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

McMahon Publishing

Independent News for the Oncologist and Hematologist/Oncologist clinicaloncology.com • March 2011 • Vol. 6, No. 3

FDA NEWS

News regarding rituximab, radiology application, and 3-D mammography. SOLID TUMORS

6 10 19

Clinicians discuss meaning of meta-analysis of Avastin studies.

Studies support prognostic value of circulating tumor cells in early and metastatic breast cancer.

New regimen shows promise in rectal cancer. PRN

Maurie Markman, MD, discusses evidence-based guidelines.

HematOlogic DISEASE

Richard Stone, MD, discusses novel treatment avenues for AML/MDS.

EDUCATIONAL REVIEW

Management of Patients With Treatment-Refractory Metastatic Renal Cell Carcinoma

After page 12.

WWW.CMEZONE.COM

Gene Test Predicts Risk for Recurrence in Colon Cancer San Francisco—An 18-gene molecular assay developed in Europe accurately classifies stage II colorectal cancer (CRC) patients for their risk for recurrence, according to a study presented at the 2011 Gastrointestinal Cancers Symposium (GCS; abstract 358). “ColoPrint facilitates the identification of patients with a low risk for recurrence and who therefore don’t need chemotherapy,” reported Robert Rosenberg, MD, assistant professor at Technical University Munich in Germany. He noted that the survival benefit of adjuvant chemotherapy is small in patients with stage II CRC, ranging between 2% and 3% according to the literature. It is much higher, however, for the 20% to 30% of stage II patients see COLOPRINT, page 12 

Experts Debate Standard Of Care for Anal Cancer San Francisco—Two sets of data on the treatment of locally advanced anal carcinoma have drawn different conclusions about whether 5-fluorouracil (5-FU) plus mitomycin (MMC) should remain the standard chemotherapy in combination with radiation (RT) or whether cisplatin-based (CP) chemoradiotherapy is an acceptable alternative. The larger of the two studies was a randomized Phase III investigation that concluded that RT plus 5-FU/ MMC should remain the standard based on a significant overall survival (OS) and disease-free survival (DFS) benefit over RT plus 5-FU/CP in the most Simple squamous cell carcinoma of the anal canal. Courtesy of Dr. Stanley Hamilton, MD Anderson Cancer Center. recent follow-up. The smaller study was a single-institution retrospective evaluation, which associated CP-based chemoradiation with a better OS at five years than both the Phase III study and historical controls. Both see STANDARD, page 18 

In Anaplastic Lymphoma ...

New Drug Produces Remarkable Response Orlando, Fla.—Used as a single agent, the investigational drug, brentuximab vedotin (Seattle Genetics), produced tumor control in 95% of patients with anaplastic large cell lymphoma (ALCL) who were refractory to previous therapies. Despite the fact that these results come from a Phase II study with 58 patients, the magnitude of the response is remarkable in a population that had already cycled through an average of two previous multi-agent treatments. The median duration of response has not yet been met. The study agent is an anti-tubulin see BRENTUXIMAB, page 8 

POLICY & MANAGEMENT

Found Money: Part 1 of a Four-Part Series

Financial Survival Tactics for Struggling Oncology Practices

inding relief in today’s challenging health care economy is no easy task. Oncology practices struggle daily with the demands associated with managing patients on an ever-widening array of expensive, highly specific therapies, while coping with reimbursement rates that have failed to keep pace with cost trends and seeing a growing number of

McMahonMedicalBooks.com Cancer Pain: Assessment and Management Eduardo D. Bruera (Editor), Russell K. Portenoy (Editor)

For more information, see page 24.

people lose the means to cover their treatment bills. “There are some who would like to dismiss the basic laws of economics,” said Ted Okon, MBA, executive director of the Community Oncology Alliance, “but the reality is that if you’re operating a medical practice it has to operate as a business, and unless the see FOUND MONEY, page 20 

Product News Rituximab (Rituxan, Genentech) gets new indication for follicular lymphoma. See page 4.

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

FDA NEWS

Clinical Oncology News • March 2011

Rituxan Gets New Indication For Follicular Lymphoma

0.42-0.70; P<0.0001). The international, multicenter trial enrolled 1,217 patients with previously untreated advanced follicular lymphoma. Eight cycles of rituximab plus either CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone), CVP (cyclophosphamide, vincristine and prednisone) or FCM (fludarabine, cyclophosphamide and mitoxantrone) chemotherapy was used as initial treatment. Patients who responded to this initial treatment (n=1,018) were randomized to observation or maintenance therapy with rituximab, 375-mg/m2 infusion every two months for two years. The safety profile was

he FDA has approved rituximab (Rituxan, Genentech) as a maintenance treatment for patients with advanced follicular lymphoma who responded to initial treatment with rituximab plus chemotherapy. Approval was based on the PRIMA (Primary Rituxan and Maintenance) study, which demonstrated that rituximab maintenance therapy every two months for two years nearly doubled progression-free survival (PFS) compared with no further treatment (hazard ratio, 0.54; 95% confidence interval,

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).]

consistent with that previously reported in pivotal studies of rituximab alone or in combination with chemotherapy.

3-D Mammography System

he FDA has approved the first x-ray mammography device that provides three-dimensional (3-D) images of the breast: Selenia Dimensions System (Hologic). Because conventional two-dimensional (2-D) mammography has limitations, roughly 10% of women undergo additional testing after the initial screening exam for abnormalities that are later

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.

FDA NEWS

Clinical Oncology News • March 2011

determined to be noncancerous. The 3-D images may help physicians more accurately detect and diagnose breast cancer. The device, an upgrade to Hologic’s 2-D system, can provide 2-D and 3-D x-ray images of the breasts. The FDA approved the system after reviewing results from two studies in which board-certified radiologists were asked to review 2-D and 3-D images from more than 300 mammography exams. In both studies, radiologists viewing both 2-D and 3-D images attained an improvement of 7% in their ability to distinguish between cancerous and noncancerous cases than if they had used 2-D images

alone. Hologic’s FDA submission estimated that with 2-D and 3-D together, radiologists may increase their cancer detection rate by an average of 10% to 15%, while also reducing their recall rates. Although the combination of the Selenia’s 2-D and 3-D images approximately doubled the radiation dose the patient received, it improved the accuracy with which radiologists detected cancers, decreasing the number of women recalled for a diagnostic workup. The increase in cancer risk from having both a 2-D and 3-D exam is expected to be less than 1.5% compared with the

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

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

natural cancer incidence, and less than 1% compared with the risk from conventional 2-D mammography. The company said that although the use of 2-D and 3-D requires additional radiation compared with 2-D alone, the radiation dose is still very low and less than the Mammography Quality Standards Act radiation dose limits for a single 2-D mammography exposure.

Mobile Radiology Application Approved

new mobile radiology application will allow physicians to view medical see FDA NEWS, page 21 

SOLID TUMORS

Clinical Oncology News • March 2011

Multiple Cancers

Meta-analysis of Avastin Studies Sparks Debate Cancer patients receiving bevacizumab could be at higher risk for treatment-related death when the drug is combined with chemotherapy, a recent study suggests. In a meta-analysis of randomized clinical trials covering more than 10,000 patients with a variety of advanced tumors, researchers at Stony Brook University School of Medicine in Stony Brook, N.Y., observed that the overall incidence of fatal adverse events (FAEs) with bevacizumab (Avastin,

Genentech) was 2.5%. Patients receiving bevacizumab in addition to chemotherapy were 1.46 times more likely to have an FAE (P=0.01) than those receiving chemotherapy alone. The association with greater risk for FAEs varied significantly with chemotherapeutic agents (P=0.045), but not with tumor types

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

(P=0.13) or bevacizumab doses (P=0.16). Bevacizumab was associated with a nearly 3.5-fold increased risk for FAEs in patients receiving taxanes or platinum agents (3.3% vs. 1%) but was not associated with increased risk for FAEs when used in conjunction with other agents, such as nonplatinum and nontaxane-based therapies and cytokines, according to the study, which was published in the Journal of the American Medical Association (2011;305:487-494, PMID: 21285426). The most common

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.

causes of FAEs were hemorrhage (24%), neutropenia (12%) and gastrointestinal tract perforation (7%). Principal investigator Shenhong Wu, MD, PhD, assistant professor of medicine at Stony Brook, told Clinical Oncology News that despite the findings, the drug still is “OK to use. “The take-home message for us is physicians and patients should be aware of the risks, and physicians should monitor patients closely to prevent fatal toxicities,” Dr. Wu said. For the study, Dr. Wu and colleagues reviewed all citations of randomized clinical trials of bevacizumab published in PubMed between 1966 and Oct. 30. They also reviewed abstracts and virtual meeting presentations from American Society of Clinical Oncology conferences from 2000 to 2010, and performed independent searches of other databases. They used statistical analyses to assess the association of the drug and development of FAEs, which previously had not been defined. A total of 10,217 patients (5,589 taking bevacizumab and 4,628 in control groups) from 16 clinical trials were included in the analysis. There were 148 total FAEs among those taking bevacizumab. The highest incidence (13.4%) was observed in a Phase II lung cancer trial; the lowest incidence was observed in a Phase III breast cancer trial that had no FAEs. Using a random-effects model, researchers found the overall incidence of FAEs in bevacizumab patients to be 2.5%.

‘The take-home message for us is physicians and patients should be aware of the risks, and physicians should monitor patients closely to prevent fatal toxicities.’ —Shenhong Wu, MD, PhD

“Given that the absolute risk of treatment-related mortality appears low, the use of bevacizumab should be considered in the context of overall survival benefits,” the authors wrote. Richard Gralla, MD, chief of hematology-oncology and vice president for cancer services at North Shore-Long Island Jewish Health System in Lake Success, N.Y., says the study highlights that bevacizumab “deserves our serious concern. If you see higher mortality rates but not higher survival, what does this say for the value of this mechanism of action?” see META-ANALYSIS, page 13 

PRN

Clinical Oncology News • March 2011

Evidence-based Medicine

The Evidence for Evidence-based Guidelines ADVISORY BOARD EDITORIAL Maurie Markman, MD Vice President of Patient Oncology Services and National Director for Medical Oncology, Cancer Treatment Centers of America, Philadelphia

There are two words with rather straightforward definitions1: Evidence: Something that furnishes proof Based: The point or line from which a start is made in an action or undertaking Yet, when used together and preceding the words “medicine” or “guidelines,” they are recognized to imply a superior approach to health care delivery. The concept of a practitioner who employs “evidence” in the selection of treatment with a serious medical condition, such as cancer, is a powerful one. Who would not want to be treated based on “evidence”? But what exactly does the expression “evidence-based medicine” really mean, specifically in the context of management of an individual patient? It is perhaps most appropriate to begin this discussion with a less abstract concept. Level of evidence is an expression used to convey a defined hierarchy of the quality of certain “evidence.” Randomized trials and meta-analyses of multiple such studies are considered the highest level of evidence. Anecdotal case reports (at the alternative extreme) represent a

far lower degree of evidence on which to potentially base medical decisions. It is likely there would be little (if any) debate regarding either the reliability or wisdom of using this general conceptual approach to assist busy clinicians in their decision-making process. Recently, however, the use of the term evidence has evolved from this rather narrow concept to define the overall quality of data to the establishment of “treatment guidelines,” where acceptable levels of evidence are used to select therapy for an individual patient in a particular clinical setting. Such recommendations often are defined very specifically and at times rather rigidly. It is important to note that those engaged in what might reasonably be described as a meaningful peer-to-peer educational exercise designed to optimize the quality of patient care did not necessarily intend for their efforts to be used to either directly select or potentially routinely deny care for individual patients felt to be medically appropriate by their own physicians. Unfortunately, this is precisely how some organizations (including third-party medical insurance carriers) have elected to employ these documents. But what is the evidence supporting the fundamental objectivity of these socalled “evidence-based guidelines”? Is it appropriate to state these current efforts represent a “high level” of evidence? In fact, despite the good intentions of those who have accepted the challenge to develop therapeutic guidelines, the existing data suggest these efforts are

A recent review of National Comprehensive Cancer Network clinical practice guidelines found that, overall, less than 10% of therapeutic recommendations were classified as category 1 evidence.

far from what a truly objective, disinterested observer would reasonably classify as being “evidence-based.” For example, a recent report of an analysis of “levels of evidence” supporting guidelines produced by the Infectious Diseases Society of America found that only 14% of the recommendations were based on at least one “properly conducted randomized trial” (level 1 evidence).2 Furthermore, the majority of the recommendations in these guidelines (55%) were based on level 3 evidence (“evidence from opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees”).2 A similar outcome was noted in an analysis of guidelines in the cardiology arena.3 And a recent review of National Comprehensive Cancer Network clinical

see EVIDENCE, page 18 

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Solid Tumors

Infection Control

Bone Metastases

Susan K. Seo, MD

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practice guidelines found that, overall, less than 10% of therapeutic recommendations were classified as category 1 evidence (“high level of evidence such as randomized controlled trials with uniform consensus”).4 Additionally, other concerns have been expressed regarding the medical guideline development process. These include potential conflict of interest among individuals designing the guidelines and the appropriate composition of specific guideline committees.3 Finally, very serious questions have been appropriately raised regarding the actual quality of the individual randomized trials and metaanalyses that form the foundation for any claim that a particular guideline is “evidence-based.”5,6 These data, and the

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HEMATOLOGIC DISEASE

Clinical Oncology News • March 2011

AML & MDS

Developing New Treatment Avenues for AML and MDS In recent years, the genetic underpinnings accounting for the development of acute myeloid leukemia (AML) and myelodysplasia (MDS) have become increasingly understood. ADVISORY BOARD EDITORIAL Richard Stone, MD Director of the Adult Leukemia Program, Dana-Farber Cancer Institute, and Professor of Medicine, Harvard Medical School, Boston

Some mutations, such as an activating mutation of the FLT3 tyrosine kinase in AML, represent an important arena for therapeutic development: small molecule inhibition of a gain-of-function tyrosine kinase mutation. New studies presented at the most recent American Society of Hematology (ASH) annual meeting show researchers are making progress in finding additional

therapeutic targets. It remains to be seen whether such small molecule inhibition either alone or in conjunction with standard chemotherapy is beneficial in patients with mutant FLT3 AML. Genome sequencing studies suggest that the development of AML requires abnormalities in 10 or more genes, so it will likely be necessary to inhibit multiple targets in a given patient. Point mutations in TET2 occur in approximately 10% to 20% of patients with acute and chronic myeloid malignancies. Based on previously published studies and those presented at the 2010 ASH meeting, the prognostic impact of TET2 mutations is likely minimal, but such mutations cause epigenetically mediated changes in gene expression panels. The function of the protein

Figure. Enzymatic reaction catalyzed by TET2. Relation with DNA methylation. Courtesy of Anna Jankowska.

encoded by the TET2 gene is to convert 5-methylcytosine to 5-hydroxymethylcytosine (5-hmC). Methylation of cytosine residues represents an important epigenetic modification that cells use to control gene expression. Cancer cells

may have abundance of over-methylated promoters upstream of genes that control growth, such as tumor suppressor genes. The so-called hypomethylating agents, azacitidine (Vidaza, Celgene) and decitabine (Dacogen, Eisai),

