 24% of those receiving R-CHOP alone. Overall, 80% of patients in the experimental arm had no minimal residual disease (MRD) after the induction regimen compared with 47% of those on the R-CHOP arm. When the data were pooled in the molecular response analysis, a better quality of response after induction therapy was associated with better TTF, regardless of therapy. Those on the R-CHOP arm who achieved CR had similar outcomes to those on the experimental arm. The investigators concluded that the induction regimen with the best quality of response on a molecular level will provide the highest likelihood of a sustained

remission even when objective response rates and rates of ASCT are similar. The safety of the more aggressive induction regimen was characterized as “compara- Scan for abstract 110; instructions ble” to the other regpage 8. imen, although there were more grade 3 or higher hematologic toxicities, including neutropenia (75% vs. 48%, respectively) and thrombocytopenia (74% vs. 9%). Furthermore, 38% of patients on the experimental regimen, compared with 8% of those on R-CHOP, had grade 1 or 2 creatinine elevations. More patients on the R-CHOP/R-DHAP alternating regimen had nausea and vomiting, although these adverse effects were mostly grade 2 or lower. Overall, the relatively modest increase in adverse events was considered to be acceptable for the significant increase in TTF, concluded Dr. Hermine. The researchers said the data from this trial also suggest that the best next steps to additional incremental improvements in outcome may involve further improvement in the molecular response achieved with the induction regimen. Asked to comment on the implications of this study, Michael E. Williams, MD, chief of the Hematologic Malignancy Section at the University of Virginia Cancer Center, in Charlottesville, endorsed the European researchers’ conclusion about the study, as well as the potential importance of selecting an induction regimen most likely to produce a molecular response. “This study provides important Phase III data that the addition of high-dose cytarabine to induction therapy and the pretransplant conditioning regimen can improve TTF in younger MCL patients, although longer follow-up is needed to assess any impact on overall survival,” Dr. Williams said. “The results further show the achievement of MRD negativity to be a powerful predictor of outcome. Molecular response assessments should be validated in additional prospective trials, both as a prognostic marker and as a means to test the role of ‘preemptive’ therapeutic intervention for patients with molecular relapse.” —Ted Bosworth

If you have missed any recent issues of Clinical Oncology News, please visit www.clinicaloncology.com.

HEMATOLOGIC DISEASE

Clinical Oncology News • May 2011

Multiple Myeloma

VTD Beats VT in Multiple Myeloma Patients The multicenter trial showed that adding bortezomib (Velcade, Millennium) to the combination of thalidomide and dexamethasone at both induction and consolidation therapy improved outcomes in patients newly diagnosed with MM who are undergoing double autologous stem cell transplantation (ASCT). Not least among its relative advantages over the thalidomide-dexamethasone combination (TD), the addition of bortezomib (VTD) overcame the adverse effect of poor cytogenetics. The study authors claim that VTD should be the new standard of care in transplant candidates. Relative to TD alone, “VTD significantly increased rates of CR [complete response], near CR [nCR], and VGPR [very good partial response] or better rates after induction, after transplant and after consolidation,” said the senior investigator Michele Cavo, MD, Seràgnoli Institute of Hematology, Bologna University School of Medicine, Bologna, Italy. He presented the results at the most recent American Society of Hematology (ASH) annual meeting (abstract 42).

VTD over TD, after double ASCT (52% vs. 23%; P<0.0001) and after consolidation (62% vs. 45%; P=0.0002). “The superior CR and nCR rates were maintained across subgroups with a poor prognosis, including those with high-risk cytogenetics,” Dr. Cavo reported. Specifically, in a cytogenetics substudy that compared outcomes between patients who did or did not demonstrate del(13q), t(4;14) and del(17p) by fluorescence in situ hybridization, the presence of t(4;14) with or without the 17p deletion was associated with a lower CR rate and a shorter progression-free survival (PFS) when all patients were evaluated. However, in the group that received VTD, this effect was eliminated. “While t(4;14) had an adverse effect

TD vs. VTD

on PFS in the TD group, the addition of bortezomib overcame this relative disadvantage,” Dr. Cavo stated. He indicated that this finding is consistent with the importance of employing more effective induction regimens to improve the quality of response in order to improve posttransplant outcomes. Overall, the hazard ratio (HR) for progression was reduced by 37% (HR, 0.63; P=0.0061) in the group receiving VTD relative to TD. After a median follow-up of three years, 68% of VTD patients compared with 56% of TD patients remain in PFS. A difference in overall survival (OS) has not yet been detected, but patients are still being followed. On the induction regimen, grade 3 or 4 adverse events (AEs) were more common on VTD than on TD (56% vs. 33%; P<0·0001). This included a greater incidence of peripheral neuropathy (10% vs. 2%; P=0·0004). However, there was no significant difference in the proportion of patients experiencing grade 3 or

In this study, 480 patients were randomized to TD or VTD. Patients were required to be younger than 65 years. The median age was 55 years. In the induction regimen, the TD group received three 21-day cycles of thalidomide (100 mg daily for the first 14 days and 200 mg daily thereafter) plus 40 mg of dexamethasone (on eight of the first 12 days, but not consecutively). The VTD group differed only in that they also received 1.3 mg/m2 bortezomib (on days 1, 4, 8 and 11). When administered as consolidation after double ASCT, TD and VTD were administered in two 35-day cycles. The primary study end point was the CR and nCR rates after induction. On this point of comparison, VTD produced a highly significant, almost threefold advantage over VT (31% vs. 11%; P<0.0001) (Figure). The rates of CR and nCR on an intention-to-treat (ITT) basis remained highly significant, favoring

