Clinical Oncology News - February 2010 - Digital Edition

McMahon Publishing

Advances in Cancer Care CLINICALONCOLOGY.COM • February 2010 • Vol. 5, No. 2

HEMATOLOGIC DISEASE

7 10

Can nilotinib replace imatinib in first-line treatment of CML? FCR solidified as standard of care for patients with CLL.

POLICY & MANAGEMENT

12

Environmental movement eyes regenerative hospitals.

SOLID TUMORS

16 Andrew Seidman, MD, and Maura Dickler, MD, discuss practice-changing breast cancer news from SABCS. CLINICAL TRIALS

18

New Standard Suggested for Elderly MM Patients

Second-line Bevacizumab Plus Chemo Works in MBC

New Orleans—A large two-part study has outlined a potential new standard for the treatment of multiple myeloma (MM) in elderly patients. The results of the first part reaffirmed the previously demonstrated efficacy of the induction combination of bortezomib (Velcade, Millennium), melphalan (Alkeran, Celgene) and prednisone (VMP), while demonstrating that a modification to the bortezomib dosing schedule improved tolerability. The second part demonstrated that a bortezomib and thalidomide (VT) maintenance regimen following induction almost doubled the proportion of patients who achieved a complete response (CR) and substantially extended progression-free survival (PFS). On the basis of the study, VMP induction followed by VT maintenance appears to provide the best treatment sequence for MM in older patients.

San Antonio—The first study to evaluate the addition of bevacizumab (Avastin, Genentech) to chemot h e ra py a s

see NEW STANDARD, page 28

A list of all Phase II and III trials initiated within the past 30 days.

PRN

29

Around the Water Cooler brings you news about people and places in oncology.

30

Tips on optimizing your nonverbal communication.

EDUCATIONAL REVIEW

Evolving Treatment Paradigms in Non-Small Cell Lung Cancer After page 16.

“This is the first Phase III study to show that bevacizumab plus chemotherapy is effective as second-line therapy for metastatic breast cancer. These results are clinically meaningful. We have few options for second-line chemotherapy in metastatic disease,” said Adam Brufsky,

RIBBON-2 trial yields results.

Above: A stain of human metastatic breast cancer cells superimposed on a ribbon.

second-line therapy for patients with metastatic breast cancer (MBC) has revealed that the combination improves progression-free survival (PFS).

MD, co-director of the Comprehensive Breast Cancer Center and medical director at the Magee-Womens Hospital, University of Pittsburgh Cancer Institute. see SECOND LINE, page 24

Hematology News Sparks Excitement

Another Year of Belt Tightening

W

T

POLICY & MANAGEMENT

hat news was all the rage at the recent meeting of the American Society of Hematology (ASH)? On page 26, Richard Stone, MD, discusses the important news on the randomized up-front trial comparing nilotinib (Tasigna, Novartis) with imatinib (Gleevec, Novartis) (abstract LBA1). In this article, Dr. Stone highlights other news from the meeting on acute leukemias, chronic myelogenous leukemia and myelofibrosis. Dr. Stone is director of the Adult Leukemia Program, DanaFarber Cancer Institute, and professor of medicine, Harvard Medical School, both in Boston. see ASH NEWS, page 8

he 2010 regulatory changes from the Centers for Medicare & Medicaid Services (CMS) have been released, and once again, oncology practices will be

adversely impacted. Reimbursement trends continue their downward spiral for oncology. The major changes include elimination of consulting codes by Medicare, revision of total code relative value units and practice expenses, payment delays

that started in January 2010 and a limited sustained growth rate (SGR) reprieve of two months.

Problematic Changes In an effort to boost payment for evaluation and management (E&M) services for all physicians and to put a halt to fraud and waste, the CMS has eliminated the use of consultation codes. It has moved some of the funds that were distributed through these codes and they will now be doled out through E&M codes for new and established patients. This change and the shortfall it creates are predicted to result in significant payment decreases see TIGHTENING, page 14

McMahonMedicalBooks.com Skin Cancer Management: A Practical Approach EASTON, PA PERMIT #117

Deborah F. MacFarlane

PAID Colon cancer awareness month, see page 24.

For more information, see inside back cover of the Educational Review following page 14.

PRSRT STD U.S. POSTAGE

Indications and Important Safety Information for ALIMTA Indications ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.

ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

ALIMTA is indicated as a single agent for the treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer after prior chemotherapy.

Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer.

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

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

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

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

ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia). Reduce doses for subsequent cycles based on hematologic and nonhematologic toxicities.

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

PM58001 0709 PRINTED IN USA © 2009, Lilly USA, LLC. ALL RIGHTS RESERVED.

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

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

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.

Pregnancy Category D—ALIMTA may cause fetal harm when administered to a pregnant woman. Women should be apprised of the potential hazard to the fetus and should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA. The effect of third space fluid, such as pleural effusion and ascites, on ALIMTA is unknown. In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to ALIMTA administration.

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

Histology Matters with ALIMTA because

EXTENDED SURVIVAL MATTERS. Approved for the 1st-line treatment of advanced nonsquamous NSCLC and now approved for the maintenance treatment of advanced nonsquamous NSCLC. ALIMTA is not indicated for the treatment of patients with squamous cell NSCLC. Myelosuppression is usually the dose-limiting toxicity with ALIMTA therapy.

Within the ALIMTA maintenance trial design, ALIMTA/cisplatin was not included as an induction therapy.

For more information, visit www.ALIMTA.com Use in SpeciďŹ c 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 insufďŹ ciency.

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) for NSCLC 1st-line: 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).

Abbreviated Adverse Reactions (% incidence) for NSCLC Maintenance: The most severe adverse reactions (Grades 3/4) with ALIMTA as a single agent versus placebo, respectively, for the maintenance treatment of patients with locally advanced nonsquamous non-small cell lung cancer (NSCLC) were anemia (3 vs 1); neutropenia (3 vs 0); leukopenia (2 vs 1); fatigue (5 vs 1); nausea (1 vs 1); anorexia (2 vs 0); mucositis/ stomatitis (1 vs 0); diarrhea (1 vs 0); infection (2 vs 0); neuropathy-sensory (1 vs 0). Common adverse reactions (all Grades) with ALIMTA as a single agent versus placebo, respectively, were anemia (15 vs 6); neutropenia (6 vs 0); leukopenia (6 vs 1); increased ALT (10 vs 4); increased AST (8 vs 4); fatigue (25 vs 11); nausea (19 vs 6); anorexia (19 vs 5); vomiting (9 vs 1); mucositis/stomatitis (7 vs 2); diarrhea (5 vs 3); infection (5 vs 2); neuropathy-sensory (9 vs 4); and rash/desquamation (10 vs 3).

Abbreviated Adverse Reactions (% incidence) for NSCLC 2nd-line: The most severe adverse reactions (Grades 3/4) with ALIMTA as a single agent versus docetaxel, respectively, for the 2nd-line treatment of patients with advanced non-small cell lung cancer (NSCLC) were neutropenia (5 vs 40); leukopenia (4 vs 27); thrombocytopenia (2 vs 0); anemia (4 vs 4); fatigue (5 vs 5); nausea (3 vs 2); anorexia (2 vs 3); vomiting (2 vs 1); increased ALT (2 vs 0); increased AST (1 vs 0); and stomatitis/pharyngitis (1 vs 1). Common adverse reactions (all Grades) with ALIMTA as a single agent versus docetaxel, respectively, were fatigue (34 vs 36); nausea (31 vs 17); anorexia (22 vs 24); anemia (19 vs 22); vomiting (16 vs 12); stomatitis/pharyngitis (15 vs 17); rash (14 vs 6); diarrhea (13 vs 24); leukopenia (12 vs 34); and neutropenia (11 vs 45).

For additional safety and dosing guidelines, please see brief summary of Prescribing Information on adjacent page.

5 5.1

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.

WARNINGS AND PRECAUTIONS Premedication Regimen Need for Folate and Vitamin B12 Supplementation 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.

Corticosteroid Supplementation 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%) during therapy with ALIMTA as a single-agent were fatigue, nausea, and anorexia. Additional common adverse reactions (incidence ≥20%) during therapy with ALIMTA when used in combination with cisplatin included vomiting, neutropenia, leukopenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation.

Non-Small Cell Lung Cancer (NSCLC)—Combination with Cisplatin 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 ALIMTA/cisplatin Gemcitabine/cisplatin Reaction b (N=839) (N=830) All Grades Grade 3-4 All Grades Grade 3-4 Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) All Adverse Reactions 90 37 91 53 Laboratory Hematologic Anemia 33 6 46 10 Neutropenia 29 15 38 27 Leukopenia 18 5 21 8 Thrombocytopenia 10 4 27 13 Renal Creatinine elevation 10 1 7 1 Clinical Constitutional Symptoms Fatigue 43 7 45 5 Gastrointestinal Nausea 56 7 53 4 Vomiting 40 6 36 6 Anorexia 27 2 24 1 Constipation 21 1 20 0 Stomatitis/Pharyngitis 14 1 12 0 Diarrhea 12 1 13 2 Dyspepsia/Heartburn 5 0 6 0 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 Whole—febrile neutropenia, infection, pyrexia General Disorders—dehydration Metabolism and Nutrition—increased AST, increased ALT Renal—creatinine clearance decrease, renal failure Special Senses—conjunctivitis

ALIMTA姞 (pemetrexed for injection)

ALIMTA姞 (pemetrexed for injection)

ALIMTA姞 (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.

1.2

Nonsquamous Non-Small Cell Lung Cancer—Maintenance ALIMTA is indicated for the maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based first-line chemotherapy.

1.3

Nonsquamous Non-Small Cell Lung Cancer—After Prior Chemotherapy ALIMTA is indicated as a single agent for the treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer after prior chemotherapy.

1.4

Mesothelioma ALIMTA in combination with cisplatin is indicated for the treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery.

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, and 14.3)] 2

DOSAGE AND ADMINISTRATION

2.1

Combination Use with Cisplatin Nonsquamous Non-Small Cell Lung Cancer and Malignant Pleural Mesothelioma 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.

2.2

Single-Agent Use Nonsquamous Non-Small Cell Lung 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.