Lymphoma

BRENTUXIMAB continued from page 1 

drug monomethyl auristatin (MMAE) conjugated with a monoclonal antibody. It binds specifically to the CD30 receptor of malignant cells and is then internalized. Once inside the cell, it can deliver MMAE, which disrupts the microtubule network to induce cell cycle arrest and apoptosis. Presenting the data at the most recent American Society of Hematology annual meeting (abstract 961), Andrei R. Shustov, MD, said there were high rates of objective response (OR) and prolonged progression-free survival (PFS), not only in anaplastic lymphoma kinase (ALK)positive tumors but also in the 72% of patients with the traditionally more resistant ALK-negative malignancies. At the time of entry into this study, “62% of patients had been refractory to front-line therapy, 50% were refractory to the last treatment they received and 24% had never responded to any therapy,” said Dr. Shustov, a research associate at the Fred Hutchinson Cancer Research Center, University of Washington, Seattle. About one-fourth of patients had failed a previous high-dose therapy with autologous stem cell transplant (SCT). Nearly one-third of this population had B symptoms at baseline, approximately 20% had cutaneous lesions and 14% had bone marrow involvement. All patients received brentuximab vedotin in a dose of 1.8 mg/kg

100

Patients, %

40 20 0

Objective response

Complete response

Figure. Effectiveness of brentuximab in anaplastic large cell lymphoma. administered every three weeks as a 30‑minute outpatient IV infusion. Patients were permitted up to 16 cycles of treatment, but the median number of cycles was six. Staging of the disease was performed periodically throughout the course of the study. The primary end point of the study was objective response (OR), which was evaluated by independent expert panel. With 30% of the patients in the study still on treatment, the OR rate is 86% with complete response (CR) achieved in 53% (Figure). Only 5% (one patient) progressed on therapy. The concordance for responses was very high among the expert panel members, who reported shrinkage in more than 95% of tumors. In those who achieved a partial response, the median PFS, which was a

‘This treatment is destined to be a major breakthrough in the management of CD30positive lymphoma. It appears to be very efficacious with very acceptable side effects.’ — Raymond Liang, MD

secondary end point, was 19 weeks but has not yet been reached in those who achieved a CR. Median PFS for the study overall is 41 weeks. Of patients with B symptoms at the start of treatment, 82% reported the symptoms resolved. Cutaneous lesions resolved in 93% of patients. Responses were similar in ALK-positive and ALK-negative patients. For example, the OR rates were 81% and 88%, respectively, whereas the CR rates were 53% and 50%, respectively. After treatment, 24% of patients were able to proceed to an allogeneic or autologous SCT. The efficacy was accompanied by relatively low rates of toxicity. Of the grade 3 or higher adverse events (AEs), the most common, occurring in 15% of patients, was thrombocytopenia. Grade 3 or higher neutropenia was observed in 12% of patients. Although 10% of patients developed grade 3 sensory neuropathy, there was no grade 4 neuropathy, and the neuropathy resolved in about 50% of patients soon after treatment was discontinued. There were no treatmentrelated deaths, and less than 10% of

patients discontinued therapy due to AEs related to the study drug. Although dose delays were common, occurring in 31% of the cycles, dose reducScan for tions were needed in abstract 961; only 9% of cycles. instructions page 7. A clinical trial combining brentuximab vedotin with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) in newly diagnosed ALCL is already being implemented, Dr. Shustov said. Both the activity and the tolerability make expanded studies in a variety of other malignancies with CD30 cells likely. Dr. Shustov was not alone in suggesting that this may be an important new therapy. “This treatment is destined to be a major breakthrough in the management of CD30-positive lymphoma. It appears to be very efficacious with very acceptable side effects,” said Raymond Liang, MD, director, Hematology Center, Hong Kong Sanatorium and Hospital, Hong Kong. Asked if he had any reservations, Dr. Liang indicated that clearly more studies are needed to investigate both efficacy and safety, commenting that the “neuropathy is not severe but worth noting.” Dr. Liang, however, is among many oncologists who think this drug has an important future not just for anaplastic lymphoma but for other hematologic malignancies. —Ted Bosworth

HEMATOLOGIC DISEASE

Clinical Oncology News • March 2011

AML & MDS

both approved for MDS patients, may improve disease outcome by allowing the expression of genes that can control neoplastic growth. The first paper presented at the plenary session of the 2010 ASH annual meeting provided important insights into the mechanism of leukemogenesis in a subset of patients with AML and MDS. This work was carried out by investigators at the Cleveland Clinic in collaboration with several Harvard Medical School–affiliated institutions, including Children’s Hospital and Dana-Farber Cancer Institute (abstract 1). Knowing the function of the TET2encoded enzyme, these researchers asked whether patients with TET2 mutations might in fact have lower levels of the expected gene product of the TET2 gene protein, namely 5-hmC. Indeed, the levels of 5-hmC in genomic DNA from patients with mutations are significantly decreased in comparison with those without mutations. They also found patients without TET2 mutations who had decreased 5-hmC levels; one may speculate that there may be as yet another unidentified mutation that allows for these biochemical abnormalities.

Article Reprints

This epigenetic dysregulation induced by the TET2 mutation suggests that it might be reasonable to target DNA methylation in the subset of patients with AML and MDS who have a TET2 mutation.

The authors introduced TET2 mutations into model cells and noted that these cells showed greatly diminished 5-hmC levels. Moreover, overexpression of TET2 in cell lines yielded alteration of promoter methylation compared with control cells, indicating that TET2 controls epigenetic events.

This epigenetic dysregulation induced by the TET2 mutation suggests that it might be reasonable to target DNA methylation in the subset of patients with AML and MDS who have a TET2 mutation. The French MDS study group showed that MDS patients with a TET2 mutation were more likely to respond

to azacitidine (abstract 439). Although the overall response duration and survival were not improved in the TET2 patients exposed to azacitidine, the higher response rate lent some credence to the importance of TET2 mutations being clinically predictive. Additional clinical trials will be needed to prove that DNA hypomethylating agent therapy would be best applied just to those with known epigenetic dysregulation, but the work presented at ASH on TET2 mutations represents an important first step in understanding the interplay disease-based genetics and drug treatment.

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.

Reprints of Clinical Oncology News articles are available.

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).

Call Julianna Dawson at (212) 957-5300 x271. Reprints can be ordered in black & white or 4-color. 101108 - 115024

SOLID TUMORS

Clinical Oncology News • March 2011

Breast

Prognostic Value of Circulating Tumor Cells Bolstered San Antonio—Measurements of circulating tumor cells (CTCs) may provide important prognostic information for breast cancer patients, according to two studies presented at the 2010 San Antonio Breast Cancer Symposium (SABCS). One study showed that the presence of one or more CTCs nearly doubled the risk for relapse and death in patients with early-stage breast cancer, and a second study found that CTCs were a strong and independent prognostic factor during first-line treatment for metastatic breast cancer.

blood samples of 435 patients (21.5%). At a median follow-up of 35 months, 114 recurrences and 66 deaths were documented. Patients who were CTC-positive before treatment was initiated had a significantly worse disease-free survival (DFS) than those who were CTC-negative (mean DFS of 38.5 months vs. 41.4

‘Patients who seem to be at high risk due to the presence of CTCs may benefit from additional treatment options, while those who don’t have any CTCs may be spared side effects of some treatments.’

—Brigitte Rack, MD

A bloodstream with red and white blood cells shown clearly along with circulating tumor cells in blue. (© Veridex LLC, used with permission.)

evaluate the role of CTC quantification and treatment options for CTC-positive patients with early-stage disease.

Metastatic Breast Cancer However, during an SABCS press conference discussing the studies, experts agreed that the findings are preliminary and that CTC testing should not be used routinely for early breast cancer, for which it is not FDA-approved. They were divided as to the utility of this technique in metastatic breast cancer, for which it is approved. Minetta Liu, MD, director of translational breast cancer research at Georgetown University’s Lombardi Comprehensive Cancer Center in Washington, D.C., who moderated the press conference, said, “Although we can now enumerate CTCs, there is a large effort to extend our abilities beyond quantifying these cells. The exact nature of CTCs is unknown, but they appear to originate from established tumors and circulate in the peripheral blood in a dormant state, unrecognized by the host’s immune system.”

Early Breast Cancer The SUCCESS (Simultaneous Study of Gemcitabine-Docetaxel Combination Adjuvant Treatment, as well as Extended Bisphosphonate and Surveillance) study, of 2,026 patients with primary breast cancer stages I through III, was designed to sample blood for CTC and tumor markers using CellSearch technology (Veridex, LLC) at four different time points: before chemotherapy, after chemotherapy, after two years of endocrine/zoledronic acid treatment and after five years of endocrine/zoledronic acid treatment (S6-5). Samples with at least one CTC were considered CTC-positive. During the SABCS, investigator Brigitte Rack, MD, presented data based on the pretreatment samples. At this time point, CTCs were detected in the

months, respectively; P<0.0001). Overall survival (OS) also was significantly worse for those who were CTC-positive prior to treatment initiation (P=0.0002). The presence of CTCs before treatment was confirmed as an independent predictive factor for both DFS (hazard ratio [HR], 1.88) and OS (HR, 1.91). Patients who were CTC-positive before treatment were more likely to be node-positive, but no correlation was observed between CTC status and tumor size, grade or hormone-receptor status. Outcome was correlated with number of CTCs, with the worst prognosis observed in patients with five or more CTCs, who had a fourfold risk for recurrence and a threefold risk for cancer-related death (P<0.05). “This study confirms the independent prognostic relevance of CTCs in early breast cancer in a large patient cohort,” said Dr. Rack, head of the Department of Gynecologic Oncology at the Women’s Hospital at the University of Munich in Germany. “We think our study suggests that testing CTCs may be helpful in individualizing therapy for early-stage breast cancer where no measurable tumor is present. Patients who seem to be at high risk due to the presence of CTCs may benefit from additional treatment options, while those who don’t have any CTCs may be spared side effects of some treatments,” Dr. Rack said. She cautioned that clinicians should not “measure CTCs in the adjuvant setting outside of a clinical trial” because the treatment options for CTC-positive patients have not been delineated. She noted that prospective, randomized trials are ongoing or about to be started in the United States and Europe to further

A second study confirmed the independent prognostic value of CTCs using CellSearch, this time during firstline therapy of metastatic breast cancer. This study also found that persistence of high CTCs during therapy was an early marker of poor outcome (S6-6). CTCs were compared with serum tumor markers (i.e., CA 15.3, carcinoembryonic antigen [CEA], and lactate dehydrogenase [LDH]) in 267 patients treated with first-line therapy for metastatic breast cancer; patients were enrolled at one of five different cancer centers in France between June 2007 and September 2009. Median follow-up was 16 months. Almost two-thirds of patients (65%) had at least one CTC; 44% had five or more CTCs. Of tumor markers, 64% had elevated CA 15.3, 51% had elevated CEA, and 45% had elevated LDH. The presence of CTC levels predicted poor progression-free survival (PFS) and OS, independent of tumor markers (P<0.00001). Elevated levels of CA 15.3, CEA and LDH were prognostic for PFS, but only LDH remained prognostic for OS. “This is the largest, prospective series validating the prognostic value of CTCs in first-line chemotherapy [for] metastatic breast cancer, independent of serum tumor markers, for overall survival,” said lead author Jean-Yves Pierga, MD, PhD, professor at the Institut Curie and Université Paris Descartes in France. “Persistence of high levels of CTCs before the second cycle of chemotherapy was a strong and early predictive marker of poor outcome.”

Clinical Utility of CTC Test Allison Stopeck, MD, associate professor of medicine at the Arizona Cancer

Scan for abstract S6-5; instructions page 7.

Scan for abstract S6-6; instructions page 7.

Center in Tucson, said that she does not test for CTCs in her practice because it is a quantitative measure. “We need phenotyping to make it useful. I can tell which of my patients [with metastatic breast cancer] is progressing without this test,” she said. “Testing for CTCs won’t replace scans for me.” Dr. Liu said that results from CellSearch complement other tests she uses, especially radiology studies. In her opinion, CTC testing does not replace scans, but it can reduce the number of scans ordered per patient. “Repeated imaging is time away from family and exposure to additional risk, so use of a reliable blood test to determine the most appropriate timing for scans can have a positive impact on a patient’s quality of life,” noted Dr. Liu. “The technique is useful for day-to-day decisions in many patients. For patients diagnosed with metastatic breast cancer, imaging and CTC enumeration are part of the data collection.” Additionally, she said, “Patients with no disease-related symptoms and persistent measurements of zero are likely to do very well on therapy.” However, she acknowledged that the absence of CTCs also could be seen in patients with poor outcomes related to metastatic disease, presumably because the cells are undetected by the existing technology. “But,” she added, “these patients will have additional signs or symptoms of rapidly progressing disease.” —Bonnie Gillis

SOLID TUMORS

Clinical Oncology News • March 2011

Breast

Bevacizumab Not Effective in Early Breast Cancer San Antonio—Adding bevacizumab to neoadjuvant chemotherapy did not significantly improve pathologic complete response (pCR) in patients with early or locally advanced human epidermal growth factor receptor 2 (HER2)-negative breast cancer during a large German Phase III trial. The trial, called GeparQuinto, is the first randomized Phase III trial of bevacizumab in early or locally advanced HER2-negative breast cancer. Presenting the results during the San Antonio Breast Cancer Symposium (abstract S4-6), investigator Gunter von Minckwitz, MD, said that the overall pCR rate was 17.5% for the bevacizumab-containing arm versus 15% for those treated with neoadjuvant chemotherapy without bevacizumab, a difference that was not statistically significant. Dr. von Minckwitz, managing director of the German Breast Group in Neu-Isenburg, Germany, noted that the absolute difference between the two treatment arms—2.5%—was driven by the triplenegative (i.e., estrogen-receptor [ER], progesterone-receptor [PR], and HER2/ neu receptor-negative) subgroup, in which there was a 40% improvement in pCR with the addition of bevacizumab. Dr. von Minckwitz postulated that “perhaps if we only included triple-negative patients in this study, we would have seen significantly improved pCR with the addition of bevacizumab.” The GeparQuinto investigators randomized 1,948 women with HER2-negative breast carcinoma to receive epirubicin (90 mg/m2) plus cyclophosphamide (600 mg/m2; EC) with or without bevacizumab (15 mg/kg every 3 weeks), followed by docetaxel (100 mg/m2) with or without bevacizumab (15 mg/kg every 3 weeks). Response was assessed after four cycles of EC, and responders in each arm received four cycles of docetaxel with or without bevacizumab. Patients who did not respond to four cycles of treatment were taken out of the analysis and randomized to paclitaxel versus paclitaxel plus everolimus. Dr. von Minckwitz explained that the treatment choice for nonresponders was based on previous experience in the GeparTrio trial, in which patients who did not respond in midcourse had little chance of achieving response on conventional chemotherapy and thus were given a different, less toxic, treatment. Surgery was performed one month after the last infusion of bevacizumab. The definition for the primary end point of pCR used in the GeparQuinto trial was stringent: no invasive or noninvasive residual viable tumor cells in any resected specimens of the breast and axillary nodes. Secondary end points were compliance and toxicity, other pCR definitions, breast-conserving surgery

rate and efficacy in predefined stratified subgroups. At baseline, patient and tumor characteristics were comparable between the two treatment arms. Mean age was roughly 48 years; median tumor size was

approximately 4 cm; multifocal disease was present in about 23%; approximately 43% were grade 3; approximately 35% were ER- and PR-negative; and no patient was HER2-positive. Roughly two-thirds of patients in both groups were able to

have breast-conserving surgery. “Bevacizumab did not markedly increase serious adverse events [AEs]” when it was added to epirubicin-cyclophosphamide, noted Dr. von Minckwitz, but he said it almost doubled them when it was added to docetaxel. In the first phase, 15.7% of those in the EC plus docetaxel arm, and 11.8% of those given epirubicin-docetaxel alone reported serious adverse events. In the second phase, when the patients went see HER2, page 12 

