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

McMahon Publishing

Independent News for the Oncologist and Hematologist/Oncologist CLINICALONCOLOGY.COM • February 2011 • Vol. 6, No. 2

SOLID TUMORS

6 9 9

Maurie Markman, MD, in his first regular monthly column, discusses the Avastin controversy. Exemestane and anastrozole face off in head-to-head trial. High-dose fulvestrant more effective than anastrozole for metastatic breast cancer. FDA NEWS

Abstral, a new breakthrough cancer pain medication, is approved.

Timing of Chemo Key To Survival In Colon Cancer

CYP2D6 Genotyping Not Needed Before Tamoxifen

San Francisco—Results from a metaanalysis suggest that waiting too long before starting adjuvant chemotherapy after surgery for colorectal cancer could have a negative impact on survival. “The results of our analysis indicate a significant adverse association between [delayed] time to adjuvant chemotherapy and survival in colorectal cancer,” said James J. Biagi, MD, acting head of oncology at Queen’s University, Kingston, Ontario, Canada, who led the study. “They indicate the need for clinicians and health systems managers to take the steps necessary to keep the time to adjuvant chemotherapy as short as reasonably achievable.” Dr. Biagi presented the results of the

Sa n A n t o n i o — C Y P 2 D 6 genotype is not associatsociated with improved clinical outcomes in women omen with breast cancer who are treated with tamoxamoxifen, according to retrospective analysess of two large stud-ies presented at thee recent San Antonio o Breast Cancer Sympoposium (SABCS). Manyy clinicians say thee findings finally proovide some clarity on the issue of whetherr patients should undergo pharmacogenetic harmacogenetic testing before receiving i g ttamoxifen. if “The evidence is not sufficient to recommend CYP2D6 genotyping,” for patients being considered for treatment with adjuvant tamoxifen or anastrozole, said James

see TIMING, page 10

HEMATOLOGIC DISEASE

Researchers say regimen improves cure rate for unfavorable Hodgkin’s disease.

The pros and cons of choosing imatinib, nilotinib or dasatinib for first-line CML therapy. CLINICAL TRIALS

Recently launched Phase II and Phase III clinical trials.

EDUCATIONAL REVIEW

Updates in the Treatment of Advanced Breast Cancer After page 12.

ADVISORY BOARD EDITORIAL

Hyped Follicular Lymphoma Rx Not Ready for Practice

see CYP2D6, page 8

POLICY & MANAGEMENT

Orlando, Fla.—At the recent American Society of Hematology annual meeting, Ardeshna et al (abstract 6) presented results from a randomized trial of early rituximab (Rituxan, Genentech) therJennifer apy with or without main- Brown, MD tenance compared with observation, in patients with asymptomatic non-bulky follicular lymphoma (FL). The authors found a significant delay in the time to initiation of first therapy (chemotherapy or radiotherapy) following early therapy with rituximab compared with observation. Although this delay may at first see BROWN, page 19

Rae, PhD, assistant p professor in the Department Departmen of Internal Medicine at the th University of Michigan, A Ann Arbor. He presented results from re one of the o studies, a s retrospecr tive analysis ys of the prospective pr clinical trial cli Structure ATAC (Arimidex, ( of CYP2D6 Tamoxifen, Alone Tamoxi or in Combination) (abstract S1-7). The second thatt pharmacoged study t d iindicating di ti g th h netic testing is not needed was a CYP2D6 genotype analysis of the BIG 1-98 data of postmenopausal women with endocrine-

Improving Inpatient-Outpatient Transitions: What Can Be Done?

any hospitals and oncology group practices are failing to effectively manage cancer patient’s transition from inpatient hospital care to the outpatient setting, according to a new report by the Association of Community C anc er C enter s (AC C C ). Practices are falling short in their efforts to adequately coordinate medical services, maintain complete medical records and obtain essential case information during

the complex process. According to the report, about half of the oncology groups surveyed designate staff to manage postdischarge transitions, yet few have implemented specific transition policies or checklists. At hospitals, oncology-specific transition policies are largely nonexistent; few monitor readmissions or follow up discharged patients. And despite having computerized prescriber see TRANSITION, page 12

McMahonMedicalBooks.com Thalassemia, An Issue of Hematology/ Oncology Clinics of North America Bernard G. Forget

For more information, see

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ALIMTA (pemetrexed for injection) Drug Interactions: Concomitant administration of nephrotoxic drugs or substances that are tubularly secreted could result in delayed clearance of ALIMTA. See Warnings and Precautions for specific information regarding ibuprofen administration. Use in Specific Patient Populations: It is recommended that nursing be discontinued if the mother is being treated with ALIMTA or discontinue the drug, taking into account the importance of the drug for the mother. The safety and effectiveness of ALIMTA in pediatric patients have not been established. Dose adjustments may be necessary in patients with hepatic insufficiency. Dosage and Administration Guidelines: Complete blood cell counts, including platelet counts and periodic chemistry tests, should be performed on all patients receiving ALIMTA. Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Modify or suspend therapy according to the Dosage Reduction Guidelines in the full Prescribing Information.

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

insideALIMTA.com

ALIMTA® (pemetrexed for injection) BRIEF SUMMARY. For complete safety, please consult the full Prescribing Information. 1 INDICATIONS AND USAGE 1.1 Nonsquamous Non-Small Cell Lung Cancer — Combination with Cisplatin ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer. 1.5 Limitations of Use ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer [see Clinical Studies (14.1, 14.2, 14.3) in the full Prescribing Information]. 2 DOSAGE AND ADMINISTRATION 2.1 Combination Use with Cisplatin Nonsquamous q Non-Small Cell Lungg Cancer The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m2 infused over 2 hours beginning approximately 30 minutes after the end of ALIMTA administration. Patients should receive appropriate hydration prior to and/or after receiving cisplatin. See cisplatin package insert for more information. 2.3 Premedication Regimen Vitamin Supplementation pp To reduce toxicity, patients treated with ALIMTA must be instructed to take a low-dose oral folic acid preparation or multivitamin with folic acid on a daily basis. At least 5 daily doses of folic acid must be taken during the 7-day period preceding the first dose of ALIMTA; and dosing should continue during the full course of therapy and for 21 days after the last dose of ALIMTA. Patients must also receive one (1) intramuscular injection of vitamin B12 during the week preceding the first dose of ALIMTA and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as ALIMTA. In clinical trials, the dose of folic acid studied ranged from 350 to 1000 mcg, and the dose of vitamin B12 was 1000 mcg. The most commonly used dose of oral folic acid in clinical trials was 400 mcg [see Warnings and Precautions (5.1)]. Corticosteroid Skin rash has been reported more frequently in patients not pretreated with a corticosteroid. Pretreatment with dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction. In clinical trials, dexamethasone 4 mg was given by mouth twice daily the day before, the day of, and the day after ALIMTA administration [see Warnings and Precautions (5.1)]. 2.4 Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations Monitoringg Complete blood cell counts, including platelet counts, should be performed on all patients receiving ALIMTA. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min. Periodic chemistry tests should be performed to evaluate renal and hepatic function [see Warnings and Precautions (5.5)]. Dose Reduction Recommendations Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Treatment may be delayed to allow sufficient time for recovery. Upon recovery, patients should be retreated using the guidelines in Tables 1-3, which are suitable for using ALIMTA as a single-agent or in combination with cisplatin. Table 1: Dose Reduction for ALIMTA and Cisplatin — Hematologic Toxicities Nadir ANC <500/mm3 and nadir platelets ≥50,000/mm3

75% of previous dose (pemetrexed and cisplatin) Nadir platelets <50,000/mm3 without bleeding 75% of previous dose regardless of nadir ANC (pemetrexed and cisplatin) Nadir platelets <50,000/mm3 with bleedinga, 50% of previous dose regardless of nadir ANC (pemetrexed and cisplatin) a These criteria meet the CTC version 2.0 (NCI 1998) definition of ≥CTC Grade 2 bleeding. If patients develop nonhematologic toxicities (excluding neurotoxicity) ≥Grade 3, treatment should be withheld until resolution to less than or equal to the patient’s pre-therapy value. Treatment should be resumed according to guidelines in Table 2. Table 2: Dose Reduction for ALIMTA and Cisplatin — Nonhematologic Toxicitiesa,b Dose of ALIMTA (mg/m2) 75% of previous dose 75% of previous dose

Dose of Cisplatin (mg/m2) 75% of previous dose 75% of previous dose

Any Grade 3 or 4 toxicities except mucositis Any diarrhea requiring hospitalization (irrespective of Grade) or Grade 3 or 4 diarrhea Grade 3 or 4 mucositis 50% of previous dose 100% of previous dose a NCI Common Toxicity Criteria (CTC). b Excluding neurotoxicity (seee Table 3). In the event of neurotoxicity, the recommended dose adjustments for ALIMTA and cisplatin are described in Table 3. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced. Table 3: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin — Neurotoxicity CTC Grade 0-1 2

Dose of ALIMTA (mg/m2) 100% of previous dose 100% of previous dose

Dose of Cisplatin (mg/m2) 100% of previous dose 50% of previous dose

Discontinuation Recommendation ALIMTA therapy should be discontinued if a patient experiences any hematologic or nonhematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed. Renallyy Impaired p Patients In clinical studies, patients with creatinine clearance ≥45 mL/min required no dose adjustments other than those recommended for all patients. Insufficient numbers of patients with creatinine clearance below 45 mL/min have been treated to make dosage recommendations for this group of patients [see Clinical Pharmacology (12.3) in the full Prescribing Information]. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Laboratory Monitoring and Dose Reduction/ Discontinuation Recommendations (2.4) in the full Prescribing Information]. Caution should be exercised when administering ALIMTA concurrently with NSAIDs to patients whose creatinine clearance is <80 mL/min [see Drug Interactions (7.1)]. 3 DOSAGE FORMS AND STRENGTHS ALIMTA, pemetrexed for injection, is a white to either light-yellow or green-yellow lyophilized powder available in sterile single-use vials containing 100 mg or 500 mg pemetrexed. 4 CONTRAINDICATIONS ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed or to any other ingredient used in the formulation. 5 WARNINGS AND PRECAUTIONS 5.1 Premedication Regimen Need for Folate and Vitamin B12 Supplementation pp Patients treated with ALIMTA must be instructed to take folic acid and vitamin B12 as a prophylactic measure to reduce treatment-related hematologic and GI toxicity [see Dosage and Administration (2.3)]. In clinical studies, less overall toxicity and reductions in Grade 3/4 hematologic and nonhematologic toxicities such as neutropenia, febrile neutropenia, and infection with Grade 3/4 neutropenia were reported when pretreatment with folic acid and vitamin B12 was administered. ALIMTA® (pemetrexed for injection) PV 5208 AMP

Corticosteroid Supplementation pp Skin rash has been reported more frequently in patients not pretreated with a corticosteroid in clinical trials. Pretreatment with dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction [see Dosage and Administration (2.3)]. 5.2 Bone Marrow Suppression ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia) [see Adverse Reactions (6.1)]; myelosuppression is usually the dose-limiting toxicity. Dose reductions for subsequent cycles are based on nadir ANC, platelet count, and maximum nonhematologic toxicity seen in the previous cycle [see Dosage and Administration (2.4)]. 5.3 Decreased Renal Function ALIMTA is primarily eliminated unchanged by renal excretion. No dosage adjustment is needed in patients with creatinine clearance ≥45 mL/min. Insufficient numbers of patients have been studied with creatinine clearance <45 mL/min to give a dose recommendation. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Dosage and Administration (2.4)]. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone. 5.4 Use with Non-Steroidal Anti-Inflammatory Drugs with Mild to Moderate Renal Insufficiency Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Other NSAIDs should also be used with caution [see Drug Interactions (7.1)]. 5.5 Required Laboratory Monitoring Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min [see Dosage and Administration (2.4)]. 5.6 Pregnancy Category D Based on its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. Pemetrexed administered intraperitoneally to mice during organogenesis was embryotoxic, fetotoxic and teratogenic in mice at greater than 1/833rd the recommended human dose. If ALIMTA 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. Women should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA [see Use in Specific Populations (8.1)]. 5.7 Third Space Fluid The effect of third space fluid, such as pleural effusion and ascites, on ALIMTA is unknown. In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to ALIMTA administration. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice. In clinical trials, the most common adverse reactions (incidence ≥20%) were fatigue, nausea, and anorexia. Additional common adverse reactions (incidence ≥20%) included vomiting, neutropenia, leukopenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation. Non-Small Cell Lungg Cancer ((NSCLC)) — Combination with Cisplatin p Table 4 provides the frequency and severity of adverse reactions that have been reported in >5% of 839 patients with NSCLC who were randomized to study and received ALIMTA plus cisplatin and 830 patients with NSCLC who were randomized to study and received gemcitabine plus cisplatin. All patients received study therapy as initial treatment for locally advanced or metastatic NSCLC and patients in both treatment groups were fully supplemented with folic acid and vitamin B12. Table 4: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in NSCLCa Reactionb

ALIMTA/cisplatin (N=839) All Grades Grade 3-4 Toxicity (%) Toxicity (%) 90 37

Gemcitabine/cisplatin (N=830) All Grades Grade 3-4 Toxicity (%) Toxicity (%) 91 53

All Adverse Reactions Laboratory Hematologic 10 46 6 33 Anemia 27 38 15 29 Neutropenia 8 21 5 18 Leukopenia 13 27 4 10 Thrombocytopenia Renal Creatinine elevation 10 1 7 1 Clinical Constitutional Symptoms Fatigue 43 7 45 5 Gastrointestinal 4 53 7 56 Nausea 6 36 6 40 Vomiting 1 24 2 27 Anorexia 0 20 1 21 Constipation 0 12 1 14 Stomatitis/Pharyngitis 2 13 1 12 Diarrhea 0 6 0 5 Dyspepsia/Heartburn Neurology Neuropathy-sensory 9 0 12 1 Taste disturbance 8 0c 9 0c Dermatology/Skin Alopecia 12 0c 21 1c Rash/Desquamation 7 0 8 1 a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA. b Refer to NCI CTC Criteria version 2.0 for each Grade of toxicity. c According to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2. No clinically relevant differences in adverse reactions were seen in patients based on histology. In addition to the lower incidence of hematologic toxicity on the ALIMTA and cisplatin arm, use of transfusions (RBC and platelet) and hematopoietic growth factors was lower in the ALIMTA and cisplatin arm compared to the gemcitabine and cisplatin arm. The following additional adverse reactions were observed in patients with non-small cell lung cancer randomly assigned to receive ALIMTA plus cisplatin. Incidence 1% to 5% Body as a Wholee — febrile neutropenia, infection, pyrexia General Disorderss — dehydration Metabolism and Nutritionn — increased AST, increased ALT Renall — creatinine clearance decrease, renal failure Special Sensess — conjunctivitis Incidence Less than 1% Cardiovascularr — arrhythmia General Disorderss — chest pain ALIMTA® (pemetrexed for injection) PV 5208 AMP

Metabolism and Nutritionn — increased GGT Neurologyy — motor neuropathy 6.2

Additional Clinical Trials Experience Across clinical trials, sepsis, which in some cases was fatal, occurred in approximately 1% of patients.

6.3

Post-Marketing Experience The following adverse reactions have been identified during post-approval use of ALIMTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinall — colitis General Disorders and Administration Site Conditionss — edema Injury, poisoning, and procedural complicationss — Radiation recall has been reported in patients who have previously received radiotherapy. Respiratoryy — interstitial pneumonitis Skin — Bullous conditions have been reported, including Stevens-Johnson syndrome and toxic epidermal necrolysis, which in some cases were fatal. 7 DRUG INTERACTIONS 7.1

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Ibuprofen p Although ibuprofen (400 mg four times a day) can decrease the clearance of pemetrexed, it can be administered with ALIMTA in patients with normal renal function (creatinine clearance ≥80 mL/min). Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min) [see Clinical Pharmacology (12.3) in the full Prescribing Information]. Other NSAIDs Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity.

PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling. Patients should be instructed to read the patient package insert carefully. 17.1 Need for Folic Acid and Vitamin B12 Patients treated with ALIMTA must be instructed to take folic acid and vitamin B12 as a prophylactic measure to reduce treatment-related hematologic and gastrointestinal toxicity [see Dosage and Administration (2.3)]. 17.2 Low Blood Cell Counts Patients should be adequately informed of the risk of low blood cell counts and instructed to immediately contact their physician should any sign of infection develop including fever. Patients should also contact their physician if bleeding or symptoms of anemia occur. 17.3 Gastrointestinal Effects Patients should be instructed to contact their physician if persistent vomiting, diarrhea, or signs of dehydration appear. 17.4 Concomitant Medications Patients should be instructed to inform the physician if they are taking any concomitant prescription or overthe-counter medications including those for pain or inflammation such as non-steroidal anti-inflammatory drugs [see Drug Interactions (7.1)]. To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088, or www.fda.gov/medwatch.