2.3

Premedication Regimen Vitamin Supplementation 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 Monitoring 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 (single-agent or in combination) 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 regardless of nadir ANC 75% of previous dose (pemetrexed and cisplatin) Nadir platelets <50,000/mm3 with bleeding a, regardless of nadir ANC 50% of previous dose (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 (single-agent or in combination) and Cisplatin—Nonhematologic Toxicities a,b Dose of ALIMTA Dose of Cisplatin (mg/m 2) (mg/m 2) Any Grade 3 or 4 toxicities except mucositis 75% of previous dose 75% of previous dose Any diarrhea requiring hospitalization (irrespective of Grade) or Grade 3 or 4 diarrhea 75% of previous dose 75% of previous dose Grade 3 or 4 mucositis 50% of previous dose 100% of previous dose a NCI Common Toxicity Criteria (CTC). b Excluding neurotoxicity (see 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 Dose of ALIMTA Dose of Cisplatin CTC Grade (mg/m2) (mg/m2) 0-1 100% of previous dose 100% of previous dose 2 100% 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.

Renally Impaired 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].

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

PV 5206 AMP

PV 5206 AMP

Incidence Less than 1% Cardiovascular—arrhythmia General Disorders—chest pain Metabolism and Nutrition—increased GGT Neurology—motor neuropathy Non-Small Cell Lung Cancer (NSCLC) - Maintenance Table 5 provides the frequency and severity of adverse reactions that have been reported in >5% of 438 patients with NSCLC who received ALIMTA and 218 patients with NSCLC who received placebo. All patients received study therapy immediately following 4 cycles of platinum-based treatment for locally advanced or metastatic NSCLC. Patients in both study arms were fully supplemented with folic acid and vitamin B12.

Table 5: Adverse Reactions in Patients Receiving ALIMTA versus Placebo in NSCLCa ALIMTA Placebo (N=438) (N=218) Reaction b All Grades Grade 3-4 All Grades Grade 3-4 Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) All Adverse Reactions 66 16 37 4 Laboratory Hematologic Anemia 15 3 6 1 Neutropenia 6 3 0 0 Leukopenia 6 2 1 1 Hepatic Increased ALT 10 0 4 0 Increased AST 8 0 4 0 Clinical Constitutional Symptoms Fatigue 25 5 11 1 Gastrointestinal Nausea 19 1 6 1 Anorexia 19 2 5 0 Vomiting 9 0 1 0 Mucositis/stomatitis 7 1 2 0 Diarrhea 5 1 3 0 Infection 5 2 2 0 Neurology Neuropathy-sensory 9 1 4 0 Dermatology/Skin Rash/Desquamation 10 0 3 0 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 CTCAE Criteria version 3.0 for each Grade of toxicity.

No clinically relevant differences in Grade 3/4 adverse reactions were seen in patients based on age, gender, ethnic origin, or histology except a higher incidence of Grade 3/4 fatigue for Caucasian patients compared to non-Caucasian patients (6.5% versus 0.6%).

Safety was assessed by exposure for patients who received at least one dose of ALIMTA (N=438). The incidence of adverse reactions was evaluated for patients who received ≤6 cycles of ALIMTA, and compared to patients who received >6 cycles of ALIMTA. Increases in adverse reactions (all grades) were observed with longer exposure; however no clinically relevant differences in Grade 3/4 adverse reactions were seen.

Consistent with the higher incidence of anemia (all grades) on the ALIMTA arm, use of transfusions (mainly RBC) and erythropoiesis stimulating agents (ESAs; erythropoietin and darbepoetin) were higher in the ALIMTA arm compared to the placebo arm (transfusions 9.5% versus 3.2%, ESAs 5.9% versus 1.8%).

The following additional adverse reactions were observed in patients with non-small cell lung cancer who received ALIMTA. Incidence 1% to 5% Dermatology/Skin—alopecia, pruritis/itching Gastrointestinal—constipation General Disorders—edema, fever (in the absence of neutropenia) Hematologic—thrombocytopenia Renal—decreased creatinine clearance, increased creatinine, decreased glomerular filtration rate Special Senses—ocular surface disease (including conjunctivitis), increased lacrimation Incidence Less than 1% Cardiovascular—supraventricular arrhythmia Dermatology/Skin—erythema multiforme General Disorders—febrile neutropenia, allergic reaction/hypersensitivity Neurology—motor neuropathy Renal—renal failure Non-Small Cell Lung Cancer (NSCLC)—After Prior Chemotherapy Table 6 provides the frequency and severity of adverse reactions that have been reported in >5% of 265 patients randomly assigned to receive single-agent ALIMTA with folic acid and vitamin B12 supplementation and 276 patients randomly assigned to receive single-agent docetaxel. All patients were diagnosed with locally advanced or metastatic NSCLC and received prior chemotherapy.

Table 6: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA versus Docetaxel in NSCLCa ALIMTA Docetaxel Reaction b (N=265) (N=276) All Grades Grade 3-4 All Grades Grade 3-4 Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) Laboratory Hematologic Anemia 19 4 22 4 Leukopenia 12 4 34 27 Neutropenia 11 5 45 40 Thrombocytopenia 8 2 1 0 Hepatic Increased ALT 8 2 1 0 Increased AST 7 1 1 0 Clinical Gastrointestinal Nausea 31 3 17 2 Anorexia 22 2 24 3 Vomiting 16 2 12 1 Stomatitis/Pharyngitis 15 1 17 1 Diarrhea 13 0 24 3 Constipation 6 0 4 0 Constitutional Symptoms Fatigue 34 5 36 5 Fever 8 0 8 0 Dermatology/Skin Rash/Desquamation 14 0 6 0 Pruritis 7 0 2 0 c 38 2c Alopecia 6 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 for lab values for each Grade of toxicity (version 2.0). c According to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2.

ALIMTA姞 (pemetrexed for injection) PV 5206 AMP

No clinically relevant differences in adverse reactions were seen in patients based on histology.

Clinically relevant adverse reactions occurring in <5% of patients that received ALIMTA treatment but >5% of patients that received docetaxel include CTC Grade 3/4 febrile neutropenia (1.9% ALIMTA, 12.7% docetaxel).

The following additional adverse reactions were observed in patients with non-small cell lung cancer randomly assigned to receive ALIMTA. Incidence 1% to 5% Body as a Whole—abdominal pain, allergic reaction/hypersensitivity, febrile neutropenia, infection Dermatology/Skin—erythema multiforme Neurology—motor neuropathy, sensory neuropathy Renal—increased creatinine Incidence Less than 1% Cardiovascular—supraventricular arrhythmias Malignant Pleural Mesothelioma (MPM) Table 7 provides the frequency and severity of adverse reactions that have been reported in >5% of 168 patients with mesothelioma who were randomly assigned to receive cisplatin and ALIMTA and 163 patients with mesothelioma randomly assigned to receive single-agent cisplatin. In both treatment arms, these chemonaive patients were fully supplemented with folic acid and vitamin B12.

Table 7: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in MPMa ALIMTA/cisplatin Cisplatin (N=168) (N=163) Reaction b All Grades Grade 3-4 All Grades Grade 3-4 Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) Laboratory Hematologic Neutropenia 56 23 13 3 Leukopenia 53 15 17 1 Anemia 26 4 10 0 Thrombocytopenia 23 5 9 0 Renal Creatinine elevation 11 1 10 1 Creatinine clearance decreased 16 1 18 2 Clinical Eye Disorder Conjunctivitis 5 0 1 0 Gastrointestinal Nausea 82 12 77 6 Vomiting 57 11 50 4 Stomatitis/Pharyngitis 23 3 6 0 Anorexia 20 1 14 1 Diarrhea 17 4 8 0 Constipation 12 1 7 1 Dyspepsia 5 1 1 0 Constitutional Symptoms Fatigue 48 10 42 9 Metabolism and Nutrition Dehydration 7 4 1 1 Neurology Neuropathy-sensory 10 0 10 1 Taste Disturbance 8 0c 6 0c Dermatology/Skin Rash 16 1 5 0 Alopecia 11 0c 6 0c 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 except the term “creatinine clearance decreased” which is derived from the CTC term “renal/genitourinary-other”. c According to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2.

The following additional adverse reactions were observed in patients with malignant pleural mesothelioma randomly assigned to receive ALIMTA plus cisplatin.

Incidence 1% to 5% Body as a Whole—febrile neutropenia, infection, pyrexia Dermatology/Skin—urticaria General Disorders—chest pain Metabolism and Nutrition—increased AST, increased ALT, increased GGT Renal—renal failure Incidence Less than 1% Cardiovascular—arrhythmia Neurology—motor neuropathy Effects of Vitamin Supplementations Table 8 compares the incidence (percentage of patients) of CTC Grade 3/4 toxicities in patients who received vitamin supplementation with daily folic acid and vitamin B12 from the time of enrollment in the study (fully supplemented) with the incidence in patients who never received vitamin supplementation (never supplemented) during the study in the ALIMTA plus cisplatin arm.

Table 8: Selected Grade 3/4 Adverse Events Comparing Fully Supplemented versus Never Supplemented Patients in the ALIMTA plus Cisplatin arm (% incidence) Fully Supplemented Never Supplemented Patients Patients a Adverse Event (%) (N=168) (N=32) Neutropenia/granulocytopenia 23 38 Thrombocytopenia 5 9 Vomiting 11 31 Febrile neutropenia 1 9 Infection with Grade 3/4 neutropenia 0 6 Diarrhea 4 9 a Refer to NCI CTC criteria for lab and non-laboratory values for each grade of toxicity (Version 2.0).

The following adverse events were greater in the fully supplemented group compared to the never supplemented group: hypertension (11%, 3%), chest pain (8%, 6%), and thrombosis/embolism (6%, 3%).

Subpopulations No relevant effect for ALIMTA safety due to gender or race was identified, except an increased incidence of rash in men (24%) compared to women (16%).

6.2 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.

These reactions have occurred with ALIMTA when used as a single-agent and in combination therapies.

Gastrointestinal—colitis General Disorders and Administration Site Conditions—edema Injury, poisoning, and procedural complications—Radiation recall has been reported in patients who have previously received radiotherapy Respiratory—interstitial pneumonitis ALIMTA姞 (pemetrexed for injection)

PV 5206 AMP

7

DRUG INTERACTIONS

7.1

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Ibuprofen 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.

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 Effects—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

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.

17

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 over-the-counter medications including those for pain or inflammation such as non-steroidal anti-inflammatory drugs [see Drug Interactions (7.1)].

17.5 FDA-Approved Patient Labeling Patients should be instructed to read the patient package insert carefully.

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.

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.

In the maintenance non-small cell lung cancer trial, 33.3% of patients treated with ALIMTA were ≥65 years and no differences were seen in Grade 3/4 adverse reactions as compared to patients <65 years. For patients <65 years, the HR for overall survival was 0.74 (95% CI: 0.58, 0.93) and for patients ≥65 years the HR was 0.88 (95% CI: 0.65, 1.21) in the intent-to-treat population.