4 AEs on consolidation therapy. Additionally, severe peripheral neuropathy was observed in only 1% of patients on consolidation therapy, whereas infections, skin rash and thrombosis occurred in less than 1% of patients randomized to either arm. Relative to the clinical advantage of VTD over TD, Dr. Cavo characterized the modest increase in toxicity as “negligible.” In younger patients with MM, novel agents have shifted the treatment framework to transplantation, according to Dr. Cavo. Because transplantation appears to provide the best outcomes when induction provides a CR, Dr. Cavo believes that VTD should be considered the new treatment standard. Despite the fact that a survival advantage has yet to be seen, the greater PFS in the context of a better response with acceptable toxicity suggests that VTD is a step forward over the previous standard of TD, he argued.

‘[There are] two important caveats to be kept in mind before uniform adoption of this or one of the other three-drug regimens as the standard induction therapy for the younger patient with myeloma.’ —Shaji Kumar, MD

Putting It in Perspective Asked to comment on the study’s significance, Shaji Kumar, MD, associate professor of medicine in the Hematology Division at Mayo Clinic, Rochester, Minn., said that the high CR rate “is in line with that observed with other three-drug regimens such as those combining bortezomib and dexamethasone with either lenalidomide or cyclophosphamide,” but he suggested that there are “two important caveats to be kept in mind before uniform adoption of this or one of the other three-drug regimens as the standard induction therapy for the younger patient with myeloma.” The first is that increases in PFS achieved by increasing the depth of response through an increase in the number of drugs in the regimen is encouraging, “but change in practice in this setting should be based on improvement in overall survival.” He noted that the estimated three-year OS of 86% seen in the

Minimally Invasive Cancer Management Frederick L. Greene (Editor), B. Todd Heniford (Editor) For more information, see

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50 VTD

Patients, %

Orlando, Fla.—European researchers are advocating for a new standard of care for certain patients with multiple myeloma (MM), based on results from a Phase III trial.

VT 31

20 10

Figure. Multiple myeloma patients achieving a CR and nCR after induction therapy. CR, complete response; nCR, near complete response; VTD, bortezomib, thalidomide and dexamethasone

European study is similar to that seen in the E4A03 trial comparing two different doses of dexamethasone in combination with lenalidomide for younger patients undergoing stem cell transplant. “These findings once again raise the question whether an approach using the two classes of drug in combination has any advantage over their sequential use,” Dr. Kumar asserted. “While we wait for mature data to answer this question, we should make the decision based on the toxicities.” Consideration of the relative toxicities is the second caveat. Although this study “once again demonstrates the importance of incorporating bortezomib in patients with high-risk disease,” Dr. Kumar pointed out that the threedrug combination was associated with a 10% risk for grade 3 or 4 peripheral neuropathy, which can compromise quality of life. Although the data from Italy are encouraging, Dr. Kumar suggested that they are not yet practice-changing. “Acceptance of VTD as the new standard of care should await the OS data,” Dr. Kumar said. “Meanwhile, the decision to use a three-drug regimen such as VTD or a two-drug regimen with lenalidomide or bortezomib with dexamethasone should be made after a detailed discussion with the patient regarding the pros and cons and taking into consideration the risk status.” —Ted Bosworth

POLICY & MANAGEMENT

Clinical Oncology News • May 2011

Finance

Found Money continued from page 1 

saved by comparing actual and expected costs for Medicare patients attributed to the ACO, and at least 50% of the savings that would be paid to the ACO would depend on the year’s quality-ofcare results. Some CMS pilot programs have shown that the ACO pay-for-performance approach can work. The University of Michigan Health System, for example, reported saving more than $15 million in four years of participation in the Medicare Physician Group Practice Demonstration Project, a program that serves as a prototype for how ACOs would function. The university’s 1,600-physician Faculty Group Practice was one of 10 large physician organizations selected for the five-year CMS project. Based on its experiences with the pilot project, the university formed an ACO to take part in the nationwide shared-savings program once it begins in January 2012. Many other physician groups are setting up ACOs in anticipation of the program’s launch.

Mountain of Paperwork According to the CMS proposal, only primary care practices and hospitals serving at least 5,000 traditional Medicare patients will qualify for ACO recognition. Medicare Advantage participants are excluded. Some health care professionals don’t think this will be enough. David A. Spahlinger, MD, senior associate dean for clinical affairs at the University of Michigan Medical School, in Ann Arbor, believes that at least 25,000 patients will be needed to demonstrate the impact of quality care on cost savings. But for markets where an ACO is able to dominate health care delivery, the question arises as to whether this raises antitrust concerns. Officials from the CMS, the Department of Justice (DOJ) and the Federal Trade Commission have promised that smaller ACOs—those in markets where they control less than 30% of the health care business—will not have to worry about antitrust action by the DOJ. Even ACOs with a market share of 30% to under 50% will be relatively free from DOJ scrutiny. However, larger ACOs, with 50% or more, will need clearance. The DOJ promises rapid decisions, but the process will require some heavy paperwork. That potential paperwork on top of what also will be required to comply with ACO regulations was one of the concerns raised by Barbara L. McAneny, MD, chief executive officer (CEO) of New Mexico Oncology Hematology Consultants Ltd. Dr. McAneny said that oncology practices with staffs already