7.2

Nephrotoxic Drugs ALIMTA is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed clearance of ALIMTA. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of ALIMTA. 8 USE IN SPECIFIC POPULATIONS 8.1

Pregnancy Teratogenic Effectss - Pregnancy Category D [see Warnings and Precautions (5.6)]. Based on its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. There are no adequate and well controlled studies of ALIMTA in pregnant women. Pemetrexed was embryotoxic, fetotoxic, and teratogenic in mice. In mice, repeated intraperitoneal doses of pemetrexed when given during organogenesis caused fetal malformations (incomplete ossification of talus and skull bone; about 1/833rd the recommended intravenous human dose on a mg/m2 basis), and cleft palate (1/33rd the recommended intravenous human dose on a mg/m2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced litter sizes. If ALIMTA 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 use effective contraceptive measures to prevent pregnancy during the treatment with ALIMTA. 8.3

Nursing Mothers It is not known whether ALIMTA or its metabolites are 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 ALIMTA, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother. 8.4

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

8.5

Geriatric Use ALIMTA is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Renal function monitoring is recommended with administration of ALIMTA. No dose reductions other than those recommended for all patients are necessary for patients 65 years of age or older [see Dosage and Administration (2.4)]. In the initial treatment non-small cell lung cancer clinical trial, 37.7% of patients treated with ALIMTA plus cisplatin were ≥65 years and Grade 3/4 neutropenia was greater as compared to patients <65 years (19.9% versus 12.2%). For patients <65 years, the HR for overall survival was 0.96 (95% CI: 0.83, 1.10) and for patients ≥65 years the HR was 0.88 (95% CI: 0.74, 1.06) in the intent-to-treat population. 8.6

Patients with Hepatic Impairment There was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics of pemetrexed [see Clinical Pharmacology (12.3) in the full Prescribing Information]. Dose adjustments based on hepatic impairment experienced during treatment with ALIMTA are provided in Table 2 [see Dosage and Administration (2.4)]. 8.7

Patients with Renal Impairment ALIMTA is known to be primarily excreted by the kidneys. Decreased renal function will result in reduced clearance and greater exposure (AUC) to ALIMTA compared with patients with normal renal function [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) in the full Prescribing Information]. Cisplatin coadministration with ALIMTA has not been studied in patients with moderate renal impairment. 8.8

Gender In the initial treatment non-small cell lung cancer trial, 70% of patients were males and 30% females. For males the HR for overall survival was 0.97 (95% CI: 0.85, 1.10) and for females the HR was 0.86 (95% CI: 0.70, 1.06) in the intentto-treat population. 8.9

Race In the initial treatment non-small cell lung cancer trial, 78% of patients were Caucasians, 13% East/Southeast Asians, and 9% others. For Caucasians, the HR for overall survival was 0.92 (95% CI: 0.82, 1.04), for East/Southeast Asians the HR was 0.86 (95% CI: 0.61, 1.21), and for others the HR was 1.24 (95% CI: 0.84, 1.84) in the intent-to-treat population. 10

OVERDOSAGE There have been few cases of ALIMTA overdose. Reported toxicities included neutropenia, anemia, thrombocytopenia, mucositis, and rash. Anticipated complications of overdose include bone marrow suppression as manifested by neutropenia, thrombocytopenia, and anemia. In addition, infection with or without fever, diarrhea, and mucositis may be seen. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician. In clinical trials, leucovorin was permitted for CTC Grade 4 leukopenia lasting ≥3 days, CTC Grade 4 neutropenia lasting ≥3 days, and immediately for CTC Grade 4 thrombocytopenia, bleeding associated with Grade 3 thrombocytopenia, or Grade 3 or 4 mucositis. The following intravenous doses and schedules of leucovorin were recommended for intravenous use: 100 mg/m2, intravenously once, followed by leucovorin, 50 mg/m2, intravenously every 6 hours for 8 days. The ability of ALIMTA to be dialyzed is unknown. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was clastogenic in the in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, CHO cell assay). Pemetrexed administered at i.v. doses of 0.1 mg/kg/day or greater to male mice (about 1/1666 the recommended human dose on a mg/m2 basis) resulted in reduced fertility, hypospermia, and testicular atrophy. ALIMTA® (pemetrexed for injection) PV 5208 AMP

Literature revised August 9, 2010

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CLINICAL ONCOLOGY NEWS • FEBRUARY 2011

Breast

The Bevacizumab/Breast Cancer Controversy:

The Median Isn’t the Message or of Much Clinical Relevance In 1982, the renowned paleontologist and zoologist, Stephen Jay Gould was diagnosed with peritoneal mesothelioma, a malignancy with a “median mortality of eight months.” In a classic essay entitled, “The Median isn’t the Message,” Dr. Gould quite elegantly and most appropriately shattered the “statistical” argument of clinical cancer management.1 ADVISORY BOARD EDITORIAL Maurie Markman, MD Cancer Treatment Centers of America Eastern Regional Medical Center Philadelphia, Pennsylvania

“The problem may be briefly stated: What does ‘median mortality of eight months’ signify in our vernacular? I suspect that most people, without training in statistics, would read such a statement as, ‘I will probably be dead in eight months,’ the very conclusion that must be avoided, since it isn’t so, and since

of life-threatening conditions only can be made following a thorough discussion of the documented benefits versus the potential risks associated with available options and after considering relevant unique clinical features (eg, existing comorbidity, prior therapy-related adverse events). Like Stephen Gould, and following the opportunity to obtain as much information as necessary to make personal decisions, one has the right to choose to fight, to be aggressive, and certainly to maintain optimism for the future.

irreducible essence. Variattitude matters so much.” ation is the hard reality, Dr. Gould, who died of cannot a set of imperfect meacer 20 years after his initial sures for a central tendendiagnosis of mesothelioma, cy. Means and medians are understood that median was the abstractions. Therefore, merely a number, and with I looked at the mesotheliocertainty this figure did not represent the ultimate survival Scan for additional ma statistics quite differentcoverage of the ly, and not only because I am Unfortunately, Something Has of a particular cancer patient; Avastin controversy; an optimist who tends to see Changed … an individual, whose natural instructions below. the donut instead of the hole, history of disease, response The FDA apparently has decided that (or lack thereof ) to treatment, and oth- but primarily because I know that vari- despite the results of clinical trials indier poorly defined factors (eg, attitude) ation itself is the reality. I had to place cating the addition of bevacizumab to myself amidst the variation.” 1 would determine the outcome. cytotoxic chemotherapy improves the In words that resonate across the spectrum of cancer care, Dr. Gould further declared: The rationale for this decision is even more questionable when “But all evolutionary biologists know one considers that most oncologists in this country now have that variation itself is nature’s only

considerable experience with bevacizumab.

2-D Bar Codes in Clinical Oncology News In my opinion, individual decisions for more- or less-aggressive cancer management strategies and acceptance or rejection of potentially serious treatment-related side effects must remain in the domain of the patient. It also is clear that a truly informed decision involving complex management

time to disease progression in metastatic breast cancer (MBC), it will be withdrawing its previously granted regulatory approval for the use of this management paradigm.2,3 Space limitations do not permit a thorough scientific critique of this decision, but it is fair to conclude the decision is based on the

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CLINICAL ONCOLOGY NEWS • FEBRUARY 2011

Breast

FDA’s determination of “marginal benefit” for a population of women with MBC treated with this combination approach versus the potential toxicity of the strategy. The rationale for this decision is even more questionable when one considers that most oncologists in this country now have considerable experience with bevacizumab, widely employed in several clinical settings (eg, cancers of the colon, lung, brain, kidney, and ovaries). In fact, management of bevacizumab’s side effects can reasonably be considered a rather routine component of standard oncologic management. However, of greatest relevance, and a truly chilling concern, is that the FDA appears to be saying it has decided how to interpret for individual breast cancer patients whether the possible clinical utility of treatment with bevacizumab is worth the potential risk. There will be no discussion with the patient as to whether a delay in her experiencing cancer-related symptoms is enough to proceed with administration of this agent. There will be no discussion with the patient, even if she strongly believes she will be one of those individuals “at the end of the very long progressionfree survival curve,” and that belief/fundamental optimism is enough of a reason for the patient to want to proceed with this specific approach to management of her cancer. There will be no discussion, because the FDA has decided for the patient. But we must be fair. The FDA is not alone in its statement regarding decisions on individual breast cancer management. Even that “well-known cancer specialist,” the editorial page of The New York Times, has gotten into the act, by declaring the FDA had given bevacizumab approval “for breast cancer treatment based on a single, unimpressive clinical trial.”4 This is a remarkable statement, considering the fact that in that National Cancer Institute cooperative group trial, the addition of bevacizumab to paclitaxel essentially doubled median progression-free survival (11.8 vs 5.9 months; hazard ratio, 0.60; P<0.001).5 One wonders if women with MBC treated with bevacizumab whose cancers do not progress to produce distressing or life-threatening symptoms for considerable periods of time, leading to improved and maintained quality of life, would agree with The New York Times assessment of “unimpressive.” Nothing stated here is meant to diminish the truly serious concerns about the cost of bevacizumab and other new/novel anticancer agents.6 As a society, we simply must find a solution to this major and clearly increasing problem. However, I would doubt whether any patients would ever want specific management decisions regarding their cancer to be made either by governmental

regulators, no matter how genuinely well intentioned they may be, or by any other external entity that could not possibly know what is in their best interest (eg, self-declared medical experts in the media). This assumes, of course, that patients in the future actually are given the opportunity to make this choice.

References 1. http://www.phoenix5.org/articles/Gould Message.html. Accessed January 14, 2011. 2. FDA. FDA News Release. Dec. 16, 2010: FDA begins process to remove breast cancer indication from Avastin label. http://

www.fda.gov/newsevents/newsroom/pressannouncements/ucm237172.htm. Accessed January 14, 2011.

What’s Your View?

3. Goldberg P. FDA moves to revoke Avastin’s breast cancer accelerated approval. Cancer Letter. 2010;36(46): 1, 16-19.

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Send replies to

6. Markman M. Refocusing the debate: evidence-based clinical cancer research versus marketplace reality. J Oncol Pract. 2008;4(5):231, PMID: 20856701.

korourke@mcmahonmed.com

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

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

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

Learn More About the START Trial Please call 1-800-507-5284 or refer to www.nsclcstudy.com or www.clinicaltrials.gov (NCT00409188)

101108 - 115622

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Where do you stand on the Avastin controversy? Do you agree or disagree with the FDA decision? Send us your comments which we will consider publishing in a forthcoming issue of Clinical Oncology News.

5. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357(26):2666-2676, PMID: 18160686.

MAIN INCLUSION CRITERIA

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4. Avastin (editorial). The New York Times. December 26, 2010:WK13.

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CLINICAL ONCOLOGY NEWS • FEBRUARY 2011

Breast

CYP2D6 continued from page 1

responsive early invasive breast cancer (abstract S1-8). At SABCS, Matthew Goetz, MD, associate professor of oncology at Mayo Clinic, in Rochester, Minn., who served as the discussant for both trials, said that caregivers should not recommend routine CYP2D6 testing for postmenopausal women with estrogen receptor (ER)-positive breast cancer to preferentially select either tamoxifen or an aromatase inhibitor (AI). However, women should be informed of the controversy regarding the pharmacogenetics of tamoxifen and clinicians should consider testing some patients, including postmenopausal women with high-risk disease who prefer tamoxifen to AIs. He said some uncertainty about CYP2D6 testing and tamoxifen will remain until a prospective randomized trial can provide a definitive answer. Studies have shown that the tamoxifen metabolite endoxifen is extremely important in the overall anticancer effect of tamoxifen. Endoxifen is formed predominantly by the CYP2D6 enzyme-mediated oxidation of N-desmethyltamoxifen. Although enzymes coded by known genetic variants— CYP2D6 and UGT2B7—are responsible for endoxifen production and elimination, studies have reported inconsistent results regarding whether the presence of genetic variants predicts response to tamoxifen. Some studies have shown that women receiving tamoxifen who either carry genetic variants associated with low or absent CYP2D6 activity or who receive concomitant medications known to inhibit CYP2D6 activity have significantly lower levels of endoxifen, worse relapse-free time and worse disease-free survival. Other studies have shown this is not the case. The retrospective analyses of the ATAC study of 9,366 postmenopausal women with invasive breast cancer focused on a subset, 615 of 3,125 women who had received anastrozole and 588 of 3,116 women who had received tamoxifen. The investigators focused on whether the seven most common single-nucleotide polymorphisms (SNPs) of CYP2D6 (*1, *2, *3, *4, *6, *10, *41) and the most common functional UGT2B7 SNP, *2, could be correlated with outcomes. The primary end points were any disease recurrence ( including local and distant recurrence and contralateral cancer) and distant recurrence only. Presenting the data, Dr. Rae said that there was no difference in the KaplanMeier curves of events out to 10 years between arms in relation to CYP2D6 genotypes. Using an established CYP2D6 scoring system (Clin Pharmacol Ther 2007;81:510-516, PMID: 17301735), he

Table 1. CYP2D6 Phenotype in the BIG 1-98 Trial

Dear Readers:

Phenotype

Definition

Poor metabolizer

Homozygous or compound heterozygous for null alleles (*3, *4, *6, *7)

Intermediate metabolizer

• Homozygous for reduced function alleles (*41) or heterozygous for reduced and null function alleles • Heterozygous extensive metabolizer: heterozygous for one reduced or null function allele

Extensive metabolizer

Absence of null or reduced function alleles

and his colleagues found that the score did not predict recurrence in either arm. Additionally, UGT2B7*2 did not predict recurrence in either arm. Medications that interfere with CYP2D6 activity also did not have an impact. The investigators concluded that there was no evidence for avoiding CYP2D6 inhibitors such as fluoxetine, paroxetine, quinidine and bupropion. In the BIG 1-98 trial, patients were randomized to tamoxifen, letrozole (Femara, Novartis) or the combination of letrozole and tamoxifen, with either tamoxifen or letrozole given first. For the subanalyses presented at SABCS, researchers led by Brian Leyland-Jones, MD, PhD, professor of medicine at Emory University, in Atlanta, investigated whether CYP2D6 phenotypes of reduced enzyme activity were associated with worse disease control and reduced hot flashes in women who received tamoxifen. Of 8,010 patients enrolled in the study, the subanalysis focused on 2,675 women who had undergone successful genotyping and had either tamoxifen or letrozole monotherapy with or without chemotherapy. The primary end point was breast cancer–free interval determined from time of randomization to local or regional recurrence or contralateral breast cancer. Investigators used a different scoring system than in the ATAC trial, dividing patients into poor, intermediate or extensive metabolizers based on CYP2D6 phenotype (Table 1). “We found no association between CYP2D6 phenotype [and] breast cancer–free interval in an unadjusted analysis or when adjusting for patient and disease characteristics,” Dr. Leyland-Jones said. CYP2D6 phenotypes of reduced enzymatic activity, poor metabolism or intermediate metabolism also were not associated with fewer hot flashes. “CYP2D6 pharmacogenetic testing is not justified to determine whether tamoxifen should be given,” Dr. Leyland-Jones said. The two analyses presented at SABCS were among 14 studies conducted since 2003 demonstrating a positive association between CYP2D6 genotype and inhibitor use with breast cancer outcome and 15 studies demonstrating

LETTER FROM THE EDITOR

no such association, according to Dr. Goetz. Some studies have even shown an inverse association. Dr. Goetz agreed with the two principal study investigators that routine genotype testing is not warranted, but he said clinicians should exercise caution and avoid potent CYP2D6 inhibitors in women treated with tamoxifen (Table 2). He questioned whether an in vivo assay measuring both CYP2D6 and CYP3A enzyme activity can more accurately identify patients with low endoxifen concentrations and highlighted the need to define the potential interaction between tumor subtypes, such as ERβ and HER2, and the pharmacokinetics of tamoxifen.

Table 2. Strong CYP2D6 Inhibitors • Fluoxetine • Paroxetine • Quinidine • Bupropion

n this issue of Clinical Oncology News, I would like to bring to your attention two new features. On page 6, you will find the first of what will be a regular monthly column by Maurie Markman, MD. Dr. Markman is vice president of patient oncology services and national director for medical oncology at the Cancer Treatment Centers of America. He has been an active member of the Clinical Oncology News advisory board from the beginning, and he is looking forward to bringing you timely and provocative editorial on matters that affect your practice. The second new feature is the use of two-dimensional (2-D) bar codes. Several of these codes, also known as matrix codes, are scattered throughout this issue and will connect you to additional information about the articles you’re perusing. The technology is based on Microsoft’s “Tag” mobile barcode system, which apparently is taking off far faster than hospital adoption of bar codes. Bar codes are showing up in consumer packaged goods, interactive gift cards, publishing and elsewhere. I hope you enjoy these two new features. And as always, I’d love your feedback on Clinical Oncology News. I can be reached at (212) 957-5300 ext. 265 or korourke@mcmahonmed.com. Regards,

According to Dr. Goetz, the SABCS analyses had several strengths. They are derived from large prospective adjuvant hormonal studies that defined the standard of care for women with earlystage breast cancer. Given the limitations of tumor-derived DNA, the number of CYP2D6 alleles tested was adequate and the analyses controlled for factors such as ER expression and chemotherapy administration. The lack of standardization regarding CYP2D6 phenotype, however, is a weakness, as is variation in the concomitant use of CYP2D6 inhibitors with tamoxifen. The BIG 1-98 study also did not adjust for concomitant use of drugs known to reduce the severity and number of hot flashes. And, importantly, Dr. Goetz said, the analyses were retrospective. “This controversy is unlikely to be resolved through retrospective analyses, given that CYP2D6 only partially explains the extensive variability in endoxifen pharmacokinetics,” Dr. Goetz said. He said prospective trials are needed to address the issue. One such trial,

Kate O’Rourke Editor, Clinical Oncology News

the Eastern Cooperative Group trial E3108, is ongoing. Dr. Leyland-Jones pointed out that the target accrual for this trial is only 300 patients while the ATAC and BIG-198 studies involved a large number of women. “Whatever the limitations of these studies, we are unlikely to see such large prospectively studied, homogeneously treated trial populations with such excellent follow-up to address this important issue,” Dr. Leyland-Jones said. Dr. Goetz disclosed that he is a consultant for Gtx (without compensation) and is a named inventor listed on nonprovisional patent applications regarding CYP2D6. Dr. Rae disclosed funding from Pfizer and advisory board involvement with Olema Pharma and Gtx. Dr. Leyland-Jones had no disclosures. —Kate O’Rourke

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CLINICAL ONCOLOGY NEWS â&#x20AC;˘ FEBRUARY 2011

Breast

No Clear Winner in Exemestane, Anastrozole Face-off This news comes from the final analysis of the NCIC CTG (National Cancer Institute of Canada Clinical Trials Group) MA.27. The results were presented at the recent annual San Antonio Breast Cancer Symposium (SABCS; abstract S1-1). The study, the first headto-head comparison of two aromatase inhibitors (AIs) in early-stage breast cancer, randomly assigned 7,576 patients to five years of treatment with anastrozole (1 mg per day) or exemestane (25 mg per day). No differences were seen in the primary outcome, diseasefree survival rate; indeed, the curves were superimposable, with 91% of women disease-free at a median follow-up of 4.1 years. The rate of major events (recurrence, new breast cancer, death) was almost identical as well, at 9.2% in the exemestane arm and 9.1% in the anastrozole arm (P=0.85). â&#x20AC;&#x153;This result underscores that the benefits of aromatase inhibitors are really a class effect, and that the drugs can be used interchangeably. In a first-, secondand even third-order analysis, these drugs look the same,â&#x20AC;? said Harold Burstein, MD, PhD, associate professor of medicine at Harvard Medical School and a medical oncologist in the Breast Oncology Center at Dana-Farber Cancer Institute, both in Boston. â&#x20AC;&#x153;Previous to these results, ASCO (American Society of Clinical Oncology)

already had issued guidelines that essentially said the same thing.â&#x20AC;? There were some small differences in side-effect profiles between the two agents. Most notably, osteoporosis occurred in 31% of exemestane patients compared with 35% of anastrozole patients (P=0.001). The study, however, found no difference in fracture rates. â&#x20AC;&#x153;Perhaps thereâ&#x20AC;&#x2122;s slightly less osteoporosis risk with exemestane, but given that thereâ&#x20AC;&#x2122;s no difference in terms of fracture, I donâ&#x20AC;&#x2122;t think thatâ&#x20AC;&#x2122;s a compelling feature of the results,â&#x20AC;? said Dr. Burstein, who was not involved with the study. â&#x20AC;&#x153;Clinicians now have three aromatase inhibitors that they can use pretty much interchangeably. Anecdotally, we all have in our practices patients who seem to tolerate one product better than another. If one is trying to administer an aromatase inhibitor and the patient isnâ&#x20AC;&#x2122;t tolerating it, and tamoxifen isnâ&#x20AC;&#x2122;t an alternative, a different brand of AI is an option.â&#x20AC;? Paul Goss, MD, PhD, professor of medicine at Harvard Medical School and lead researcher of the study from Massachusetts General Hospital Cancer Center in Boston, presented the results at SABCS. â&#x20AC;&#x153;The results are important, supporting a new option for women with early stage breast cancer,â&#x20AC;? Dr. Goss said. â&#x20AC;&#x153;Aromatase inhibitors are the commonest treatment

for early-stage breast cancer, and exemestane has not been approved as upfront therapy to date.â&#x20AC;? Dr. Goss believes that end-organ effects, particularly on bone metabolism, likely are clinically important. The risk for actual clinical fractures in this trial is small, given the age and overall health of the population, he noted. â&#x20AC;&#x153;More important is the finding of a significant increased incidence of new diagnoses of osteoporosis in patients on anastrozole than exemestane,â&#x20AC;? Dr. Goss said. â&#x20AC;&#x153;We must reserve our judgment of this until definitive results related to bone metabolism are presented later in 2011. â&#x20AC;&#x153;In clinical practice, doctors often avoid aromatase inhibitors in women with established osteoporosis or risk factors for this and instead default to an inferior anticancer treatment like tamoxifen for fear of aggravating osteopenia or osteoporosis,â&#x20AC;? Dr. Goss said. â&#x20AC;&#x153;If the more definitive studies of bone metabolism in a 500-patient subset of women in MA.27, to be released this year, confirm the differences in osteoporosis seen in the main study, exemestane would be confirmed as a better option than anastrozole in this important regard.â&#x20AC;? Anastrozoleâ&#x20AC;&#x2122;s U.S. patent expired in June 2010, and currently it is significantly less expensive than other AIs sold in the American market. Currently,

100 80

Patients, %

San Antonioâ&#x20AC;&#x201D;Exemestane (Aromasin, Pfizer) and anastrozole appear to be almost identical in their efficacy as first-line monotherapy for hormone-positive early-stage breast cancer, and have a very similar side-effect profile.