In the non-small cell lung cancer trial after prior chemotherapy, 29.7% patients treated with ALIMTA were ≥65 years and Grade 3/4 hypertension was greater as compared to patients <65 years. For patients <65 years, the HR for overall survival was 0.95 (95% CI: 0.76, 1.19), and for patients ≥65 years the HR was 1.15 (95% CI: 0.79, 1.68) in the intent-to-treat population.

The mesothelioma trial included 36.7% patients treated with ALIMTA plus cisplatin that were ≥65 years, and Grade 3/4 fatigue, leukopenia, neutropenia, and thrombocytopenia were greater as compared to patients <65 years. For patients <65 years, the HR for overall survival was 0.71 (95% CI: 0.53, 0.96) and for patients ≥65 years, the HR was 0.85 (95% CI: 0.59, 1.22) 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 intent-to-treat population.

In the maintenance non-small cell lung cancer trial, 73% of patients were males and 27% females. For males the HR for overall survival was 0.78 (95% CI: 0.63, 0.96) and for females the HR was 0.83 (95% CI: 0.56, 1.21) in the intent-to-treat population.

In the non-small cell lung cancer trial after prior chemotherapy, 72% of patients were males and 28% females. For males the HR for overall survival was 0.95 (95% CI: 0.76, 1.19) and for females the HR was 1.28 (95% CI: 0.86, 1.91) in the intent-totreat population.

In the mesothelioma trial, 82% of patients were males and 18% females. For males the HR for overall survival was 0.85 (95% CI: 0.66, 1.09) and for females the HR was 0.48 (95% CI: 0.27, 0.85) in the intent-to-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.

In the maintenance non-small cell lung cancer trial, 65% of patients were Caucasians, 23% East Asian, and 12% others.

For Caucasians the HR for overall survival was 0.77 (95% CI: 0.62, 0.97), for East Asians was 1.05 (95% CI: 0.70, 1.59) and for others the HR was 0.46 (95% CI: 0.26, 0.79) in the intent-to-treat population.

In the non-small cell lung cancer trial after prior chemotherapy, 71% of patients were Caucasians and 29% others. For Caucasians the HR for overall survival was 0.91 (95% CI: 0.73, 1.15) and for others the HR was 1.27 (95% CI: 0.87, 1.87) in the intent-to-treat population.

In the mesothelioma trial, 92% of patients were Caucasians and 8% others. For Caucasians, the HR for overall survival was 0.77 (95% CI: 0.61, 0.97) and for others the HR was 0.86 (95% CI: 0.39, 1.90) in the intent-to-treat population.

Literature revised July 2, 2009

Eli Lilly and Company Indianapolis, IN 46285, USA

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.

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7

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • FEBRUARY 2010

CML

Nilotinib May Best Imatinib in 1st-line Treatment of CML New Orleans—In a large, multinational Phase III study, nilotinib (Tasigna, Novartis) demonstrated compelling superiority to imatinib (Gleevec, Novartis) as first-line therapy for chronic myeloid leukemia (CML).

More patients achieved the primary end point of a major molecular response (MMR) and fewer patients had disease progression. Nilotinib was at least as well tolerated as imatinib, and the advantage of nilotinib over imatinib was consistent across Sokal risk stratifications, a common scoring system for predicting survival in patients with CML. “Based on these results, we strongly believe that nilotinib may become the new standard of care in newly diagnosed CML,” said Giuseppe Saglio, MD, a researcher at the University of Turin’s San Luigi Gonzaga Hospital in Orbassano, Italy. Dr. Saglio, lead investigator of the study, presented these results at the annual meeting of the American Society of Hematology (abstract LBA1). He indicated that the greater efficacy of nilotinib compared with imatinib is consistent with its greater inhibition of BCR-ABL, a defining molecular defect in CML. In the trial, at 12 months, roughly 20% more patients achieved an MMR with nilotinib compared with imatinib. Less than 1% of patients in each of the two arms that received nilotinib entered accelerated phase (AP) or blast crisis (BC) in the 12-month period compared with 3.9% of patients in the imatinib arm.

TM

Study Details In the study, which included 217 participating centers in 35 countries, 846 previously untreated patients with CML were randomized to the standard oncedaily (qd) 400-mg dose of imatinib, 300-mg twice daily (bid) of nilotinib or 400-mg bid of nilotinib.

Although the study protocol allowed imatinib patients to increase the dose to 400 mg bid (16% did so), dose escalation was not permitted in either of the nilotinib arms. The primary end point was MMR at 12 months.

Complete cytogenetic response (CCyR) at 12 months was a secondary end point. Other end points included duration of MMR and CCyR, progression-free survival (PFS) and overall survival (OS).

The MMR rates were achieved more quickly at every time point by the nilotinib group starting at three months. At 12 months, the rates of MMR were 44% in the 300 mg bid and 43% in the 400 mg bid nilotinib arms compared with 22% in the imatinib arm (P<0.0001 for either nilotinib arm relative to imatinib). The CCyR rates at 12 months were 80% for 300 mg bid nilotinib (P<0.0001 vs. imatinib), 78% for 400 mg bid nilotinib (P=0.0005 vs. imatinib) and 65% for imatinib. Only two patients (0.7%) in the 300-mg nilotinib arm (P<0.001 vs. imatinib) and only one patient

Gastrointestinal Cancer Edward Chu, MD Cathy Eng, MD

ADVISORY BOARD Bioethics Joseph P. DeMarco, PhD Paul J. Ford, PhD

Michael J. Fisch, MD, MPH John W. Finnie, MD

Hematologic Malignancies Jennifer R. Brown, MD, PhD Agnes Y.Y. Lee, MSc, MD

Betty Ferrell, RN, PhD

Pharmacy Polly E. Kintzel, PharmD Melvin E. Liter, MS, PharmD

Policy and Management Mary Lou Bowers, MBA Barbara Constable, RN, MBA Rhonda M. Gold, RN, MSN

Solid Tumors Bone Metastases

—Giuseppe Saglio, MD

tinib was compared with 300- or 400-mg bid nilotinib for specific side effects of any grade, rates were higher for imatinib for nausea (31% vs. 12% and 20%), muscle spasm (24% vs. 7% and 6%), diarrhea (21% vs. 8% and 7%) and vomiting (14% vs. 5% and 9%). In contrast, rash (11% vs. 31% and 26%) and headache (8% vs. 14% and 21%) were more frequently reported see NILOTINIB, page 26

Robin B. Weisberg, Manager, Copyediting Services Elizabeth Zhong, Associate Copy Chief

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Oncology Nursing

‘Based on these results, we strongly believe that nilotinib may become the new standard of care in newly diagnosed CML.’

Leonard Saltz, MD

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Community Oncology

(0.4%) in the 400-mg nilotinib arm (P<0.004 vs. imatinib) entered AP or BC within 12 months compared with 11 patients (3.9%) in the imatinib arm.

Both nilotinib and imatinib were relatively well tolerated, but there were differences in the types of side effects. Whereas grade 3 or 4 myelosuppression was generally low overall, imatinib was associated with higher rates of grade 3/4 neutropenia (20% vs. 12% and 10% for the 300- and 400-mg bid doses of nilotinib, respectively). Grade 3 or 4 nonhematologic side effects were uncommon in all groups, but when ima-

Infection Control Susan K. Seo, MD, Director

Symptom Control and Palliative Care William S. Breitbart, MD Steven D. Passik, PhD Joseph V. Pergolizzi Jr., MD Russell K. Portenoy, MD Charles F. von Gunten, MD

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Breast Cancer

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HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • FEBRUARY 2010

Multiple Cancers

ASH NEWS continued from page 1

JAK2 Inhibitors in Myeloproliferative Diseases: Are We Getting Someplace?

At the ASH meeting, several studies showed varying results with inhibitors of the Janus kinase 2 (JAK2) gene in patients with myeloproliferative neoplasms (MPNs). Further studies are needed to elucidate the role these agents will play in these diseases.

The MPNs (polycythemia vera, essential thrombocytosis and agnogenic myeloid metaplasia with myelofibrosis), characterized by overproduction of normal bone marrow elements, were defined on clinical grounds alone. In recent years, the discovery that almost all patients with polycythemia vera and approximately 60% of patients with essential thrombocytosis and myelofibrosis have an activating mutation in the JAK2 tyrosine kinase (V617F) led investigators to believe that targeting this mutation might lead to a new, specific therapeutic approach.

Since the identification of this mutation, the clinical development of JAK2 inhibitors in MPNs has proceeded relatively rapidly. Preclinical studies revealed that JAK2 inhibitors reduced proliferation of relevant cell lines and mitigated disease manifestations in murine disease models. At prior ASH meetings, abstracts detailing results from Phase I and II studies with JAK2 inhibitors have been presented. One of the compounds (XL109) is no longer being developed as a result of neurologic toxicities. We have previously heard that the JAK2 inhibitors from the TargeGen (TG101348) and Incyte Corporations (INCB018424) are capable of reducing spleen size and ameliorating systemic symptoms in patients with myelofibrosis.

The inhibitors were used first in patients with myelofibrosis in part because the presumed need for chronic therapy in less aggressive MPNs (essential thrombocytosis and polycythemia vera) meant that it was important to establish safety. Two of the most interesting features that have emerged in this early period are that 1) even patients with no detectable V671F JAK2 mutation may benefit, potentially because of the ability of these agents to inhibit other enzymes besides JAK2, including those with anti-inflammatory properties; and 2) clinical benefit in terms of spleen reduction is fairly common.

Updates on two of these compounds used in patients with myelofibrosis were presented at the ASH meeting. In a Phase I trial involving 59 patients, TG101348

led to a spleen size reduction of at least 50% in 67% of patients, a decreased white blood cell (WBC) count in all the patients in whom WBC was elevated at baseline, and a 50% reduction in the V617F allelic burden in 44% of patients with a mutation (abstract 755) (Figure 1). In another study, 155 patients with myelofibrosis received INCB018424 in a patient-optimized dosing regimen based on initial platelet count scheme (abstract 766). The study revealed that 48% of patients receiving INCB018424 had significant spleen size reduction and 58% of patients had a 50% reduction in overall symptoms at six months (Figure 2). Patients also had improved exercise capacity. Lestaurtinib (Cephalon), primarily developed as an FMS-like tyrosine kinase 3 (FLT3) inhibitor, was recently tested in myelofibrosis; preliminary results also showed that this agent could reduce spleen size and mutant allelic burden (abstract 754). The updated results continued to show that these drugs might have some beneficial effect on myelofibrosis; whether or not this effect is of a great enough magnitude to justify approval remains to be seen.