Will ACOs Hurt Small Community Practices?

ccountable care organizations (ACOs) may turn out to deliver all of the benefits that government officials envision, but for some in the oncology community the proposed rule has left many unanswered questions about their impact on the future of smaller oncology practices. One of the biggest concerns is that ACOs might accelerate the trend to medical practice consolidation and large-scale health system domination, while innovative smaller oncology practices are swallowed up or its physicians pushed into hospital employment. “Without question in medical oncology, we are seeing practices consolidate, we are seeing small practices go away, we are seeing physicians and practices being absorbed into hospital systems,” said Allen S. Lichter, MD, chief executive officer of the American Society of Clinical Oncology. “It’s not going to take too much of a nudge from an ACO that is tilted in favor of those things happening to make this occur with much, much greater frequency.” Dr. Lichter said ASCO believes that consolidation “may not be something that the health care system wants or needs. The ability of organizations to compete one against the other, showing value and pushing each other to achieve better and better results, we believe is important for innovation. He stressed the importance of not creating “a system that has so many disadvantages for the single community-based specialty practice that they’re trying to run this race with an anchor tied to their leg.”

saddled with regulatory compliance requirements may be reluctant to take on additional burdens, and hospitals may step into the breach, an outcome that could accelerate the trend toward more hospital-employed oncologists. “Once we have oncologists being employed by hospitals,” she said, “we will regret it because that is the more expensive side of service.” Dr. McAneny also expressed concern about how practices like hers, which have become extremely efficient to survive, would be able to find additional cost savings to qualify for shared savings promised under the ACO program. Her practice sees about 3,000 new patients per year. “We are set up to try to manage acutely ill patients and keep them out of the hospital,” said Dr. McAneny. “I don’t know where I’m going to find a lot more efficiencies, because over the past three to four years when reimbursement started declining, the practice had to get significantly more efficient.”

Is Provider Choice a Barrier? Under the proposed rule, Medicare beneficiaries attributed to a particular ACO are not obliged to stay within an ACO’s network of primary care physicians, specialists and hospitals. They are free to select any provider, just as in the traditional fee-for-service Medicare program. That freedom of choice has raised some worries about how ACOs will be able to control quality and costs if the patients attributed to them obtain their care from physicians or hospitals outside the network. “We really depend on a lot of physicians outside of our institution [University of Michigan] for the overall care of these patients,” Dr. Spahlinger said. He noted that half of the patients assigned to the university’s demonstration project received their primary care outside

of the university network, and one-third of patients were hospitalized elsewhere. A high degree of coordination with other physicians is needed to do a good job. “We need to think of ourselves as a partner in care, where we take care of [patients] and then hand them off in a really coordinated fashion, [knowing clearly] “the responsibility of the physicians we’re handing them off to and when we need to see [the patients] again and under what conditions,” Dr. Spahlinger said. “These are things we don’t often communicate very well.” For oncology practices that opt not to join an ACO, the attribution issue could be a challenge. Dr. McAneny feels that doctors within ACOs may be under strong pressure to refer only to oncologists affiliated with their network. For this reason, she said, “oncologists in the market need to start courting their primary care referral sources to make sure that they recognize that [the oncologists] will try and control costs to make this work better.” Dr. McAneny said her practice has been working with a software organization to devise a mechanism to manage costs and “make sure I know where the money is going, because I think that within an ACO model whoever gets the money first and is the distributor is going to do very well and everybody at the end of the line is going to do very badly.” Another worry is the cost of newer cancer treatments. “If you’re an oncology practice and you’re participating in an ACO,” said Ted Okon, MBA, executive director of the Community Oncology Alliance (COA), “you’re going to have a tremendous amount of pressure placed on you to reduce costs, especially when you’re in an area that may account for a couple of percentage points of patients but 10% of the costs.” Mr. Okon added: “How do you deal with a new $93,000 a year prostate

vaccine or $120,000 for a four-course melanoma treatment drug? All of a sudden, they sort of break the bank.”

CMS Proposal Lacking

Scan for a Medical Homes article. Instructions page 8.

According to Mr. Okon, the CMS ACO proposal “basically forgot cancer care.” He said, “If you study the measures, they cover virtually every other key area of medicine related to both the inpatient and outpatient side, except cancer care.” Calling the patient-centered medical home “a better alternative for oncology,” Mr. Okon said that COA has been working on some medical home projects that offer a proper balance between quality and cost. “This isn’t an exercise in railing against ACOs,” he said, noting that the model has potential benefits including fulfilling the need for more coordination of care. Allen S. Lichter, MD, CEO of the American Society of Clinical Oncology, has several concerns about ACOs (sidebar). Despite his concerns, Dr. Lichter thinks that oncology practices may be a “reasonably good candidate for an ACOtype model” because so much of oncologists’ work is interdisciplinary, “involving multiple specialties working in concert to create an outcome for patients.” Dr. Lichter added that the concept of working together to create higher-quality, lower-cost care and sharing the savings with the practitioners who created the efficiencies was an extremely exciting challenge. “The bottom line,” he said, “is that if it is done well, patients will have a better health care experience, will have a better outcome, and we’ll do it at less cost.” —Bruce Buckley

And the winner is ... Gloria Kennedy, MD, a pediatric hematologist/ oncologist and assistant professor of pediatrics at Upstate Medical University, Syracuse, N.Y., is the lucky winner of the latest Clinical Oncology News reader survey contest. Dr. Kennedy was selected randomly from the survey respondents and will receive an Apple iPad. Thanks to all of the entrants!