Exemestane Anastrozole

60 40

20 0

Figure. Prevalence of osteoporosis.

exemestane and letrozole run about $400 to $500 per month and a onemonth supply of anastrazole is around $80. â&#x20AC;&#x153;There are many people for whom generic availability will inform a decision, and thatâ&#x20AC;&#x2122;s reasonable,â&#x20AC;? Dr. Burstein said. But that advantage will likely soon change, as AIs generally are coming off patent worldwide and cost and availability of each varies. The lowering of cost and greater availability of AIs in general is good news for patients. Dr. Goss noted that women in both arms of this trial did well and better than expected in terms of breast cancer recurrence, underscoring continuing improved outcomes for women with early-stage breast cancer. Pfizer supported the MA.27 trial. Dr. Goss disclosed speaker engagements sponsored by Pfizer, AstraZeneca, and Novartis. Dr. Burstein had no relevant relationships to disclose. â&#x20AC;&#x201D;Gina Shaw

Higher-dose Fulvestrant More Effective Than Anastrozole

Thatâ&#x20AC;&#x2122;s the conclusion of the follow-up analysis of the FIRST (Fulvestrant FirstLine Study Comparing Endocrine Treatments) study, presented at the recent San Antonio Breast Cancer Symposium (SABCS). The Phase II, open-label, multicenter study randomized 205 women with advanced breast cancer to either 500 mg of fulvestrant (Faslodex, AstraZeneca) via intramuscular injection or 1 mg daily of the oral drug anastrozole (Arimidex, AstraZeneca). Median time to progression was 23.4 months in the fulvestrant group compared with 13.1 months in the anastrozole

group, corresponding to a 35% reduction in the risk for progression (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.47-0.92; P=0.01) (Figure). re). Previous research has shown that fulvestrant at the customary dose of 250 mg is at least as effective as anastrozole. Biological and clinical data had suggested that the 500-mg dose of fulvestrant was more effective, and this hypothesis has

been borne out by the FIRST trial. â&#x20AC;&#x153;The curves begin to separate at six months in terms of resistance and time to progression,â&#x20AC;? said principal investigator John Robertson, MD, professor of surgery at the University of Nottingham, United Kingdom, who presented the study at SABCS th ((abstract S1-3). The median time-totreatment failure was 17.6 months in the fulvestrant arm aand 12.7 months iin the anastrozole aarm, representing an HR of 0.73 (95% CI, 0.54-1.00). â&#x20AC;&#x153;I think the data is now clear that yes, 500 mg of fulvestrant has better antitumor activity than anastrozole at 1 mg, which is consistent with the previous randomized controlled trial in which

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San Antonioâ&#x20AC;&#x201D;Fulvestrant is more effective than anastrozole in the treatment of metastatic breast cancer when given at double the customary dose (500 vs. 250 mg), with significant improvements in median time to progression accompanied by no clinically important differences in terms of side effects.

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Figure. Median time to progression in patients with metastatic breast cancer. the two agents looked identical at 250 mg fulvestrant,â&#x20AC;? said Aman Buzdar, MD, professor of medicine in the Department see FULVESTRANT, page 21

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CLINICAL ONCOLOGY NEWS • FEBRUARY 2011

Colon

TIMING continued from page 1

meta-analysis at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium held in January (ASCO-GI; abstract 364). Adjuvant chemotherapy is the current standard of care after surgical resection of stage III colon and rectal cancer, stage II rectal cancer and stage II colon cancer with high-risk features. Two common clinical assumptions are that chemotherapy should start as soon as practical after surgery and that chemotherapy offered beyond three months may not provide any benefit. “These assumptions have not been subjected to randomized trials, nor are they likely to be,” Dr. Biagi said. In general, there are two factors that result in delays. The first is postoperative complications and delayed recovery, and the second relates to logistics of starting the adjuvant chemotherapy and can include institutional delays and inefficiencies, he noted. In this study, Dr. Biagi and his team sought to describe the relationship between time to adjuvant chemotherapy and survival and also to quantify the impact of time to chemotherapy on survival according to the unit time of delay, which in this case was four weeks. They searched the literature on Medline between 1975 and 2009, as well as online proceedings of ASCO between 2007 and 2009, for studies that described the relationship between time to adjuvant chemotherapy and survival. “In addition to fully published manuscripts, we included abstracts to reduce the impact of publication bias,” Dr. Biagi explained. Eventually, they selected four published articles and five abstracts involving 14,357 colon and rectal cancer patients. Five studies had data available to analyze disease-free survival (DFS). The analysis of all nine studies showed that for each four weeks of delay in the start of adjuvant chemotherapy, there

was a 12% increase in the risk for death (hazard ratio [HR], 1.12; 95% confidence interval [CI], 1.09-1.15). The analysis of DFS in the five studies available showed that for each four weeks of delay, patients had a 14% increase in the risk for death (HR, 1.14; 95% CI, 1.09-1.19). “The implications of our study are that if a patient was fit to initiate adjuvant chemotherapy four weeks after surgery, that same patient would have a 12% increased mortality if treated at eight weeks and a 25% increase if treated at 12 weeks,” Dr. Biagi said. As a practical example, Dr. Biagi said he turned to Adjuvant! Online, a Webbased decision-making tool for health care professionals. “We took a 65-year-old male in good general health with moderate- to highrisk colon cancer treated with 5-fluorouracil–based chemotherapy. According to Adjuvant! Online, this patient would have a 45% survival without chemotherapy and a 60% survival at five years with adjuvant chemotherapy. Assuming this estimate depends on a time to treatment of four weeks, this patient would have a reduced survival of 55% at five years with a delay to eight weeks, and 50% survival at five years with a delay to 12 weeks,” he said. Applying this logic to the 49,000 individuals diagnosed with colon cancer in 2009 in the United States and assuming that half of them would be eligible to start adjuvant chemotherapy at four weeks, a delay to eight weeks would risk more than 1,200 lives and a delay to 12 weeks would risk more than 2,400 lives, Dr. Biagi said. However, he pointed out, Adjuvant! Online shows a benefit of adjuvant chemotherapy even when given beyond the three-month window. “Without it, the patient would have a five-year survival of 45%; giving chemotherapy at three months, the survival is 50%, so this would suggest that there may actually be some benefit to adjuvant chemotherapy beyond that arbitrary three-month window.”

‘The implications of our study are that if a patient was fit to initiate adjuvant chemotherapy four weeks after surgery, that same patient would have a 12% increased mortality if treated at eight weeks and a 25% increase if treated at 12 weeks.’ —James J. Biagi, MD

Dr. Biagi also noted the limitations of his study: “There is the inherent bias that patients’ postoperative course may independently prolong wait time; our results are based on trials from the era of fluoropyrimidine-alone therapy in the era prior to oxaliplatin introduction; and our results are based on nonrandomized and retrospective data.” After the presentation, discussant Johanna Bendell, MD, director of GI oncology research and associate director of the drug development program at the Sarah Cannon Research Institute in Nashville, Tenn., noted that previous trials in the adjuvant setting have allowed patients to start adjuvant chemotherapy within eight weeks of surgery in more recent studies and within 12 weeks in older studies. “Very interestingly, there does seem to be a difference in how patients do, as shown by this analysis of retrospective studies, depending on when they start their adjuvant therapy compared to when they actually had their surgery,” she said. “This study tells us that we need to treat patients as quickly as possible after surgery and that we need to control for this in clinical trials. We also need to encourage health care systems, whether they be U.S.-based or in other parts of the world, to recognize the importance of coordinated care.” Leonard Saltz, MD, professor of medicine and head of the colorectal oncology section at Memorial Sloan-Kettering Cancer Center, New York City, who attended the session, noted that the study should be viewed as hypothesisgenerating and not as a definitive trial. “It is based on a retrospective look, and we simply do not know what the

reasons were for delay in starting therapy. It is very reasonable to speculate that many of the people who were delayed were either in poorer health, or had postoperative complications, or both, which may have put them into a poorer prognostic category independent of the actual start date of chemotherapy,” he told Clinical Oncology News. “What this study says is that there is a correlation between later start of adjuvant treatment and poorer outcome,” he added. “However, correlation does not imply causality, and what the reason for that poorer outcome might be is far from clear.” But Dr. Biagi countered that the evidence assessing levels of potential harm has a requirement for proof that is different from the evidence for treatments. “With the knowledge that this relationship will not be subjected to prospective assessment, the level of evidence from this study provides sufficient proof of an adverse association,” he said. Other clinicians not involved with the study said the trial results had implications for practice now. “This is an interesting meta-analysis that suggests that patients who receive adjuvant chemotherapy as soon as they have recovered fully from their surgical resection appear to derive greater clinical benefit,” said Ed Chu, chief of the Division of Hematology/Oncology and deputy director of the University of Pittsburgh Cancer Institute. Scan for abstract —Fran Lowry

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FDA NEWS

CLINICAL ONCOLOGY NEWS • FEBRUARY 2011

Opioid Analgesic Approved for Breakthrough Cancer Pain

he FDA has approved Abstral (fentanyl immediate-release transmucosal tablets, ProStrakan) to manage breakthrough pain (BTP) for adults with cancer. Fentanyl immediate-release (IR) transmucosal medications are administered on the soft surfaces of the mouth (inside of the cheek, gums or tongue), or the nasal passages or throat where they dissolve and are absorbed. “This is an important step for patients with cancer pain to have options for the treatment of their breakthrough pain,” said John Jenkins, MD, director of the FDA’s Office of New Drugs in the Center for Drug Evaluation and Research. Abstral is indicated for the management of BTP in patients with cancer, aged 18 years and older, who already use opioid pain medication around the clock and who need and are able to safely use high doses of an additional opioid medicine. Only health care professionals skilled in the use of Schedule II opioids to treat pain should prescribe this product. Abstral is available only through a Risk Evaluation and Mitigation Strategy (REMS) program, which is intended to minimize the risk for misuse, abuse, addiction and overdose. Under this program, pharmacies, distributors and health care professionals who prescribe

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to outpatients are required to enroll in the program to prescribe, dispense and distribute this product. The FDA has standardized key components of the REMS program to facilitate the adoption of a single shared system. These components include the REMS document, the Patient–Prescriber Agreement and the enrollment form. These components can be used by all sponsors of IR transmucosal fentanyl products to develop individual REMS programs such as the one approved for Abstral. The FDA also has directed the sponsors of this class of products to work together on a single shared system to implement the REMS.

“This approval is also a significant step toward reducing the burden on the health care system of implementing REMS programs,” added Dr. Jenkins. “When fully implemented, FDA expects that prescribers, pharmacies and distributors of all immediate-release transmucosal fentanyl products will be able to use standardized materials and a single shared system to implement the REMS.” The safety of Abstral was evaluated in 311 opioid-tolerant cancer patients with BTP. Two hundred and seventy of these patients were treated in multipledose studies. The duration of therapy for patients in multiple-dose studies ranged from one to 405 days, with an average

duration of 131 days and with 44 patients treated for at least 12 months. Common adverse events (AEs) include nausea, constipation, drowsiness and headache. Serious AEs, including deaths, have been reported in patients with other IR transmucosal fentanyl products. The deaths occurred as a result of improper patient selection and/or improper dosing. Consumers and health care professionals are encouraged to report adverse side effects or medication errors from the use of Abstral to the FDA’s MedWatch Adverse Event Reporting program at www.fda.gov/MedWatch or by calling (800) 332-1088.

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. Call Julianna Dawson at (212) 957-5300 x271.

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).

Reprints can be ordered in black & white or 4-color.

101108 - 115024

POLICY & MANAGEMENT

CLINICAL ONCOLOGY NEWS • FEBRUARY 2011

Patient Transition

TRANSITION

‘Every time a care-setting transition occurs, there is the potential challenge for miscommunication, delayed treatment and potentially a bad outcome because of incorrect treatment.’

continued from page 1

order entry (CPOE) systems, most oncology groups perform fewer than half of the 11 medication reconciliation activities queried. Among organizations with transition programs in place, few measure or analyze their processes for quality improvement. But the report, Transitions Between Care Settings, identified some high notes, pointing out “substantial progress in recent years,” such as the growing use of electronic health records (EHRs) and

—Mark Krasna, MD

problems in order of priority, then open up avenues to address them. Dr. Kovach also is a member of the ACCC advisory committee. The findings were based on survey responses from 108 ACCC-member hospitals and 41 ACCC-member oncology practices.

Cancer Maze improvements in medication reconciliation. More than 60% of oncology groups surveyed take proactive steps to ensure they know when a patient is admitted to the hospital by a physician at another practice. A similar percentage routinely arranges postdischarge office appointments. The

report also cited “exemplary patient care transition activities,” illustrated through nine case examples. According to George Kovach, MD, president of Iowa Cancer Specialists, a community practice in Davenport, the study is an attempt to codify and rank the

To register for this CME-certiﬁed symposium, please visit www.mededpre-reg.com/metastaticCME

Tailoring Therapy in Metastatic Breast Cancer Novel Clinical Approaches March 12, 2011 > À ÊUÊ/ iÊ, ÌÌi ÕÃiÊ Ìi Ó£äÊ7iÃÌÊ, ÌÌi ÕÃiÊ-µÕ>Ài Philadelphia, PA 9:00 AM – 11:30 AM Faculty Tessa Cigler, MD, MPH Assistant Professor of Medicine Weill Cornell Medical Center Attending Physician iÜ9 À *ÀiÃLÞÌiÀ > Ê Ã« Ì> New York, New York

Paula D. Ryan, MD, PhD Associate Professor

V> Ê ÛiÃÌ }>Ì À]Ê-iVÌ Ê vÊ Ài>ÃÌÊ" V }Þ i` V> Ê" V }Þ Fox Chase Cancer Center Philadelphia, Pennsylvania

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

Target Audience This activity is designed for oncologists, physicians, physician assistants, and other health care professionals involved in the treatment of patients with breast cancer or metastatic breast cancer. There are no prerequisites for attendees.

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

Program Agenda 9:00 AM – 10:00 AMÊÊÊ 10:00 AM – 11:20 AM 11:20 AM – 11:30 AMÊÊ

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

,i} ÃÌÀ>Ì Ê> `Ê Ài> v>ÃÌÊ Lectures and Case Presentation +E Ê-iÃÃ

Physician Continuing Education

“This resonates for us in a big way,” said Mark Krasna, MD, medical director of the Cancer Institute at St. Joseph’s Catholic Medical Center in Baltimore. “Every time a care-setting transition occurs, there is the potential challenge for miscommunication, delayed treatment and potentially a bad outcome because of incorrect treatment.” “Cancer care is so multifaceted and requires such a wide swath of the medical continuum, that a strong glue is needed to hold all of the parts together,” said Alan Weinstein, MD, medical director of the Fox Chase Virtua Cancer Program in Mount Holly, N.J., and chair of the ACCC Guidelines Committee. “Disseminating information to the clinicians along the many spokes of care is so difficult.” The intricacies of cancer care also mean that during inpatient–outpatient transitions, the risks to patients are particularly high, given the increased potential for gaps or interruptions in complex and time-sensitive treatment regimens. “For the patient’s sake,” the ACCC report stated, “communication processes should be formalized to ensure that discharge summaries, medication lists, and other information are available to oncologists and care teams in a timely fashion.” Unfortunately, that process doesn’t happen regularly enough. Simply obtaining hospital discharge information can be exasperating, Dr. Kovach said. Sometimes he doesn’t learn about a patient’s hospitalization until long after the patient has been discharged. During one examination, he found a long scar down the patient’s sternum from open heart surgery months earlier—news that never reached his office. “You often have to dig for information that should have been transmitted to you as part of routine procedures,” he noted. Integrated, multidisciplinary oncology facilities, such as the Helen F. Graham Cancer Center in Newark, Del., have some advantages when it comes to managing the transition, because all of their oncology services are under one roof, not geographically or institutionally fragmented, said Nicholas J. Petrelli, MD, medical director of the center. “But we still need to improve the links between the various areas of care, and we still have patients who get lost in the cancer maze.”