SOLID TUMORS

Clinical Oncology News • March 2011

Colon

COLOPRINT

Table. Distant Metastasis-Free Survival

continued from page 1 

at high risk for recurrence. Currently, patients are classified as high-risk by clinical factors, such as the presence of an emergency operation; pathologic factors, such as micrometastases in lymph nodes or circulating tumor cells; and more recently, molecular profiling. The study presented at GCS was the second independent validation of ColoPrint and included 233 patients. “No other prognostic genetic profile in colorectal cancer has been subjected to a second validation,” Dr. Rosenberg said. The study was sponsored by Agendia, Inc, the maker of ColoPrint; the company also makes the MammaPrint test for breast cancer. Several of the authors listed the company as their affiliation. Of patients classified as high-risk by the ColoPrint assay—27% of all patients—80.5% were free of distant metastases at five years compared with 94.9% of those classified as low-risk, according to Dr. Rosenberg. The gene signature test outperformed the clinical parameters recommended by ASCO for evaluating the risk status of stage II patients. These are inadequate tumor staging with less than 12 assessed lymph nodes, T4 tumors, tumor perforation or poorly differentiated tumors. Although both assessments found that about 75% of patients were low-risk and 25% highrisk, there was discordance between the two assessment methods in about 50% of patients. The ColoPrint assay found that for the 24% of patients who were microsatellite instability-high, a good prognostic feature by clinical parameters, 84% were

Variable

Comparison

Hazard Ratio

95% Confidence Interval

P Value

ColoPrint

High vs. low

4.126

1.309-13.01

0.009

Clinical Parameters Recommended by ASCO for Assessing Risk

High vs. low

2.13

0.641-7.074

0.206

Microsatellite instability

Microsatellite instability high vs. Microsatellite stability

0.29

0.038-2.28

0.21

Lymph nodes >12

Yes/no

0.546

0.120-2.494

0.428

Tumor perforation

3 vs. 4

1.141

0.25-5.206

0.865

Grade

High vs. moderate

1.724

0.547-5.434

0.346

classified as low-risk by the gene test. None of the clinical factors remained significant in the multivariate analysis. In contrast, a patient’s classification by ColoPrint retained its significance as an independent predictor of distant diseasefree survival. The risk for recurrence was fourfold higher for high- versus low-risk patients, using the gene-based approach (hazard ratio, 4.126; 95% confidence interval, 1.309-13.01; P<0.009) (Table). For the last two years, clinicians have had the option of using another gene signature assay, Oncotype DX, to predict recurrence risk in CRC. According to Dr. Rosenberg, ColoPrint differs from Oncotype DX in that it was developed from an “unbiased” whole genome array and is microarray-based, rather than reverse transcription polymerase chain reaction-based. Additionally, it classifies patients only as high- or low-risk; Oncotype DX also includes an intermediaterisk category.

According to Dr. Rosenberg, a third clinical validation study of ColoPrint is ongoing, as is a prospective evaluation, the PARSC (Prospective study for the Assessment of Recurrence risk in Stage II CC patients using ColoPrint) trial, which aims to include 600 patients with stage II colon cancer in the United States, Asia and Europe. Commenting on the study for Clinical Oncology News, Wells Messersmith, MD, director of the GI Medical Oncology Program at the University of Colorado in Denver, said the study does not provide enough answers for him. “It is important to note that this study answers only half of the key questions,” he said. “We need to know the subset of stage II patients we should treat, and there are no data as to whether the patients classified as ‘high-risk’ benefit from treatment,” he pointed out. “As an oncologist, I want a test that tells me who to treat, and this assay does not do that. It only tells me

who I probably should not be treating— the good-risk patients. I also want to know the subset of ‘poor-risk’ patients who will benefit from adjuvant chemotherapy.” Several clinicians believe that the test also will be limited by the need for a fresh tissue sample, the same limitation that Oncotype DX currently faces. This issue could significantly limit the clinical use of this test as most specimens are paraffin-embedded, unless specifically collected for protocol purposes or with the presumption that the patient has stage II colon cancer. Nevertheless, if the PARSC trial validates the current findings, ColoPrint will be another tool to help oncologists assess colon cancer. The test is scheduled to launch in the U.S. in 2012. GCS is sponsored by the American Society of Clinical Oncology, American Gastroenterological Association, American Society for Radiation Oncology and the Society of Surgical Oncology. —Audrey Andrews

Therapy in Triple Negative Breast Cancer] and long-term survival [data] have to be presented before drawing definite conclusions.” Commenting on the findings, Maura N. Dickler, MD, associate attending physician in the breast cancer medicine service at Memorial Sloan-Kettering Cancer Center, in New York City, said, “Unfortunately, the addition of bevacizumab did not increase the pCR rate in this population of unselected HER2-negative patients in the neoadjuvant setting,” but she called “the trend toward an improved pCR rate in patients with triple-negative breast cancer … intriguing.” Dr. Dickler said that the results of GeparQuinto highlight the need to identify biomarkers to aid in the selection of patients most likely to respond to anti-vascular endothelial growth factor (VEGF) therapy. More data is needed from ongoing adjuvant and neoadjuvant trials such as CALGB40603, she added, “to determine if bevacizumab will improve disease-free survival and

overall survival for our patients, which is the ultimate goal of therapy.” Larry Norton, MD, deputy physicianin-chief for breast cancer programs at Memorial Sloan-Kettering Cancer Center, also said more studies are needed with different approaches and study designs, noting that the findings of the GeparQuinto trial raise fundamental questions about the interrelationships of cancer biology and clinical trials. He commented that “since cancer involves at least three processes—mitotic aberrations, invasion and metastatic behavior—all of which relate to neoangiogenesis, we may ask what it is that we expect to perturb by an anti-VEGF agent that would be reflected in higher complete response rates to chemotherapy. One could envision that an agent that profoundly inhibits invasion and metastasis, and hence might have clinical value, might not inhibit mitosis or augment apoptosis, and hence could fail in a clinical trial assessing only tumor shrinkage.” Furthermore, he said, “the likelihood

that tumors of different cellular origins, say luminal versus basal, might respond differently to such an agent further complicates the story.” Additionally, one cannot assume that a dose schedule that has an optimal antimitotic or proapoptotic effect is the same as one that has an optimal antimetastatic effect.” For these reasons, Dr. Norton said, “one cannot look at data such as that presented by Dr. von Minckwitz and reach the simple conclusion that ‘bevacizumab doesn’t work.’ Modern cancer biology is not simple! If we are to realize the promise of targeted therapy we need to rethink, reconstruct and reassess clinical trial design, respecting this complexity.”

Breast

HER2 continued from page 11 

on to receive docetaxel, serious events were reported in 23.1% of those in the docetaxel-bevacizumab arm and 12.9% of those given docetaxel alone. Serious wound healing problems were reported in five patients treated with bevacizumab versus none of the patients in the control group. “Thus far, there were fewer than expected problems with wound healing associated with bevacizumab, but we will analyze nonserious wound healing problems further,” Dr. von Minckwitz said. A large number of tumor specimens were collected both before and after neoadjuvant therapy and they will be analyzed to identify biomarkers and subgroups that preferentially benefit from bevacizumab, he said. Regarding the future of bevacizumab in early breast cancer, Dr. von Minckwitz said, “Ongoing studies such as NSABP B-40 and BEATRICE [Bevacizumab Adjuvant

—Bonnie Gillis Dr. von Minckwitz and the GeparQuinto investigators received support from Sanofi-aventis and Roche. Dr. Dickler is a consultant for Roche and Genentech. Dr. Norton had no financial disclosures.

PRINTER-FRIENDLY VERSION AT CLINICALONCOLOGY.COM Brought to you by the publisher of

Management of Patients With

Treatment-Refractory Metastatic Renal Cell Carcinoma SABY GEORGE, MD Assistant Professor, Oncology Roswell Park Cancer Institute Buffalo, New York

RONALD M. BUKOWSKI, MD Director of Experimental Therapeutics Cleveland Clinic Taussig Cancer Institute Cleveland, Ohio

enal cell carcinoma st (RCC) is the eighth most common malignancy in the United States,

with an annual incidence of 58,240 cases in 2010.1 Roughly,

one-third of patients with RCC present with metastases and approximately 13,000 deaths occur from this disease annually.1

The treatment of metastatic RCC has been revolutionized by the introduction of 6 new targeted therapies over the past 5 to 6 years.2-8 This review will focus on the treatment of refractory patientsâ&#x20AC;&#x201D;those who have progressive disease per RECIST (Response Evaluation Criteria In Solid Tumors) after failing first-line therapies, including the new targeted therapies and older therapies such as high-dose interleukin-2 (IL-2) and interferon (IFN).9

have been shown in randomized controlled Phase III trials to be effective as second-line therapy for metastatic RCC.2,5,8 Sunitinib (Sutent, Pfizer) showed efficacy in a Phase II trial.10 Although these therapies have been tested and shown effective in patients previously treated with either cytokines or tyrosine kinase inhibitors (TKIs), there is a lack of prospective data to guide therapy in patients who become refractory to mammalian target of rapamycin (mTOR) inhibitors.

Options for Treatment-Refractory Patients

SORAFENIB

Sorafenib (Nexavar, Bayer), everolimus (Afinitor, Novartis), and pazopanib (Votrient, GlaxoSmithKline)

Sorafenib is a multikinase inhibitor of vascular endothelial growth factor receptor-1 (VEGFR), platelet-

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C L I N I C A L O N CO LO GY N E WS â&#x20AC;˘ M A R C H 2 0 1 1

derived growth factor receptor (PDGFR), KIT, RAF, and so on.2 It has very low inhibitory concentration (IC50) for the above receptor tyrosine kinases.11 In the large Phase III, double-blind trial TARGET (Cancer Global Evaluation Trial), investigators from 19 countries randomized 933 patients in a 1:1 manner (after stratification for country and Memorial Sloan-Kettering Cancer Center [MSKCC] risk factors) to receive sorafenib or placebo.2,12 Sorafenib was administered at a dosage of 400 mg twice daily on a continuous basis. The majority of the patients had undergone nephrectomy, had clear cell–type kidney cancer, and had undergone prior cytokine-based therapy. At the time of enrollment, the majority of the patients (>99%) were in MSKCC favorable- or intermediate-risk groups. The primary end point of this trial was overall survival (OS). The investigators found sorafenib to be superior with respect to progression-free survival (PFS; 5.5 vs 2.8 months; hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.43-0.60; P<0.001). Treatment with sorafenib did not result in significant OS benefit. A reason for the insignificant result is thought to be the crossover of placebo patients to the sorafenib arm. The overall response rate (ORR) was 2% with sorafenib versus 0% with placebo; the rate of stable disease was 74% in the sorafenib arm compared with 55% in the placebo arm. This trial demonstrated a hazard for death favorable to sorafenib (HR, 0.71), but that result was not statistically significant per the O’Brien-Fleming threshold. However, when crossover patients from placebo were censored, the survival difference favored sorafenib and was significant (17.8 vs 14.3; HR, 0.78; 95% CI, 0.620.97; P=0.0287). Based on the TARGET results, sorafenib was approved for metastatic RCC, but with the subsequent approvals of sunitinib, bevacizumab (Avastin, Genentech) plus IFN, and temsirolimus (Torisel, Pfizer) as first-line therapies, the use of sorafenib has been limited to use as second-line agent for RCC patients, both post-cytokine therapy and post-TKI therapy.

EVEROLIMUS Everolimus, an orally available mTOR inhibitor and serine-threonine kinase inhibitor, was tested in the double-blind, randomized Phase III RECORD-1 (Renal Cell cancer treatment with Oral RAD001 given Daily) trial in RCC patients who had failed sorafenib or sunitinib.5 The majority of patients in this large international trial had at least 2 lines of therapy prior to enrollment. The RECORD-1 investigators randomized 410 TKI-refractory patients to everolimus (n=272) or matching placebo (n=138) in a 2:1 manner. Everolimus was dosed at 10 mg orally daily in a continuous fashion. PFS, the primary end point, was 4 months for everolimus-treated patients and 1.9 months for placebo patients, with an HR of 0.30 (95% CI, 0.22-0.4; P<0.0001). The ORR was only 1% with everolimus versus 0% with placebo. Disease was stabilized in 63% of everolimus-treated patients compared with 32% of

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those in the placebo arm. Everolimus was associated with more adverse events (AEs) but generally was well tolerated. The commonly reported AEs with everolimus and placebo, respectively, were stomatitis (40% vs 8%), rash (25% vs 4%), and fatigue (20% vs 16%). Noninfectious pneumonitis was another major toxicity associated with everolimus, occurring in 8% of patients; nearly 3% of patients had grade 3 pneumonitis. Commonly observed metabolic abnormalities in those treated with everolimus were hyperglycemia, hypercholesterolemia, hypertriglyceridemia, and the like. This trial was able to demonstrate that everolimus can prolong PFS in patients with RCC who were heavily pretreated. Thus, the FDA approved everolimus for use in RCC patients in the second-line setting.

PAZOPANIB Pazopanib, a novel, orally available small molecule TKI of VEGFR, PDGFR, KIT, fibroblast growth factor receptor, and so on, was tested in a large randomized double-blind, placebo-controlled Phase III trial in treatment-naïve (54%) and treatment-refractory (46%) RCC patients.8 This international multicenter trial stratified patients based on Eastern Cooperative Oncology Group (ECOG) performance status (PS), prior nephrectomy, and prior cytokine therapy. The randomization was in a 2:1 manner to pazopanib and placebo groups, respectively. Pazopanib was given at 800 mg orally daily on a continuous basis. The primary end point of this trial was PFS. PFS was superior in the pazopanib arm compared with placebo (9.2 vs 4.2 months; HR, 0.46; 95% CI, 0.34-0.62; P<0.0001). Among those pretreated with cytokines, PFS was 7.4 months with pazopanib and 4.2 months with placebo (HR, 0.54; 95% CI, 0.35-0.84; P<0.001). The ORR favored pazopanib (30% vs 3%; P<0.001). The cytokine-pretreated group had comparable response rates of 29% with pazopanib and 3% with placebo. The commonly observed AEs in the pazopanib group were diarrhea (52%), hypertension (40%), hair color changes (38%), nausea (26%), anorexia (22%), and vomiting (21%). Hepatic abnormalities were the most common laboratory abnormality associated with pazopanib use. Pazopanib was approved for use in the United States based on the above results. Because the trial was conducted in both treatment-naïve and cytokine-pretreated populations, it established pazopanib as a robust agent in both the first- and second-line settings.