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SOLID TUMORS

Clinical Oncology News • May 2011

Lung

BATTLE

Study Population Biopsied continued from page 1 

the April issue of Cancer Discovery, a recently launched peer-reviewed journal from the American Association for Cancer Research (AACR). While tumor biomarker evaluations recently have emerged for treating lung cancer and a few biological agents are available for these patients, developing a personalized approach to lung cancer has progressed more slowly than in other tumor types such as breast or colon malignancies. “The prevailing concept is that identifying the molecular target from the aberrant pathway is more important than histology, with respect to selection of targeted agents,” said Waun Ki Hong, MD, head of cancer medicine at MD Anderson. He presented the BATTLE trial during the plenary session at the AACR meeting in April. Dr. Hong pointed out that progress in treating patients with NSCLC seems to be at a standstill. “The benefits from standard treatment seem to have reached a plateau,” Dr. Hong said. “The cure rate we have right now is 17%, and that is not acceptable. We needed some new directions.” That direction, according to Dr. Hong, is a personalized approach based on molecular and genomic profiling.

A New Era The road map for success in personalized lung cancer prevention and therapy is composed of four steps in basic and clinical research: improved understanding of tumor biology, identification of high-risk patients through risk modeling, identification of molecular targets and inhibition of the targets with appropriate agents. The promise of personalized care begins with an improved recognition of the heterogeneity of lung cancer. Until recently, the molecular pathways of lung cancer pathogenesis had been largely unknown, said Dr. Hong. Recent developments in the laboratory have revealed some of the key factors in lung cancer evolution and progression. However, the new understanding has brought with it better appreciation of the molecular and biologic complexity of the disease process. The new emphasis on personalized medicine has given rise to the concept of reverse migration. The concept encompasses several key hypotheses: Premalignancies share biologic properties with malignancies; effective targeted therapy of advanced cancer may be applicable in the adjuvant setting and perhaps even to prevention; and clinical experience with tamoxifen in breast cancer has supported the rationale of reverse migration from therapy to prevention.

Biomarker Profile • EGFR mutation/copy number • KRAS/BRAF mutation • VEGF/VEGFR-2 expression • RXRs/Cyclin D1 expression and CCND1 copy number

Figure. BATTLE schema. BATTLE, Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination; EGFR, epidermal growth factor receptor; RXRs, retinoid X receptors; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor

A five-gene signature showed promise for identifying erlotinib responders in the remaining 88% of lung cancer patients without EGFR changes.

Identifying Who Can Benefit From Erlotinib The BATTLE trial—Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination—employed a novel adaptive trial design that involved serial lung biopsies, rapid turnaround of molecular profiling results, biomarker discovery and adjustment of therapy to each patient’s tumor characteristics. “We used real-time biopsies to detect aberrant signaling pathways of lung cancer,” said Dr. Hong. “We tested the hypothesis that matching targeted agents with abnormal pathways will improve disease control.” In the study of 255 patients, disease control at eight weeks, the primary end point of the trial, was 46%. This represented a 50% improvement over historical patient cohorts. Another analysis of data from the BATTLE trial produced gene expression profiles that showed potential for identifying patients who are most likely to respond to the epidermal growth factor receptor (EGFR) inhibitor erlotinib. The current approach to predicting response to the agent involves identifying amplifications and mutations in EGFR, a strategy that covers only about 12% of patients. A five-gene signature showed promise for identifying erlotinib responders in the remaining 88% of lung cancer patients without EGFR changes, said John Heymach, MD, associate professor of thoracic/head and neck oncology at MD Anderson. Investigators analyzed lung biopsy specimens from 101 patients in the trial and 54 lung cancer cell lines for evidence of genes involved in epithelial-to-mesenchymal transition (EMT), an early step in the progression of lung cancer. Among patients with this signature, 83% met the

trial’s primary end point of eight-week disease control, compared with none of the patients without the signature. Additionally, Dr. Heymach and colleagues identified a set of EMT genes that predicted response to erlotinib by a different means. Among patients with epithelial-type cells, 64% had disease control at eight weeks in contrast to 10% of patients with mesenchymaltype cells.

Adjuvant Trials “The outcome of the BATTLE trial represents a substantial step toward personalized lung cancer therapy,” said Dr. Hong. “BATTLE paves the way forward for adjuvant and prevention trials.” The BATTLE approach to personalized care received support in the adjuvant setting in the form of a retrospective study published earlier this year in the Journal of Thoracic Oncology. The study involved 167 patients with NSCLC and EGFR mutations in exons 19 and 21, changes known to be associated with improved response to treatment with an EGFR tyrosine kinase inhibitor. About one-third (56) of the patients received an EGFR inhibitor as part of adjuvant therapy. That subgroup had a 47% improvement in the risk for twoyear disease-free survival compared with 111 patients who did not receive an EGFR inhibitor. The potential for personalized therapy in the adjuvant setting also has been evaluated in the VITAL (Vanguard Investigations of Therapeutic Approaches to Lung Cancer) research program, said Dr. Hong. Led by Drs. Kim and Hong, investigators have performed molecular profiling of bronchial brush cytologies and biopsies of patients with surgically resected stage I-IIIa NSCLC.