Technology Gap EHRs have begun to improve care coordination within facilities, but they continued on PAGE 13

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Updates in the Treatment of

Advanced Breast Cancer CHRISTINA I. HEROLD, MD Division of Hematology/Oncology Department of Medicine Beth Israel Deaconess Medical Center and Harvard Medical School Boston, Massachusetts

dvanced breast cancer remains challenging, with the major goals of treatment being prolongation of life

and preservation of patient-defined quality of life. The treatment of advanced breast cancer has become increasingly guided by molecular tumor markers, including the presence or absence of hormone receptors (HRs) and amplification or overexpression of human epidermal growth factor receptor (ErbB2 or HER2/neu).

The past few years have brought significant improvements in the treatment of subtypes of breast cancer, including HR-positive disease, HER2-positive disease, disease associated with BRCA mutations, triple-negative (estrogen receptor [ER]-, progesterone receptor [PR]-, and HER2-negative) disease, and treatment of patients with bony metastases. This review explores the recent data on treatment of various breast cancer subtypes, the role of metastatic tumor biopsies, and prevention of skeletal-related complications in patients with advanced breast disease.

Evolving Role for Metastatic Tumor Biopsies In the past year, multiple studies have sought to evaluate the frequency with which metastatic tumor

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biopsies display transitions in tumor markers when compared with the characteristics of the original primary tumor. Of these, perhaps Amir et al presented the most informative one at the American Society of Clinical Oncology (ASCO) 2010 annual meeting. In a combined analysis of the DESTINY and BRITS studies involving 271 patients, the investigators prospectively analyzed changes in marker status.1 The primary objective of this study was to ascertain the frequency with which medical oncologists changed their treatment plan based on the results of the metastatic biopsy. To this end, oncologists were asked to record their treatment plan both before and after the result of the metastatic biopsy was known. Analysis of these plans revealed that, based on the results of the metastatic biopsy, 15.1% of patients received a different treatment than originally had been

C L I N I C A L O N CO LO GY N E WS â&#x20AC;˘ F E B R UA RY 2 0 1 1

planned. As secondary objectives, the researchers investigated the frequency of discordant results and reported an overall discordance of 39%, including 5.4% for HER2 status, 12.6% for ER status, and 34% for PR status. These results highlight the frequency with which tumor markers may change during the evolution of disease and suggest that metastatic tumor biopsies likely have an important role in targeting therapies to the most current profile of a patient’s disease.

Endocrine Therapy for HR-Positive Disease At the 2010 San Antonio Breast Cancer Symposium, several important studies were presented on the management of HR-positive disease. One of these studies, FIRST (Fulvestrant First-Line Study Comparing Endocrine Treatments), examined the first-line treatment of advanced breast cancer, whereas the other 2 studies used novel therapeutics—the mammalian target of rapamycin (mTOR) inhibitor everolimus (Afinitor, Novartis) and AMG 479 (Amgen)—to overcome endocrine resistance.

FIRST During the randomized Phase II FIRST study, investigators compared “high-dose” (500 mg intramuscularly on days 0, 14, and 28, and monthly thereafter) fulvestrant (Faslodex, AstraZeneca) with anastrozole (1 mg/d) as first-line therapy for advanced breast cancer.2 The primary outcome was time to progression (TTP); median TTP was significantly improved for the fulvestrant group (23.4 months) compared with the anastrozole group (13.1 months); this corresponds to a 35% reduced risk for progression for the fulvestrant group (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.47-0.92; P=0.01). Additionally, fulvestrant was well tolerated, and there were no new safety concerns. Although FIRST is a Phase II study, these results have the potential to influence clinical care, given the significant improvement in TTP associated with fulvestrant. Of note, the results from FIRST differ from those reported from EFECT (Evaluation of Fulvestrant versus Exemestane Clinical Trial), a Phase III randomized, double-blind, placebo-controlled study enrolling women with HR-positive advanced breast cancer who had demonstrated disease progression while taking a nonsteroidal aromatase inhibitor (AI).3 EFECT randomized women to receive “loading-dose” intramuscular fulvestrant (500 mg on day 0, followed by 250 mg intramuscular fulvestrant on days 14 and 28, and monthly thereafter) or the steroidal AI exemestane (Aromasin, Pfizer). EFECT essentially documented equivalence between the study arms; for example, median TTP was 3.7 months in both treatment groups. It is worth noting that FIRST was conducted using endocrine therapy first-line, whereas EFECT employed it as second-line therapy. Finally, the optimal dosing of fulvestrant has been controversial; the results from FIRST add weight to the recommendation that fulvestrant should be given intramuscularly at 500 mg (“high-dose” schedule).

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EVEROLIMUS Based on the hypothesis that endocrine resistance may be associated with activation of the PI3K/AKT pathway, the Phase II TAMRAD (tamoxifen and RAD001-everolimus) study investigated everolimus in postmenopausal women who had demonstrated progression while using an AI.4 Prior AI use was considered in the adjuvant setting (31% of patients), the metastatic setting (60%), and both settings (9%). However, all patients were deemed poorly hormone-sensitive in that 91% demonstrated progression either during AI use in the metastatic setting or within 6 months of adjuvant AI use. Patients were stratified by TTP after AI therapy and randomized to receive either tamoxifen or the combination of tamoxifen and everolimus. The combination arm demonstrated a statistically significant superior clinical benefit ratio (CBR), the primary study objective: 42.1% in the tamoxifen arm versus 61.1% in the tamoxifen-everolimus arm. Regarding TTP, a secondary study objective, an exploratory analysis showed improved TTP in the combination arm: 4.5 months in the tamoxifen arm versus 8.5 months in the tamoxifen-everolimus arm. Regarding safety, both treatment arms were well tolerated; grade 3/4 stomatitis was more common in the combination arm (11% vs 0%) and grade 3/4 pain was more common in the tamoxifen arm (19% vs 7%). The results from TAMRAD suggest that everolimus can play a therapeutic role in overcoming endocrine resistance, warranting further investigation in a larger Phase III study.

AMG 479 Based on the hypothesis that combined inhibition of both ER and type 1 insulin-like growth factor receptor (IGF1R) will impede cell proliferation more than targeting either pathway alone, Kaufman et al conducted a randomized Phase II study involving AMG 479, a fully human monoclonal antibody (mAb) that targets IGF1R by inhibiting binding of both IGF-1 and IGF-2.5 This study included postmenopausal woman with advanced breast cancer who had either progressed during prior endocrine therapy or had experienced disease recurrence within 12 months of completing adjuvant endocrine therapy. Study participants were randomized in a 2-to-1 manner to receive either endocrine therapy (exemestane or fulvestrant per investigator’s discretion) with AMG 479 or placebo. The primary study objective was assessment of progression-free survival (PFS). Of the 156 patients enrolled, PFS was 3.9 months in the AMG 479-endocrine therapy arm versus 5.7 months in the placebo-endocrine therapy arm (HR, 1.17; 95% CI, 0.91-1.50; P=0.435), demonstrating statistically equivalent results for PFS. Regarding safety, grade 3/4 adverse events (AEs) were more common in the AMG 479-endocrine therapy arm: hyperglycemia (6% vs 0%), neutropenia (6% vs 2%), thrombocytopenia (4% vs 0%), and increased aspartate aminotransferase (4% vs 0%). In summary, patients who received AMG 479 with endocrine therapy did not seem to experience clinical benefit beyond that of endocrine therapy alone.

Novel Therapies and Combinations For HER2-Positive Disease Over the past several years, many promising new treatments have been developed to treat HER2-positive advanced breast cancer. Many of the research efforts have focused on developing new therapeutics to overcome resistance to trastuzumab (Herceptin, Genentech).

PERTUZUMAB

Table 1. Phase II Neratinib Results Prior Trastuzumab (n=66)

No Prior Trastuzumab (n=70)

16-wk PFS, %

Median PFS, wk

22.3

39.6

ORR, %

In a recent Phase II single-arm study, Baselga et al investigated the combination of trastuzumab, a mAb directed against HER2, and pertuzumab (Genentech), a mAb that binds to the HER2 dimerization domain and prevents binding of HER2 with associated receptors in the HER family (HER1, HER3, and HER4).6 During the study, 66 patients who had received 3 or fewer prior chemotherapy regimens and who had progressed through prior trastuzumab-based therapy were enrolled to receive standard dosing of trastuzumab either weekly (4 mg/kg loading dose, followed by 2 mg/kg) or every 3 weeks (8 mg/kg loading dose, followed by 6 mg/kg) combined with pertuzumab (840 mg loading dose, followed by 420 mg every 3 weeks). In this single-arm study, the overall response rate (ORR) was 24.2%; of the responders, 7.6% experienced complete response and 16.7% had a partial response. An additional 25.8% had stable disease for at least 6 months, corresponding to a CBR of 50%. This combination was generally well tolerated. Cardiac function was monitored rigorously with minimal changes noted; no patients withdrew as a result of cardiac AEs. Further investigation of this combination is under way in the Phase III CLEOPATRA (CLinical Evaluation Of Pertuzumab And TRAstuzumab) trial.

antimicrotubule agent DM1 (maytansine) to HER2-positive cells. During the 2010 European Society for Medical Oncology (ESMO) Congress, Perez et al reported preliminary results of a Phase II trial that randomized 137 patients with HER2-positive advanced breast cancer to first-line treatment with either T-DM1 (3.6 mg/ kg IV every 3 weeks) or trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) with docetaxel (75 mg/m2 or 100 mg/m2 IV every 3 weeks) (TD).8 Of note, crossover from the TD arm to the T-DM1 arm was allowed at the time of disease progression. In this preliminary analysis, the authors reported ORR and safety results. Regarding ORR, comparable results were reported, with an ORR of 48% in the T-DM1 arm and 41% in the TD arm. T-DM1 was better tolerated than TD, with rates of grade 3/4 toxicities of 37.3% and 75%, respectively. More complete results, including PFS, CBR, and 1-year overall survival (OS) are expected in the coming year.

NERATINIB

LAPATINIB WITH TRASTUZUMAB

Neratinib (Pfizer), an orally available irreversible panErbB inhibitor (ErbB 1, 2, and 4), has emerged as another strategy to treat patients whose disease has progressed through prior trastuzumab therapy. In a Phase II trial, with primary objective of 16-week PFS, 2 cohorts of patients, 66 of whom had received prior trastuzumab and 70 of whom had not, were treated with oral neratinib 240 mg daily (Table 1).7 Gastrointestinal AEs were observed, with diarrhea, the most common grade 3/4 AE, occurring in 30% of patients who had received prior trastuzumab and 13% of patients who were trastuzumab-naĂŻve. Due to the concern for potential cardiac toxicity, serial monitoring was done to assess left ventricular ejection fraction (LVEF). At baseline, the median LVEF for patients with and without prior trastuzumab were 62% and 60%, respectively, with median LVEF remaining unchanged at the final study visit. No grade 3/4 cardiac toxicities were reported.

One common clinical scenario occurs in patients with HER2-positive advanced breast cancer who have progressed through multiple lines of therapy. In a Phase III trial, Blackwell et al randomized 296 patients who had received a median of 3 prior trastuzumab-based therapies to receive lapatinib (Tykerb, GlaxoSmithKline), an oral tyrosine kinase inhibitor (TKI) with activity against ErbB1 (EGFR) and ErbB2 (HER2), with or without trastuzumab.9 For the lapatinib monotherapy arm, the daily dose was 1,500 mg. For the combination arm, the lapatinib dose was 1,000 mg daily and the trastuzumab dose was a 4 mg/kg loading dose, followed by 2 mg/kg weekly. Patients who progressed on the lapatinib-only arm were allowed to cross over to the lapatinib-trastuzumab combination arm. Results were reported based on intention to treat. For the primary objective of this study, PFS, the combination arm was superior; compared with lapatinib alone, there was a 23% relative reduced risk for progression for patients who received combination therapy (HR, 0.75; P=0.008). CBR also was improved in the combination arm, at 24.7% versus 12.4% (P=0.01). A nonâ&#x20AC;&#x201C;statistically significant trend for improved OS

T-DM1 Trastuzumab-DM1 (T-DM1) is an antibody-drug conjugate that targets delivery of the cytotoxic

ORR, overall response rate; PFS, progression-free survival Based on reference 7.

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Alkylating agents, oxygen e radicals, spontaneous reactions, x-rays s ➞ DNA damage Single-strand a break

Normal cell

BRCA mutation

PARP deficient

BRCA mutation, PARP deficient

DNA repair r

DNA repair re

Viable cell

Cell death

Figure 1. The effects of BRCA dysfunction and PARP inhibition of cellular repair. BER, base excision repair; HRR, homologous recombination repair; PARP, poly(ADP)-ribose polymerase Adapted from reference 14 with permission. ©2010 UBM Medica. All rights reserved.

was observed in the combination arm (HR, 0.75; 95% CI, 0.53-1.07; P=0.106). There were no differences in ORR. Analyses of tolerability and safety showed that diarrhea was more common in the combination arm, 60% versus 48% (P=0.03). Common AEs for both arms included diarrhea, nausea, fatigue, and rash. Regarding cardiac safety, the incidence of both symptomatic and asymptomatic cardiac events was low. In summary, the combination of lapatinib and trastuzumab has emerged as a treatment option for patients who have experienced disease progression through multiple lines of prior trastuzumab-based therapies. The combination is generally well tolerated and represents a viable non–chemotherapy–based option.

PARP Inhibitors for BRCA-Associated And Triple-Negative Disease Poly(ADP)-ribose polymerase (PARP) inhibition has recently emerged as a powerful treatment strategy in both BRCA-deficient advanced breast cancer and triple-negative metastatic breast cancer (TNMBC).10-12 PARP1 is a critical enzyme in DNA repair. Both BRCA deficiency and PARP inhibition impair the cancer cell’s ability to repair DNA; BRCA deficiency impairs homologous recombination, whereas PARP inhibition prevents base excision repair.13 Exposing BRCA-deficient cells to a PARP inhibitor results in synthetic lethality; the combined losses of homologous recombination and base excision repair leads to cell death as the cell cannot repair DNA damage (Figure 1).14 In 2009, Tutt et al reported results from a Phase II single-arm study investigating the oral PARP inhibitor olaparib (AstraZeneca) in confirmed BRCA1 or BRCA2

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carriers with advanced breast cancer who had progressed through a median of 3 prior lines of chemotherapy.10 In this heavily pretreated group of patients, the ORR was 38% and the toxicity of olaparib was limited, with grade 3/4 toxicities consisting of fatigue, nausea, and anemia being reported in a minority of patients. As a proof-of-concept study, these results support the premise that PARP inhibitors may have dramatic impact on the treatment of BRCA-associated breast cancer. BRCA-associated breast cancer shares many molecular features with TNMBC: Both typically are classified in the basal-like intrinsic subtype by genomic analysis and BRCA-associated breast cancers are typically triple-negative.15 Given these molecular similarities, there has been considerable interest in determining whether the therapeutic benefit of PARP inhibitors in BRCAassociated breast cancer can be translated to TNMBC. In a Phase II trial to test this hypothesis, O’Shaughnessy et al enrolled 123 patients with TNMBC who had previously received 2 or fewer prior lines of chemotherapy in the metastatic setting.11,12 Patients were randomized to receive either gemcitabine 1,000 mg/m2 and carboplatin (GC) to an area under the curve of 2 on days 1 and 8, every 21 days, or GC with the IV PARP inhibitor iniparib (BSI-201; Sanofi-aventis) at a dose of 5.6 mg/kg on days 1, 4, 8, and 11, every 21 days (GCI). End points were ORR, CBR, PFS, and OS. Preliminary results of this trial (86 of planned 120 patients) were presented at ASCO 2009,11 and final results (123 patients) were presented at ESMO 2010.12 Overall, comparing the preliminary results with the final results, the magnitude of difference in the results

between the GC and GCI arms is reduced, as reflected by higher but still statistically significant P values. The addition of iniparib to chemotherapy was well tolerated; safety profiles were comparable between the 2 arms. Although these Phase II results were promising, Sanofi-aventis reported in late January that the Phase III randomized trial further investigating this treatment strategy in the same treatment arms failed to meet the pre-specified criteria for significance for the primary end points of OS and PFS.16 The company noted, however, that the results of a pre-specified analysis in patients treated in the second- and thirdline setting did show improvement in OS and PFS that was consistent with the results of the Phase II study. The full Phase III results are expected to be presented at the 2011 ASCO meeting.

Eribulin: A Novel Microtubule Inhibitor Targeting microtubule dynamics of cancer cells is an approach that has been used with many existing cancer therapies including vinca alkaloids, taxanes, and epothilone B analogues such as ixabepilone (Ixempra, Bristol-Myers Squibb). The newest addition to this general group is eribulin (E7389; Halaven, Eisai), a synthetic analogue of the marine sponge halichondrin B (Figure 2). Eribulin inhibits microtubule growth by binding to tubulin and inhibiting microtubule polymerization; this results in cell cycle G2-M arrest.17 In EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice Versus Eribulin E7389), a Phase III open-label study, women with advanced breast cancer who had received 2 to 5 prior chemotherapy regimens (including an anthracycline and a taxane unless contraindicated), with at least 2 of these prior lines of chemotherapy being in the setting of advanced disease, were randomized in a 2-to-1 fashion to receive either eribulin (1.4 mg/m2 IV on days 1 and 8 of a 21-day cycle) or treatment of physician’s choice (TPC).18 The primary objective of this study was analysis of OS with secondary objectives including ORR, PFS, and safety. Median OS was 13.1 months

Halichondrin B

for patients treated with eribulin versus 10.7 months for patients in the TPC group; this corresponds to an overall improvement of OS of 2.5 months (HR, 0.81; 95% CI, 0.66-0.99; P=0.04). Regarding PFS by independent review, the eribulin group had improved PFS, 3.7 months versus 2.3 months, but this difference was not statistically significant (HR, 0.85; 95% CI, 0.70-1.03; P=0.09). Grade 3/4 toxicities associated with eribulin use included fatigue (7.6%), neutropenia (44%), and peripheral neuropathy (8.4%). In summary, this study met the primary objective by demonstrating improved OS with eribulin compared with TPC. One caveat to interpretation of EMBRACE is the nonstandard design using TPC as the control arm. An advantage of this design is that there is no customary accepted sequence of chemotherapy agents to use in the advanced setting. Additionally, this design enabled enrollment of variably but heavily pretreated women with advanced breast cancer. A disadvantage of this design is that it is impossible to compare eribulin with one chemotherapy agent or regimen. The only conclusion to be made is that eribulin outperformed TPC; it is unclear how appropriate TPC was on a patient-bypatient basis.