SUNITINIB Escudier et al. conducted a Phase II trial of sunitinib in patients with metastatic RCC who had at least one line of cytokine therapy.10 The dosing of sunitinib used was different from the traditional 4-week-on and 2-week-off regimen; this trial dosed sunitinib at 37.5 mg on a continuous basis. Of the 107 patients assigned to the study drug, 54 were in the morning dosing arm and 53 were in the evening dosing arm. The investigators reported a

Table. Summary of NCCN Treatment Guidelines for Managing Metastatic RCC Histology

First-line Therapy

Subsequent Therapy

Metastatic or advanced clear cell RCC

Sunitinib (category 1) or Pazopanib (category 1) or Bevacizumab/IFN (category 1) or Temsirolimus (category 1 for poor-risk group and 2B for other risk groups) or High-dose IL-2 for selected patients or Sorafenib for selected patients or Clinical trials and Best supportive care

Everolimus (category 1 following TKI) or Sorafenib (category 1 after cytokines and 2A after TKI) or Sunitinib (category 1 after cytokines and 2A after TKI) or Pazopanib (category 1 following cytokines and 3 following other TKI) or Temsirolimus (category 2A after cytokines and 2B after TKI) or Bevacizumab/IFN (category 2A following cytokine and 2B following TKI) or IFN or IL-2 (category 2B) and Best supportive care

Metastatic or advanced non-clear cell RCC

Clinical trial or Temsirolimus (category 1 for poor-risk patients and 2A for other risk groups) or Sunitinib or Sorafenib or Pazopanib (category 3) or Erlotinib (category 3) or Chemotherapy in sarcomatoid type only: gemcitabine and doxorubicin (category 3) and Best supportive care

No data exists regarding the treatment after patients have failed mTOR inhibitors

IFN, interferon; IL-2, interleukin 2; mTOR, mammalian target of rapamycin; NCCN, National Comprehensive Cancer Network; RCC, renal cell carcinoma; TKI, tyrosine kinase inhibitor

PFS of 8.2 months, with an ORR of 20%. The most common grade 3 AEs were asthenia/fatigue (16%), diarrhea (11%), hypertension (11%), hand–foot syndrome (9%), and anorexia (8%). This dosing regimen was found to be generally tolerable, and there were minimal dose interruptions. Based on these results, the FDA approved sunitinib for use in this setting.

Clinical Trials and Other Options Although patients with metastatic RCC show robust response and PFS rates to various agents in the firstline setting, when it comes to the second-line or treatment-refractory setting, options are limited because to date only a few trials have been completed in this setting. In clinical practice, oncologists can use one agent after another, but response rates have been dismal during subsequent lines of therapy. Various clinical trials are being conducted in this setting to optimize subsequent therapies for this unique group of patients, but these results are not yet available. Until these data are available, clinicians must rely on anecdotal reports, retrospective data, and small Phase II trials that have been conducted in the second-line setting of RCC.13-16 The investigational agent axitinib (Pfizer), a small

molecule TKI of VEGFR, was tested in a Phase II study in 62 patients, all of whom were refractory to sorafenib and 74% of whom had received more than one line of previous therapy, including bevacizumab, sunitinib, cytokine, and so on.15 In this trial, all patients had ECOG PS 1 or better; axitinib was given at a dose of 5 mg orally twice daily, with dose escalation as tolerated to 7 and 10 mg twice daily. The investigators reported an ORR of 22%, with a median PFS of 7.4 months. Axitinib was further tested in the Phase III AXIS (Axitinib [AG 013736] As Second Line Therapy For Metastatic Renal Cell Cancer) trial, which compares sorafenib with axitinib in patients who have failed sunitinib. In a press release, Pfizer reported that initial results were positive; final results are expected soon. Another Phase II trial, BEST (A Randomized Phase II Study of VEGF, RAF Kinase, and mTOR Combination Targeted Therapy [CTT] With Bevacizumab, Sorafenib and Temsirolimus in Advanced Renal Cell Carcinoma) is attempting to define the optimal combination of various agents—including sorafenib, bevacizumab, and temsirolimus—that is associated with superior survival. A large Phase III trial is comparing tivozanib (Aveo Pharmaceuticals) with sorafenib in RCC patients who

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are refractory to non-VEGFâ&#x20AC;&#x201C;targeted therapy. Tivozanib is a VEGF-targeted TKI that has high potency against its targets, including VEGFR.

References

Yet another ongoing Phase III trial is comparing TKI258 (dovitinib, Novartis), a VEGFR-targeted TKI, with sorafenib in patients who failed prior anti-VEGF and mTOR inhibitor therapy.

2. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356(2):125-134, PMID: 17215530.

Choosing the Best Treatment Option for Second-line Therapy Choosing the best option in the second-line setting has to be strictly based on evidence if it is available. The table lists the National Comprehensive Cancer Network recommendations for treatment of advanced RCC in the first- and subsequent-line settings. For patients who were pretreated with cytokines and belong to favorable or intermediate MSKCC risk groups, the best available options with respect to PFS are sorafenib and pazopanib. None of these drugs has shown to prolong survival in the post-cytokine setting. But the TARGET trial demonstrated a statistically significant OS advantage with sorafenib when placebo patients were censored at crossover. For patients who had failed prior TKIs in the first-line setting, the best available option is everolimus. Other agents like sunitinib, bevacizumab, and IL-2 also may have some benefits, but their utility has not been established by any large trial. There is a lack of data for selecting second-line treatment for patients who have received mTOR inhibitors as first-line therapy. Patients who receive mTOR inhibitors as firstline therapy generally have non-clear cellâ&#x20AC;&#x201C;type RCC or RCC with poor risk features. There also is a lack of data in choosing therapy for patients with RCC who have received multiple lines of treatment that include mTOR inhibitors and anti-VEGF therapy.

Conclusion Patients with metastatic RCC have many options in 2011 compared with 6 years ago. In general, the second and latter lines of therapies are less robust in producing high rates of tumor response, with the exception of pazopanib. The data from the previously mentioned trials demonstrate that OS is not a meaningful end point because there are other approved agents available for use in these patients and such end points will be skewed by subsequent therapies. Optimizing the right sequence of agents should depend heavily on the mechanism of resistance to first-line therapy. Subsequent therapy selection may depend on the molecular profiling of tumors and their vasculature at the time of resistance formation.

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

Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60(5):277-300, PMID: 20610543.

3. Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007;370(9605):2103-2111, PMID: 18156031. 4. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356(22):2271-2281, PMID: 175380086. 5. Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372(9637): 449-456, PMID: 18653228. 6. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356(2):115-124, PMID: 17215529. 7. Rini BI, Halabi S, Rosenberg JE, et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol. 2008;26(33):5422-5428, PMID: 18936475. 8. Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010;28(6):1061-1068, PMID: 20100962. 9. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92(3): 205-216, PMID: 10655437. 10. Escudier B, Roigas J, Gillessen S, et al. Phase II study of sunitinib administered in a continuous once-daily dosing regimen in patients with cytokine-refractory metastatic renal cell carcinoma. J Clin Oncol. 2009;27(25):4068-4075, PMID: 19652072. 11. Strumberg D, Richly H, Hilger RA, et al. Phase I clinical and pharmacokinetic study of the novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. J Clin Oncol. 2005;23(5):965972, PMID: 15613696. 12. Escudier B, Eisen T, Stadler WM, et al. Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol. 2009;27(20):3312-3318, PMID: 19451442. 13. Shaheen PE, Rini BI, Bukowski RM. Clinical activity of sorafenib and sunitinib in renal cell carcinoma refractory to previous vascular endothelial growth factor-targeted therapy: two case reports. Clin Genitourin Cancer. 2006;5(1):78-81, PMID: 16859583. 14. Rini BI, Michaelson MD, Rosenberg, JE, et al. Antitumor activity and biomarker analysis of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma. J Clin Oncol. 2008;26(22):3743-3748, PMID: 18669461. 15. Rini BI, Wilding G, Hudes G, et al. Phase II study of axitinib in sorafenib-refractory metastatic renal cell carcinoma. J Clin Oncol. 2009;27(27):4462-4468, PMID: 19652060. 16. Tamaskar I, Garcia JA, Elson P, et al. Antitumor effects of sunitinib or sorafenib in patients with metastatic renal cell carcinoma who received prior antiangiogenic therapy. J Urol. 2008;179(1):81-86; discussion 86, PMID: 17997441.

SOLID TUMORS

Clinical Oncology News • March 2011

Multiple Cancers

META-ANALYSIS continued from page 6 

He said that historically the drug has been associated, inconsistently, with a higher response rate to treatment, longer progression-free survival (PFS), and no improvement in survival. “You have to wonder, looking at the main end points, what value does the response have if it doesn’t translate to better survival?” He added that a Phase III study of the drug in lung cancer, published in a 2006 issue of The New England Journal of Medicine (355:2542-2550; PMID: 17167137), showed a brief survival advantage with, ultimately, a sevenfold risk for mortality. In addition, results from a follow-up trial in Europe, called AVAIL (Avastin in Lung Cancer) and released in 2008, showed no survival advantage. Dr. Gralla, who doesn’t have a financial relationship with Genentech, said oncologists should question whether anti-vascular endothelial growth factor (VEGF) approaches will lead to higher survival, and which patients would most likely benefit from the drug. Lee M. Ellis, MD, an expert on tumor

angiogenesis, approached the paper from a different angle. “It is interesting that people wax and wane on the value of meta-analyses,” he said, stating that some meta-analyses are taken literally and others are brusquely criticized. Dr. Ellis is professor of surgical oncology and interim chair of the Department of Cancer Biology at the University of Texas MD Anderson Cancer Center, in Houston. He is also an ad hoc consultant to Genentech. “A meta-analysis across all tumor types is not informative as patients have different performance statuses, get different chemotherapeutics and are receiving the drug in different lines of therapy,” Dr. Ellis said. He added that the JAMA meta-analysis also included randomized trials for which bevacizumab is not approved. “The trial with the strongest P value showing an increase in FAEs was in prostate cancer, where the drug is not approved,” he said. As an example, he pointed out that a meta-analysis of colorectal cancer trials in press in the journal Digestive and Liver Disease shows an improvement in overall survival (OS). “I think the risk–benefit ratio must be on a tumor-by-tumor basis and further should be evaluated on the chemotherapy

‘If you see higher mortality rates but not higher survival, what does this say for the value of this mechanism of action?’ —Richard Gralla, MD

backbone,” Dr. Ellis said. “People oftentimes quote a lack of improved OS despite there being an improvement in PFS with VEGF-targeted agents. But readers must examine the trial design for each study, as many include crossover to a VEGF-targeted therapy if they were on the control arm and demonstrated tumor growth. This, we know, clouds the value of OS as an end point. This occurred in several of the breast cancer trials.” He added that even if there is no crossover, once these drugs are approved for other indications, oncologists will administer the drugs in second-line therapy, so essentially crossover occurs whether or not it is part of the actual trial. Dr.

Ellis also said it would have been helpful if the authors did a meta-analysis of PFS and OS in the JAMA paper, so that a risk–benefit ratio and not just the risk ratio could be determined. “This study makes patients and oncologists aware of potential risks of any combination therapy, not just the therapies described in this paper. As we move further into the era of personalized cancer care, we need to be able to assess the risk–benefit ratio for the person sitting in front of us, taking into account his/her individual risk factors,” Dr. Ellis said. “[Oncologists] are encouraged to read this paper carefully to see which population may really be at risk for adverse events.” Bevacizumab, which inhibits tumor growth by neutralizing VEGF, is approved for use in patients with many types of advanced cancers, including colorectal cancer, non-small cell lung cancer, renal cell cancer and glioblastoma multiforme. In December, the FDA moved to remove its approval of the drug as a treatment for breast cancer, after several studies failed to demonstrate that the drug improved overall survival. —Karen Blum

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Independent News for the Oncologist and Hematologist/Oncologist

In advanced RCC:

Afinitor doubled median PFS after progression on sunitinib*1 Progression-free survival (PFS) after progression on sunitinib or sorafenib1 100

Hazard Ratio=0.33 95% CI [0.25, 0.43] Kaplan-Meier medians Afinitor: (n=277) 4.9 months (95% CI, 4.0-5.5) Placebo: (n=139) 1.9 months (95% CI, 1.8-1.9) Log rank P value=<0.0001

Probability (%)

4.9

1.9

months

Placebo 40

Afinitor 20

Time (months)

4.9 months median PFS with Afinitor + BSCâ&#x20AC; (vs 1.9 months with placebo + BSC; P<0.0001)1 HR 0.33=67% reduction in risk of progression Effective for patients with all prognostic scores1 For more information about Afinitor, call 1-888-4Afinitor (1-888-423-4648) or visit www.AFINITOR.com For reimbursement questions, call 1-888-5AfiniTRAC (1-888-523-4648). *In the RECORD-1 trial, Afinitor extended PFS after progression on sunitinib or sorafenib. 1,2 â&#x20AC; BSC=best supportive care.

Important Safety Information There have been reports of non-infectious pneumonitis and infections, some with fatal outcomes. Oral ulceration has been reported. Elevations of serum creatinine, glucose, lipids, and triglycerides and reductions of hemoglobin, lymphocytes, neutrophils, and platelets have been reported. Please see Important Safety Information on right side of page. Please see Brief Summary of full Prescribing Information on the following pages.

Afinitor is indicated for the treatment of patients with advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib. Important Safety Information Afinitor is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients. Non-infectious pneumonitis is a class effect of rapamycin derivatives, including Afinitor. Fatal outcomes have been observed. If symptoms are moderate or severe, patients should be managed with dose interruption until symptoms improve or discontinuation, respectively. Corticosteroids may be indicated. Afinitor may be reintroduced at 5 mg daily depending on the individual clinical circumstances. Afinitor has immunosuppressive properties and may predispose patients to bacterial, fungal, viral or protozoan infections, including infections with opportunistic pathogens. Localized and systemic infections, including pneumonia, other bacterial infections, invasive fungal infections, and viral infections including reactivation of hepatitis B virus have occurred. Some of these infections have been severe (e.g. leading to respiratory or hepatic failure) or fatal. Complete treatment of pre-existing invasive fungal infections prior to starting treatment. While taking Afinitor be vigilant for signs and symptoms of infection; if a diagnosis of infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of Afinitor. If a diagnosis of invasive systemic fungal infection is made, discontinue Afinitor and treat with appropriate antifungal therapy. Oral ulcerations (i.e. mouth ulcers, stomatitis, and oral mucositis) have occurred in patients treated with Afinitor. In such cases, topical treatments are recommended, but alcohol- or peroxide-containing mouthwashes should be avoided. Antifungal agents should not be used unless fungal infection has been diagnosed. Elevations of serum creatinine, glucose, lipids, and triglycerides and reductions of hemoglobin, lymphocytes,

neutrophils, and platelets have been reported in clinical trials. Renal function, hematological parameters, blood glucose, and lipids should be evaluated prior to treatment and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on Afinitor. Avoid concomitant use with strong CYP3A4 or PgP inhibitors. If co-administration with moderate CYP3A4 or PgP inhibitors is required, use caution and reduce dose of Afinitor to 2.5 mg daily. Increase the Afinitor dose if co-administered with a strong CYP3A4 inducer. Afinitor should not be used in patients with severe hepatic impairment. Afinitor dose should be reduced to 5 mg daily for patients with moderate hepatic impairment. The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with Afinitor. Fetal harm can occur if Afinitor is administered to a pregnant woman. The most common adverse reactions (incidence ≥30%) were stomatitis (44%), infections (37%), asthenia (33%), fatigue (31%), cough (30%), and diarrhea (30%). The most common grade 3/4 adverse reactions (incidence ≥3%) were infections (9%), dyspnea (8%), fatigue (5%), stomatitis (4%), dehydration (4%), pneumonitis (4%), abdominal pain (3%), and asthenia (3%). The most common laboratory abnormalities (incidence ≥50%) were anemia (92%), hypercholesterolemia (77%), hypertriglyceridemia (73%), hyperglycemia (57%), lymphopenia (51%), and increased creatinine (50%). The most common grade 3/4 laboratory abnormalities (incidence ≥3%) were lymphopenia (18%), hyperglycemia (16%), anemia (13%), hypophosphatemia (6%), and hypercholesterolemia (4%). Deaths due to acute respiratory failure (0.7%), infection (0.7%), and acute renal failure (0.4%) were observed on the Afinitor arm.