Results showed that gene expression profiles differ in a site-dependent manner (adjacent vs. non-adjacent fields). The profiling showed that different patterns of gene expression in adjacent fields are associated with cancer recurrence. The work also has demonstrated the feasibility of identifying potential targets for personalized adjuvant strategies, said Dr. Hong. The strategy will be tested in an upcoming BATTLE trial of adjuvant therapy.

Chemoprevention The new lung cancer strategy also provides opportunities for chemoprevention. To date, trials of lung cancer chemoprevention uniformly have produced negative results. Dr. Hong cited five reasons for the failure of these trials: no clear targets, no target inhibition, unclear or unmeasurable preneoplasia, use of agents selected on the basis of epidemiologic data, and failure to account for adverse interactions between tobacco carcinogens and chemopreventive agents in smokers. An important part of an effective chemoprevention strategy is the ability to perform molecular profiling in a noninvasive manner. Recent studies involving long-term smokers have shown good correlation between oral and lung epithelium promoter DNA methylation, suggesting a potential for noninvasive assessment of changes associated with cancer. A personalized approach to lung cancer chemoprevention should use interventions that are appropriate for an individual patient’s risk profile. For example, patients with average or moderate risk might be managed by lifestyle changes. Chemoprevention and screening by computed tomography would apply to high- and very high-risk patients. Dr. Hong said, “selection of chemopreventive agents must be based on known molecular targets and on safety and efficacy data from a biomarker-integrated prevention trial.” —Charles Bankhead

FDA NEWS

Clinical Oncology News • May 2011

FDA NEWS continued from page 8 

of ipilimumab plus placebo, or gp100 vaccine plus placebo. All patients were HLA-A0201-positive, an entry criterion required because of the inclusion of the gp100 vaccine. Overall survival was the primary end point. Those who received the combination of ipilimumab plus the vaccine or ipilimumab alone lived an average of about 10 months, whereas those who received only the experimental vaccine lived an average of 6.5 months. Because of the unusual and severe side effects associated with ipilimumab, the drug is being approved with a Risk Evaluation and Mitigation Strategy to inform health care professionals about these serious risks. A medication guide also will be provided to patients to inform them about the therapy’s potential side effects. Common side effects include fatigue, diarrhea, skin rash, endocrine deficiencies (gland or hormone), and colitis. Severe to fatal autoimmune reactions were seen in 12.9% of patients treated with ipilimumab. When severe side effects occurred, ipilimumab was stopped and corticosteroid treatment was started. Not all patients

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responded to this treatment. Patients who did respond in some cases did not see any improvement for several weeks. The greatest risk for significant morbidity and death was associated with attacks on the gastrointestinal system.

NovoCure Approved for Glioblastoma

he FDA has approved the NovoTTF100A System (NovoCure), a device to treat adults with glioblastoma multiforme (GBM) that recurs or progresses after receiving chemotherapy and radiation therapy. When using the NovoTTF-100A System, a health care professional places electrodes on the surface of the patient’s scalp to deliver low-intensity, changing electrical fields called “tumor treatment fields” (TTFs) to the tumor site. The unique shape and electrical characteristics of dividing tumor cells make them susceptible to damage when exposed to TTFs. The device

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is portable and can be powered with batteries or plugged into an electrical outlet. Patients can use the device at home, allowing them to continue their normal daily activities. The FDA based its approval of the NovoTTF 100A System on results from a single international clinical study involving 237 patients with glioblastoma tumors that had recurred or progressed despite previous surgical, radiation and chemotherapy treatments. Patients were randomized to receive either the NovoTTF-100A System or chemotherapy of a physician’s choice. Median overall survival was comparable in the two arms. Patients treated with the NovoTTF experienced a slightly higher incidence of neurologic side effects including convulsions and headaches compared with patients receiving chemotherapy. However, they did not experience the significant side effects associated with chemotherapy, including nausea, anemia, fatigue and serious infections. The most commonly reported side effect from NovoTTF treatment was a mild to moderate rash beneath the electrodes. Patients treated with NovoTTF also had improved quality-of-life scores compared with patients receiving

chemotherapy. Specifically, quality-oflife scores improved relating to vomiting, nausea, pain, diarrhea, constipation and cognitive and emotional functioning. Patients should not use the NovoTTF100A System if they have an implanted medical device or a skull defect, or have a known sensitivity to conductive hydrogels, such as those used with electrocardiograms.

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permanent placement www.cancercarepoint.com