Antiangiogenic Therapies SUNITINIB Sunitinib (Sutent, Pfizer), an orally available multitargeted receptor TKI with activity that inhibits vascular endothelial growth factors (VEGFR1, VEGFR2, VEGFR3) and platelet-derived growth factors (PDGFRα, PDGFRβ), was recently investigated as combination therapy for advanced breast cancer in combination with capecitabine (Xeloda, Genentech) in SUN 1099 and with docetaxel (Taxotere, Sanofi-aventis) in SUN 1064.19,20 SUN 1099 was a multicenter, randomized Phase III trial that enrolled 422 women with heavily pretreated advanced breast cancer (2 or more lines of therapy in the advanced setting), who had received prior therapy

E7389

Figure 2. Structures of marine sponge halichondrin B and eribulin (E7389).

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with both an anthracycline and a taxane in any setting, to receive either oral capecitabine alone (2,500 mg/m2 per day, days 1-14 of a 21-day cycle) or combination therapy consisting of oral capecitabine (2,000 mg/m2 per day, days 1-14 of a 21-day cycle) plus oral sunitinib (37.5 mg daily).19 The primary end point of SUN 1099 was PFS, with secondary outcomes of OS and ORR. For all outcomes of interest, the study arms were statistically equivalent; for the capecitabine-alone arm versus the combination therapy arm, the results were as follows: PFS, 5.9 versus 5.5 months; OS, 16.5 versus 16.4 months; ORR, 16.3% versus 18.6%. Regarding safety and tolerability, grade 3/4 AEs (including neutropenia, thrombocytopenia, asthenia, and fatigue), and discontinuation of therapy also were more common in the combination arm. In summary, results from SUN 1099 do not support combined use of capecitabine and sunitinib in the treatment of advanced breast cancer. Whereas SUN 1099 studied women with heavily pretreated advanced breast cancer, SUN 1064 investigated the efficacy of chemotherapy (docetaxel), with or without sunitinib, as first-line therapy for advanced breast cancer.20 SUN 1064 was a Phase III, open-label study that randomized 593 patients to either IV docetaxel alone (100 mg/m2 every 3 weeks) or combination therapy with IV docetaxel (75 mg/m2 every 3 weeks) and oral sunitinib (37.5 mg daily on days 2-15 of a 21-day treatment cycle). Of note, if docetaxel was discontinued for any reason other than progressive disease among those in the combination arm, sunitinib could be continued as monotherapy until disease progression. The primary end point, PFS, was not met, with comparable median PFS results of 8.3 months in the docetaxel arm versus 8.6 months in the combination arm. As a secondary end point, OS also was equivalent: 25.5 months in the docetaxel arm versus 24.8 months in the combination arm. However, ORR was significantly improved in the combination arm: 51% versus 39% (P=0.0018). Based on these results, with superior results seen only for ORR, the authors did not endorse the regimen of docetaxel and sunitinib as a viable option for the first-line treatment of advanced breast cancer.

AVASTIN E2100 was a Phase III open-label trial that randomized 722 patients to first-line therapy consisting of either weekly paclitaxel alone (90 mg/m2 on days 1, 8, and 15 of a 28-day treatment cycle) or paclitaxel plus bevacizumab (Avastin, Genentech; 10 mg/kg on days 1 and 15).21 E2100 reported significantly improved PFS and ORR in the combination arm: 11.8 versus 5.9 months, and 36.9% versus 21.2%, respectively. However, OS was similar between the 2 groups: 26.7 months for the combination and 25.2 months for paclitaxel alone. Based on the results from E2100, specifically a doubling of PFS, bevacizumab was granted accelerated approval in February 2008 for combination use with paclitaxel in the treatment of patients with advanced

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breast cancer. At the time, this original decision had been controversial, with opponents of the approval stating that no improvement in OS was seen with the addition of the drug. Later trials using bevacizumab with chemotherapy in the treatment of advanced breast cancer, including AVADO (AVastin plus Docetaxel) and RIBBON-1 (Randomized, Double-Blind, Placebo-Controlled, Phase III Trial of Chemotherapy With or Without Bevacizumab for FirstLine Treatment of HER2-Negative Locally Recurrent or Metastatic Breast Cancer), did not replicate the impressive improvement in PFS seen in E2100 and also did not show any improvement in OS.22,23 Based on analysis of these trials, suggesting limited benefit of bevacizumab as well as significant risks associated with its use, such as hypertension, bleeding, perforations, and heart disease, in December 2010 the FDA recommended removing the drugâ&#x20AC;&#x2122;s breast cancer indication. Of note, the FDA does endorse ongoing research to attempt to identify a possible subset of breast cancer patients who may derive more significant benefit from bevacizumab. Ongoing trials examining the use of bevacizumab for breast cancer patients in the neoadjuvant and adjuvant settings will continue.

Treatment for Bony Metastases The most common site of metastasis in advanced breast cancer is bone, with the most serious complications being skeletal-related events (SREs). SREs are defined to include pathologic fracture, the need for radiation or surgery to bone, and spinal cord compression. The most common treatment to prevent complications of bone metastases, including SREs, pain, and hypercalcemia, consists of either oral or IV bisphosphonates, a class of drugs that function by inhibiting osteoclast activity, thereby slowing bone loss. Denosumab (Xgeva, Amgen), a fully human mAb against the receptor activator of nuclear factor-ÎşB ligand (RANKL), uses a completely separate mechanism of action. Tumor cells in the bone release growth factors that activate osteoblasts to release RANKL. Meanwhile, RANKL stimulates osteoclasts to break down bone, and in this destructive process more growth factors are released that promote tumor cell growth. By inhibiting RANKL, denosumab breaks this vicious cycle of bone destruction and tumor cell proliferation (Figure 3).24 In a recent Phase III, double-blind, double-dummy trial, Stopeck et al randomized 2,046 patients to either denosumab at a dose of 120 mg subcutaneously every 4 weeks (with IV placebo) or zoledronic acid (Zometa, Novartis) at a dose of 4 mg IV every 4 weeks (with subcutaneous placebo).25 The primary study objective was the time to first on-study SRE with additional study objectives being time to first and subsequent (multiple) on-study SREs, OS, disease progression, and safety. Denosumab significantly increased the time to first onstudy SRE (HR, 0.82; 95% CI, 0.71-0.95; P=0.01), corresponding to an 18% reduced risk compared with zoledronic acid. The median time to first on-study SRE was 26.4 months in the zoledronic acid arm, whereas

Tumor cell

Tumor cell Preosteoclast

PTHrP IL-1, IL-6, IL-8 PGE2 TNF M-CSF

RANK

PTHrP BMP PDGF FGFs IGFs TGF-β

Denosumab RANKL

Differentiation

Tumor cell Osteoclast in apoptosis

Osteoblast RANK

Osteoclast

Denosumab:

Bisphosphonates:

• Binds to RANKL and neutralizes its activity • Reduces osteoclast activity and bone resorption

• Inhibit tumor cell adhesion to bone • Inhibit osteoclast activity • Induce osteoclast apoptosis

Bone

Figure 3. Mechanisms of action for denosumab and the bisphosphonates. Tumor cells secrete a number of cytokines and factors that stimulate osteoblast production of RANKL, which binds to RANK on the suface of osteoclasts. This leads to osteoclast differentiation, activation, and survival, creating osteolytic lesions. Bone resorption releases factors such as BMP, PDGF, FGF, IGF, and TGF-β, which, in turn, stimulate production of PTHrP from tumor cells. Agents such as denosumab and bisphosphonates can interrupt this cycle and reduce osteoclast activity. BMP, bone morphogenic protein; FGF, fibroblast growth factors; IGF, insulin-like growth factors; IL, interleukin; M-CSF, macrophage colony-stimulating factor; PGE2, prostaglandin E2; PTHrP, parathyroid hormone-related peptide; RANK, receptor activator of nuclear factor-κB; RANK-L, receptor activator of nuclear factor κB ligand; TGF, transforming growth factor; TNF, tumor necrosis factor Adapted from reference 24 with permission. ©2010 American Society of Clinical Oncology. All rights reserved.

the median time to first on-study SRE has not yet been reached in the denosumab arm. The time to multiple SREs also was superior in the denosumab arm (HR, 0.77; 95% CI, 0.66-0.89; P=0.001), corresponding to a 23% risk reduction. There were no differences noted between the arms with respect to OS or disease progression. Regarding safety, renal AEs and acute-phase reactions were more common with zoledronic acid (8.5% vs 4.9%, and 27.3% vs 10.4%, respectively), whereas hypocalcemia was more common with denosumab (5.5% vs 3.4%). Of note, the rates of osteonecrosis of the jaw were comparable between the groups (2% for denosumab and 1.4% for zoledronic acid). The authors conclude that improved time to SREs, comparable tolerance, and the ease of subcutaneous injections with no need for renal monitoring makes denosumab another viable option for treatment of women with advanced breast cancer metastatic to bone.

Conclusions Treatment of advanced breast cancer increasingly is based on defining subgroups of patients who are more likely to respond to a given therapy. In the clinic,

classical markers such as ER, PR, and HER2 status commonly define these subgroups. In the research setting, more advanced genomic techniques, such as intrinsic subtyping, are used to characterize and treat populations of breast cancer patients.15 In the past few years, advances in clinical research have yielded several significant improvements in the care of patients with advanced breast cancer, including new treatment targets and new therapies. Mature results from several of the Phase II trials reviewed above, as well as follow-up Phase III trials, will help define these benefits in larger populations in more detail.

References 1.

Amir E, Clemons M, Freedman OC, et al. Tissue confirmation of disease recurrence in patients with breast cancer: pooled analysis of two large prospective studies. J Clin Oncol. 2010:28(15 suppl): Abstract 1007.

2. Robertson JFR, Lindemann JPO, Llombart-Cussac A, et al. A comparison of fulvestrant 500 mg with anastrozole as first-line treatment for advanced breast cancer: follow-up analysis from the “FIRST” study. Presented at: 33rd Annual San Antonio Breast Cancer Symposium; December 8-12, 2010; San Antonio, TX. Abstract S1-3.

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3. Chia S, Gradishar W, Mauriac L, et al. Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor–positive, advanced breast cancer: results from EFECT. J Clin Oncol. 2008:26(10):1664-1670, PMID: 18316794.

14. Comen EA. Inhibition of poly(ADP)-ribose polymerase as a therapeutic strategy for breast cancer. Oncology. 2010;24(1); http://www. searchmedica.com/resource.html?rurl=http%3A%2F%2Fwww.cancernetwork.com%2Fbreast-cancer%2Fcontent%2Farticle%2F10165% 2F1514491&q=comen&c=on&ss=cancerNetworkLink&p=Convera&fr= true&ds=0&srid=3. Accessed January 11, 2011.

4. Bachelot T, Bourgier C, Cropet C, et al. TAMRAD: a GINECO randomized phase II trial of everolimus in combination with tamoxifen versus tamoxifen alone in patients (pts) with hormone-receptor positive, HER2 negative metastatic breast cancer (MBC) with prior exposure to aromatase inhibitors (AI). Presented at: 33rd Annual San Antonio Breast Cancer Symposium; December 8-12, 2010; San Antonio, TX. Abstract S1-6.

15. Perou CM, Sorlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature. 2000:406(6797):747-752, PMID: 10963602.

5. Kaufman PA, Ferrero JM, Bourgeois H, et al. A randomized, double-blind, placebo-controlled, phase 2 study of AMG 479 with exemestane (E) or fulvestrant (F) in postmenopausal women with hormone-receptor positive (HR+) metastatic (M) or locally advanced (LA) breast cancer (BC). Presented at: 33rd Annual San Antonio Breast Cancer Symposium; December 8-12, 2010; San Antonio, TX. Abstract S1-4. 6. Baselga J, Gelmon KA, Verma S, et al. Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2–positive metastatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol. 2010:28(7): 1138-1144, PMID: 20124182. 7. Burstein HJ, Sun Y, Dirix LY, et al. Neratinib, an irreversible erbB receptor tyrosine kinase inhibitor, in patients with advanced erbB2-positive breast cancer. J Clin Oncol. 2010:28(8):1301-1307, PMID: 20142587. 8. Perez EA, Dirix L, Kocsis J, et al. Efficacy and safety of trastuzumab-DM1 versus trastuzumab plus docetaxel in HER2-positive metastatic breast cancer patients with no prior chemotherapy for metastatic disease: preliminary results of a randomized, multicenter, open-label phase 2 study (TDM4450G). Ann Oncol. 2010:21(8 suppl): Abstract LBA3. 9. Blackwell KL, Burstein HJ, Storniolo AM, et al. Randomized study of lapatinib alone or in combination with trastuzumab in women with erbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol. 2010:28(7):1124-1130, PMID: 20124187. 10. Tutt A, Robson M, Garber JE, et al. Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced breast cancer. J Clin Oncol. 2009:27(18 suppl): Abstract CRA501. 11. O’Shaughnessy J, Osborne C, Pippen J, et al. Efficacy of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1) inhibitor, in combination with gemcitabine/carboplatin (G/C) in patients with metastatic triple-negative breast cancer (TNBC): results of a randomized phase II trial. J Clin Oncol. 2009:27(18 suppl): Abstract 3. 12. O’Shaughnessy J, Osborne C, Pippen J, et al. Final efficacy and safety results of a randomized phase II study of the parp inhibitor iniparib (BSI-201) in combination with gemcitabine/carboplatin (G/C) in metastatic triple negative breast cancer (TNBC). Ann Oncol. 2010:21(8 suppl): Abstract LBA11. 13. Carey LA. Directed therapy of subtypes of triple-negative breast cancer. The Oncologist. 2010:15(5 suppl):49-56.

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16. Sanofi-aventis reports top-line results from Phase III study with BSI-201 in metastatic triple-negative breast cancer. http://en.sanofiaventis.com/binaries/20110127_BSI_en_tcm28-30168.pdf. Accessed February 1, 2011. 17. Jordan MA, Kamath K, Manna T, et al. The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth. Mol Cancer Ther. 2005:4(7):1086-1095, PMID: 16020666. 18. Twelves C, Loesch D, Blum JL, et al. A phase III study (EMBRACE) of eribulin mesylate versus treatment of physician’s choice in patients with locally recurrent or metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2010;28(15 suppl): Abstract CRA1004. 19. Crown J, Dieras V, Staroslawska E, et al. Phase III trial of sunitinib (SU) in combination with capecitabine (C) versus C in previously treated advanced breast cancer (ABC). J Clin Oncol. 2010;28 (15 suppl): Abstract LBA1011. 20. Bergh J, Greil R, Voytko N, et al. Sunitinib (SU) in combination with docetaxel (D) versus D alone for the first-line treatment of advanced breast cancer (ABC). J Clin Oncol. 2010;28(15 suppl): Abstract LBA1010. 21. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007:357(26):2666-2676, PMID: 18160686. 22. Miles D, Chan A, Romieu G, et al. Randomized, double-blind, placebo-controlled, phase III study of bevacizumab with docetaxel or docetaxel with placebo as first-line therapy for patients with locally recurrent or metastatic breast cancer (mBC): AVADO. J Clin Oncol. 2008;26(15 suppl): Abstract LBA1011. 23. Robert NJ, Dieras V, Glaspy J, et al. RIBBON-1: Randomized, doubleblind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab (B) for first-line treatment of HER2-negative locally recurrent or metastatic breast cancer (MBC). J Clin Oncol. 2009;27(15 suppl): Abstract 1005. 24. Fornier MN. Denosumab: Second chapter in controlling bone metastases or a new book? J Clin Oncol. 2010:28(35):5127-5131, PMID: 21060038. 25. Stopeck AT, Lipton A, Body JJ, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol. 2010:28(35):5132-5139, PMID: 21060033.

POLICY & MANAGEMENT

CLINICAL ONCOLOGY NEWS • FEBRUARY 2011

Patient Transition

have yet to truly repair the existing communication discontinuities among caregivers, because the many systems in use cannot exchange data. “There’s a huge information technology [IT] gap between hospitals, outpatient offices, physicians and patients,” Dr. Weinstein said. “Until everyone begins using electronic records that are transportable, verifiable and instantaneous, we’re not going to have what we want, which is for the next set of caregivers to receive a patient’s complete history.” Medication reconciliation has fared better and is a relative bright spot within transition activities. According to the ACCC report, nearly 80% of the oncology groups conduct medication reconciliation—a process in which a patient’s drug therapy regimens are checked and then reviewed for potential safety issues throughout transitions in care. Breakdowns in that process account for 46% of drug errors and as many as 20% of adverse drug events, according to one study (Am J Health-Syst Pharm 2007;64:850-854). About 75% of the oncology groups said they have CPOE systems in place, but only a few of the respondents said those systems could access external prescription drug databases. Such access can help build a complete and accurate list of drugs during medication reconciliation. That lack of access to such databases is unfortunate, noted Ernest Anderson Jr., MS, RPh, system vice president of pharmacy, Caritas Christi Health Care, Boston, and past-president of ACCC. Because all prescriptions are adjudicated through a centralized claims processor, the information travels through a common conduit. “You should be able to retrieve that information and have a record of all, or most, of the medications a patient has been receiving,” Mr. Anderson said. “When a patient goes to the next site of care, someone should be able to pull up that information.” (Although such IT roadblocks are significant, overall medication reconciliation requirements just got easier, at least for hospitals, now that the Joint Commission has released a less stringent version of rules governing the practice. Formerly part of National Patient Safety

Goal [NPSG] No. 8, the new rule [NPSG No. 3], released in December 2010, forgoes many of the older goal’s provisions, which many facilities argued were too prescriptive and difficult to implement. The new goal takes effect July 1, 2011.)

Proactive oncology practices and hospitals that have launched patient navigator and other care transition efforts have yielded gains in patient satisfaction and billing efficiencies that outweigh the personnel costs of the programs. ograms.