References: 1. Afinitor [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2010. 2. Motzer RJ, Escudier B, Oudard S, et al; for the RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372:449-456. 2.5mg 5mg 10mg

Printed in U.S.A.

10/10

AFI-1002330

AFINITOR

(everolimus) tablets for oral administration Initial U.S. Approval: 2009 BRIEF SUMMARY: Please see package insert for full prescribing information. 1 INDICATIONS AND USAGE AFINITOR® is indicated for the treatment of patients with advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib. 4 CONTRAINDICATIONS Hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients. Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus and other rapamycin derivatives. 5 WARNINGS AND PRECAUTIONS 5.1 Non-infectious Pneumonitis Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. In the randomized study, non-infectious pneumonitis was reported in 14% of patients treated with AFINITOR. The incidence of Common Toxicity Criteria (CTC) grade 3 and 4 non-infectious pneumonitis was 4% and 0%, respectively [see Adverse Reactions (6.1)]. Fatal outcomes have been observed. Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Advise patients to report promptly any new or worsening respiratory symptoms. Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue AFINITOR therapy without dose alteration. If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITOR may be reintroduced at 5 mg daily. For cases where symptoms of non-infectious pneumonitis are severe, discontinue AFINITOR therapy and the use of corticosteroids may be indicated until clinical symptoms resolve. Therapy with AFINITOR may be re-initiated at a reduced dose of 5 mg daily depending on the individual clinical circumstances. 5.2 Infections AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoan infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1)]. Localized and systemic infections, including pneumonia, other bacterial infections, invasive fungal infections, such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virus have occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading to respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with AFINITOR. While taking AFINITOR be vigilant for signs and symptoms of infection; if a diagnosis of an infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy. 5.3 Oral Ulceration Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR. In the randomized study, approximately 44% of AFINITOR-treated patients developed mouth ulcers, stomatitis, or oral mucositis, which were mostly CTC grade 1 and 2 [see Adverse Reactions (6.1)]. In such cases, topical treatments are recommended, but alcohol- or peroxide-containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed [see Drug Interactions (7.1)]. 5.4 Laboratory Tests and Monitoring Renal Function Elevations of serum creatinine, usually mild, have been reported in clinical trials [see Adverse Reactions (6.1)]. Monitoring of renal function, including measurement of blood urea nitrogen (BUN) or serum creatinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter. Blood Glucose and Lipids Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in clinical trials [see Adverse Reactions (6.1)]. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR. Hematological Parameters Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials [see Adverse Reactions (6.1)]. Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter. 5.5 Drug-drug Interactions Due to significant increases in exposure of everolimus, co-administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or P-glycoprotein (PgP) should be avoided. Grapefruit, grapefruit juice and other foods that are known to affect cytochrome P450 and PgP activity should also be avoided during treatment [see Dosage and Administration (2.2) in the full prescribing information and Drug Interactions (7.1)]. A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4 inhibitor (e.g., amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem) or PgP inhibitor [see Dosage and Administration (2.2) in the full prescribing information and Drug Interactions (7.1)]. An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4 inducer (e.g., St. John’s Wort (Hypericum perforatum), dexamethasone, prednisone, prednisolone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) [see Dosage and Administration (2.2) in the full prescribing information and Drug Interactions (7.2)]. 5.6 Hepatic Impairment The safety and pharmacokinetics of AFINITOR were evaluated in a study in eight patients with moderate hepatic impairment (Child-Pugh class B) and eight subjects with normal hepatic function. Exposure was increased in patients with moderate hepatic impairment, therefore a dose reduction is recommended. AFINITOR has not been studied in patients with severe hepatic impairment (Child-Pugh class C) and should not be used in this population [see Dosage and Administration (2.2) in the full prescribing information and Use in Specific Populations (8.7)]. 5.7 Vaccinations The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR. Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines. 5.8 Use in Pregnancy Pregnancy Category D There are no adequate and well-controlled studies of AFINITOR in pregnant women. However, based on mechanism of action, AFINITOR may cause fetal harm when administered to a pregnant woman. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures at the recommended dose of 10 mg daily. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use an effective method of contraception

while using AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations (8.1)]. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in another section of the label: • Non-infectious pneumonitis [see Warnings and Precautions (5.1)]. • Infections [see Warnings and Precautions (5.2)]. 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice. The data described below reflect exposure to AFINITOR (n=274) and placebo (n=137) in a randomized, controlled trial in patients with metastatic renal cell carcinoma who received prior treatment with sunitinib and/or sorafenib. The median age of patients was 61 years (range 27-85), 88% were Caucasian, and 78% were male. The median duration of blinded study treatment was 141 days (range 19-451) for patients receiving AFINITOR and 60 days (range 21-295) for those receiving placebo. The most common adverse reactions (incidence ≥30%) were stomatitis, infections, asthenia, fatigue, cough, and diarrhea. The most common grade 3/4 adverse reactions (incidence ≥3%) were infections, dyspnea, fatigue, stomatitis, dehydration, pneumonitis, abdominal pain, and asthenia. The most common laboratory abnormalities (incidence ≥50%) were anemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and increased creatinine. The most common grade 3/4 laboratory abnormalities (incidence ≥3%) were lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hypercholesterolemia. Deaths due to acute respiratory failure (0.7%), infection (0.7%) and acute renal failure (0.4%) were observed on the AFINITOR arm but none on the placebo arm. The rates of treatment-emergent adverse events (irrespective of causality) resulting in permanent discontinuation were 14% and 3% for the AFINITOR and placebo treatment groups, respectively. The most common adverse reactions (irrespective of causality) leading to treatment discontinuation were pneumonitis and dyspnea. Infections, stomatitis, and pneumonitis were the most common reasons for treatment delay or dose reduction. The most common medical interventions required during AFINITOR treatment were for infections, anemia, and stomatitis. Table 1 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥10% for patients receiving AFINITOR 10 mg daily versus placebo. Within each MedDRA system organ class, the adverse reactions are presented in order of decreasing frequency. Table 1 Adverse Reactions Reported in at least 10% of Patients and at a Higher Rate in the AFINITOR Arm than in the Placebo Arm AFINITOR 10 mg/day N=274

Placebo N=137

All grades %

Grade 3 %

Grade 4 %

All grades %

Grade 3 %

Grade 4 %

Any Adverse Reaction

Gastrointestinal Disorders Stomatitisa Diarrhea Nausea Vomiting

44 30 26 20

4 1 1 2

<1 0 0 0

8 7 19 12

0 0 0 0

Infections and Infestationsb

<1 0 0 0 0

23 27 8 9 1

4 3 <1 0 0

0 <1 0 0 0

Respiratory, Thoracic and Mediastinal Disorders Cough 30 <1 Dyspnea 24 6 Epistaxis 18 0 c 14 4 Pneumonitis

0 1 0 0

16 15 0 0

0 3 0 0

0 0 0 0

Skin and Subcutaneous Tissue Disorders Rash 29 Pruritus 14 Dry skin 13

1 <1 <1

0 0 0

7 7 5

0 0 0

<1 0

9 2

<1 0

0 0

Musculoskeletal and Connective Tissue Disorders Pain in extremity 10 1

General Disorders and Administration Site Conditions Asthenia 33 3 Fatigue 31 5 Edema peripheral 25 <1 Pyrexia 20 <1 Mucosal inflammation 19 1

Metabolism and Nutrition Disorders Anorexia 25 Nervous System Disorders Headache Dysgeusia

19 10

Median Duration of Treatment (d)

141

CTCAE Version 3.0 a Stomatitis (including aphthous stomatitis), and mouth and tongue ulceration. b Includes all preferred terms within the ‘infections and infestations’ system organ class, the most common being nasopharyngitis (6%), pneumonia (6%), urinary tract infection (5%), bronchitis (4%), and sinusitis (3%), and also including aspergillosis (<1%), candidiasis (<1%), and sepsis (<1%). c Includes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage, pulmonary toxicity, and alveolitis. Other notable adverse reactions occurring more frequently with AFINITOR than with placebo, but with an incidence of <10% include: Gastrointestinal disorders: Abdominal pain (9%), dry mouth (8%), hemorrhoids (5%), dysphagia (4%) General disorders and administration site conditions: Weight decreased (9%), chest pain (5%), chills (4%), impaired wound healing (<1%) Respiratory, thoracic and mediastinal disorders: Pleural effusion (7%), pharyngolaryngeal pain (4%), rhinorrhea (3%) Skin and subcutaneous tissue disorders: Hand-foot syndrome (reported as palmar-plantar erythrodysesthesia syndrome) (5%), nail disorder (5%), erythema (4%), onychoclasis (4%), skin lesion (4%), acneiform dermatitis (3%) Metabolism and nutrition disorders: Exacerbation of pre-existing diabetes mellitus (2%), new onset of diabetes mellitus (<1%) Psychiatric disorders: Insomnia (9%) Nervous system disorders: Dizziness (7%), paresthesia (5%) Eye disorders: Eyelid edema (4%), conjunctivitis (2%)

Vascular disorders: Hypertension (4%)

In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft) and retarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities occurred at approximately 4% the exposure (AUC0-24h) in patients receiving the recommended dose of 10 mg daily. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose approximately 1.6 times the recommended human dose on a body surface area basis. The effect in rabbits occurred in the presence of maternal toxicities.

Renal and urinary disorders: Renal failure (3%) Cardiac disorders: Tachycardia (3%), congestive cardiac failure (1%) Musculoskeletal and connective tissue disorders: Jaw pain (3%) Hematologic disorders: Hemorrhage (3%) Key treatment-emergent laboratory abnormalities are presented in Table 2. Table 2 Key Laboratory Abnormalities Reported at a Higher Rate in the AFINITOR Arm than the Placebo Arm Laboratory Parameter

AFINITOR 10 mg/day N=274

Placebo N=137

All grades %

Grade 3 %

Grade 4 %

All grades %

Grade 3 %

Grade 4 %

92 51 23 14

12 16 1 0

1 2 0 <1

79 28 2 4

5 5 0 0

<1 0 <1 0

77 73 57 50 37

4 <1 15 1 6

0 0 <1 0 0

35 34 25 34 8

0 0 1 0 0

0 0 0 0 0

21 3

1 <1

0 <1

4 2

0 0

Hematology Hemoglobin decreased Lymphocytes decreased Platelets decreased Neutrophils decreased Clinical Chemistry Cholesterol increased Triglycerides increased Glucose increased Creatinine increased Phosphate decreased Aspartate transaminase (AST) increased Alanine transaminase (ALT) increased Bilirubin increased

CTCAE Version 3.0 a Includes reports of anemia, leukopenia, lymphopenia, neutropenia, pancytopenia, thrombocytopenia. Information from further clinical trials In clinical trials, everolimus has been associated with serious cases of hepatitis B reactivation, including fatal outcomes. 7 DRUG INTERACTIONS Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug efflux pump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6.

In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At approximately 10% of the recommended human dose based on body surface area, there were no adverse effects on delivery and lactation and there were no signs of maternal toxicity. However, there was reduced body weight (up to 9% reduction from the control) and slight reduction in survival in offspring (~5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring. Doses that resulted in embryo-fetal toxicities in rats and rabbits were ≥0.1 mg/kg (0.6 mg/m2) and 0.8 mg/kg (9.6 mg/m2), respectively. The dose in the pre- and post-natal development study in rats that caused reduction in body weights and survival of offspring was 0.1 mg/kg (0.6 mg/m2). 8.3 Nursing Mothers It is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from everolimus, 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 in pediatric patients have not been established. 8.5 Geriatric Use In the randomized study, 41% of AFINITOR-treated patients were ≥65 years in age, while 7% percent were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3) in the full prescribing information]. No dosage adjustment is required in elderly patients [see Clinical Pharmacology (12.3) in the full prescribing information]. 8.6 Renal Impairment No clinical studies were conducted with AFINITOR in patients with decreased renal function. Renal impairment is not expected to influence drug exposure and no dosage adjustment of everolimus is recommended in patients with renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information].

7.1 Agents that may Increase Everolimus Blood Concentrations CYP3A4 Inhibitors and PgP Inhibitors: In healthy subjects, compared to AFINITOR treatment alone there were significant increases in everolimus exposure when AFINITOR was coadministered with:

8.7 Hepatic Impairment For patients with moderate hepatic impairment (Child-Pugh class B), the dose should be reduced to 5 mg daily [see Dosage and Administration (2.2) in the full prescribing information, Warnings and Precautions (5.6) and Clinical Pharmacology (12.3) in the full prescribing information].

• ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and 15.0-fold, respectively.

The impact of severe hepatic impairment (Child-Pugh class C) has not been assessed and use in this patient population is not recommended [see Warnings and Precautions (5.6)].

• erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.0- and 4.4-fold, respectively. • verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3- and 3.5-fold, respectively. Concomitant strong inhibitors of CYP3A4 and PgP should not be used [see Warnings and Precautions (5.5)]. Use caution when AFINITOR is used in combination with moderate CYP3A4 or PgP inhibitors. If alternative treatment cannot be administered reduce the AFINITOR dose. [See Dosage and Administration (2.2) in the full prescribing information] 7.2 Agents that may Decrease Everolimus Blood Concentrations CYP3A4 Inducers: In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer of CYP3A4, decreased everolimus AUC and Cmax by 64% and 58% respectively, compared to everolimus treatment alone. Consider a dose increase of AFINITOR when co-administered with strong inducers of CYP3A4 (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital) or PgP if alternative treatment cannot be administered. St. John’s Wort may decrease everolimus exposure unpredictably and should be avoided [see Dosage and Administration (2.2) in the full prescribing information].

10 OVERDOSAGE In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity were observed in either mice or rats given single oral doses of 2000 mg/kg (limit test). Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been administered. The acute toxicity profile observed with the 70 mg dose was consistent with that for the 10 mg dose. 16 STORAGE Store AFINITOR (everolimus) tablets at 25°C (77°F); excursions permitted between 15°-30°C (59°-86°F). [See USP Controlled Room Temperature.] Store in the original container, protect from light and moisture. Keep this and all drugs out of the reach of children. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. AFINITOR tablets should not be crushed. Do not take tablets which are crushed or broken.