The following additional adverse reactions (not in table) were observed in patients with ovarian cancer with doses administered every four weeks. Incidence 1% to 10%: Cardiovascular: vasodilation, tachycardia, deep thrombophlebitis, hypotension, cardiac arrest. Digestive: oral moniliasis, mouth ulceration, esophagitis, dysphagia, rectal bleeding, ileus. Hemic and Lymphatic: ecchymosis. Metabolic and Nutritional: dehydration, weight loss, hyperbilirubinemia, hypokalemia, hypercalcemia, hyponatremia. Nervous: somnolence, dizziness, depression. Respiratory: rhinitis, pneumonia, sinusitis, epistaxis. Skin and Appendages: pruritus, skin discoloration, vesiculobullous rash, maculopapular rash, exfoliative dermatitis, herpes zoster, dry skin, herpes simplex, fungal dermatitis, furunculosis, acne. Special Senses: conjunctivitis, taste perversion, dry eyes. Urinary: urinary tract infection, hematuria, vaginal moniliasis. Patients With AIDS-Related Kaposi’s Sarcoma: The safety data below is based on the experience reported in 753 patients with AIDS-related Kaposi’s sarcoma enrolled in four studies. The median age of the population was 38.7 years (range 24-70 years), which was 99% male, 1% female, 88% Caucasian, 6% Hispanic, 4% Black, and 2% Asian/other/unknown. The majority of patients were treated with 20 mg/m2 of DOXIL every two to three weeks. The median time on study was 127 days and ranged from 1 to 811 days. The median cumulative dose was 120 mg/m 2 and ranged from 3.3 to 798.6 mg/m2. Twenty-six patients (3.0%) received cumulative doses of greater than 450 mg/m2. Of these 753 patients, 61.2% were considered poor risk for KS tumor burden, 91.5% poor for immune system, and 46.9% for systemic illness; 36.2% were poor risk for all three categories. Patients’ median CD4 count was 21.0 cells/mm3, with 50.8% of patients having less than 50 cells/mm3. The mean absolute neutrophil count at study entry was approximately 3,000 cells/mm3. Patients received a variety of potentially myelotoxic drugs in combination with DOXIL. Of the 693 patients with concomitant medication information, 58.7% were on one or more antiretroviral medications; 34.9% patients were on zidovudine (AZT), 20.8% on didanosine (ddI), 16.5% on zalcitabine (ddC), and 9.5% on stavudine (D4T). A total of 85.1% patients were on PCP prophylaxis, most (54.4%) on sulfamethoxazole/trimethoprim. Eighty-five percent of patients were receiving antifungal medications, primarily fluconazole (75.8%). Seventy-two percent of patients were receiving antivirals, 56.3% acyclovir, 29% ganciclovir, and 16% foscarnet. In addition, 47.8% patients received colony-stimulating factors (sargramostim/filgrastim) sometime during their course of treatment. Adverse reactions led to discontinuation of treatment in 5% of patients with AIDS related Kaposi’s sarcoma. Those that did so included bone marrow suppression, cardiac adverse reactions, infusion-related reactions, toxoplasmosis, HFS, pneumonia, cough/dyspnea, fatigue, optic neuritis, progression of a non-KS tumor, allergy to penicillin, and unspecified reasons. Table 4: Hematology Data Reported in Patients With AIDS-Related Kaposi’s Sarcoma Patients With Refractory or Intolerant AIDS-Related Kaposi’s Sarcoma (n = 74) Neutropenia <1000/mm3 <500/mm3 Anemia <10 g/dL <8 g/dL Thrombocytopenia <150,000/mm3 <25,000/mm3

Total Patients With AIDS-Related Kaposi’s Sarcoma (n = 720)

34 8

(45.9%) (10.8%)

352 96

(48.9%) (13.3%)

43 12

(58.1%) (16.2%)

399 131

(55.4%) (18.2%)

45 1

(60.8%) (1.4%)

439 30

(60.9%) (4.2%)

Table 5: Probably and Possibly Drug-Related Non-Hematologic Adverse Reactions Reported in With AIDS-Related Kaposi’s Sarcoma Adverse Reactions

Nausea Asthenia Fever Alopecia Alkaline Phosphatase Increase Vomiting Diarrhea Stomatitis Oral Moniliasis

Patients With Refractory or Intolerant AIDS-Related Kaposi’s Sarcoma (n = 77) 14 5 6 7 1 6 4 4 1

(18.2%) (6.5%) (7.8%) (9.1%) (1.3%) (7.8%) (5.2%) (5.2%) (1.3%)

Infections and infestations Herpes zoster Herpes simplex Investigations Weight decreased Metabolism and Nutritional disorders Anorexia Nervous system disorders Peripheral Neuropathy* Neuralgia Paresthesia/dysesthesia Respiratory, thoracic and mediastinal disorders Cough Skin and subcutaneous tissue disorders Rash** Hand-foot syndrome

11 10

2 0

0 0

9 6

2 1

0 0

42 17 13

7 3 <1

<1 0 0

45 20 10

10 4 0

1 1 0

22 19

1 6

0 0

18 <1

1 0

0 0

*Peripheral neuropathy includes the following adverse reactions: peripheral sensory neuropathy, neuropathy peripheral, polyneuropathy, peripheral motor neuropathy, and neuropathy NOS. **Rash includes the following adverse reactions: rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic, exfoliative rash, and rash generalized. Post Marketing Experience: The following additional adverse reactions have been identified during post approval use of DOXIL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Musculoskeletal and Connective Tissue Disorders: rare cases of muscle spasms. Respiratory, Thoracic and Mediastinal Disorders: rare cases of pulmonary embolism (in some cases fatal). Hematologic disorders: Secondary acute myelogenous leukemia with and without fatal outcome has been reported in patients whose treatment included DOXIL. Skin and subcutaneous tissue disorders: rare cases of erythema multiforme, StevensJohnson syndrome and toxic epidermal necrolysis have been reported. DRUG INTERACTIONS: No formal drug interaction studies have been conducted with DOXIL. DOXIL may interact with drugs known to interact with the conventional formulation of doxorubicin HCl. USE IN SPECIFIC POPULATIONS: Pediatric Use: The safety and effectiveness of DOXIL in pediatric patients have not been established.