Who Is Running the Show? According to the ACCC report, economic and interorganizational factors also loom large in endeavors to improve the inpatient–outpatient transition. Transitional patients move between two distinct settings operated by different, and often competing, organizations. “Who is responsible for the care transition?” wrote the authors of the report. “Two distinct organizations are charged with managing a patient’s care during a transition, although during the transition itself, neither is reimbursed directly for the effort.” The authors also observed, however, that “proactive oncology practices and hospitals that have launched patient navigator and other care transition efforts have yielded gains in patient satisfaction and billing efficiencies that outweigh the personnel costs of the programs.” Patient navigators have become central players in the transition process at some organizations. The navigators, often RNs or social workers, track and monitor a patient’s cancer treatment and keep clinicians in the information loop. At a time when patients face a daunting maze of disconnected activities, navigators can coordinate patient care, educate patients, refer patients and families to needed psychosocial services and link patients and families to appropriate financial and community resources. “Our team is centered around patient navigators,” Dr. Petrelli said. “They know about every one of our patients who is admitted to the hospital, then follow them through discharge and beyond.” Iowa Cancer Specialists, St. Joseph’s in Baltimore and Comprehensive Cancer & Hematology Specialists (CCHS), an oncology group practice based in Voorhees, N.J., also have patient navigators on staff. CCHS was one of several oncology practices profiled in the ACCC survey that excels at transitioning patients

ACCC Survey: Key Oncology Group Findings • Hospital notification of the oncologist when his or her patient is admitted to a hospital by another physician appears to occur “almost always” in less than half of the oncology groups surveyed. This notification is a key input to an effective transisition process. Additionally, about 60% of the responding di oncology groups take proactive steps to determine whether their patients have been admitted (by checking the EHR or the hospital lists). • About half of the responding oncology groups have designated staff (clinical or administrative) to manage the patient transition after hospital discharge, and most (>60%) do follow-up on or make the postdischarge office appointment. However, few oncology groups have implemented specific policies or checklists to help manage patient transition. • Medication reconciliation activities seem to be fairly advanced. Almost 80% of the groups engage in medication reconciliation (led by a nurse or pharmacist), and about three in four oncology groups have a CPOE system. About half of the groups can use their CPOE to electronically transmit prescriptions to the pharmacist, but only a small number can use the system to access external prescription databases. • Almost all oncology groups obtain the hospital medical records and discharge summaries, and place that information in the patient’s office chart, but only about one in four groups had a nurse or other clinician review and flag the records for special attention by the oncologist. —S.F.

throughout areas of care. According to Judith Hall-Laughlin, MBA, RN, executive director of CCHS, patient navigators play an important role in that process. “The navigator is with the patient initially, usually the first few visits,” Ms. Hall-Laughlin stated in the report. “At that point, the CCHS nursing staff coordinates care with the navigator to make sure that the patient’s financial, psychological, and clinical needs are all met.” As yet, there are no incentives built into reimbursement structures to make transition efforts financially attractive. That may change as some transition

activities become widely recognized as best practices by influential medical groups. The ACCC report suggested what the future may hold: “As quality organizations and payers increase the focus on patient safety issues and systemic cost drivers, such as hospital readmission rates, structured programs that address the patient transition may become an oper- Scan for more info ational necessity.” on navigator programs;

—Steve Frandzel instructions page 6.

If you have missed any recent issues of Clinical Oncology News, please visit www.clinicaloncology.com. Let Us Visit Your Practice Please consider inviting the staff of Clinical Oncology News to visit your practice. We want to meet you and your colleagues, solicit article ideas and authors, listen to your concerns, meet your staff and patients and observe the physical site of your practice. You can help us improve Clinical Oncology News and fulfill our mission—to provide evidence-based, clinically relevant information that you can use to benefit your patients and practice.

If you are interested, please contact Kate O’Rourke, editor, at (212) 957-5300 ext. 265 or via e-mail at korourke@mcmahonmed.com.

NOVEMBER

DECEMBER

JANUARY 2011

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 (%)

1.9

4.9

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

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS â&#x20AC;˘ FEBRUARY 2011

Hodgkinâ&#x20AC;&#x2122;s Lymphoma

New Standard of Care Proposed for Hodgkinâ&#x20AC;&#x2122;s Orlando, Fla.â&#x20AC;&#x201D;Final results from a large randomized trial have identified high rates of apparent cure in patients with early unfavorable stages of Hodgkinâ&#x20AC;&#x2122;s lymphoma who were given two cycles of escalated BEACOPP (BEACOPPesc) and two cycles of ABVD instead of ABVD in a four-cycle course. All patients received radiotherapy after chemotherapy. According to the final analysis with a median of 42.4 months of follow-up, the experimental arm did not have an increased risk for treatmentrelated death, secondary malignancies or infertility (a previous concern with BEACOPPesc). The authors of the study concluded that BEACOPPesc should be the new standard of care for this patient population. 3\b_ PfPYR` ./C1 Ad\ PfPYR` /2.0<==R`P ]Yb` ad\ PfPYR` ./C1 =)

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University of Texas MD Anderson Cancer Center in Houston. The main problem, he said, is that unlike those in Germany, patients in the United States with stage II bulky disease are considered to have advanced disease and therefore receive six cycles of ABVD and then radiation. A study that used four cycles of ABVD as the comparator is not fully relevant to current U.S. practice. â&#x20AC;&#x153;It remains to be seen whether patients in the GHSG who did not have stage II bulky disease and were treated with four cycles of ABVD plus radiation still did worse than those who received two cycles of BEACOPP plus two cycles of ABVD plus radiation,â&#x20AC;?

particular attention paid to vinblastine and dacarbazine) or safety results in the new study. to two cycles of BEACOPPesc Although toxicity was substan(bleomycin, etoposide, doxtial, Dr. Borchmann said it did orubicin, cyclophosphamide, not alter the conclusion that vincristine, procarbazine and two cycles of BEACOPPesc is prednisone) followed by two preferable. cycles of ABVD. All patients Specifically, although grade in both arms received 30 Gy Scan for the ABVD vs BEACOPPesc 3 or 4 toxicities occurred in involved-field radiotherapy. abstract; instructions 87% of those randomized to The study was stopped page 6. the arm that included BEAat a planned interim analysis when the advantage of the arm that COPPesc compared with 51% among included BEACOPPesc was so substan- those who received ABVD alone, most tial that further randomization was con- were hematologic and manageable, sidered unethical. Reflecting that advan- according to Dr. Borchmann (Figure 2). tage, the most recent analysis found that In fact, there were no significant differthe FFTF at four years increased from ences in the rates of death or treatment89.3% observed in ABVD alone to 94.7% related deaths, which were uncommon in those who received BEACOPP in the in both arms. There also were no sigfirst two cycles (hazard ratio [HR], 2.04; nificant differences in the rates of sec95% confidence interval [CI], 1.39-2.94; ondary malignancies. Rates of infertility P=0.0001). A difference in overall surviv- are more difficult to quantify objectiveal (OS) was not shown and not expected ly, but Dr. Borchmann provided a variafter this length of follow-up, but pro- ety of data suggesting that differences, gressive disease has been less common if any, are modest.

=NaVR[a`

â&#x20AC;&#x2DC;It remains to be seen whether patients in the GHSG who did not have stage II bulky disease and were treated with four cycles of ABVD plus radiation still did worse than those who received two cycles of BEACOPP plus two cycles of ABVD plus radiation.â&#x20AC;&#x2122;

â&#x20AC;&#x201D;Anas Younes, MD

Figure 1. Freedom from treatment failure at four years. On the primary end point of freedom from treatment failure (FFTF), the superiority of the experimental arm was so great that the question is not which treatment is better but â&#x20AC;&#x153;do we really need to combine chemotherapy and radiotherapy in all patients to achieve this level of cure,â&#x20AC;? said Peter Borchmann, MD, University Hospital, Cologne, Germany. He presented the results on behalf of the German Hodgkin Study Group (GHSG) at the recent annual meeting of the American Society of Hematology (abstract 765). Dr. Borchmann acknowledged that the acute toxicities were greater on the BEACOPPesc arm, but the improved outcome was achieved without clear evidence of sustained long-term risk. According to Anas Younes, MD, although Dr. Borchmannâ&#x20AC;&#x2122;s declaration that two cycles of BEACOPPesc followed by two cycles of ABVD is the new standard may be reasonable in Germany, this may not be the right characterization for the United States. Dr. Younes is director of the Clinical Investigation and Translational Research Department of Lymphoma/Myeloma at The

Dr. Younes commented. â&#x20AC;&#x153;While this is a significant study, its findings may not be widely accepted as a standard of care in the U.S., mainly because of differences in how advanced stage classical Hodgkin lymphoma is defined.â&#x20AC;? The study involved 1,623 patients between the ages of 16 and 60 with clinical stage I or IIa Hodgkinâ&#x20AC;&#x2122;s lymphoma with additional risk factors, such as large mediastinal mass, extranodal disease, three or more nodal areas or an elevated sedimentation rate. Patients were randomized to four cycles of a standard course of ABVD (doxorubicin, bleomycin,

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on BEACOPPesc (0.9% vs. 2.8%). In trials conducted in advanced-stage Hodgkinâ&#x20AC;&#x2122;s lymphoma, BEACOPPesc also has shown an advantage in regard to important end points, such as relapse, but these results did not produce a widespread change in the standard of care. Although some centers do use BEACOPPesc as firstâ&#x20AC;&#x201C;line therapy in this setting, particularly those associated with GHSG which demonstrated the advantage, others have been reluctant to switch because of the reported toxicity, particularly infertility in younger patients. As a result of this concern, there has been

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Figure 2. Comparison of select grade 3/4 toxicities.

â&#x20AC;&#x153;If you are just counting children born to the patients in the two arms, then we cannot say there is a difference,â&#x20AC;? said Dr. Borchmann. Additionally, â&#x20AC;&#x153;the incidence of self-reported amenorrhea after four cycles of ABVD was the same as after two cycles of BEACOPPesc and then two cycles of ABVD, so we really do not have any hints, that these two regimens should have clinical relevant differences with regard to the female reproductive capacity.â&#x20AC;? He emphasized that there is clear evidence that the addition of BEACOPPesc provides very high rates of sustained response. The lower rate of late relapse after almost four years of follow-up in the BEACOPPesc arm (0.9% vs. 2.3%) is not yet significant, but it is consistent with the FFTF overall. According to Dr. Borchmann, two cycles of BEACOPPesc followed by two cycles of ABVD should be considered the new standard in place of four cycles of ABVD in the treatment of Hodgkinâ&#x20AC;&#x2122;s lymphoma with an unfavorable prognosis. He said although no survival benefit has been observed yet, patients will continue to be followed. â&#x20AC;&#x201D;Ted Bosworth

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • FEBRUARY 2011

CML

In First-line Therapy of CML ...

Orlando, Fla.—Updated results from two Phase III studies that pitted either nilotinib or dasatinib against imatinib provide strong evidence that the newer agents will replace imatinib as first-line agents in treatment-naïve Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP). In both studies, one with 18-month and the other with 24-month results, the newer agents produced faster and higher rates of major molecular response (MMR), complete cytogenetic response (CCyR) and complete molecular response (CMR). There are no differences yet in overall survival (OS), but one of the studies already has demonstrated a significant reduction in progression to acute phase blast crisis (AP/BC) favoring the newer agent over imatinib (Gleevec, Novartis). The faster and more robust responses on the newer tyrosine kinase inhibitors (TKIs) were first reported at 12 months and already have been published. The newer data, presented at the annual meeting of the American Society of Hematology (ASH), further confirms

the more favorable prognostic trajectory without a major price to pay in relative adverse events (AEs). Although AEs differ between TKIs, the overall safety appears to be comparable. Significant differences in OS may not be reached for years, but the differences in well-established prognostic markers have been substantial. Newer TKIs appear to be more potent than imatinib, but this does not necessarily establish an optimal order of agents when treatment is noncurative and must be administered indefinitely, according to many experts. With the presumption that a substantial proportion of patients will become resistant to the front-line agent, it may be prudent to consider second-line options in the context of first-line therapy. Both

nilotinib (Tasigna, Novartis) and dasatinib (Sprycel, Bristol-Myers Squibb) demonstrate efficacy in imatinib-refractory patients, but it is not clear that imatinib is effective in those who are refractory to dasatinib or nilotinib. According to Richard M. Stone, MD, director of the Adult Leukemia Program at DanaFarber Cancer Institute, Harvard Medical School, Boston, the data and safety of the newer agents are encouraging, but there is no clear conclusion about which agent to use first. “The rapidity and depth of reduction in the CML burden when dasatinib or nilotinib are used after patients are diagnosed is greater than with imatinib; the side-effect profile for the newer drugs appears favorable,” Dr. Stone said. “While

Major molecular response rate, %

Evidence Builds for Use of Second-generation TKIs 300 mg nilotinib 400 mg nilotinib 400 mg imatinib

100 80 62

60 40

20 0

Figure 1. ENESTnd study at 24 months of follow-up.

it is appropriate to choose a newer agent for upfront administration, imatinib has the current advantage of longer follow-up safety data and the potential future advantage of significantly lower cost.” Dr. Stone see TKIs, page 20

Follicular

BROWN continued from page 1

glance appear to be a significant clinical benefit, many other issues that are not fully evaluable need to be considered. (See Design of Rituximab Study.) For example, early therapy with rituximab might decrease subsequent response to rituximab-containing chemotherapy regimens or promote the early development of rituximab resistance. If true, this early exposure could negatively impact subsequent clinical outcomes, including, potentially, overall survival (OS). The impact of early rituximab therapy on the risk for transformation to diffuse large B-cell lymphoma also is completely unknown. Early therapy also may be associated with a significant impact on quality of life and Ardeshna and colleagues have stated they will be evaluating quality of life data. Future studies will need to look at cost and convenience issues and the potential for as-yet unforeseen longerterm toxicities. Because of these issues, longer-term follow-up of the Ardeshna et al study, as well as others are required before any firm conclusions can be drawn about early rituximab therapy. The gold standard for changing the standard of care in asymptomatic patients who usually would be observed ideally should be an improvement in OS. For an indolent disease like FL, in which OS requires a lengthy follow-up, the reasonable

surrogate end point would be time to second therapy. Using this end point would allow both treatment arms to undergo a first round of therapy at the time designated by their study arm, and would then measure the impact on a later outcome that is not prespecified by the trial in either arm. In fact, in a prior study by Ardeshna and colleagues, time to second therapy was actually shorter in patients who had undergone earlier therapy, underscoring the importance of this end point. The current study, therefore, provides intriguing but only preliminary results, which may raise as many questions as they answer. Longer follow-up of this study may provide data on time to second therapy or OS. Additionally, it is notable that a subset of patients in the observation arm had spontaneous remissions. This fact reminds us that in the future, better potentially biologically based risk stratification may allow us to select the optimal patient subgroups for observation or different therapeutic options. For years, the standard of care for patients with asymptomatic low-volume FL has been observation, based on prospective randomized trials that showed no impact of early therapy on OS or disease-specific survival. Since these trials, the advent of rituximab in combination with chemotherapy has improved both progression-free survival and OS for previously untreated patients in need of therapy, and in this patient population, rituximab alone for induction and maintenance

can be quite effective, resulting in prolonged disease control. It is therefore reasonable to ask whether early therapy with rituximab might result in meaningful clinical benefit for patients with FL who are not yet in need of therapy. Although

Ardeshna et al’s study takes a first step in answering this question, more data is needed before clinicians should make any changes in their clinical practice. —Jennifer R. Brown, MD, PhD

Design of Rituximab Study

ompared with a watch-and-wait strategy, rituximab (Rituxan, Genentech) significantly delayed the time to initiation of new therapy (chemotherapy or radiotherapy) and extended progression-free survival (PFS) in patients with asymptomatic stage 2, 3 or 4 follicular lymphoma (grades 1-2 and 3a). This news comes from an abstract presented during the plenary session at the annual meeting of the American Society of Hematology (ASH; abstract 6). In this 462-patient study, patients were randomized to watch- and-wait, 375 mg/m2 weekly rituximab for four weeks or the same regimen of rituximab followed by rituximab maintenance every two months for two years. The primary end point was time to initiation of first therapy. Although there was a decision about midway through randomization to abandon the rituximab arm that did not include maintenance, the final results favored either of the rituximab regimens over watch-and-wait, which is widely considered the standard. According to Kirit M. Ardeshna, MD, University College, London, U.K., who presented the results during the ASH meeting, the hazard ratio (HR) for starting a next therapy was reduced by 80% (HR, 0.20; 95% confidence interval [CI], 0.13-0.29; P<0.001) in those in the rituximab maintenance arm relative to watch-and-wait. In those receiving rituximab without maintenance, the relative protection against the next therapy also was significant (HR, 0.37; P<0.001). The superiority of rituximab was reflected in a variety of other outcomes, including the rates of objective responses and the risk for clinical progression. Most importantly, there was a 79% improvement (HR, 0.21; 95% CI 0.15-0.29; P<0.001) in PFS for the patients who received rituximab maintenance versus those in the watch-and-wait group. Similar to the primary outcome, there also was a significant advantage for rituximab even without maintenance relative to watch-and-wait for PFS. No difference has been seen yet in overall survival, and quality-of-life data now are being assessed. Dr. Ardeshna concluded that these findings “may change the management of patients with newly diagnosed asymptomatic follicular lymphoma.” —Ted Bosworth

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • FEBRUARY 2011

Major Molecular Response Rate, %

CML

TKIs continued from page 19

disclosed receiving clinical research support from Novartis.

Head-to-Head Trials Both trials presented at ASH were head-to-head randomized comparisons of the newer TKI against the current standard of imatinib in treatmentnaïve CML patients. In the ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials—Newly Diagnosed Patients) trial, which now has 24 months of follow-up, nilotinib was associated with “a lower rate of failure and a significant improvement in progression-free survival (PFS; abstract 207). These data support the superiority of nilotinib as the first-line treatment,” reported Timothy P. Hughes, MD, Royal Adelaide Hospital, Adelaide, Australia. He disclosed receiving honoraria from BMS and Novartis and research funding from Novartis. Dr. Hughes noted that the greater tolerability of the lower dose of nilotinib with comparable efficacy has led to the preference of this dose for first-line therapy. In the DASISION (Dasatinib versus Imatinib Study in Treatment-Naive CML Patients) trial (abstract 206), for which results at 18 months were presented, dasatinib “continues to demonstrate superior efficacy compared with imatinib, with higher and faster rates of complete cytogenetic response and major molecular response,” reported Neil Shah, MD, PhD, assistant professor at the University of California, San Francisco. He said the results so far predict better longterm outcomes for treatment-naïve CML patients initiated on dasatinib rather than imatinib. Dr. Shah serves as an adviser or consultant to BMS and Novartis. The designs of these trials were described in detail in the June 17, 2010 edition of The New England Journal of Medicine, which simultaneously published the 12-month results from both trials. In the ENESTnd, 846 patients with Ph+ CML-CP were randomized to one of two doses of nilotinib (300 or

400 mg imatinib

100 80 60

57 41

40 20

(18% vs. 19%), but nausea rates were lower (9% vs. 21%). Grade 3 or higher neutropenia was similar on dasatinib and imatinib but thrombocytopenia of this severity was more common on dasatinib (Figure 4). Dasatinib was less likely to be associated with fluid retention and muscle inflammation, although 12% of dasatinib-treated patients developed pleural effusion, almost exclusively grade 1 or 2.