7.3 Agents whose Plasma Concentrations may be Altered by Everolimus Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions between AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (a non-CYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.8)] There are no adequate and well-controlled studies of AFINITOR in pregnant women. However, based on mechanism of action, AFINITOR may cause fetal harm when administered to a pregnant woman. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures at the recommended dose of 10 mg daily. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use an effective method of contraception while receiving AFINITOR and for up to 8 weeks after ending treatment.

Revised: June 2010 Manufactured by: Novartis Pharma Stein AG Stein, Switzerland Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 ©Novartis

T2010-56

SOLID TUMORS

Clinical Oncology News • March 2011

Anal

STANDARD continued from page 1 

studies were presented at the 2011 Gastrointestinal Cancers Symposium. The difference in the results may stem from dissimilarities in the study designs, treatment intensity and/or patient study groups (earlier-stage cancers were included in the retrospective analysis). In the Phase III study, called RTOG 98-11, 5-FU/MMC was administered concurrently with RT, and 5-FU/ CP was initiated as an induction regimen (abstract 367). Those randomized to 5-FU/CP began radiation only in the third of the four chemoradiation cycles. Conversely, all cycles of CP-based chemoradiation were administered concurrently with RT in the retrospective study. When the initial results of RTOG 98-11 were published several years ago, there was no difference in major outcomes such as DFS or OS, but 5-FU/MMC was associated with a lower colostomy rate (10% vs. 19%; P=0.02) (JAMA 2008;299:1914-1921, PMID:18430910). The updated results now show both a DFS and an OS advantage for RT plus 5-FU/MMC over RT plus 5-FU/CP. Specifically, with complete data on 649 patients after five years of follow-up, the DFS rate was 67.7% in those receiving 5-FU/MMC compared with 57.6% for those receiving 5-FU/CP (P=0.0044), according to Leonard L. Gunderson,

‘Platinum-based therapy for anal cancer appears to be an acceptable alternative to 5-FU/MMC and should be considered as a standard option for locally advanced disease.’ —Cathy Eng, MD

P=0.021) also translated into an HR of 1.42 favoring 5-FU/MMC. On the basis of these results, “radiotherapy plus 5-FU/MMC remains the standard of care for patients with anal canal carcinoma,” Dr. Gunderson said. In the retrospective study (abstract 482), which described a 20-year experience with CP-based chemotherapy for locally advanced squamous cell carcinoma of the anal canal, 181 patients were evaluable for response with a median

‘Radiotherapy plus 5-FU/MMC remains the standard of care for patients with anal canal carcinoma.’

—Leonard L. Gunderson, MD

MD, emeritus professor in the Department of Radiation Oncology, Mayo Clinic, Scottsdale, Ariz. On multivariate analysis, those in the 5-FU/CP group had a 42% greater likelihood of failing to remain disease-free at five years (hazard ratio [HR], 1.42; 95% confidence interval, 1.11-1.80; P=0.0043). The OS advantages for 5-FU/MMC (78.2% vs. 70.5%;

follow-up of 8.6 years. The five-year DFS was 81% and the five-year OS was 85%. Although it is not appropriate to directly compare results across different studies that may have had many large and small differences, the overall activity of the CP-based regimens was impressive with complete responses (CR) in 93% of patients and partial responses in the

remaining 7%. After the median 8.6 years of follow-up, only 8% of patients developed a local recurrence and 9% developed distant metastases. “Platinum-based therapy for anal cancer appears to be an acceptable alternative to 5-FU/MMC and should be considered as a standard option for locally advanced disease,” said Cathy Eng, MD, senior author of the retrospective analysis and an associate medical director, Colorectal Center, University of Texas MD Anderson Cancer Center, Houston. Although a multicenter, randomized Phase III study is the accepted standard for addressing questions of relative efficacy in cancer management, Dr. Eng suggested that the RTOG 98-11 failed to resolve the issue by delaying radiation in the CP arm. “It is well documented that patients should not delay their radiation therapy or have any treatment delays during radiation therapy. Hence, what should be concluded is that a delay in treatment is likely the causality for the failure of the cisplatin arm,” Dr. Eng suggested. She noted that another Phase III study called ACT II also compared this

combination. The ACT II trial compared MMC and CP in otherwise similar regimens, but relative OS and DFS rates at five years are not yet available. Scan for a Web After a median folexclusive, “Expert: low-up of three years, Pros, Cons of which was reported in Minimally Invasive 2009, there was no difRectal Cancer ference in DFS, OS or Surgery”; CR rates (J Clin Oncol instructions page 7. 2009;27[suppl]:LBA4009). At that time, based on a lack of an advantage for CP, the authors of ACT II concluded that MMC should remain the standard of care. “Basically, cisplatin was found to be noninferior to MMC,” but Dr. Eng pointed out that MMC is myelosuppressive and may be less attractive in the elderly or patients who are chronically immunocompromised, such as organ transplant recipients and individuals infected with HIV. Based on the data overall, CP “is our standard here at MD Anderson.” Phase III trials typically provide the resolution for these types of controversies, but this one may persist, because RTOG 98-11 may be better characterized as a comparison of two different strategies as well as two different chemotherapy combinations. While waiting for more data to help resolve this potential controversy, three variables were found on multivariate analysis to independently predict OS in addition to the treatment strategy in RTOG 98-11. These were a tumor size greater than 5 cm (vs. 2.5-5 cm; HR, 1.40; P=0.03), positive lymph nodes (HR, 1.84; P<0.0001) and female gender (HR, 1.40; P=0.029). In the MD Anderson retrospective study, nodal stage also was a significant negative predictor of DFS at five years in a univariate analysis. These variables may be useful for defining a group of candidates for a more aggressive treatment strategy regardless of the chemoradiation combination used. GCS is sponsored by the American Society of Clinical Oncology, American Gastroenterological Association, American Society for Radiation Oncology and the Society of Surgical Oncology. —Ted Bosworth

PRN

EVIDENCE continued from page 7 

issues they raise, present a rather disconcerting challenge to the fundamental legitimacy of establishing a solidly “evidence-based” therapeutic guideline development process. In summary, it is perhaps most reasonable to conclude at the present time that “guideline development” in medicine, in

general, and oncology, in particular, is a true early work in progress. It is both premature and inaccurate to classify the effort as satisfying objective valid criteria for being “evidence-based.” Or, one might conclude, as noted in a recent commentary, that “we should exercise caution when using guidelines as the sole source guiding patient care decisions. Especially for subspecialists, guidelines may provide a starting point for searching for information, but they

are not the finish line.”3

References 1. Webster’s New Collegiate Dictionary. Springfield, MA: G. & C. Merriam Co; 2010. 2. Lee DH, Vielmeyer O. Analysis of overall level of evidence behind Infectious Diseases Society of America Practice Guidelines. Arch Intern Med. 2011;171:18-22, PMID: 21220656. 3. Powers JH. Practice guidelines: belief, criticism, and probability. Arch Intern Med. 2011;171:15-16, PMID: 21220655.

4. Poonacha TK, Go RS. Level of scientific evidence underlying recommendations arising from the National Comprehensive Cancer Network Clinical Practice Guidelines. J Clin Oncol. 2011;29:186-191, PMID: 21149653. 5. Robinson KA, Goodman SN. A systemic examination of the citation of prior research in reports of randomized, controlled trials. Ann Intern Med. 2011;154:50-55, PMID: 21200038. 6. Booth A, Clarke M, Ghersi D, Moher D, Petticrew M, Stewart L. An international registry of systemic-review protocols. Lancet. 2011;377:108-109, PMID: 20630580.

SOLID TUMORS

Clinical Oncology News • March 2011

Rectal

New Regimen Shows Promise in Rectal Cancer San Francisco—In high-risk rectal cancer patients with KRAS and BRAF wild-type tumors, adding cetuximab to neoadjuvant chemotherapy and chemoradiation improves overall survival (OS).

Study Details EXPERT-C was based on positive results of the EXPERT trial, a single-arm Phase II trial of oxaliplatin and capecitabine (Capox) before chemoradiation and total mesorectal excision (TME) in pateints with magnetic resonance imaging (MRI)–defined poor-risk rectal cancer. EXPERT-C, led by Alice Dewdney, MD, from the Royal Marsden Hospital, Surrey, United Kingdom, evaluated the addition of cetuximab to a similar treatment strategy. The trial enrolled 164 patients with high-risk rectal cancer, defined by MRI, from 15 European centers. Eighty-one patients were randomzied to receive four cycles of Capox followed by chemoradiation with concurrent capecitabine, and then, following a four- to six-week break, TME, and four cycles of adjuvant Capox. The other 83 patients received the same regimen plus cetuximab given once per week throughout treatment. All patients were prescribed prophylactic low-molecular-weight heparin due to the relatively high rate of thromboembolic events seen in the EXPERT trial. Molecular analysis was performed on 149 of the patients. Of these, 44 patients in the Capox arm and 46 in the Capox plus cetuximab arm had KRAS and BRAF wild-type tumors. Fifteen patients did not have sufficient tissue for analysis. The primary end point of the study was complete response (CR), pCR or radiological

CR (in those who did not undergo surgery) in patients with KRAS and BRAF wild-type tumors. Secondary end points were radiological response rate, progression-free survival (PFS), OS, safety and quality of life. Radiological response was assessed using MRI and computed tomography scans. In the wild-type group, the addition of cetuximab resulted in a significant improvement in radiological response (Figure). There was no statistically significant difference in CR (9% vs. 11%) and pCR (7% vs. 11%). “The low pCR rate may be explained by the nine patients who achieved a pCR, but had insufficient tissue for molecular analysis, six of whom received cetuximab,” Dr. Dewdney commented. Interestingly, the high radiological response rate didn’t translate into a pCR improvement. “Both the complete response and pathologic complete response were similar in both arms and were relatively low,” Dr. Dewdney said. “This may in part be explained by the eight patients in whom a pathologic complete response rate was achieved but in whom there was insufficient tissue for KRAS and BRAF analysis. Six of those patients were treated within the cetuximab arm.” Although there was an early separation of the PFS curves, there was no statistical difference in PFS between the two treatments at three years in patients with wildtype tumors.. However, the researchers did detect a significant improvement in

Experts Weigh In According to Dr. Saif, EXPERT-C, similar to previous studies, did not show that adding cetuximab to chemoradiotherapy improved pCR rates. “Although not clear, some studies suggested that the low response rate observed might have been secondary to the strong antiproliferative effect of cetuximab that may have compromised the activity of chemotherapy that targets proliferating cells,” Dr. Saif said. “Therefore, the researchers suggested that EGFR [epidermal growth factor receptor] inhibition might be more effective if it is started after, and not before, chemoradiotherapy or if combined with radiotherapy in the absence of chemotherapy, or given after chemoradiation as maintenance therapy.” He noted that more recent studies are looking at induction chemotherapy before neoadjuvant chemoradiotherapy; one such study is

‘The data is encouraging, but more studies are required before we place [this treatment approach] in our practice.’ —Wasif Saif, MD

Radiological response, %

This news comes from the Phase II EXPERT-C trial, presented at the 2011 Gastrointestinal Cancers Symposium (abstract 360). Three-year OS in patients receiving cetuximab (Erbitux, Merck) was 96% compared with 81% among those who received neoadjuvant chemotherapy and chemoradiation alone. “The addition of cetuximab to neoadjuvant chemotherapy and chemoradiation resulted in a significant survival benefit and [radiological] response rate, but there was no improvement in pathologic complete response [pCR],” said Wasif Saif, MD, who was asked by Clinical Oncology News to put the results into context. “The data is encouraging, but more studies are required before we place [this treatment approach] in our practice.” Dr. Saif is director of the clinical section of gastrointestinal cancers and medical director of the Pancreas Center at Columbia University College of Physicians and Surgeons and NewYork-Presbyterian Hospital, New York City.

three-year OS among wild-type patients with the addition of cetuximab (81% vs. 96%; hazard ratio, 0.27; P=0.035). Relapse rates were similar in both arms. In line with recent data suggesting that patients with KRAS codon 13 mutations may have better outcome than those with other KRAS mutations, an exploratory analysis of the KRAS wild-type population combined with patients with KRAS codon 13 mutations demonstrated an improvement in survival, she added. As expected, patients in the cetuximab arm had more grade 3/4 skin rash during both neoadjuvant chemotherapy and chemoradiotherapy. Rates of diarrhea were also increased in patients receiving cetuximab, but only during chemoradiation. Importantly, Dr. Dewdney said, none of these adverse effects affected the number of patients completing treatment.

P=0.038

100 80 60

P=0.028

40 20 0

Neoadjuvant chemotherapy

Neoadjuvant chemotherapy plus cetuximab

Neoadjuvant chemotherapy and chemoradiation

Neoadjuvant chemotherapy and chemoradiation plus cetuximab

Figure. Comparison of radiological responses in patients in the EXPERT-C trial.

assessing capecitabine plus oxaliplatin plus cetuximab followed by chemoradiotherapy. Cathy Eng, associate professor in the Department of GasScan for Web trointestinal Medical exclusive “Experts Oncology at the UniDiscuss Key versity of Texas MD Challenges in Anderson Cancer CenTreating Rectal Cancer”; ter, in Houston, chaired instructions page 7. the session where EXPERT-C was presented. She said the trial addresses whether the majority of treatment (induction chemotherapy followed by neoadjuvant chemoradiation) prior to TME is feasible without compromising efficacy of therapy. She pointed out that this concept also was evaluated in a randomized Phase II Spanish trial published in 2010 (J Clin Oncol 2010:859865, PMID: 20065174). That study randomly assigned patients to arm A, which received preoperative chemoradiotherapy with Capox and concurrent radiation followed by surgery and four cycles of postoperative adjuvant Capox, or arm B, which received induction Capox followed by chemoradiotherapy and surgery. There was no difference between the two arms, but the neoadjuvant/induction arm resulted in improved adherence in completing therapy (92% vs. 52%; P=0.001). Dr. Eng said that a Phase III trial is needed to confirm the benefit of cetuximab seen in EXPERT-C. “Recent studies have not demonstrated a benefit in overall survival. This study is unique because they noted no increased toxicities, which is in contrast to the Phase III STAR and ACCORD-12 trials that reported no improvement in pCR but at the cost of increased toxicities with the use of oxaliplatin, similar to prior phase I/ II studies of cetuximab in combination. What is unique about EXPERT-C is that it not only changes the order of our current treatment paradigm, but it is the first trial to show a benefit in OS since the pivotal Phase III Swedish trial,” Dr. Eng said. “The findings from EXPERT-C may impact our current choice of end points.” She added that trials under discussion or expected to launch soon will continue to challenge the treatment paradigm. In the Netherlands, a randomized trial has an investigational arm of the European 5×5 Gy radiation technique followed by induction chemotherapy prior to TME. In the United States, a trial of omitting radiation altogether in selected patients is under discussion. Dr. Eng said, “It is refreshing to see that investigators have an interest in modifying the treatment of rectal carcinoma, in which few modifications have occurred since the pivotal neoadjuvant German trial in 2004.” —Fran Lowry

POLICY & MANAGEMENT

Clinical Oncology News • March 2011

Finance

FOUND MONEY continued from page 1 

practice is subsidized, your revenues have to at least equal your expenses.” Not every practice has been able to manage that. Many smaller ones lack the financial resources to invest in efficiency-enhancing office upgrades and technology needed to remain viable and are being absorbed into larger practices or acquired by hospital systems. Although consolidation might be beneficial for some practices under water, the change can mean hardship for cancer patients in areas with sparse medical resources who have come to rely on convenient access to a local oncologist’s care. In this four-part series, Found Money, Clinical Oncology News will discuss strategies that oncology practices and community cancer centers can implement to increase their chance of surviving, if not flourishing. The series will discuss actions that many oncology practices are taking to maximize revenues, lower costs and increase their prospects for long-term viability.