67

Lestaurtinib also was tested in patients with “advanced” polycythemia vera and essential thrombocytosis and was found to reduce the spleen size in some patients, but a significant drop in JAK2 V617F allele burden was not common by the six-month mark and there were problems with drug tolerability (abstract 755). However, the results presented by Verstovsek et al with the INCB018424 Phase II trial in patients with hydroxyurea-refractory polycythemia vera (n=34) and essential thrombocytosis (n=39) were more encouraging (abstract 311). In patients with polycythemia vera, pruritis and need for phlebotomy decreased with normalization of complete blood count being common.

In patients with essential thrombocytosis, similar improvements were noted. The path to common use of JAK2 inhibitors in MPNs remains somewhat unclear, but it is certainly an effort that bears watching.

FLT3 Inhibitors in AML: “Good and Bad News” At the ASH meeting, a number of abstracts detailed

58

60

56

30

40

20

40

20

20 0 50% reduction in V617F allelic burden

Figure 1. Effects of TG101348 on patients with myelofibrosis.

12

14

Complete remission

Partial remission

30

50% reduction in overall symptoms

Figure 2. Effects of INCB018424 on patients with myelofibrosis.

20

10

0

0 Significant spleen size reduction

Patients, %

Patients, %

40

Patients, %

44

50% spleen size reduction

models and can specifically kill cell lines transformed by one of the activating constructs of FLT3. To date, however, the results of using FLT3 inhibitors as single agents in AML have been, perhaps not surprisingly, disappointing. Full-blown clinical AML likely represents a multitude of leukemogenic mutations, only one of which, and perhaps a late one at that, is the FLT3 activating mutation.

Single-agent studies with FLT3 inhibitors have shown a frequent, but transient and usually not clinically significant reduction in peripheral blood blasts.

Several reasons for the lack of activity of JAK2 as a single agent in AML have been postulated. These include pharmacokinetic problems in which the active inhibitory molecule is not present in high enough levels for a long enough time, the elaboration of survival factors in a protected stem cell niche, and the acquisition of addition leukemogenic mutations not dealt with by the inhibitor.

Data presented at this meeting gave cause for both optimism and concern. AC220, a potent and selective

48

60

0

results from studies involving FLT3 inhibitors in acute myeloid leukemia (AML). Although some of the studies had disappointing results, FLT3 inhibitors will continue to be pursued in AML either (if potent enough) as single agents, or in combination with chemotherapy in the up-front setting.

The finding that blasts from 30% of patients with AML harbored an activating mutation in the FLT3 tyrosine kinase oncogene promoted an intense search for FLT3 inhibitors that could cause remissions analogous to those seen with BCR-ABL inhibitors in chronic myelogenous leukemia (CML). Approximately 25% of patients with AML have a length or internal tandem duplication (ITD, poor prognosis) mutation. Another 5% to 10% have an activating point mutation in the tyrosine kinase domain. Either of these two mutations can cause factor-independent growth in cell lines and a myeloproliferative disease in murine models. JAK2 inhibitors such as midostaurin (PKC412, Ambit Biosciences), lestaurtinib (CEP701) or AC220 (Ambit Biosciences) result in amelioration of disease in murine

Single-agent studies with FLT3 inhibitors have shown a frequent, but transient and usually not clinically significant reduction in peripheral blood blasts.

60

80

Patients, %

8

Patients who responded

Figure 3. Effects of AC220 on patients with AML.

Complete response

Figure 4. Patients with AML treated with lenalidomide.

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • FEBRUARY 2010

Multiple Cancers

Approximately 60% of patients with essential thrombocytosis and myelofibrosis have an activating mutation in the JAK2 tyrosine kinase (V617F).

Janus kinase 2

FLT3 inhibitor, tested as a single agent in AML (N=76), is associated with a significant complete remission (CR) (12%, including those with incomplete blood count recovery) and partial remission (14%) rates; 56% of FLT3 ITD patients responded (abstract 636) (Figure 3).

Whether the apparently high response rate compared with other single-agent FLT3 inhibitors is because of potency or a longer period of drug exposure is unclear, but it certainly warrants further development.

When it was recognized that single-agent FLT3 inhibitors would not represent a straightforward therapeutic development pathway in AML, the notion that they should be combined with chemotherapy was based on general consideration, as well as in vitro data that suggested that these agents would synergistically kill leukemic cells. Using the drug in combination with chemotherapy early in the disease might obviate the role of secondary mutations presumptively present in relapsed patients. As such, a Phase IB trial of midostaurin plus chemotherapy was completed a few years ago that demonstrated tolerability of oral midostaurin 50 mg twice daily plus chemotherapy in patients (<60 years) newly diagnosed with AML. Updated data from that trial showed that patients with FLT3 mutations surprisingly survived just as long as those with wild-type FLT3, perhaps yielding some hope that chemotherapy in combination with an FLT3 inhibitor in the up-front setting might be beneficial (abstract 634). A large up-front, double-blind randomized trial involving midostaurin compared with placebo plus induction and postremission chemotherapy (CALGB 10603) for patients with AML and FLT3 mutations is under way.

The mature results of an important trial involving relapsed FLT3 ITD-mutant patients was presented

by Mark Levis, MD, PhD, (abstract 788) at this meeting. Patients with relapsed FLT3 ITD AML were

Richard Stone, MD, provides these highlights from the ASH meeting.

randomized either to chemotherapy alone or chemotherapy plus the FLT3 inhibitor lestaurtinib. Unfortunately, there was no improvement in the CR rate in patients who were randomized to lestaurtinib. Dr. Levis indicated that the lack of overall benefit might have been the failure to achieve high enough levels for a long enough time.

Further studies will tease out just how these agents may be used in therapy.

Lessons Learned From MDS Applicable to AML One of the most important recent developments in the therapeutics of disease considered largely medically refractory, myelodysplastic syndromes (MDS) has been the use of lenalidomide (Revlimid, Celgene) in the subset of patients with a 5q- cytogenetic abnormality. Approximately two-thirds of patients with lowrisk MDS who have a 5q- cytogenetic abnormality alone or in combination with others will experience transfusion independence when given 10 mg of lenalidomide daily. What was particularly striking was that most patients who experienced a clinical improvement also lost cytogenetic evidence of the malignant clone; therefore, it was thought that patients with AML, particularly those with 5q- abnormalities, also might respond to

lenalidomide even though no patients with even highrisk MDS were given this agent in the original studies. Abstracts presented from Ohio State University (abstract 841) and Washington University (abstract 842) indicated that at least some patients with fullblown AML might respond to lenalidomide.

A Phase I trial of lenalidomide in relapsed or refractory acute leukemia was conducted (abstract 841). In this group of 35 heavily pretreated patients, the recommended Phase II dose was 50 mg per day. Higher doses produced intolerable fatigue. Life-threatening thromboembolism did not occur. Five of 31 patients with AML achieved a CR, including three patients with abnormal cytogenetics at pretreatment who achieved complete cytogenetic responses. Responses took about two months, so patience was required. None of those who responded had a 5q- abnormality; one had trisomy 13. Two patients responded after post-allogeneic transplant relapses, suggesting the possibility of immune augmentation induced by lenalidomide. Vij et al (abstract 842) treated 33 untreated adults with AML who were aged 60 years or older and not deemed candidates for chemotherapy with lenalidomide (50 mg/d for one month, then 10 mg/d for 12 months).

Of these patients, 30% achieved a CR, including 50% of those with a low WBC count at presentation (Figure 4). Responses usually were seen during the first month of therapy. Most of the patients who achieved CR and who had a clonal cytogenetic abnormality at diagnosis became cytogenetically normal.

Additional studies clearly are required to capitalize on these findings. Investigators will need to determine the mechanism of response, confirm the sensitivity of patients with trisomy 13, and consider whether only those with lower WBC counts at the start will respond.

Optimal dosing (50 mg/d continuously “v” stepping down to a lower dose from maintenance) is not yet clear. However, just as DNA hypomethylating agents, so successfully employed in MDS, are now being used in patients with poor-risk AML, lenalidomide also may someday be added to the currently meager therapeutic armamentarium in older adults with AML.

Where do you go ... ... if you recall reading an educational supplement, but no longer have a hard copy? ... if you heard about an interesting piece from a colleague, and would like to obtain a copy

CLINICALONCOLOGY.COM

—Richard Stone, MD

9

10

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • FEBRUARY 2010

Multiple Myeloma

FCR Solidified as Standard of Care for CLL New Orleans—The addition of rituximab (Rituxan, Genentech/Idec) to cyclophosphamide and fludarabine (FC) improves overall survival (OS) in physically fit patients with advanced chronic lymphocytic leukemia (CLL), according to a recent study.

“This is the first time a randomized trial has shown that a choice of a specific firstline treatment for CLL could improve overall survival,” said Michael Hallek, MD, University of Cologne in Germany. He presented the study at the recent annual meeting of the American Society of Hematology (ASH; abstract 535).

The news solidifies the combination of rituximab, cyclophosphamide and fludarabine (FCR) as a first-line treatment for CLL. During the December 2008 ASH meeting, researchers from the same trial deemed FCR as a new standard of care

79% in the FC arm (P=0.01). Only patients in Binet stages A and B showed a superior OS after FCR treatment (Binet A: hazard ratio [HR], 0.19; 95% confidence interval [CI], 0.023-1.613; P=0.09; Binet B: HR, 0.45; 95% CI, 0.296-0.689; P<0.001; Binet C: HR, 1.4; 95% CI, 0.843-2.620; P=0.168).

RBITUX EERBITUX

® ®

The median OS has not been reached in either arm. The median PFS was 51.8 months in the FCR arm and 32.8 months in the FC arm.

The investigators say that the partial failure to demonstrate a benefit for FCR in Binet stage C patients may be

related to insufficient treatment intensity in these patients with higher tumor load.

Patients in Binet stages A and B received more treatment cycles (5.31) than Binet C patients (4.52; P<0.001). Only 57.1% (FC) and 60.3% (FCR) of patients with Binet C stage CLL received six cycles.

The investigators concluded that the presence of a deletion of 17p, FC versus FCR therapy and an elevated serum β2-microglobulin level were the strongest predictors for treatment failure. Results

(cetuximab): FOR FOR PATIENTS PATIENTS WITH WITH HEAD HEAD AND AND NECK NECK CCANCER* ANCER* (cetuximab):

ERBITUX++RT: RT: ERBITUX 26% reduction in 26% reduction in Riskof ofDeath Death Risk 1,2 from SCCHN from SCCHN1,2

‘OS benefits are hard to come by in indolent diseases.’