Figure 2. DASISION study by 18 months of follow-up. 400 mg, both administered twice daily) or 400 mg of imatinib. The primary end point was MMR. At 12 months, MMR rates were 44% for lower-dose nilotinib, 43% for higher-dose nilotinib, and 22% for imatinib. At 24 months, MMR rates for these groups, respectively, were 62%, 59% and 37% (P<0.001 for either dose of nilotinib vs. imatinib) (Figure 1). In DASISION, 519 patients were randomized to 100 mg dasatinib once daily or 400 mg imatinib once daily, and the primary end point was confirmed CCyR by 12 months. Dasatinib has achieved significantly higher response rates by 12 months (77% vs. 67%) and with 18 months of follow-up (78% vs. 70%). MMR rates at 18 months are 57% and 41% for dasatinib and imatinib, respectively (P=0.0002) (Figure 2). In both studies, most markers of response have favored the newer TKI. For example, the unconfirmed CCyR rates in DASISION by 18 months were 85% for dasatinib compared with 80% for imatinib (P=0.036). In ENESTnd, the rates at 24 months had climbed to 87% and 88% in the nilotinib arms compared with 77% on imatinib (P=0.0018). The side effects of these agents differ. At 24 months, rates of grade 3 or higher neutropenia were lower on nilotinib relative to imatinib, but hyperbilirubinemia and lipase elevations were higher (Figure 3). Gastrointestinal toxicities, such as diarrhea, tended to be more common on imatinib. On dasatinib, diarrhea rates were similar to those observed among patients taking imatinib

Choosing an Agent Each of the lead investigators of these studies, Drs. Hughes and Shah, concluded that their data support employing the newer TKI as first-line therapy. Although Dr. Hughes implied that nilotinib might be used in place of imatinib, Dr. Shah was more circumspect about whether dasatinib or nilotinib should become a new standard. Specifically, he cautioned that “a few more years of follow-up will be necessary to definitively document true clinical benefit of these agents in preference to imatinib,” but he added “the early data are encouraging.” In a separate Phase II open-label dasatinib study presented as a late breaker (abstract LBA6), 246 evaluable previously untreated CML patients were randomized to 400 mg imatinib or 100 mg nilotinib. At 12 months, the higher rates of CCyR in the dasatinib arm had not yet reached statistical significant, but the molecular response was characterized by the lead author, Jerald P. Radich, MD, Fred Hutchinson Cancer Center, University of Washington, Seattle as “deeper.” Specifically, the median reduction in BCR-ABL transcript level was 3.3 log for dasatinib compared with 2.8 log for imatinib (P=0.048). Dasatinib was associated with more grade 3 and 4 toxicity. However, these toxicities, which were mainly hematologic, may be considered warranted if dasatinib provides greater PFS or OS in longer follow-up. Dr. Radich disclosed consultancy and research funding from Novartis and consultancy with BMS. Currently, no large-scale data exist to compare the relative benefits of these agents against each other. Moreover, the proposal to switch to a newer TKI in previously untreated CML is based

;VY\aV[VO ZT 6ZNaV[VO ! ZT

Newer TKIs appear to be more potent than imatinib, but this does not necessarily establish an optimal order of agents when treatment is noncurative and must be administered indefinitely, according to many experts.

100 mg dasatinib

=NaVR[a`

almost entirely on markers of response. Indeed, although PFS was slightly higher on the newer TKI in both studies at the most recent follow-up, differences did not reach statistical significance. Not surprisingly, for the relatively short period of follow-up, the difference in OS rates, which exceed 96% in all arms, is even narrower. Although Dr. Hughes noted a numerical difference in CMLrelated deaths (five on 300 mg and three on 400 mg nilotinib vs. 10 on imatinib) and a significant reduction for nilotinib in regard to AP/BC (0.7% and 1.2% vs. 4.2%; P<0.02), changes in standard of care are not often made on the basis of response markers rather than outcomes. However, the evidence that imatinib is not the most potent of the TKIs continues to accrue. In another Phase III study (abstract 208) that compared bosutinib (Wyeth) with imatinib in treatmentnaïve patients with CML-CP, the newer TKI again did better. In this study with approximately 14 months of follow-up in 499 evaluable patients, 500 mg bosutinib once daily produced MMR in 39% of patients versus 26% of those randomized to 400 mg imatinib (P=0.002). The CCyR rates have not yet differed significantly (70% vs. 68%; P=0.601), but the median time to CCyR has been significantly shorter (12.9 vs. 24.6 weeks; P<0.0001). Moreover the senior author of the study, Carlo Gambacorti-Passerini, MD, University of Milano Bicocca, Monza, Italy, reported that the rate of transformation to AP/BC, favors bosutinib (2% vs. 4%; P=0.053). Again, side effects have been different, with less grade 3 neutropenia (22.7% vs. 8.9%) but more diarrhea (44% vs. 24%) on bosutinib. —Ted Bosworth

1N`NaV[VO ZT 6ZNaV[VO ! ZT

)

4_NQR ≥ ;Rba_\]R[VN

4_NQR ≥ 5f]R_OVYV_bOV[RZVN

4_NQR ≥ 9V]N`R 2YRcNaV\[`

Figure 3. Comparison of selected adverse events in ENESTnd Trial.

4_NQR ≥ ;Rba_\]R[VN

4_NQR ≥ AU_\ZO\Pfa\]R[VN

3YbVQ ?RaR[aV\[

:b`PYR 6[SYNZZNaV\[

Figure 4. Comparison of selected adverse events in DASISION.

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • FEBRUARY 2011

Breast

FULVESTRANT continued from page 9

of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston. It also echoes the results of the CONFIRM (Comparison of Faslodex in Recurrent or Metastatic breast cancer) study, presented at San Antonio in 2009, which found that 500 mg of fulvestrant yielded a one-month increase in time to progression over the 250-mg dose. “Based on all this evidence, I think the optimal dose for fulvestrant is 500 mg every 4 weeks,” Dr. Buzdar said. “These data are provocative,” agreed Harold Burstein, MD, PhD, associate professor of medicine at Harvard Medical School and a medical oncologist in the Breast Oncology Center at DanaFarber Cancer Institute, both in Boston. “They suggest that fulvestrant remains an attractive option for the treatment of metastatic breast cancer.” Most patients now get aromatase inhibitors in the adjuvant setting, and fulvestrant is considered an option if and when the patient progresses. “But if a patient were naïve to either an aromatase

Some patients may have difficulty getting to the physician’s office for monthly injections. Other patients may have problems with remembering to take a daily pill.

Administration of Faslodex 500 Faslodex 500 should be administered intramuscularly as two 5 mL injections, one in each buttock, on days 1, 15, and 29 and once monthly thereafter.

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

inhibitor or fulvestrant, I would think the choice between the agents, based strictly on their antitumor activity, is fulvestrant,” Dr. Burstein said. But antitumor activity, although a primary concern, is not the only concern for every patient. Some patients may have difficulty getting to the physician’s office for monthly injections. “The tradeoff would be the convenience of the oral medication,” Dr. Burstein said. On the other hand, other patients may have problems with remembering to take a daily pill. “Compliance can definitely be an issue,” Dr. Buzdar said. “When I talk to some patients, they say,

‘I can’t remember to take a pill every day.’ In those cases, an injectable form of a drug that also has better antitumor activity is a better choice. You come to the doctor’s office, get an injection, and don’t have to worry about taking your pill or forgetting it.” Cost may also be a factor for some patients. A one-month supply of anastrozole costs around $80 and a single injection of fulvestrant, at the wholesale price, costs roughly $700. Dr. Robertson has acted as a consultant for AstraZeneca. Neither Dr. Burstein nor Dr. Buzdar disclosed any relevant relationships. —Gina Shaw

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CLASSIFIEDS

Forbes and Fortune Small Business Magazine rank Billings, MT - the Best! Practice medicine in a city ranked as one of the Best Small Places for Business and Careers (Forbes, 2009) and the Best Small City in which to start a business (Fortune Small Business Magazine, November 2009). Award winning St. Vincent Healthcare and St. Vincent Children’s Healthcare in Billings, MT, seeks well-trained, compassionate physician to build our Pediatric Oncology program. • SVH is staffed for 250 beds and is a regional destination hospital which serves a four-state area and more than 900,000 people each year

• Possible academic appointment available • Access to clinical trials • 22 bed dedicated pediatric floor and 7 bed PICU supported by Board Certified Pediatric Intensivists who are available 24 hours a day/7 days a week • Pediatric specialty clinics which serve patients from Montana and Wyoming • Pediatric rehabilitation including physical therapy speech therapy, and occupational therapy • Thriving medical community in a family-oriented suburban location • Excellent School System • Abundant recreational activities year round – hiking, skiing, fishing, biking and camping • Excellent Benefits and Competitive Salary Structure, based on MGMA • Sign-on Incentives, Moving Allowances, and CME reimbursement. Will consider loan forgiveness.

• Known for providing superb patient care • Maternal Fetal Medicine Physician and 4 Neonatologists on Medical Staff • Pediatric specialists on Medical Staff include: Neurology, Cardiology, Behavioral and Developmental, Urology, GI and Orthopedics • Pediatric Specialty Clinics include: Cleft/Craniofacial; Cystic Fibrosis; Endocrine; Gastrointestinal; Genetic High Risk Infant Follow-up; Hematology; Metabolic; Nephrology Neural Tube Defect; Neurology and Rehabilitation • AASM accredited sleep center; Level II Trauma Center; HELP Helicopter and Fixed Wing air transport program with specialty transport teams; and CARF Accredited Inpatient Rehabilitation Program • SVH invests in the latest technology: Allura Xper FD20/10 interventional angiographic X-ray lab, Toshiba Aquilion ONE dynamic volume 320-slice CT system and Da Vinci Robotics SVH is ranked Best for Heart Attack Care and #15 for Quality in the nation

Find out more, visit www.svh-mt.org/physicians Contact: Colleen Martin Therese Harris (406) 237-4003 (406) 237-4017 Colleen.Martin@svh-mt.org Therese.Harris@svh-mt.org

CLINICAL TRIALS

CLINICAL ONCOLOGY NEWS â&#x20AC;˘ FEBRUARY 2011

New Phase II and III Clinical Trials

Solid Tumors

Trials added to the National Cancer Instituteâ&#x20AC;&#x2122;s list of clinical trials in the 30 days prior to January 18, 2011. For eligibility criteria and additional information, visit www.cancer.gov/clinicaltrials, click on the advanced link and enter the protocol ID.

Hematologic

Protocol Type

Age

Protocol ID

Trial Sites

Combination of AUY922 With Trastuzumab in Human Epidermal Growth Factor Receptor Two (HER2) Positive Advanced Breast Cancer Patients Previously Treated With Trastuzumab, Phase I/II

18 and over

CAUY922A2109

A Study of Lapatinib in Combination With Everolimus in Patients With Advanced, Triple Negative Breast Cancer, Phase II

18 and over

WCI1711-09

Eribulin With Trastuzumab as First-line Therapy for Locally Recurrent or Metastatic HER2 Positive Breast Cancer, Phase II

18 and over

E7389-A001-208

GA, MO, OR, TX

Evaluating and Comparing Two Surgical Methods for Treatment of Early Stage Breast Cancer, Phase III

18 and over

WCI1659-09

A Study of Single-Agent Eribulin Mesylate as First-Line Therapy for Locally Recurrent or Metastatic HER2 Negative Breast Cancer, Phase II

18 and over

E7389-A001-206

GA, MO, TX, WA

Open-label Study of STA-9090 for Patients With Metastatic Breast Cancer, Phase II

18 and over

10-145

NJ, NY

A Study of Carboplatin and Paclitaxel With or Without MEDI-575 in Adults With Previously Untreated, Advanced Non-Small Cell Lung Cancer (NSCLC), Phase I/II

18 and over

CD-ONMEDI-575-1031

LA, OH

Pazopanib In Stage IIIB/IV NSCLC After Progression on First Line Therapy Containing Bevacizumab, Phase II

18 and over

LCCC0921

Study of ADI-PEG 20 in Patients With Relapsed Sensitive or Refractory Small Cell Lung Cancer, Phase II

18 and over

LUD2009-007

NC, NY

Randomized Study of FOLFOX6 and Bevacizumab With Versus Without Gamma-Secretase Inhibitor RO4929097 as First-Line Treatment in Patients With Metastatic Colorectal Cancer, Phase II

18 and over

MSKCC-10191

Hydroxychloroquine in Previously Treated Patients With Metastatic Pancreatic Cancer, Phase II

18 and over

10-310

Trial of Gemcitabine With or Without Bavituximab in Patients With Previously Untreated Stage IV Pancreatic Cancer, Phase II

18 and over

PPHM 1002

CA, WA

Randomized Study of Carboplatin and Paclitaxel With Versus Without Wild-Type Reovirus (Reolysin) as First-Line Treatment in Patients With Recurrent or Metastatic Pancreatic Cancer, Phase II

18 and over

OSU-10045

DC, NY, OH

Trial Of Repeated Super-selective Intraarterial Cerebral Infusion Of Bevacizumab For Treatment Of Relapsed/Refractory Glioblastoma Multiforme And Anaplastic Astrocytoma, Phase I/II

18 and over

1001010839

A Study of MEDI-575 in Subjects With Recurrent Glioblastoma Multiforme, Phase II

18 and over

CD-ONMEDI-575-1042

NY, WA

Image Guided Therapy in the Treatment of Gliomas, Phase I/II

7 and over

09-0069

Study of Bavituximab and Sorafenib In Patients With Advanced Liver Cancer, Phase I/II

18 and over

062010-150

Study of Sorafenib With or Without VT-122 in Patients With Hepatocellular Carcinoma, Phase II

18 and over

VT1-CAX-002

Pilot Study for Locally Advanced Head and Neck Cancer, Phase II

18 and over

09-039

Randomized Study of Capecitabine and Vorinostat in Patients With Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck or Nasopharyngeal Carcinoma, Phase II

18 and over

PMH-PHL-068

CA, PA

A Trial Evaluating Single Agent and Combined Efficacy of Pasireotide and Everolimus in Adult Patients With RadioiodineRefractory Differentiated and Medullary Thyroid Cancer, Phase II

18 and over

WCI1777-09

Study of Everolimus and Sorafenib in Patients With Advanced Thyroid Cancer Who Progressed on Sorafenib Alone, Phase II

18 to 89

UPCC 19309

Randomized Study of Saracatinib in Patients With Castration-Resistant Prostate Cancer, Phase II

Not specified

UCCRC-10-436-B

IL, IN, MD, MI, MO, SC, WI

Study of Hypo-fractionated Proton Radiation for Prostate Cancer, Phase III

18 and over

GU002-10

Hsp90 Inhibitor STA-9090 in Treating Patients With Metastatic Hormone-Resistant Prostate Cancer Previously Treated With Docetaxel-Based Chemotherapy, Phase II

18 and over

2010-070

Gemcitabine and Cisplatin as Neoadjuvant Chemotherapy in Patients With High-Grade Upper Tract Urothelial Carcinoma, Phase II

18 and over

10-208

NJ, NY

Tasigna Neoadjuvant Gastrointestinal Stromal Tumor, Phase II

18 and over

2009072220090722

Lapatinib in Stage IV Melanoma With ERBB4 Mutations, Phase II

18 and over

110048

MD, NY, TN

Drosophila-generated CTL for Melanoma, Phase II

18 and over

110052

An Efficacy and Safety Study to Assess [18F]-ML-10 in Detecting Response of Tumors to Chemotherapy and Radiation [Lung and Head and Neck Cancer], Phase II

18 and over

NST-CA007

MA, NJ, NY, PA

Randomized Study of Adjuvant WT-1 Analog Peptide Vaccine in Patients With Malignant Pleural Mesothelioma After Completion of Combined Modality Therapy, Phase II

18 and over

10-134

Gemcitabine, Paclitaxel and Oxaliplatin (GemPOx) in Germ Cell Tumors, Phase II

Not specified

GemPOx

Study of Selumetinib in Patients With MCT-1 Related Relapsed or Refractory Diffuse Large B-cell Lymphoma, Phase II

18 and over

NU-10H03

IL, MD, NY

Study of Lenalidomide in Patients With High-Risk Chronic Lymphocytic Leukemia (CLL), Phase II

18 and over

RPCI-I-174910

PGG Beta-Glucan, Alemtuzumab, and Rituximab in Treating Patients With High Risk CLL, Phase I/II

18 and over

LS1084

Lenalidomide in HTLV-1 Adult T-Cell Leukemia, Phase II

18 and over

AAAE5097

Trial of a WT-1 Analog Peptide Vaccine in Patients With Acute Myeloid Leukemia, Phase II

18 and over

10-143

MAGE-A3/12 Metastatic Cancer Treatment With Anti-MAGE-A3/12 TCR-Gene Engineered Lymphocytes, Phase I/II

18 and over

110062

A Safety and Efficacy Study of SB1518 for the Treatment of Advanced Lymphoid Malignancies, Phase II

18 and over

SB1518-2010-005

FARESTON® (toremifene citrate) tablets DESCRIPTION FARESTON (toremifene citrate) Tablets for oral administration each contain 88.5 mg of toremifene citrate, which is equivalent to 60 mg toremifene. FARESTON is a nonsteroidal antiestrogen. The chemical name of toremifene is: 2-{p-[(Z)-4-chloro-1,2diphenyl-1-butenyl]phenoxy}-N,N-dimethylethylamine citrate (1:1). The structural formula is: OCH2CH2N