5% of Patients

Total Patients With AIDS-Related Kaposi’s Sarcoma (n = 705) 119 70 64 63 55 55 55 48 39

Table 6: Frequency of treatment emergent adverse reactions reported in 10% patients treated for multiple myeloma with DOXIL in combination with bortezomib, by Severity, Body System, and MedDRA Terminology. (continued) Adverse DOXIL + bortezomib Bortezomib Reaction (n=318) (n=318) Any Grade Grade Any Grade Grade (%) 3 4 (%) 3 4

(16.9%) (9.9%) (9.1%) (8.9%) (7.8%) (7.8%) (7.8%) (6.8%) (5.5%)

The following additional (not in table) adverse reactions were observed in patients with AIDS-related Kaposi’s sarcoma. Incidence 1% to 5%: Body as a Whole: headache, back pain, infection, allergic reaction, chills. Cardiovascular: chest pain, hypotension, tachycardia. Cutaneous: herpes simplex, rash, itching. Digestive: mouth ulceration, anorexia, dysphagia. Metabolic and Nutritional: SGPT increase, weight loss, hyperbilirubinemia. Other: dyspnea, pneumonia, dizziness, somnolence. Incidence Less Than 1%: Body As A Whole: sepsis, moniliasis, cryptococcosis. Cardiovascular: thrombophlebitis, cardiomyopathy, palpitation, bundle branch block, congestive heart failure, heart arrest, thrombosis, ventricular arrhythmia. Digestive: hepatitis. Metabolic and Nutritional Disorders: dehydration. Respiratory: cough increase, pharyngitis. Skin and Appendages: maculopapular rash, herpes zoster. Special Senses: taste perversion, conjunctivitis. Patients With Multiple Myeloma: The safety data below are from 318 patients treated with DOXIL (30 mg/m2 as a 1-hr i.v. infusion) administered on day 4 following bortezomib (1.3 mg/m2 i.v. bolus on days 1, 4, 8 and 11) every three weeks, in a randomized, open-label, multicenter study. In this study, patients in the DOXIL + bortezomib combination group were treated for a median number of 138 days (range 21-410 days). The population was 28-85 years of age, 58% male, 42% female, 90% Caucasian, 6% Black, and 4% Asian and other. Table 6 lists adverse reactions reported in 10% or more of patients treated with DOXIL in combination with bortezomib for multiple myeloma. Table 6: Frequency of treatment emergent adverse reactions reported in 10% patients treated for multiple myeloma with DOXIL in combination with bortezomib, by Severity, Body System, and MedDRA Terminology. Adverse DOXIL + bortezomib Bortezomib Reaction (n=318) (n=318) Any Grade Grade Any Grade Grade (%) 3 4 (%) 3 4 Blood and lymphatic system disorders Neutropenia 36 22 10 22 11 5 Thrombocytopenia 33 11 13 28 9 8 Anemia 25 7 2 21 8 2 General disorders and administration site conditions Fatigue 36 6 1 28 3 0 Pyrexia 31 1 0 22 1 0 Asthenia 22 6 0 18 4 0 Gastrointestinal disorders Nausea 48 3 0 40 1 0 Diarrhea 46 7 0 39 5 0 Vomiting 32 4 0 22 1 0 Constipation 31 1 0 31 1 0 Mucositis/Stomatitis 20 2 0 5 <1 0 Abdominal pain 11 1 0 8 1 0

Geriatric Use: Of the patients treated with DOXIL in the randomized ovarian cancer study, 34.7% (n=83) were 65 years of age or older while 7.9% (n=19) were 75 years of age or older. Of the 318 patients treated with DOXIL in combination with bortezomib for multiple myeloma, 37% were 65 years of age or older and 8% were 75 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients. OVERDOSAGE: Acute overdosage with doxorubicin HCl causes increases in mucositis, leucopenia, and thrombocytopenia. Treatment of acute overdosage consists of treatment of the severely myelosuppressed patient with hospitalization, antibiotics, platelet and granulocyte transfusions, and symptomatic treatment of mucositis. 0016716-5B Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 Distributed by: Ortho Biotech Products, LP Raritan, NJ 08869-0670

An ALZA STEALTH® Technology Product

STEALTH® and DOXIL® are registered trademarks of ALZA Corporation.

For your patients receiving or about to start treatment with DOXIL® for recurrent ovarian cancer or relapsed/refractory multiple myeloma…

DOXIL® C.A.R.E.S. Provides Help and Support DOXIL® C.A.R.E.S. Complements the Efforts of the Healthcare Team With: ◗ Treatment follow-up — Regularly scheduled telephone calls from oncology nurses to review lifestyle tips to help manage potential side effects of DOXIL® therapy such as hand-foot syndrome and stomatitis ◗ Patient education materials Invite your patients to enroll in DOXIL® C.A.R.E.S.: 1-877-CARES-49 (1-877-227-3749) Monday to Friday, 9:30 AM to 10:00 PM (ET). To learn more, visit www.doxil.com.