—Jennifer Brown, MD

after analysis of results revealed that adding rituximab to FC nearly doubled complete response rates and lengthened progression-free survival (PFS) by 10 months. “[The news from this trial] was probably practice changing last year, with the benefit in PFS reported then, but now with the OS benefit, it is that much more convincing. OS benefits are hard to come by in indolent diseases,” said Jennifer Brown, MD, an attending physician with the CLL & Lymphoma Program, DanaFarber Cancer Institute, and an assistant professor of medicine at Harvard Medical School, both in Boston.

The study, conducted by the German CLL Study Group, involved 817 patients with previously untreated but advanced CLL who were randomized to six courses of FC or FCR. Overall survival three years post-randomization was 87.2% in patients receiving FCR and 82.5% in patients receiving FC (P=0.012; Figure). As of June 2009, the median observation time was 37.7 months and at this time point, OS was 84.1% in the FCR arm compared with

Clinical Oncology News would like your feedback.

Please send opinions, criticism, ideas and suggestions to Kate O’Rourke, Editor, Clinical Oncology News, at

korourke@mcmahonmed.com

Important Safety Safety Information Information Including Including Boxed Boxed WARNINGS WARNINGS Important

Infusion Reactions Infusion ■ GradeReactions 3/4 infusion reactions occurred in approximately 3% of patients receiving ERBITUX®® (cetuximab) in clinical trials, with fatal outcome reported in less ■ Grade infusion reactions occurred in approximately 3% of patients receiving ERBITUX (cetuximab) in clinical trials, with fatal outcome reported in less than 13/4 in 1000 than 1 in 1000 — Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of ERBITUX, included rapid onset of airway — Serious infusion reactions, requiring intervention and immediate, discontinuation of ERBITUX, included onset of airway obstruction (bronchospasm, stridor, medical hoarseness), hypotension, shock, losspermanent of consciousness, myocardial infarction, and/or rapid cardiac arrest (bronchospasm, stridor, hoarseness), hypotension, shock, loss consciousness, myocardial infarction, and/or cardiac arrest —obstruction Immediately interrupt and permanently discontinue ERBITUX infusions forof serious infusion reactions — Immediately interrupt and permanently discontinue ERBITUX infusions for serious infusion reactions ■ Most (90%) of the severe infusion reactions were associated with the first infusion of ERBITUX despite premedication with antihistamines ■ Most (90%)must of thebe severe infusion were associated with thewere first infusion ERBITUX despite premedication with antihistamines — Caution exercised withreactions every ERBITUX infusion, as there patientsof who experienced their first severe infusion reaction during later infusions — be exercised every ERBITUX ERBITUX infusions infusion, as were patients who experienced severe infusion reaction during later infusions —Caution Monitormust patients for 1 hourwith following in athere setting with resuscitation equipmenttheir andfirst other agents necessary to treat anaphylaxis — Monitor patients for 1 hour following ERBITUX infusions in a setting with resuscitation equipment and other agents necessary anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Longer observation periods mayto betreat required in patients (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen).

Longer observation periods may be required in patients who require treatment for infusion reactions who require treatment for infusion reactions Cardiopulmonary Arrest Cardiopulmonary Arrest ■ Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients with squamous cell carcinoma of the head and neck treated with radiation ■ Cardiopulmonary arrestas and/or sudden deathofoccurred in 4 (2%) of 208 squamous carcinoma of the head and1 to neck with radiation therapy and ERBITUX, compared to none 212 patients treated withpatients radiationwith therapy alone.cell Fatal events occurred within 43 treated days after the last therapy and ERBITUX, ERBITUX treatment as compared to none of 212 patients treated with radiation therapy alone. Fatal events occurred within 1 to 43 days after the last ERBITUX treatment — Carefully consider the use of ERBITUX in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, — Carefully consider the use ERBITUX inincombination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure orofarrhythmias light of these risks heart serum failureelectrolytes or arrhythmias in lightserum of these risks —congestive Closely monitor including magnesium, potassium, and calcium during and after ERBITUX therapy — Closely monitor serum electrolytes including serum magnesium, potassium, and calcium during and after ERBITUX therapy Pulmonary Toxicity Pulmonary Toxicity ■ Interstitial lung disease (ILD), which was fatal in one case, occurred in 4 of 1570 (<0.5%) patients receiving ERBITUX in clinical trials. Interrupt ERBITUX for acute ■ Interstitial lung disease (ILD), whichsymptoms. was fatal inPermanently one case, occurred in 4 of 1570 (<0.5%) patients receiving ERBITUX in clinical trials. Interrupt ERBITUX for acute onset or worsening of pulmonary discontinue ERBITUX where ILD is confirmed onset or worsening of pulmonary symptoms. Permanently discontinue ERBITUX where ILD is confirmed Dermatologic Toxicities Dermatologic Toxicities ■ In clinical studies of ERBITUX, dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae ■ In clinical studies of ERBITUX, toxicities, includingconjunctivitis, acneform rash, skin drying and fissuring, paronychialoccurred inflammation, infectious sequelae (eg, S. aureus sepsis, abscessdermatologic formation, cellulitis, blepharitis, keratitis, cheilitis), and hypertrichosis, in patients receiving ERBITUX (eg, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), hypertrichosis, occurred in patients receiving ERBITUX therapy. Acneform rash occurred in 76-88% of 1373 patients receiving ERBITUX in clinical trials.and Severe acneform rash occurred in 1-17% of patients therapy.

Acneform rash occurred in 76-88% of 1373 patients receiving ERBITUX in clinical trials.

Severe acneform rash occurred in 1-17% of patients — Acneform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although — Acneform rashthe usually the28 first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, eventdeveloped continuedwithin beyond days nearly half, the event continued beyond 28 days toxicities and infectious sequelae —inMonitor patients receiving ERBITUX for dermatologic — Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae — Sun exposure may exacerbate these effects — Sun exposure may exacerbate these effects ERBITUX Plus Radiation Therapy and Cisplatin ERBITUX Plusof Radiation and Cisplatin ■ The safety ERBITUXTherapy in combination with radiation therapy and cisplatin has not been established ■ The safetyand of ERBITUX in combination withobserved radiationintherapy and cisplatin has not beenradiation established — Death serious cardiotoxicity were a single-arm trial with ERBITUX, therapy, and cisplatin (100 mg/m2) in patients with locally — Death and serious cardiotoxicity were a single-arm trial with ERBITUX, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced squamous cell carcinoma ofobserved the headinand neck advanced squamous cell carcinoma of the head and neck — Two of 21 patients died, one as a result of pneumonia and one of an unknown cause — 21 patients died, onetreatment as a resultdue of pneumonia and oneTwo of an cause —Two Fourofpatients discontinued to adverse events. ofunknown these discontinuations were due to cardiac events — Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • FEBRUARY 2010

Multiple Myeloma FCR FC

Overall Survival, %

100

87.2

82.5

80

‘We are starting to see a way of personalizing therapy.

FCR is not effective to prevent early relapse and death of patients with deletions of 17p.’

60 40

—Michael Hallek, MD

20 0

Figure. Comparison of overall survival at three years.

FC, cyclophosphamide and fludarabine; FCR, rituximab, cyclophosphamide and fludarabine

from the trial reveal that clinicians may have a new way of personalizing therapy for patients with CLL. “We are starting to see a way of personalizing therapy,” Dr. Hallek said. “FCR is particularly effective in some genetically defined subgroups such as deletions of 11q, deletions

ERBITUX + RT (%) ERBITUX + RT (%) (n = 208) (n = 208)

No. (%) of Patients No. (%) of Patients ERBITUX + RT RT Alone ERBITUX + RT RT Alone (n = 211) (n = 213) (n = 211) (n = 213) Mucositis/stomatitis Mucositis/stomatitis Dysphagia Dysphagia Xerostomia Xerostomia Radiation dermatitis Radiation dermatitis

Delivery of planned RT dose Delivery of planned RT dose Adequate delivery per protocol Adequate delivery per protocol

184 (87.2) 184 (87.2)

187 (87.8) 187 (87.8)

Inadequate delivery per protocol Inadequate delivery per protocol

27 (12.8) 27 (12.8)

26 (12.2) 26 (12.2)

of 13q and trisomy 12. FCR is not effective to prevent early relapse and death of patients with deletions of 17p.”

In the study, the doses of fludarabine (25 mg/m2) and cyclophosphamide (250 mg/m2), administered on days 1 and 3 of each 28-day cycle, were the

Grades Grades 1-4 1-4

Grade Grade 3/4 3/4

93 93 65 65 72 72 86 86

56 56 26 26 5 5 23 23

RT Alone (%) RT Alone (%) (n = 212) (n = 212) Grades Grade Grades Grade 1-4 3/4 1-4 3/4 94 94 63 63 71 71 90 90

52 52 30 30 3 3 18 18

■ The incidences of grades 3/4 xerostomia, mucositis/stomatitis, ■ The incidences of grades 3/4 xerostomia, mucositis/stomatitis,

† No difference in radiation dose delivered between the 2 treatment groups in a randomized trial † No differenceERBITUX in radiation delivered between thewith 2 treatment in a randomized trial 2 comparing + RTdose versus RT alone in patients locally orgroups regionally advanced SCCHN. comparing ERBITUX + RT versus RT alone in patients with locally or regionally advanced SCCHN.2

and radiation dermatitis were more frequent in the ERBITUX and radiation dermatitis were more frequent in the ERBITUX plus RT arm plus RT arm

*INDICATIONS *INDICATIONS (cetuximab),in incombination combinationwith withradiation radiationtherapy, therapy,isisindicated indicatedfor forthe theinitial initialtreatment treatmentof oflocally locallyor orregionally regionallyadvanced advanced ■ERBITUX ERBITUX®®(cetuximab), ■ squamous cellcarcinoma carcinomaof ofthe thehead headand andneck neck squamous cell ■ERBITUX,as asaasingle singleagent, agent,isisindicated indicatedfor forthe thetreatment treatmentof ofpatients patientswith withrecurrent recurrentor ormetastatic metastaticsquamous squamouscell cellcarcinoma carcinomaof ofthe the ■ERBITUX, headand andneck neckfor forwhom whomprior priorplatinum-based platinum-basedtherapy therapyhas hasfailed failed head SCCHN = squamous cell carcinoma of the head and neck; RT = radiation therapy.