Getting Paid for Your Time Oncologists are well aware of the growing expense of treating the nation’s more than 11 million cancer patients. This expense has skyrocketed, in part, because the treatment of cancer patients has become more complex. “We understand the biology of cancer remarkably well at this point compared with what we did 20 years ago or even five years ago, and we are beginning to bring very specific treatments for particular diseases,” said Roy Beveridge, MD, medical director of U.S. Oncology. But the gains in knowledge have also resulted in a huge leap in treatment complexity. “You need to make sure that the right

‘One of the ways to find money in today’s environment is to make sure you understand all the regulations for each payer.’ —Mary Lou Bowers, MBA

patient is getting the right treatment,” Dr. Beveridge said. “What is happening is that there is an awful lot of variation in care. If you haven’t specifically identified a particular patient molecularly or genomically, you may actually be giving the wrong treatment or a treatment that is expensive but may not be effective.” Along with the advances in treatment complexity, Dr. Beveridge noted, have come “extremely high” costs of care. “People are finding it harder and harder to pay for drugs,” he said, “and reimbursement is not keeping up, in part because the drugs are very, very expensive.” The escalation in medication costs also has driven up the amount of money oncology practices need to invest to maintain an adequate inventory. The drugs and supplies alone that are required to provide chemotherapy in an office setting “may account for upward of $2.5 million,” Mr. Okon said. “That is a huge billing challenge, and that drug bill is tied to the services bill.” That services component of the cost equation is where oncology practices sometimes stumble. Perhaps out of fear of capturing the attention of a Medicare Recovery Audit Contractor (RAC), they may ratchet down patients’ billing codes by a notch, thus undervaluing the time and level of professional oversight required even for a patient doing well on a difficult regimen. Or oncologists might become so caught up in their patients’ progress or lack of it that they neglect to properly document

their work. “Lots of doctors don’t value their time properly in part because they don’t understand the methodology for how people get paid for things,” said Dr. Beveridge. “It’s very complicated; I have trouble understanding it, and I actually spend some time thinking about it. People who are very rushed seeing patients all the time aren’t spending hours and hours trying to figure out the billing codes.” Matt Farber, director of Provider Economics and Public Policy at the Association of Community Cancer Centers (ACCC), said, “One of the easiest ways to save money is making sure you are billing correctly. Many of our members, whether they realize it or not, may not be billing 100% correctly and may be leaving money on the table.” Mary Lou Bowers, MBA, chief executive officer of The Pritchard Group, agreed that the need to code and bill accurately was essential but often gets lost. “Oncologists get so used to dealing with really sick patients that when they evaluate the level of a patient’s visit based on medical decision making, they may say, ‘This patient wasn’t too hard. They’re doing OK with their therapy.’ “Never mind that the doctor looked at multiple documents, CTs [computed tomography scans] and lab work to determine that the patient was doing well,” she said. “In their minds, the difficult medical decision component relates to a patient who is failing therapy or having a lot of side effects, and they’re having to do a lot of work to mitigate those results.”

Financial Counselors

The WAITING ROOM

by Joan Chiverton

Billing and coding also are complicated by the multiplicity of government and commercial payers. “One of the ways to ‘find money’ in today’s environment is to make sure you understand all the regulations for each payer,” said Ms. Bowers. “Different payers require different ways to document and bill. You can’t leave that to your billing staff.” One move that everyone agrees is essential is to designate a single individual or group as the oncology practice guru who stays current with the latest twists and turns in government and commercial insurer payment policies. “You can have your office manager be your expert. That is a reasonable person to trust,” Ms. Bowers said, adding that physician groups or administrator groups can also supply valuable expertise. Mr. Farber said that “a very popular trend” among ACCC members is to use financial counselors, “whether

a person with a specific background in handling insurance issues, or other staff members. Our members find that they are more than paying for themselves in the time they are able to give in helping with patient assistance programs or talking with insurance companies about prior authorizations and dealing with denials.” As the need to contain the nation’s spiraling health care bill gains momentum, oncology practices and community cancer centers are facing a radically shifting payment environment. “The demonstration of quality is becoming extremely important because payers, meaning employers, are demanding it,” Dr. Beveridge said. “They are spending a lot of money on oncology and they want proof that these dollars are being spent in a wise and beneficial way. That is where we are going. That is the trend.” —Bruce Buckley In coming issues, Clinical Oncology News will further explore the changing economic landscape, including new payment models that reward practices for providing quality, cost-saving care. We’ll dig deeper into what individual oncology practices are doing to streamline their operations, including improvements in billing and coding and contract negotiation. The series also will spotlight the trend to accountable care organizations and the medical home model, as well as the incentives available for quality reporting and information technology investments.

McMahon Publishing Group is a 38-year-old, familyowned medical publishing and medical education company. McMahon publishes seven clinical newspapers, seven special editions,continuing medical education and custom publications. Clinical Oncology News (ISSN 1933-0677) is published monthly by McMahon Publishing, 545 W 45th Street, New York, NY 10036. Copyright 2011 McMahon Publishing, New York, NY. All rights reserved. Application for Periodicals Postage rate is pending at New York, NY, and additional mailing offices. POSTMASTER: Please send address changes to Clinical Oncology News, 545 W. 45th St., 8th Floor, New York, NY 10036. www.mcmahonmed.com

Would you like to receive Clinical Oncology News or change your delivery address? All U.S. oncologists, hematologist/oncologists, surgical oncologists, gynecological oncologists and pediatric hematologist/oncologists should receive Clinical Oncology News free of charge. If you are changing your address or name, you must notify the AMA at (800) 262-3211 or the AOA (if appropriate) at (800) 621-1773. To continue receiving Clinical Oncology News, you need not be a member of either organization; however, they maintain the ultimate source of our mailing addresses. For added assurance of uninterrupted receipt, you may also mail or fax a copy of your current mailing label along with your change of address and signature to: Circulation Coordinator, Clinical Oncology News, 545 W. 45th St., 8th Floor, New York, NY 10036. Fax: (212) 664-1242. If you are not a member of the groups listed above and would like to subscribe, please send a check payable to Clinical Oncology News. Please allow 8-12 weeks for delivery of the first issue. Subscription: $70.00 domestic, $90.00 international. Single copies $7.00 domestic, $10.00 international.

FDA NEWS

Clinical Oncology News • March 2011

FDA NEWS continued from page 5 

images on the iPhone and iPad (Apple Inc). The application is the first mobile application cleared by the FDA for viewing images and making medical diagnoses based on computed tomography, magnetic resonance imaging and nuclear medicine technology, such as positron emission tomography). It is not intended to replace full workstations and is indicated for use only when there is no access to a workstation. Radiology images taken in the hospital or physician’s office are compressed for secure network transfer and then sent to the appropriate portable wireless device via software called Mobile MIM (MIM Software). The application allows the physician to measure distance on the image and image intensity values and display measurement lines, annotations and regions of interest. In its evaluation, the FDA reviewed performance test results on various portable devices. These tests measured luminance, image quality and noise in accordance with international standards and guidelines. The FDA also reviewed results from demonstration studies with qualified radiologists under different lighting conditions. All participants agreed that the application allowed for sufficient diagnostic image interpretation under the recommended lighting conditions. The display performance of mobile devices can vary significantly in luminance levels even within the same model. The application includes an interactive contrast test in which a small part of the screen is a slightly different shade from the rest of the screen. If the physician can identify and tap this portion of the screen, then the lighting conditions are not interfering with the physician’s ability to discern subtle differences in contrast.

FDA Finds Association Between Breast Implants and ALCL

may have a very small but significant risk for anaplastic large cell lymphoma (ALCL) in the scar capsule adjacent to the implant. The FDA is asking health care professionals to report all confirmed cases of ALCL in women with breast implants to the FDA’s safety information and adverse event reporting program, MedWatch. Reports can be made online or by calling (800) 332-1088. Each year, ALCL is diagnosed in about one of 500,000 women in the United States. Nationally, ALCL located in breast tissue is found in only about three of every 100 million

women without breast implants. The FDA is aware of about 60 cases of ALCL in women with breast implants worldwide. This number may be higher because it is possible that some cases have not been published in the scientific literature, or the number could be lower because some may be duplicate reports. The FDA notification is based on a review of scientific literature published between January 1997 and May 2010 and information from other international regulators, scientists and breast implant manufacturers. The literature review identified 34 unique cases of ALCL in women

PHA

SE I

with both saline and silicone breast implants. Most cases were diagnosed when patients sought medical treatment for implant-related symptoms such as pain, lumps, swelling, or asymmetry that developed after their initial surgical sites were fully healed. Examination of the fluid and capsule surrounding the breast implant led to the ALCL diagnosis. Breast implant manufacturers have been asked to update their product labeling materials for patients and health care professionals. An estimated 5 million to 10 million women worldwide have breast implants.

II TR

IAL

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REN

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 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

ata reviewed by the FDA suggest that patients with breast implants

Where do you go? ✪ If you recall seeing an in-depth review of a topic but no longer have a hard copy?

✪ If you heard about an interesting piece from a colleague?

✪ If you see an installment from a multipart series but wish to see the other parts?

TLY

An Investigational Therapeutic Cancer Vaccine for Unresectable Stage III NSCLC

MAIN INCLUSION CRITERIA

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)

Clinicaloncology.com

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CLINICAL TRIALS

Clinical Oncology News • March 2011

New Phase II and III Clinical Trials

Hematologic

Solid Tumors

Trials added to the National Cancer Institute’s list of clinical trials in the 30 days prior to Feb. 15, 2011. For eligibility criteria and additional information, visit www.cancer.gov/clinicaltrials, click on the advanced link and enter the protocol ID.

Supportive Care

Protocol Type

Age

Protocol ID

Trial Sites

Randomized Study of mFOLFOX7 or XELOX Plus Bevacizumab Versus Fluorouracil/Leucovorin Calcium or Capecitabine Plus Bevacizumab as First-Line Therapy in Elderly Patients With Metastatic Colorectal Cancer, Phase III

70 and over

NCCTG-N0949

FL, MN

Pilot Study of Azacitidine in Patients With Previously Treated Advanced Non-Small Cell Lung Cancer, Phase II

18 and over

OSU-10100

Cyclin Dependent Kinase (CDK)4/6 Inhibitor, PD0332991 in Advanced Non-small Cell Lung Cancer NSCLC, Phase II

18 to 80

PD0332991

Accelerated Hypofractionated Radiotherapy for the Treatment of Breast Cancer, Phase II

21 and over

10.0584

Sentinel and/or Axillary Lymph Node Biopsy With or Without Axillary Reverse Mapping in Reducing Incidence and Severity Of Arm Lymphedema in Patients With Resectable Stage 0-II Breast Cancer, Phase II

18 and over

1B-09-12

Concurrent Adjuvant Carboplatin and Accelerated Radiotherapy for Triple Negative Breast Cancer, Phase I/II

18 and over

NYU 10-01969

Paclitaxel, Trastuzumab, and Pertuzumab in the Treatment of Metastatic HER2-Positive Breast Cancer, Phase II

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IMPORTANT SAFETY INFORMATION GLEEVEC is often associated with edema and occasionally serious fluid retention. Patients should be weighed and monitored regularly for signs and symptoms of fluid retention, which can be serious or life-threatening, and be advised to report any rapid, unexpected weight gain. The probability of edema tended to be increased among older patients (>65 years) or those taking higher doses of GLEEVEC. If severe fluid retention occurs, GLEEVEC should be withheld until the event has resolved and then resumed depending on the initial severity of the event Cytopenias have been reported. Complete blood counts should be performed weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example, every 2-3 months). Dose reduction or treatment interruption may be required for severe neutropenia or thrombocytopenia (see full Prescribing Information for dose adjustment recommendations) Severe congestive heart failure and left ventricular dysfunction have occasionally been reported. Most of the patients with reported cardiac events have had other comorbidities and risk factors, including advanced age and previous medical history of cardiac disease. Patients with cardiac disease or risk factors for cardiac failure should be monitored carefully, and any patient with signs or symptoms consistent with cardiac failure should be evaluated and treated Hepatotoxicity, occasionally severe, may occur. Assess liver function before initiation of treatment and monthly thereafter or as clinically indicated. Monitor liver function when combined with chemotherapy known to be associated with liver dysfunction. A 25% decrease in the recommended dose should be used for patients with severe hepatic impairment. If severe hepatotoxicity occurs, GLEEVEC should be withheld until the event has resolved and then resumed depending on the initial severity of the event In the Phase 3 unresectable or metastatic GIST studies, 13% of patients reported (NCI Grades 3/4) hemorrhage at any site. In the Phase 2 unresectable or metastatic GIST study, 5% of patients were reported to have severe gastrointestinal (GI) bleeds and/or intratumoral bleeds. GI tumor sites may have been the source of GI bleeds In patients with hypereosinophilic syndrome and cardiac involvement, cardiogenic shock and left ventricular dysfunction have been associated with initiation of GLEEVEC. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures, and temporarily withholding GLEEVEC Bullous dermatologic reactions (eg, erythema multiforme and Stevens-Johnson syndrome) have also been reported. In some cases, the reaction recurred upon rechallenge. Several postmarketing reports describe patients able to tolerate the reintroduction of GLEEVEC at a lower dose with or without concomitant corticosteroids or antihistamines following resolution or improvement of the bullous reaction Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with GLEEVEC. TSH levels should be closely monitored in such patients Consider potential toxicities—specifically liver, kidney, and cardiac toxicity—and immunosuppression from long-term use

GLEEVEC is metabolized by the CYP3A4 isoenzyme and is an inhibitor of CYP3A4, CYP2D6, and CYP2C9. Significant reductions in imatinib concentrations may occur when GLEEVEC is administered concomitantly with agents that are strong CYP3A4 inducers such as rifampin, St. John’s wort, and enzyme-inducing anti-epileptic drugs, eg, phenytoin. The use of concomitant strong CYP3A4 inducers should be avoided. If patients must be administered a strong CYP3A4 inducer, the dosage of GLEEVEC should be increased by at least 50% and clinical response should be carefully monitored. Caution is recommended when GLEEVEC is administered with CYP3A4 inhibitors such as ketoconazole, with CYP2D6 substrates that have a narrow therapeutic window, or with CYP3A4 substrates that have a narrow therapeutic window. Other examples of commonly used drugs that may significantly interact with GLEEVEC include acetaminophen, warfarin, erythromycin, and metoprolol. Grapefruit juice should also be avoided in patients taking GLEEVEC. (Please see full Prescribing Information for other potential drug interactions) Patients with moderate renal impairment (CrCL = 20-39 mL/min) should receive a 50% decrease in the recommended starting dose and future doses can be increased as tolerated. Doses greater than 600 mg are not recommended in patients with mild renal impairment (CrCL = 40-59 mL/min). For patients with moderate renal impairment, doses greater than 400 mg are not recommended. GLEEVEC should be used with caution in patients with severe renal impairment Common Side Effects of GLEEVEC Tablets

www.GISTexchange.com

A CASE HIGHLIGHT: Diagnosis and Adjuvant Treatment of a Patient With KIT+ GIST CASE CONTRIBUTOR Bruce Brockstein, MD