C C CH2 CH2Cl

CH3 CH3

CH2COOH HO

COOH

CH2COOH

and the molecular formula is C26H28 H O . The molecular weight of toremifene citrate is 598.10. 6 8 7 The pKa is 8.0. Water solubility at 37˚C is 0.63 mg/mL and in 0.02N HCI at 37˚C is 0.38 mg/mL. FARESTON is available only as tablets for oral administration. Inactive ingredients: colloidal silicon dioxide, lactose, magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate, and starch. CLINICAL PHARMACOLOGY Mechanism of Action: Toremifene is a nonsteroidal triphenylethylene derivative. Toremifene binds to estrogen receptors and may exert estrogenic, antiestrogenic, or both activities, depending upon the duration of treatment, animal species, gender, target organ, or endpoint selected. In general, however, nonsteroidal triphenylethylene derivatives are predominantly antiestrogenic in rats and humans and estrogenic in mice. In rats, toremifene causes regression of established dimethylbenzanthracene (DMBA)-induced mam-mary tumors. The antitumor effect of toremifene in breast cancer is believed to be mainly due to its antiestrogenic effects, ie, its ability to compete with estrogen for binding sites in the cancer, blocking the growth-stimulating effects of estrogen in the tumor. Toremifene causes a decrease in the estradiol-induced vaginal cornification index in some postmenopausal women, indicative of its antiestrogenic activity. Toremifene also has estrogenic activity as shown by decreases in serum gonadotropin concentrations (FSH and LH). Pharmacokinetics: The plasma concentration time profile of toremifene declines biexponentially after absorption with a mean distribution half-life of about 4 hours and an elimination half-life of about 5 days. Elimination half-lives of major metabolites, N-demethyltoremifene and (deaminohydroxy) toremifene were 6 and 4 days, respectively. Mean total clearance of toremifene was approximately 5L/h. Absorption and Distribution: Toremifene is well absorbed after oral administration and absorption is not influenced by food. Peak plasma concentrations are obtained within 3 hours. Toremifene displays linear pharmacokinetics after single oral doses of 10 to 680 mg. After multiple dosing, dose proportionality was observed for doses of 10 to 400 mg. Steady-state concentrations were reached in about 4-6 weeks. Toremifene has an apparent volume of distribution of 580 L and binds extensively (>99.5%) to serum proteins, mainly to albumin. Metabolism and Excretion: Toremifene is extensively metabolized, principally by CYP3A4 to N-demethyltoremifene, which is also antiestrogenic but with weak in vivo antitumor potency. Serum concentrations of N-demethyltoremifene are 2 to 4 times higher than toremifene at steady state. Toremifene is eliminated as metabolites predominantly in the feces, with about 10% excreted in the urine during a 1-week period. Elimination of toremifene is slow, in part because of enterohepatic circulation. Special Populations: Renal insufficiency: The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and in patients with impaired kidney function. Hepatic insufficiency: The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients. Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene. Geriatric patients: The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC. Race: The pharmacokinetics of toremifene in patients of different races has not been studied. Drug-drug interactions: No formal drug-drug interaction studies with toremifene have been performed. CLINICAL STUDIES Three prospective, randomized, controlled clinical studies (North American, Eastern European, and Nordic) were conducted to evaluate the efficacy of FARESTON for the treatment of breast cancer in postmenopausal women. The patients were randomized to parallel groups receiving FARESTON 60 mg (FAR60) or tamoxifen 20 mg (TAM20) in the North American Study or tamoxifen 40 mg (TAM40) in the Eastern European and Nordic studies. The North American and Eastern European studies also included high-dose toremifene arms of 200 and 240 mg daily, respectively. The studies included postmenopausal patients with estrogen-receptor (ER) positive or estrogen-receptor (ER) unknown metastatic breast cancer. The patients had at least one measurable or evaluable lesion. The primary efficacy variables were response rate (RR) and time to progression (TTP). Survival (S) was also determined. Ninety-five percent confidence intervals (95% CI) were calculated for the difference in RR between FAR60 and TAM groups and the hazard ratio (relative risk for an unfavorable event, such as disease progression or death) between TAM and FAR60 for TTP and S. Two of the 3 studies showed similar results for all effectiveness endpoints. However, the Nordic Study showed a longer time to progression for tamoxifen (see table). Clinical Studies Study North American Eastern European Nordic Treatment Group FAR60 TAM20 FAR60 TAM40 FAR60 TAM40 No. Patients 221 215 157 149 214 201 Responses 1 2 14+33 11+30 7+25 3+28 19+48 19+56 CR + PR RR3 (CR + PR)% 21.3 19.1 20.4 20.8 31.3 37.3 Difference in RR 2.2 -0.4 -6.0 95% CI4 for Difference in RR -5.8 to 10.2 -9.5 to 8.6 -15.1 to 3.1 Time to Progression (TTP) Median TTP (mo.) 5.6 5.8 4.9 5.0 7.3 10.2 Hazard Ratio (TAM/FAR) 1.01 1.02 0.80 95% CI4 for Hazard Ratio (%) 0.81 to 1.26 0.79 to 1.31 0.64 to 1.00 Survival (S) Median S (mo.) 33.6 34.0 25.4 23.4 33.0 38.7 Hazard Ratio (TAM/FAR) 0.94 0.96 0.94 95% CI4 for Hazard Ratio (%) 0.74 to 1.24 0.72 to 1.28 0.73 to 1.22 1 CR = complete response; 2PR = partial response; 3RR = response rate; 4CI = confidence interval The high-dose groups, toremifene 200 mg daily in the North American Study and 240 mg daily in the Eastern European Study, were not superior to the lower toremifene dose groups, with response rates of

22.6% AND 28.7%, median times to progression of 5.6 and 6.1 months, and median survivals of 30.1 and 23.8 months, respectively. The median treatment duration in the three pivotal studies was 5 months (range 4.2-6.3 months).

signiﬁcant age-related differences in FARESTON effectiveness or safety were noted. Race: Fourteen percent of patients in the North American Study were non-Caucasian. No signiﬁcant race-related differences in FARESTON effectiveness or safety were noted.

INDICATION AND USAGE FARESTON is indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor positive or unknown tumors.

ADVERSE REACTIONS Adverse drug reactions are principally due to the antiestrogenic hormonal actions of FARESTON and typically occur at the beginning of treatment. The incidences of the following eight clinical toxicities were prospectively assessed in the North American Study. The incidence reﬂects the toxicities that were considered by the investigator to be drug related or possibly drug related. North American Study FAR60 TAM20 n = 221 n = 215 Hot Flashes 35% 30% Sweating 20% 17% Nausea 14% 15% Vaginal Discharge 13% 16% Dizziness 9% 7% Edema 5% 5% Vomiting 4% 2% Vaginal Bleeding 2% 4%

CONTRAINDICATIONS FARESTON is contraindicated in patients with known hypersensitivity to the drug. WARNINGS Hypercalcemia and Tumor Flare: As with other antiestrogens, hypercalcemia and tumor flare have been reported in some breast cancer patients with bone metastases during the first weeks of treatment with FARESTON. Tumor flare is a syndrome of diffuse musculoskeletal pain and erythema with increased size of tumor lesions that later regress. It is often accompanied by hypercalcemia. Tumor flare does not imply failure of treatment or represent tumor progression. If hypercalcemia occurs, appropriate measures should be instituted and if hypercalcemia is severe, FARESTON treatment should be discontinued. Tumorigenicity: Since most toremifene trials have been conducted in patients with metastatic disease, adequate data on the potential endometrial tumorigenicity of long-term treatment with FARESTON are not available. Endometrial hyperplasia has been reported. Some patients treated with FARESTON have developed endometrial cancer, but circumstances (short duration of treatment or prior antiestrogen treatment or premalignant conditions) make it difficult to establish the role of FARESTON. Endometrial hyperplasia of the uterus was observed in monkeys following 52 weeks of treatment at ≥1 mg/kg and in dogs following 16 weeks of treatment at ≥3 mg/kg with toremifene (about 1/4 and 1.4 times, respectively, the daily maximum recommended human dose on a mg/m2 basis). Pregnancy: FARESTON may cause fetal harm when administered to pregnant women. Studies in rats at doses ≥1.0 mg/kg/day (about 1/4 the daily maximum recommended human dose on a mg/m2 basis) administered during the period of organogenesis, have shown that toremifene is embryotoxic and fetotoxic, as indicated by intrauterine mortality, increased resorption, reduced fetal weight, and fetal anomalies; including malformation of limbs, incomplete ossification, misshapen bones, ribs/spine anomalies, hydroureter, hydronephrosis, testicular displacement, and subcutaneous edema. Fetal anomalies may have been a consequence of maternal toxicity. Toremifene has been shown to cross the placenta and accumulate in the rodent fetus. In rodent models of fetal reproductive tract development, toremifene produced inhibition of uterine development in female pups similar to diethylstilbestrol (DES) and tamoxifen. The clinical relevance of these changes is not known. Embryotoxicity and fetotoxicity were observed in rabbits at doses ≥1.25 mg/kg/day and 2.5 mg/kg/ day, respectively (about 1/3 and 2/3 the daily maximum recommended human dose on a mg/mt basis); fetal anomalies included incomplete ossification and anencephaly. There are no studies in pregnant women. If FARESTON is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus or potential risk for loss of the pregnancy. PRECAUTIONS General: Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. Patients with bone metastases should be monitored closely for hypercalcemia during the first weeks of treatment (see Warnings). Leukopenia and thrombocytopenia have been reported rarely; leukocyte and platelet counts should be monitored when using FARESTON in patients with leukopenia and thrombocytopenia. Information for Patients: Vaginal bleeding has been reported in patients using FARESTON. Patients should be informed about this and instructed to contact their physician if such bleeding occurs. Patients with bone metastases should be informed about the typical signs and symptoms of hypercalcemia and instructed to contact their physician for further assessment if such signs or symptoms occur. Laboratory Tests: Periodic complete blood counts, calcium levels, and liver function tests should be obtained. Drug-drug Interactions: Drugs that decrease renal calcium excretion, eg, thiazide diuretics, may increase the risk of hypercalcemia in patients receiving FARESTON. There is a known interaction between antiestrogenic compounds of the triphenylethylene derivative class and coumarin-type anticoagulants (eg, warfarin), leading to an increased prothrombin time. When concomitant use of anticoagulants with FARESTON is necessary, careful monitoring of the prothrombin time is recommended. Cytochrome P450 3A4 enzyme inducers, such as phenobarbital, phenytoin, and carbamazepine increase the rate of toremifene metabolism, lowering the steady-state concentration in serum. Metabolism of toremifene may be inhibited by drugs known to inhibit the CYP3A4-6 enzymes. Examples of such drugs are ketoconazole and similar antimycotics as well as erythromycin and similar macrolides. This interaction has not been studied and its clinical relevance is uncertain. Carcinogenesis, Mutagenesis, and Impairment of Fertility: Conventional carcinogenesis studies in rats at doses of 0.12 to 12 mg/kg/day (about 1/100 to 1.5 times the daily maximum recommended human dose on a mg/m2 basis) for up to 2 years did not show evidence of carcinogenicity. Studies in mice at doses of 1.0 to 30.0 mg/kg/day (about 1/15 to 2 times the daily maximum recommended human dose on a mg/m2 basis) for up to 2 years revealed increased incidence of ovarian and testicular tumors, and increased incidence of osteoma and osteosarcoma. The significance of the mouse findings is uncertain because of the different role of estrogens in mice and the estrogenic effect of toremifene in mice. An increased incidence of ovarian and testicular tumors in mice has also been observed with other human antiestrogenic agents that have primarily estrogenic activity in mice. Toremifene has not been shown to be mutagenic in in vitro tests (Ames and E. coli bacterial tests). Toremifene is clastogenic in vitro (chromosomal aberrations and micronuclei formation in human lymphoblastoid MCL-5 cells) and in vivo (chromosomal aberrations in rat hepatocytes). No significant adduct formation could be detected using 32P post-labeling in liver DNA from rats administered toremifene when compared to tamoxifen at similar doses. A study in cultured human lymphocytes indicated that adducting activity of toremifene, detected by 32P post-labeling, was about 1/6 that of tamoxifen at approximately equipotent concentrations. In addition, the DNA adducting activity of toremifene in salmon sperm, using 32P post-labeling, was 1/6 and 1/4 that observed with tamoxifen at equivalent concentrations following activation by rat and human microsomal systems, respectively. However, toremifene exposure is fourfold the exposure of tamoxifen based on human AUC in serum at recommended clinical doses. Toremifene produced impairment of fertility and conception in male and female rats at doses ≥25.0 and 0.14 mg/kg/day, respectively (about 3.5 times and 1/50 the daily maximum recommended human dose on a mg/m2 basis). At these doses, sperm counts, fertility index, and conception rate were reduced in males with atrophy of seminal vesicles and prostate. In females, fertility and reproductive indices were markedly reduced with increased pre- and post-implantation loss. In addition, offspring of treated rats exhibited depressed reproductive indices. Toremifene produced ovarian atrophy in dogs administered doses ≥3 mg/kg/day (about 1.5 times the daily maximum recommended human dose on a mg/m2 basis) for 16 weeks. Cystic ovaries and reduction in endometrial stromal cellularity were observed in monkeys at doses ≥1 mg/kg/day (about 1/4 the daily maximum recommended human dose on a mg/m2 basis) for 52 weeks. Pregnancy: Pregnancy Category D: (see WARNINGS). Nursing mothers: Toremifene has been shown to be excreted in the milk of lactating rats. It is not known if this drug is excreted in human milk. (See WARNINGS and PRECAUTIONS). Pediatric use: There is no indication for use of FARESTON in pediatric patients. Geriatric use: The median ages in the three controlled studies ranged from 60 to 66 years. No

Approximately 1% of patients receiving FARESTON (n = 592) in the three controlled studies discontinued treatment as a result of adverse events (nausea and vomiting, fatigue, thrombophlebitis, depression, lethargy, anorexia, ischemic attack, arthritis, pulmonary embolism, and myocardial infarction). Serious adverse events occurring in patients receiving FARESTON in the three major trials are listed in the table below. Adverse Events North American Eastern European Nordic FAR60 TAM20 FAR60 TAM40 FAR60 TAM40 n=221(%) n=215(%) n=157(%) n=149(%) n=214(%) n=201(%) Cardiac Cardiac Failure 2 (1) 1 (<1) 1 (<1) 2 (1) 3 (1.5) Myocardial Infarction 2 (1) 3 (1.5) 1 (<1) 2 (1) 1 (<1) Arrhythmia 3 (1.5) 1 (<1) Angina Pectoris 1 (<1) 1 (<1) 2 (1) Ocular* Cataracts 22 (10) 16 (7.5) 5 (3) Dry Eyes 20 (9) 16 (7.5) Abnormal Visual Fields 8 (4) 10 (5) 1 (<1) Corneal Keratopathy 4 (2) 2 (1) Glaucoma 3 (1.5) 2 (1) 1 (<1) 1 (<1) Abnormal Vision/Diplopia 3 (1.5) Thromboembolic Pulmonary Embolism 4 (2) 2 (1) 1 (<1) 1 (<1) Thrombophlebitis 2 (1) 1 (<1) 1 (<1) 4 (2) 3 (1.5) Thrombosis 1 (<1) 1 (<1) 3 (1.5) 4 (2) CVA/TIA 1 (<1) 1 (<1) 4 (2) 4 (2) Elevated Liver Tests** SGOT 11 (5) 4 (2) 30 (19) 22 (15) 32 (15) 35 (17) Alkaline Phosphatase 41 (19) 24 (11) 16 (10) 13 (9) 18 (8) 31 (15) Bilirubin 3 (1.5) 4 (2) 2 (1) 1 (<1) 2 (1) 3 (1.5) Hypercalcemia 6 (3) 6 (3) 1 (<1) * Most of the ocular abnormalities were observed in the North American Study in which on-study and biannual opthalmic examinations were performed. No cases of retinopathy were observed in any arm. ** Elevated defined as follows: North American Study: SGOT >100 IU/L; alkaline phosphatase >200 IU/L; bilirubin > 2 mg/dL. Eastern European and Nordic studies: SGOT, alkaline phosphatase, and bilirubin – WHO Grade 1 (1.25 times the upper limit of normal). Other adverse events of unclear causal relationship to FARESTON included leukopenia and thrombocytopenia, skin discoloration or dermatitis, constipation, dyspnea, paresis, tremor, vertigo, pruritis, anorexia, reversible corneal opacity (corneal verticulata), asthenia, alopecia, depression, jaundice, and rigors. In the 200 and 240 mg FARESTON dose arms, the incidence of SGOT elevation and nausea was higher. Approximately 4% of patients were withdrawn for toxicity from the high-dose FARESTON treatment arms. Reasons for withdrawal included hypercalcemia, abnormal liver function tests, and one case each of toxic hepatitis, depression, dizziness, incoordination, ataxia, blurry vision, diffuse dermatitis, and a constellation of symptoms consisting of nausea, sweating, and tremor. OVERDOSAGE Lethality was observed in rats following single oral doses that were ≥1000 mg/kg (about 150 times the recommended human dose on a mg/m2 basis) and was associated with gastric atony/ dilatation leading to interference with digestion and adrenal enlargement. Vertigo, headache, and dizziness were observed in healthy volunteer studies at a daily dose of 680 mg for 5 days. The symptoms occurred in two of the five subjects during the third day of the treatment and disappeared within 2 days of discontinuation of the drug. No immediate concomitant changes in any measured clinical chemistry parameters were found. In a study in postmenopausal breast cancer patients, toremifene 400 mg/m2/day caused dose-limiting nausea, vomiting, and dizziness, as well as reversible hallucinations and ataxia in one patient. Theoretically, overdose may be manifested as an increase of antiestrogenic effects, such as hot flashes; estrogenic effects, such as vaginal bleeding; or nervous system disorders, such as vertigo, dizziness, ataxia, and nausea. There is no specific antidote and the treatment is symptomatic. DOSAGE AND ADMINISTRATION The dosage of FARESTON is 60 mg, once daily, orally. Treatment is generally continued until disease progression is observed. HOW SUPPLIED FARESTON Tablets, containing toremifene citrate in an amount equivalent to 60 mg of toremifene, are round, convex, unscored, uncoated, and white, or almost white. FARESTON Tablets are identified with TO 60 embossed on one side. FARESTON Tablets are available as: NDC 11399-005-30 bottles of 30 NDC 11399-005-01 bottles of 100 Store at 25°C (77°F) excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from heat and light.

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FARESTON (toremifene citrate) 60 mg Tablets: indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen receptor positive or unknown tumors.

ALREADY ACTIVE

500,000 PATIENT YEARS

UNIQUE METABOLISM

PATIENT SAVINGS

Parent compound binds to and blocks estrogen receptors

Metabolized principally by CYP3A4 CYP2D6 does not play a signiÀcant role in the activity of FARESTON No known drug interactions with SSRI antidepressants

Proven clinical proÀle EfÀcacy comparable to tamoxifen in head to head trials Savings coupons offer up to $50 off each prescription for eligible patients Patient Assistance Program available for Medicare Part D and uninsured patients who qualify

Important safety information: FARESTON is contraindicated in patients with known hypersensitivity to the drug. FARESTON has been shown to prolong the QTc interval in a dose and concentration dependent manner. FARESTON should not be prescribed to patients with congenital/acquired QT prolongation, uncorrected hypokalemia or uncorrected hypomagnesemia. The administration of FARESTON with agents that are strong CYP3A4 inhibitors (e.g., ketoconazole, grapefruit juice and others) increases the steady-state concentration in serum and should be avoided. Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. As with other antiestrogens, tumor ﬂare, hypercalcemia, and vaginal bleeding have been reported in some breast cancer patients being treated with FARESTON. During clinical trials involving 1157 patients treated with FARESTON or tamoxifen, the incidence of serious side effects were as follows: cardiac events (2.03% vs. 2.42%), ocular events (10.30% vs. 9.38%), thromboembolic events (3.21% vs. 3.28%), and elevated liver tests (26.2% vs. 23.7%), respectively. References: FARESTON® Prescribing Information, 2004. Data on ﬁle, GTx, Inc.

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