SCCHN = squamous cell carcinoma of the head and neck; RT = radiation therapy.

Electrolyte Depletion Electrolyte Depletion ■ Hypomagnesemia occurred in 55% (199/365) of patients receiving ERBITUX® (cetuximab) and was severe (NCI CTC grades 3 & 4) in 6-17%. The onset of hypomagnesemia ■ Hypomagnesemia occurred in 55% (199/365) of patients receiving ERBITUX® (cetuximab) and was severe (NCI CTC grades 3 & 4) in 6-17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of ERBITUX therapy and accompanying electrolyte abnormalities occurred days to months after initiation of ERBITUX therapy — Monitor patients periodically for hypomagnesemia, hypocalcemia and hypokalemia, during, and for at least 8 weeks following the completion of, ERBITUX therapy — Monitor patients periodically for hypomagnesemia, hypocalcemia and hypokalemia, during, and for at least 8 weeks following the completion of, ERBITUX therapy — Replete electrolytes as necessary — Replete electrolytes as necessary Late Radiation Toxicities Late Radiation Toxicities ■ The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone.

■ The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone.

The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively — The incidence of grade 3 or 4 late radiation toxicities were similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms — The incidence of grade 3 or 4 late radiation toxicities were similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms Pregnancy Pregnancy ■ In women of childbearing potential, appropriate contraceptive measures must be used during treatment with ERBITUX and for 6 months following the last dose of ■ In women of childbearing potential, appropriate contraceptive measures must be used during treatment with ERBITUX and for 6 months following the last dose of ERBITUX. ERBITUX may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women.

ERBITUX. ERBITUX may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women.

ERBITUX should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus ERBITUX should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus Adverse Events Adverse Events ■ The most serious adverse reactions associated with ERBITUX across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation ■ The most serious adverse reactions associated with ERBITUX across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most common adverse reactions associated with ERBITUX (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), ■ The most common adverse reactions associated with ERBITUX (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection headache, diarrhea, and infection ■ The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus ■ The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The radiation alone (n=212) (incidence ≥50%) were acneform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) included: radiation dermatitis (23%), acneform rash (17%), and most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) included: radiation dermatitis (23%), acneform rash (17%), and weight loss (11%) weight loss (11%) For more information, please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

For more information, please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

References: 1. ERBITUX®® (cetuximab) Package Insert. ImClone LLC, New York, NY 10014 References: 1. ERBITUX Insert.

ImClone LLC, New York, NY 10014 and Bristol-Myers Squibb,(cetuximab) Princeton, NJPackage 08543; July 2009.

2. Bonner JA, Harari PM, Giralt J, et al. and Bristol-Myers Princeton, NJ 08543; July 2009. 2.of Bonner JA, Harari PM,N Giralt al.

Radiotherapy plusSquibb, cetuximab for squamous-cell carcinoma the head and neck.

EnglJ,Jet Med. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head 2006;354:567-578. 3. Data on file, Bristol-Myers Squibb, ERBI 001. and neck. N Engl J Med. 2006;354:567-578. 3. Data on file, Bristol-Myers Squibb, ERBI 001. © 2009, ImClone LLC, New York, New York 10014, U.S.A. and Bristol-Myers Squibb, © 2009, ImClone LLC, New York, New York 10014, U.S.A. and Bristol-Myers Squibb, Princeton, New Jersey 08543, U.S.A. Princeton, New Jersey 08543,isU.S.A. All rights reserved.

ERBITUX a registered trademark of ImClone LLC. All rights reserved. ERBITUX is a registered trademark of ImClone LLC.

693US09AB15316 693US09AB15316

7/09 7/09

Pleasesee seebrief briefsummary summaryof ofFull FullPrescribing PrescribingInformation Informationincluding including Please BoxedWARNINGS WARNINGSregarding regardinginfusion infusionreactions reactionsand and Boxed cardiopulmonaryarrest arreston onadjacent adjacentpage. page. cardiopulmonary

same in both study arms. In the FCR arm, rituximab was administered in a dose of 375 mg/m2 on day 0 of the first cycle and then in a dose of 500 mg/m2 on day 1 of the five subsequent cycles.

Both treatment arms were well balanced with regard to sex, age, stage, genomic aberrations and immunoglobulin variable heavy chain (IgVH) gene status. The median age was 61 years. As previously reported, more hematologic adverse events, particularly neutropenia, were observed with FCR treatment, but this did not result in an increased infection rate.

—Kate O’Rourke

11

12

POLICY & MANAGEMENT

CLINICAL ONCOLOGY NEWS • FEBRUARY 2010

Sustainable Practices

Clinicians, Heal Thy Planet Eco movement eyes ‘regenerative’ hospitals Chicago—As vendors scurried around the Hyatt Regency in preparation for the start of CleanMed 2009, a collection of noted architects, engineers, designers and health care professionals huddled in a subterranean room of the hotel.

Gail Vittori, co-coordinator of the Green Guide for Health Care, stood and addressed the audience. “This is about health care as the intersection between the environment and the human

experience,” Ms. Vittori announced.

The workshop, Designing the Regenerative Hospital: An Imperative for the 21st Century, will serve as the blueprint for the new Green Guide for Health

Care. The guide (available at www. gghc.org) offers a toolkit of environmentally sustainable practices for hospitals and health care facilities. It was launched in 2003, when a collection of

ERBITUX® (cetuximab) Solution for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert.

WARNING: SERIOUS INFUSION REACTIONS and CARDIOPULMONARY ARREST Infusion Reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. [See Warnings and Precautions and Adverse Reactions.] Immediately interrupt and permanently discontinue Erbitux infusion for serious infusion reactions. [See Warnings and Precautions and Dosage and Administration (2.4) in Full Prescribing Information.]

Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and Erbitux. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Warnings and Precautions.]

INDICATIONS AND USAGE Squamous Cell Carcinoma of the Head and Neck (SCCHN) Erbitux® (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.]

Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1) in Full Prescribing Information.]

Colorectal Cancer Erbitux, as a single agent, is indicated for the treatment of epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. Erbitux, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.]

Erbitux, in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of Erbitux in combination with irinotecan is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Erbitux in combination with irinotecan for the treatment of EGFR-expressing, metastatic colorectal carcinoma. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.]

Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for Erbitux in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Erbitux is not recommended for the treatment of colorectal cancer with these mutations [see Clinical Studies (14.2) and Clinical Pharmacology (12.1) in Full Prescribing Information].

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Infusion Reactions Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactions occurred in 2–5% of 1373 patients in clinical trials, with fatal outcome in 1 patient.

Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines.

Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusion reactions.

Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See Boxed Warning and Dosage and Administration (2.4) in Full Prescribing Information.]

Cardiopulmonary Arrest Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapy and Erbitux as compared to none of 212 patients treated with radiation therapy alone in a randomized, controlled trial in patients with SCCHN. Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one had congestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with no prior history of coronary artery disease died one day after the last dose of Erbitux. Carefully consider use of Erbitux in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Boxed Warning and Warnings and Precautions.]

Pulmonary Toxicity Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux in clinical trials. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinue Erbitux for confirmed ILD. Dermatologic Toxicity Dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneform rash occurred in 76–88% of 1373 patients receiving Erbitux in clinical trials. Severe acneform rash occurred in 1–17% of patients.

Acneform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patients receiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposure during Erbitux therapy. [See Dose Modifications (2.4) in Full Prescribing Information.]

Use of Erbitux in Combination With Radiation and Cisplatin The safety of Erbitux in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with Erbitux, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced SCCHN. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events.

Hypomagnesemia and Electrolyte Abnormalities In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of patients (199/365) receiving Erbitux and was severe (NCI CTC Grades 3 and 4) in 6–17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of Erbitux. Periodically monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion of Erbitux. Replete electrolytes as necessary.

leaders concerned with green health care decided to create a document to assist the greening of American medicine. Now they have a new target— “regenerative” hospitals.

“We need to restore and play a part in healing the ecosystem. We need to have buildings that restore, that regenerate,” said Robin Guenther, co-coordinator of the guide. “There is a perfect alliance

Epidermal Growth Factor Receptor (EGFR) Expression and Response Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumor expression prior to study entry.

Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidence of EGFR tumor expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomation EGFR pharmDx™ test kit. Specimens were scored based on the percentage of cells expressing EGFR and intensity (barely/faint, weak-to-moderate, and strong). Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression.

ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Infusion reactions [See Boxed Warning and Warnings and Precautions.]

• Cardiopulmonary arrest [See Boxed Warning and Warnings and Precautions.]

• Pulmonary toxicity [See Warnings and Precautions.]

• Dermatologic toxicity [See Warnings and Precautions.]

• Hypomagnesemia and Electrolyte Abnormalities [See Warnings and Precautions.]

The most common adverse reactions with Erbitux (cetuximab) (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection.

The most serious adverse reactions with Erbitux are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus.

Across all studies, Erbitux was discontinued in 3–10% of patients because of adverse reactions.

Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data below reflect exposure to Erbitux in 1373 patients with colorectal cancer or SCCHN in randomized Phase 3 (Studies 1 and 3) or Phase 2 (Studies 2 and 4) trials treated at the recommended dose and schedule for a median of 7 to 14 weeks. [See Clinical Studies (14) in Full Prescribing Information.]

Infusion reactions: Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, and hypotension occurred in 15–21% of patients across studies. Grades 3 and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient.

Infections: The incidence of infection was variable across studies, ranging from 13–35%. Sepsis occurred in 1–4% of patients.

Renal: Renal failure occurred in 1% of patients with colorectal cancer.

Squamous Cell Carcinoma of the Head and Neck Table 1 contains selected adverse events in 420 patients receiving radiation therapy either alone or with Erbitux for locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 8 infusions (range 1–11).

Table 1:

Incidence of Selected Adverse Events (≥10%) in Patients with Locoregionally Advanced SCCHN Erbitux plus Radiation Radiation Therapy Alone (n=208) (n=212) Body System Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients Body as a Whole Asthenia 56 4 49 5 29 1 13 1 Fever1 Headache 19 <1 8 <1 15 3 2 0 Infusion Reaction2 Infection 13 1 9 1 1 16 0 5 0 Chills Digestive Nausea 49 2 37 2 Emesis 29 2 23 4 Diarrhea 19 2 13 1 Dyspepsia 14 0 9 1 Metabolic/Nutritional Weight Loss 84 11 72 7 Dehydration 25 6 19 8 43 2 21 1 Alanine Transaminase, high3 Aspartate Transaminase, high3 38 1 24 1 33 <1 24 0 Alkaline Phosphatase, high3 Respiratory Pharyngitis 26 3 19 4 Skin/Appendages 4 87 17 10 1 Acneform Rash Radiation Dermatitis 86 23 90 18 Application Site Reaction 18 0 12 1 Pruritus 16 0 4 0 1 2

3 4

Includes cases also reported as infusion reaction.