INDICATIONS

◗ DOXIL® is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy ◗ DOXIL® in combination with VELCADE® (bortezomib) is indicated for the treatment of patients with multiple myeloma who have not previously received VELCADE and have received at least one prior therapy

IMPORTANT SAFETY INFORMATION

BOXED WARNINGS Cardiotoxicity, infusion reaction, myelosuppression, liver impairment, substitution ◗ The use of DOXIL® may lead to cardiac toxicity. Myocardial damage may lead to congestive heart failure and may occur as the total cumulative dose of doxorubicin HCl approaches 550 mg/m2 — Prior use of other anthracyclines or anthracenediones should be included in calculations of total cumulative dose — Cardiac toxicity may also occur at lower cumulative doses (400 mg/m2) in patients with prior mediastinal irradiation or who are receiving concurrent cyclophosphamide therapy ◗ Acute infusion-related reactions including, but not limited to, flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest or throat, and/or hypotension have occurred in up to 10% of patients treated with DOXIL®. In most patients, these reactions have resolved within several hours to a day once the infusion is terminated. In some patients, reactions resolved with slowing of the infusion rate — Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have occurred. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use — The initial rate of infusion should be 1 mg/min to minimize the risk of infusion reactions ◗ Severe myelosuppression may occur ◗ DOXIL® dosage should be reduced in patients with impaired hepatic function ◗ Accidental substitution has resulted in severe side effects. Do not substitute for doxorubicin HCl on a mg per mg basis CONTRAINDICATIONS ◗ Patients with a history of hypersensitivity reactions to a conventional doxorubicin formulation or the components of DOXIL® ◗ Nursing mothers

ADDITIONAL SAFETY INFORMATION ◗ Cardiac function should be carefully monitored

— Congestive heart failure or cardiomyopathy may occur after discontinuation of anthracycline therapy — For patients with a history of cardiovascular disease, or if the results of cardiac monitoring indicate possible cardiac injury, the benefit of therapy must be weighed against the risk of myocardial injury — In the randomized multiple myeloma study, 25 patients (8%) in the VELCADE arm and 42 patients (13%) in the DOXIL® plus VELCADE arm experienced left ventricular ejection fraction decrease (defined as absolute decrease 15% over baseline or a 5% decrease below institutional lower limit of normal)

◗ Myelosuppression may occur; frequently monitor complete blood count (including platelet count), at least prior to each dose of DOXIL® — In patients with recurrent ovarian cancer, hematologic toxicity (based on platelet count or absolute neutrophil count) may require dose reduction or delay in administration of DOXIL® — In patients with multiple myeloma, hematologic toxicity (based on platelet count, absolute neutrophil count, hemoglobin level, or neutropenia with fever) may require dose reduction, delay in administration, or suspension of DOXIL® and/or VELCADE — Persistent severe myelosuppression may result in superinfection, neutropenic fever, or hemorrhage — Sepsis occurring during neutropenia has resulted in discontinuation of treatment and in rare cases of death ◗ DOXIL® may potentiate the toxicity of other anticancer therapies, especially hematologic toxicities, when used in combination with other therapies that suppress bone marrow ◗ Hand-foot syndrome (HFS) may occur during therapy with DOXIL® — Based on HFS toxicity grade, dose reduction, delay in administration, or discontinuation of DOXIL® may be required — HFS was generally observed after 2 to 3 cycles of treatment, but may occur earlier • The reaction was mild in most patients, resolving in 1 to 2 weeks • The reaction can be severe and debilitating in some patients, resulting in discontinuation of therapy ◗ DOXIL® is an irritant, not a vesicant; use precautions to avoid extravasation ◗ DOXIL® can cause fetal harm when used during pregnancy ◗ Recall reaction has occurred with DOXIL® administration after radiotherapy ◗ DOXIL® may interact with drugs known to interact with the conventional formulation of doxorubicin HCl ◗ In patients with recurrent ovarian cancer, the most common all-grade adverse reactions (ARs) 20% (DOXIL® vs topotecan, respectively) included: asthenia (40% vs 51%), fever (21% vs 31%), nausea (46% vs 63%), stomatitis (41% vs 15%), vomiting (33% vs 44%), diarrhea (21% vs 35%), anorexia (20% vs 22%), dyspnea (15% vs 23%), HFS (51% vs 1%), and rash (29% vs 12%) — In addition, 19% vs 52.3% reported alopecia (all grades) — Grade 3/4 hematologic ARs reported in 5% (DOXIL® vs topotecan, respectively) were neutropenia (12% vs 76%) and anemia (6% vs 29%) ◗ In patients with multiple myeloma, the most common all-grade ARs 20% (DOXIL® plus VELCADE vs VELCADE, respectively) included: neutropenia (36% vs 22%), thrombocytopenia (33% vs 28%), anemia (25% vs 21%), fatigue (36% vs 28%), pyrexia (31% vs 22%), asthenia (22% vs 18%), nausea (48% vs 40%), diarrhea (46% vs 39%), vomiting (32% vs 22%), constipation (31% vs 31%), mucositis/ stomatitis (20% vs 5%), peripheral neuropathy (42% vs 45%), neuralgia (17% vs 20%), and rash (22% vs 18%) — In addition, 19% vs <1% reported HFS Please see brief summary of Prescribing Information, including Boxed WARNINGS, on adjacent pages. VELCADE is a registered trademark of Millennium Pharmaceuticals, Inc.

Distributed by: Centocor Ortho Biotech Products, L.P., Horsham, Pennsylvania 19044-3607 © Centocor Ortho Biotech Products, L.P. 2010 9/10 08D10019A