Almost all patients who received GLEEVEC in the Phase 3 unresectable or metastatic GIST studies experienced adverse reactions at some time. Overall, the incidence of all grades of adverse reactions and the incidence of severe adverse reactions (CTC Grade 3 and above) were similar between the two treatment arms except for edema and rash/related terms, which were reported more frequently in the 800-mg group. The most frequently reported adverse reactions (400 mg/day; 800 mg/day) (all Grades) were edema (77%; 86%), fatigue (69%; 75%), nausea (58%; 65%), abdominal pain (57%; 55%), diarrhea (56%; 58%), rash and related terms (56%; 70%), vomiting (37%; 41%), myalgia (32%; 30%), anemia (32%; 35%), anorexia (31%; 36%), and arthralgia (14%; 12%). Therapy with GLEEVEC was discontinued for adverse reactions in 5% of patients at both dose levels studied* In the adjuvant treatment of GIST trials, almost all GLEEVEC- and placebo-treated patients experienced adverse reactions at some time. The most frequently reported adverse reactions were similar to those reported in other clinical studies in other patient populations and include (GLEEVEC; placebo) (all Grades) diarrhea (59%; 29%), fatigue (57%; 41%), nausea (53%; 28%), periorbital edema (47%; 15%), decreased hemoglobin (47%; 27%), peripheral edema (27%; 15%), rash (26%; 13%), vomiting (26%; 14%), abdominal pain (21%; 22%), anorexia (17%; 9%), arthralgia (15%; 15%), and myalgia (12%; 12%)*

North Shore University Health System Evanston, IL

CASE COMMENTATORS

In the adjuvant GIST trial, drug was discontinued for adverse events in 17% of GLEEVEC- and 3% of placebotreated patients. Edema, GI disturbances (nausea, vomiting, abdominal distention, and diarrhea), fatigue, low hemoglobin, and rash were the most frequently reported adverse reactions at the time of discontinuation*

Fetal harm can occur when administered to a pregnant woman; therefore, women of childbearing potential should be advised to not become pregnant while taking GLEEVEC tablets and to avoid breast-feeding while taking GLEEVEC tablets because of the potential for serious adverse reactions in nursing infants. Sexually active female patients taking GLEEVEC should use adequate contraception. If the patient does become pregnant while taking GLEEVEC, the patient should be advised of the potential hazard to the fetus

Supportive care may help reduce the severity of some mild-to-moderate adverse reactions. However, in some cases, either a dose reduction or interruption of treatment with GLEEVEC may be necessary

In the Phase 2 unresectable or metastatic GIST trial (400 mg/day; 600 mg/day), severe (NCI Grades 3/4) lab abnormalities—including anemia (3%; 9%) and neutropenia (10%; 11%)—were reported among patients receiving GLEEVEC. In Phase 3 unresectable or metastatic GIST trials (400 mg/day; 800 mg/day), severe adverse reactions (NCI Grades 3/4/5), including abdominal pain (14%; 12%), edema (9%; 13%), fatigue (12%; 12%), nausea (9%; 8%), vomiting (9%; 8%), diarrhea (8%; 9%), rash (8%; 9%), and myalgia (6%; 4%), were reported among patients receiving GLEEVEC

GLEEVEC tablets should be taken with food and a large glass of water to minimize GI irritation

In the adjuvant treatment of GIST trials (GLEEVEC; placebo), severe (NCI Grades 3 and above) lab abnormalities— increase in liver enzymes (ALT) (3%; 0%), (AST) (2%; 0%), decreased neutrophil count (3%; 1%), and decrease in hemoglobin (1%; 0%)—and severe adverse reactions (NCI Grades 3 and above), including abdominal pain (3%; 1%), diarrhea (3%; 1%), rash (3%; 0%), fatigue (2%; 1%), nausea (2%; 1%), vomiting (2%; 1%), white blood cell count decreased (1%; 0%), and periorbital edema (1%; 0%), were reported among patients receiving adjuvant treatment with GLEEVEC

GIST exchange

For daily dosing of 800 mg and above, dosing should be accomplished using the 400-mg tablet to reduce exposure to iron

Sultanali Alidina, MD

Patrick Mansky, MD

David Witt, MD

Sultanali Alidina, MD, Inc. Long Beach, CA

The Cancer Team at Bellin Health Green Bay, WI

Bridgeport Hospital Bridgeport, CT

CASE OVERVIEW

Patients should be informed to take GLEEVEC exactly as prescribed, and not to change their dose or stop taking GLEEVEC unless they are told to do so by their doctor. If patients miss a dose, they should be advised to take their dose as soon as possible unless it is almost time for their next dose, in which case the missed dose should not be taken. A double dose should not be taken to make up for any missed dose

*For more detailed study information, please see full Prescribing Information. If you wish to unsubscribe from future direct mail promotional communications about Gleevec® from Novartis Pharmaceuticals Corporation, please call 1-888-669-6682.

• 46-year-old man presented with complaints of abdominal pain, fatigue, and ongoing diarrhea for 2 weeks. • Patient was diagnosed with KIT+ GIST, underwent partial gastrectomy to resect the tumor, and was then initiated on Gleevec adjuvant treatment at 400 mg/d. • The tumor recurred after the patient elected to self-discontinue Gleevec therapy; patient had stable disease following reinitiation of Gleevec therapy at 400 mg/d and resection of recurrent disease. • Summary: Even with complete resection of a KIT+ GIST, the risk with recurrence may decrease with adjuvant Gleevec therapy.

There have also been reports, including fatalities, of cardiac tamponade, cerebral edema, acute respiratory failure, and GI perforation

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

Printed in USA

1/11

GLI-901101-D

Gleevec® (imatinib mesylate) tablets are indicated for patients with KIT(CD117) positive unresectable and/or metastatic gastrointestinal stromal tumors (GIST). Please see accompanying full Gleevec® Prescribing Information. Sponsored by Novartis Pharmaceuticals Corporation.

DISCLAIMER: This case study was adapted from actual case files, and results are not necessarily representative and may vary by patient. Portions of this presentation are designed for discussion or illustrative purposes and are not intended to be comprehensive. The discussion of diagnosis, procedures and treatment principles of guidelines in this presentation is not intended to represent the opinion or advice of Novartis Pharmaceuticals Corporation. Patient care decisions are the prerogative of the patient and the physician based on the circumstances involved.

PRESENTATION

Table 1: Serious Adverse Reactions to Gleevec

A 46-year-old man presented in January of 2004 complaining of abdominal pain, fatigue, and diarrhea that had been going on for 2 weeks. The patient had a past medical history of hypertension, asthma earlier in life, and a meningioma that had been resected 5 years earlier. At presentation, the patient’s hemoglobin level was 10.4 g/dL. An upper endoscopy and endoscopic ultrasound (EUS) were performed and showed a 3-cm ulcerated fundal mass. A computed tomography (CT) scan was ordered that also revealed a 3-cm mass at the gastric fundus (Figure 1).

Fluid retention and edema Patients should be weighed and monitored regularly for signs and symptoms of edema or serious fluid retention. Severe fluid retention was reported in 9% to 13.1% of patients with KIT+ GIST.

Hemorrhage In Phase 3 unresectable or metastatic GIST studies, 12.9% of patients reported NCI Grades 3/4 hemorrhage at any site. In the Phase 2 unresectable or metastatic GIST study, 5% of patients reported severe gastrointestinal (GI) and/or intratumoral bleeds. GI tumor sites may have been the source of GI bleeds.

Severe congestive heart failure and left ventricular

DIAGNOSIS Considering the patient’s symptoms and the findings on endoscopy and CT scans, what would be the next step in the diagnostic workup? A diagnosis of gastrointestinal stromal tumor (GIST) should be considered for ulcerated gastric masses. Histologic confirmation is necessary to confirm a diagnosis of GIST. Therefore, a CT-guided or EUS-guided biopsy with immunohistochemical analysis should be taken to confirm the diagnosis and differentiate the lesion from other possible submucosal tumors of the GI tract. About 95% of GISTs stain positively for c-KIT, also known as CD117.1 A positron emission tomography (PET) scan may also provide useful information.2 Current Case Diagnosis: Upon consultation with the surgeon, the patient underwent a partial gastrectomy to remove the mass within 1 month of diagnosis. Histologic and immunohistochemical analysis showed that the mass consisted of spindle-like cells that stained positively for c-KIT. Pathologic review demonstrated a high mitotic index (20 mitoses per 50 high-power fields). These findings were consistent with the diagnosis of KIT-positive GIST.

dysfunction Patients with cardiac disease or risk factors for cardiac failure should be monitored carefully. Patients with signs or symptoms should be evaluated and treated.

Hepatotoxicity Dose adjustments may be necessary due to hepatotoxicity. Monitoring of hepatic function is recommended.

Hematologic toxicity Cytopenias, including anemia, neutropenia, and thrombocytopenia, have been reported. Complete blood counts should be performed as indicated.

Gastrointestinal disorders Gleevec should be taken with food and a large glass of water to minimize possible GI irritation. There have been rare reports, including fatalities, of GI perforation.

Hypereosinophilic cardiac toxicity

TREATMENT AND SAFETY CONSIDERATIONS This patient was diagnosed with KIT-positive GIST and had the mass removed. What could be a possible next step in the treatment pathway? Gleevec® (imatinib mesylate) is indicated for the adjuvant treatment of adult patients following resection of KIT (CD117)–positive GIST.3 A phase 3, double-blind, placebo-controlled trial showed that, at a median follow up of 14 months, Gleevec significantly improved recurrencefree survival compared with placebo in patients with resected KIT-positive GIST (Figure 2).4 Safety considerations should be discussed with the patient before initiating therapy and patients need to be carefully monitored over the course of treatment. Patients taking Gleevec may experience serious adverse events (AEs) (Table 1); some serious AEs, such as hepatotoxicity and hematologic toxicities, may require dose adjustment, interruption, or drug discontinuation.3

The most commonly reported AEs, occurring in over 30% of patients, are diarrhea, fatigue, nausea, periorbital edema, and decreased hemoglobin (Table 2).3 For a complete description of adverse events, please see the Important Safety Information on the back cover and the full Gleevec Prescribing Information.

In patients with hypereosinophilic syndrome and cardiac involvement, cardiogenic shock and left ventricular dysfunction have been associated with initiation of Gleevec. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures, and temporary withholding of Gleevec.

Dermatologic toxicities Bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported.

Hypothyroidism Hypothyroidism has been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with Gleevec. TSH levels should be closely monitored.

Toxicities from long-term use Consider potential toxicities—specifically liver, kidney, and cardiac toxicity—and immunosuppression.

Table 2: Frequency of Most Common Adverse Reactions* Gleevec (n=337)

Placebo (n=345)

59% 57% 53% 47% 47% 27% 26% 26% 21% 19%

29% 41% 28% 15% 27% 15% 13% 14% 22% 20%

Diarrhea Fatigue Nausea Periorbital edema Decreased hemoglobin Peripheral edema Rash Vomiting Abdominal pain Headache

This patient showed signs of recurrence following cessation of Gleevec. What could be an appropriate strategy to manage this patient’s potential recurrence of GIST? If the recurrence is confirmed as KIT-positive GIST, Gleevec reinitiation is possible. In the phase 3 adjuvant trial, patients were treated for 1 year. The optimal treatment duration with Gleevec has not been determined; trials are ongoing evaluating the optimal duration of therapy following resection. Treatment with Gleevec may be continued as long as there is no evidence of progressive disease or unacceptable toxicity.3 This patient continued treatment beyond a year, but relapsed 19 months after treatment cessation. A discussion should take place between the treating physician and the patient weighing the patient’s risk for GIST recurrence, efficacy of adjuvant treatment, and possible adverse effects that may accompany treatment. Current Case Outcome: Following the identification of the mass by CT, a pretreatment PET scan confirmed a recurrence of the mass in the left upper quadrant (Figure 3). No other sites of disease recurrence or metastases were found with PET. The patient reinitiated Gleevec 400 mg/d. Four months after restarting Gleevec, a CT scan showed a partial response to therapy. The patient was then referred to a surgical oncologist and underwent a partial gastrectomy, splenectomy, and partial colectomy 8 months after reinitiating Gleevec therapy. The patient remains disease-free 1 year following Gleevec reinitiation.

*All adverse reactions (all grades) occurring in ≥20% of patients are listed regardless of suspected relationship to treatment.

Current Case Treatment: Upon discussion with the patient about the risk for recurrence, adjuvant Gleevec 400 mg/d was initiated 6 weeks after surgery. After 3 months of therapy, a CT scan showed no evidence of recurrent disease, with only postoperative changes noted. The patient continued on Gleevec 400 mg/d for 2 years with intermittent CT scan monitoring. The patient experienced mild fatigue, mild myalgias and arthralgias, and occasional mild nausea felt to be a result of Gleevec treatment. Side-effect management included low doses of nonsteroidal anti-inflammatories for his myalgia and arthralgia. The patient decided to stop Gleevec treatment after 2 years, and did not inform his health care providers. Nineteen months after discontinuing Gleevec, the patient presented with weight loss, pain in the left upper quadrant of the abdomen, and fatigue. A CT scan was performed and showed a 12-cm mass in the left upper quadrant adjacent to the stomach.

Pregnancy Fetal harm can occur when administered to a pregnant woman. Women of childbearing potential should be advised not to become pregnant and to avoid breast-feeding while taking Gleevec tablets because of the potential for serious adverse reactions in nursing infants.

SUMMARY This case demonstrates that, even with complete resection, patients with KIT+ GIST can benefit from post-resection Gleevec therapy (400 mg/d) to decrease the chance of recurrence. The patient’s decision to stop treatment and subsequent KIT+ GIST recurrence highlights the importance of clear communication between treating physicians and their patients regarding risk for recurrence, the efficacy of adjuvant treatment, and possible adverse effects.

REFERENCES 1. Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: a consensus approach. Hum Pathol. 2002;33:459-465. 2. Referenced with permission from the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology™ Soft Tissue Sarcoma (V.2.2010). Available at: http://www.nccn.org. Accessed April 19, 2010. ©National Comprehensive Cancer Network, Inc. 2010. To view the most recent and complete version of the NCCN Guidelines™, go online to www.nccn.org. 3. Gleevec® (imatinib mesylate) tablets prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; Feb 2010. 4. Dematteo RP, Ballman KV, Antonescu CR, et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet. 2009;373:1097-104.

For more cases, visit www.GISTexchange.com. Sponsored by Novartis Pharmaceuticals Corporation.

Please see accompanying full Gleevec® Prescribing Information.