Infusion reaction is defined as any event described at any time during the clinical study as “allergic reaction” or “anaphylactoid reaction”, or any event occurring on the first day of dosing described as “allergic reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and fever”, or “dyspnea”.

Based on laboratory measurements, not on reported adverse events, the number of subjects with tested samples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone.

Acneform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry skin”, or “exfoliative dermatitis”.

The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study.

Late Radiation Toxicity The overall incidence of late radiation toxicities (any grade) was higher in Erbitux in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%), esophagus (44% versus 35%), skin (42% versus 33%). The incidence of Grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the Erbitux plus radiation treatment groups.

13

POLICY & MANAGEMENT

CLINICAL ONCOLOGY NEWS • FEBRUARY 2010

Sustainable Practices

between the idea of regenerative buildings and health care; the missions of healing connect.”

But the call goes beyond fields of native plantings. According to workshop presenters, regenerative hospitals would not only help the environment, but could improve recovery times, increase profits, reduce nursing turnover, assist in recruitment and put natural foods onto the menus of hospital cafeterias.

But to become a reality, regenerative hospitals will require change, cautioned Kim E. Shinn, director of sustainable design at TLC Engineering for Architecture in Nashville, Tenn. “And

Hospitals are huge consumers of water and energy, sprawling campuses of impervious surfaces, producers of copious amounts of waste.

people would rather speak in public than change.”

See No Evil Hospitals are huge consumers of water and energy, sprawling campuses of impervious surfaces, producers of copious amounts of waste. They often

Colorectal Cancer Table 2 contains selected adverse events in 562 patients receiving best supportive care (BSC) alone or with Erbitux (cetuximab) monotherapy for metastatic colorectal cancer in Study 3. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly).

Table 2:

Incidence of Selected Adverse Events Occurring in ≥10% of Patients with Advanced Colorectal Carcinoma1 Treated with Erbitux Monotherapy

Body System Preferred Term Dermatology Rash/Desquamation Dry Skin Pruritus Other-Dermatology Nail Changes Body as a Whole Fatigue Fever Infusion Reactions3 Rigors, Chills Pain Abdominal Pain Pain-Other Headache Bone Pain Pulmonary Dyspnea Cough Gastrointestinal Constipation Diarrhea Vomiting Stomatitis Other-Gastrointestinal Mouth Dryness Infection Infection without neutropenia Neurology Insomnia Confusion Anxiety Depression

Erbitux plus BSC (n=288) Any Grades Grades2 3 and 4 % of Patients

BSC alone (n=274) Any Grades Grades 3 and 4

89 49 40 27 21

12 0 2 1 0

16 11 8 6 4

<1 0 0 1 0

89 30 20 13

33 1 5 <1

76 18

26 <1

4

0

59 51 33 15

14 16 4 3

52 34 11 7

16 7 0 2

48 29

16 2

43 19

12 1

46 39 37 25 23 11

4 2 6 1 10 0

38 20 29 10 18 4

5 2 6 <1 8 0

35

13

17

6

30 15 14 13

1 6 2 1

15 9 8 6

1 2 1 <1

1

Adverse reactions occurring more frequently in Erbitux-treated patients compared with controls.

Adverse events were graded using the NCI CTC, V 2.0.

Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, chest tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, pruritus, sweating, tremors, shaking, cough, visual disturbances, or other) recorded by the investigator as infusionrelated.

BSC = best supportive care 2 3

The most frequently reported adverse events in 354 patients treated with Erbitux plus irinotecan in clinical trials were acneform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common Grades 3–4 adverse events included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneform rash (14%).

Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximab were assessed using either a double antigen radiometric assay or an ELISA assay. Due to limitations in assay performance and sampling timing, the incidence of antibody development in patients receiving Erbitux has not been adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) of evaluable patients without apparent effect on the safety or antitumor activity of Erbitux.

The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay.

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

DRUG INTERACTIONS A drug interaction study was performed in which Erbitux was administered in combination with irinotecan. There was no evidence of any pharmacokinetic interactions between Erbitux and irinotecan.

comprise scores of buildings devoid of natural air flow, natural light and natural materials. In short, they’re ecological nightmares.

For decades, hospital administrators haven’t particularly worried about this.

“They held an understanding and belief that ‘health care is about saving lives,

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of Erbitux (cetuximab) in pregnant women. Based on animal models, EGFR has been implicated in the control of prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, Erbitux may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose of cetuximab (based on body surface area) during the period of organogenesis (gestation day [GD] 20–48).

Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49. No fetal malformations or other teratogenic effects occurred in offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area).

Nursing Mothers It is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be 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 Erbitux, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of cetuximab [see Clinical Pharmacology (12.3) in Full Prescribing Information], nursing should not be resumed earlier than 60 days following the last dose of Erbitux.

Pediatric Use The safety and effectiveness of Erbitux in pediatric patients have not been established. The pharmacokinetics of cetuximab have not been studied in pediatric populations.

Geriatric Use Of the 1062 patients who received Erbitux with irinotecan or Erbitux monotherapy in five studies of advanced colorectal cancer, 363 patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.

Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 208 patients with head and neck cancer who received Erbitux with radiation therapy, 45 patients were 65 years of age or older.

OVERDOSAGE The maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No adverse events were reported for this patient.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receiving weekly doses of 0.4 to 4 times the human dose of cetuximab (based on total body surface area).

Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to control animals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the 6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control male monkeys. It is not known if cetuximab can impair fertility in humans.

Animal Pharmacology and/or Toxicology In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic findings, including inflammation at the injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highest dose level beginning after approximately 13 weeks of treatment.

PATIENT COUNSELING INFORMATION Advise patients: • To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems.

• Of the potential risks of using Erbitux during pregnancy or nursing and of the need to use adequate contraception in both males and females during and for 6 months following the last dose of Erbitux therapy.

• That nursing is not recommended during, and for 2 months following the last dose of Erbitux therapy.

• To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of Erbitux.

Erbitux® is a registered trademark of ImClone Systems Incorporated.

Manufactured by ImClone Systems Incorporated, Branchburg, NJ 08876 Distributed and Marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543

Copyright ©2009 by ImClone Systems Incorporated and Bristol-Myers Squibb Company. All rights reserved.

1236886A5 ER-B0001A-07-09

Rev July 2009

not the environment. We support it, but it’s not our problem,’ ” said Jerry Smith, director of health care and sustainable initiatives at MSI Design in Columbus, Ohio. “That attitude is changing.”

Mr. Shinn went further. “If you look at the income statement for a hospital, the utility costs are fractional. They are very minor when compared to labor costs and litigation, insurance and risk management. If a director of facilities management says, ‘Hey, Mr. CFO, if you give me $1 million, I can save us $250,000 in a year on utilities,’ the CFO will say, ‘Where do I get $1 million, and will that get me more patients? Will it improve reimbursement? Will it help me attract docs?’ ”

Surprising Benefits According to Kumkum M. Dilwali, senior director of the Green Guide for Health Care, for at least some of these questions the answer may be yes.

Last March, Rick Fedrizzi, founder and chief executive officer of the U.S. Green Building Council, designated Dell Children’s Medical Center of Central Texas, in Austin, as the world’s first Leadership in Energy and Environmental Design (LEED) Platinum hospital.

Constructed on the brownfield site of a former municipal airport, the facility—part of Seton Health System— incorporates a wide range of sustainable practices. The building was designed to maximize access to daylight, which reduces energy use. It includes six courtyards with natural plantings that use less water and give patients and staff access to natural settings. The medical center has a natural gas–fired power plant from which it gets its energy.

But something else happened after Dell Children’s opened, Ms. Dilwali said.

When the Seton Health System compared staff turnover and recruitment at the new hospital to its old facility, “their retention was much higher.”

Ms. Guenther said staffing benefits have been seen at green hospitals across the United States and Canada. When a greencertified hospital opened in Ontario, it received applications from nurses across the country. When a survey on staff happiness was conducted at Oregon’s Providence Newberg Medical Center, “the results were off the charts,” she said.

If hospital operators ask why they should go green, they should “pick up the phone and talk to any of the owners of the first 43 LEED-certified hospitals and have a conversation about what it’s meant to their image in the community, what it’s meant to their ability to attract qualified staff and the response of their staff,” Ms. Guenther said. “They aren’t doing this once and saying, ‘that was fun but I wouldn’t do that again’; they’re moving forward faster with their other projects.” see ECO MOVEMENT, page 25

14

POLICY & MANAGEMENT

CLINICAL ONCOLOGY NEWS • FEBRUARY 2010

Reimbursement

TIGHTENING continued from page 1

Oncology reimbursement estimates show a decrease in revenue of 15% to 28% for the total E&M component of practices or a 1% to 4% decrease in the net revenue.

for both medical and radiation oncology. Many CMS audits have uncovered the misuse of consultation codes, and many rules related to code uses have been established in recent years. So, it should come as no surprise that Medicare has viewed the consultation codes as problematic. The fix, however, seems a bit overreaching. Oncology reimbursement estimates show a decrease in revenue of 15% to 28% for the total E&M component of practices or a 1% to 4%

decrease to the net revenue.

This is perhaps the biggest impact oncology will face this year. It is important that billers and coders are vigilant, so that every visit is captured appropriately. It appears that confusion still exists in the field about exact coding

equivalents, thus we recommend that every practice obtain direction from its Medicare administrative contractor or carrier. Modified instructions that were implemented for hospital visits should be checked carefully as they will help ensure appropriate payment.

CMS is trying to clear up the confusion and it abounds. General practitioners and internists have reported that some private insurers are implementing similar policies. It will be important to know exactly how this change has affected the practice and to clearly state what that will mean. CMS has been bombarded with physician comments regarding the modification to this rule and only hard data will change this situation. The next change that will significantly impact reimbursement for oncology comes from revisions made by the CMS in the development of a payment structure for each code. CMS updates to practice payment information negatively impacts medical oncology. Some adjustments have been made and there is still concern that medical oncology practice expense is misrepresented, resulting in an expected net revenue reduction of 1%. Radiation oncology was impacted more than other areas. Resource Utilization Committee changes, agreed to by the CMS, were not calculated properly for radiation oncology, specifically high-dose-rate brachytherapy which resulted in a huge decrease. Additionally, malpractice expense calculations for technical codes totally ignored the high malpractice risk of physicists’ work and physician oversight of this work.

When physician work was deemed to be zero, CMS placed the malpractice costs at zero, but this isn’t the case in most technical radiation codes because physicians oversee these codes and the codes impact malpractice costs.

Radiation was helped greatly by a rescinding of the planned equipment utilization ratio change from 50% to 90%. It appears that radiation will be looking at a small decrease in technical revenue rather than the monumental one that originally was proposed. These small decreases are nothing new. Physician professional fees (consultation code

What’s Your View? =?6;A

@5.?2

?20<::2;1

2 :.69

0<::2;A

What do you think of the changes to reimbursement? How will they impact your clinic? Do you participate in the PQRI? Why or why not?

Send replies to

korourke@mcmahonmed.com

POLICY & MANAGEMENT

CLINICAL ONCOLOGY NEWS • FEBRUARY 2010

Reimbursement

on getting their January claims paid as soon as possible. They should continue with all of the efficiencies previously put in place and collect data on their outcomes so they can use their medical knowledge to pursue innovation and the best results for their patients. The reputation that physicians build with good patient care will keep them afloat in the bad times.

issues) and technical fees (drug administration/radiation technical component codes) have been under assault for at least 10 years. It is time to turn the tide.

Lowering health care costs is a national mandate. We cannot keep doing the same things while expecting different results—Einstein called that the definition of insanity! We keep objecting and we keep accommodating. We must find a different way.

Getting Your 2% or 4% While we wait for more action from Congress to fix the SGR, which hovers over us every year because it is too expensive to fix (estimates are in the billions of dollars), we can appreciate that quality and safety are being rewarded and perhaps find in that a way out of the continual battle for more appropriate payment. Drug payments remain unchanged. Payments from the Physician Quality Reporting Initiative

Physician professional fees (consultation code issues) and technical fees (drug administration/radiation technical component codes) have been under assault for at least 10 years.

(PQRI) continue and have the potential to add 2% to net revenue. Nearly 50% of physicians failed to successfully file PQRI data. It may be wise to look at using a registry to file. Many indications relevant for cancer practices only can be reported through registries. Traditionally, CMS adds new indications or conditions to the PQRI list each year; in 2010 there is one new oncology indication: cancer stage documentation.

Payment supplements continue for electronic prescription writing as well.

Another 2% may be earned for having electronic prescriptions. The rules have been simplified this year so practices qualify with 25 encounters versus 50% of eligible claims. In other words, if a practice has 25 patients with enough e-prescribing to meet the rule, it is eligible to participate, no matter what percentage that is of the practice. The code has been changed to G8443. By the time this issue of Clinical Oncology News arrives in your mailbox, it is likely that Congress will have once again addressed the SGR issue. It is likely that there will be another temporary rollback of the scheduled decrease in payment to no increase in payment. There is agreement that the SGR is broken.

The problem is figuring out how to fix it for the long term. A health reform

plan might result in a permanent fix. In the meantime, physicians should focus

—Mary Lou Bowers, MBA, President & CEO of The Pritchard Group, LLC Rockville, Md. www.thepritchardgroup.net

15

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • FEBRUARY 2010

Breast

Practice-Changing News From SABCS What does the community oncologist need to know from the San Antonio Breast Cancer Symposium (SABCS)?

The following highlights, provided by Andrew D. Seidman, MD, and Maura Dickler, MD, advisory board members of Clinical Oncology News, will keep you in the loop. Drs. Seidman and Dickler are attending physicians at the Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center (MSKCC), in New York City.

pretreated MBC were randomized, researchers now describe a 4.5-month overall survival (OS) advantage for the combination treatment over lapatinib alone (14 Medicine Service, vs. 9.5 months; hazard ratio [HR], 0.74; P=0.026) (Figure 1).

Of note, von Minckwitz et al have demonstrated the utility of continuing trastuzumab beyond progression in combination with capecitabine (Xeloda, Roche) in women with trastuzumab-refractory MBC in a randomized, prospective clinical trial (J Clin Oncol 2009;27:1999-2006, PMID: 19289619). In this triPatients receiving lapatinib plus trastuzumab al, an advantage was noted in time to progression (TTP), but not in OS. Patients receiving lapatinib

Andrew D. Seidman, MD, attending physician, Breast Cancer MSKCC Lapatinib Plus Trastuzumab Packs a Punch

80

70 The clinical utilHigh Dose of Fulvestrant Offers Benefits 60.7 ity of using tras60 The CONFIRM trial reported by DiLeo et al (abstract 25) shows there tuzumab (Herceptin, Genentech) after 50 is a modest clinical advantage in using a higher dose of fulvestrant 41.4 patients with HER2-positive metastatic (Faslodex, AstraZeneca). This randomized Phase III trial compared ful40 breast cancer have progressed on trasvestrant 250 mg with fulvestrant 500 mg in postmenopausal women 30 tuzumab has been a pressing clinical with estrogen receptor–positive advanced breast cancer. question for years. The study report20 In this trial, 736 women were stratified by response to prior hormoned by Blackwell et al (abstract 61) is 10 al therapy, and ranthe first trial to show that dually tar10 domized to standard 0 Fulvestrant 250 mg geting the HER2 pathway can lead to or double-dose selecFulvestrant 500 mg a survival benefit in patients with trasFigure 1. Comparison of overall 8 tive estrogen receptor tuzumab-refractory metastatic breast survival.

6.5 downregulation with cancer (MBC).

6 fulvestrant. The medi5.5 Patients had HER2-positive metastatic breast At the 2008 SABCS, investigators an age of the patients cancer and had progressed on trastuzumabfrom this trial showed that continuing 4 was 61 years; approxcontaining regimens. trastuzumab beyond progression and imately two-thirds of adding the dual HER1/HER2 tyrosine the patients in both 2 kinase inhibitor lapatinib (Tykerb, arms had visceral disGlaxoSmithKline) 1,000 mg orally daily prolonged time to disease progression by ease. The primary end point was 0 four weeks compared with discontinuing trastuzumab and using lapatinib 1,500 TTP, and the study met its primary mg orally daily alone. In an update of this trial, in which 298 women with heavily Figure 2. Comparison of end point statistically: The higher-

Time to Progression, mo

Survival, wk

fulvestrant doses.

Maura Dickler, MD, attending physician, Breast Cancer Medicine Service, MSKCC

Based on results from the RIBBON-2 trial, clinicians may consider bevacizumab (Avastin, Genentech) in combination with their choice of chemotherapy as second-line therapy for patients with metastatic breast cancer (MBC) who have not received bevacizumab in the first-line setting (Brufsky et al, abstract 42).

In the RIBBON-2 trial, investigators showed that adding bevacizumab at a dose of 15 mg/kg every three weeks or 10 mg/kg every two weeks to secondline chemotherapy (investigator’s choice of taxanes, gemcitabine [Gemzar, Eli Lilly], capecitabine [Xeloda, Roche] or vinorelbine) improved response rates and progression-free survival (PFS) compared with chemotherapy alone in patients with MBC. The PFS increased from approximately five to seven months, with a hazard ratio (HR) of 0.78 (P=0.0072) (Figure 3).

As demonstrated in other bevacizumab-containing studies, there was no impact on overall survival (OS).

Of interest, the AVADO study, initially presented at ASCO 2008, was updated at SABCS 2009 (Miles et al, abstract 41). Similar to the ECOG trial E2100 of

Chemotherapy plus bevacizumab

8 6

P=0.0072

7.2

5.1

4 2 0

Figure 3. Comparison of progression-free survival.

45). Sorafenib is a tyrosine kinase inhibitor that targets the vascular endothelial growth factor receptor, platelet derived growth factor receptor and RAF kinase.

The first trial presented by Gradishar et al, looked at the benefits of weekly paclitaxel plus sorafenib in the first-line setting. There was a trend toward improvement in PFS (the primary end point) in favor of sorafenib plus paclitaxel compared with paclitaxel alone (6.9 vs. 5.6 months; P=0.0857), supported by a statistically significant improvement in the secondary end points of time to progression and response.

However, the combination of paclitaxel plus sorafenib resulted in a high rate of grade 3 hand–foot syndrome (30%) and more serious adverse events

Patients receiving capecitabine plus sorafenib Patients receiving capecitabine only

paclitaxel with or without bevacizumab, the AVADO study did not show a benefit in OS from the addition of bevacizumab after a median follow-up of 25 months, although the drug did improve PFS.

Sorafenib Shows Promise Two randomized, placebo-controlled Phase II trials were presented this year investigating the effects of sorafenib (Nexavar, Bayer Healthcare Pharmaceuticals) in combination with chemotherapy in patients with locally recurrent breast cancer or MBC (Gradishar et al, abstract 44; Baselga et al, SOLTI-0701, abstract

50

% of Patients

Bevacizumab in Second-line Therapy

Chemotherapy

Months

16

45

40 30 20 13 10 0

Figure 4. Comparison of grade 3 hand–foot syndrome in SOLTI trial.

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • FEBRUARY 2010

Breast

dose regimen was associated with a 6.5-month median TTP compared with the lower dose, 5.5 months (HR, 0.8; P=0.006) (Figure 2). There were no differences in response rates, clinical benefit rates or adverse events between groups.

FACT Finds No Benefit for Fulvestrant Plus Anastrozole The FACT trial reported by Bergh et al (abstract 23) shows that clinicians should not use the combination of fulvestrant and anastrozole (Arimidex, AstraZeneca) in patients with hormone receptor–positive breast cancer after first relapse. In this open-label, Phase III trial, 512 women were randomized to either anastrozole monotherapy or the combination of anastrozole plus fulvestrant (loading dose 500 mg, then 250 mg two weeks later and then 250 mg monthly).

Despite promising preclinical data supporting the combined strategy, there was no signal of improved efficacy for the combination of an aromatase inhibitor and an elective estrogen receptor downregulator. For the primary end point, median TTP was 10.8 months for the combination compared with 10.2 months for anastrozole (HR, 0.99). The clinical benefit rate was 55% for both arms, and the OS was 38 months for both arms. This combined strategy has no role in the clinical care of cancer patients.

Update on the NCCTG 9831 Trial At SABCS, Perez et al (abstract 80) reported results of chemotherapy alone, with sequential or concurrent addition of 52 weeks of trastuzumab in the NCCTG 9831 HER2-positive adjuvant breast cancer trial. It is the only Phase III trial comparing the addition of trastuzumab (H) to doxorubicin and cyclophosphamide, then paclitaxel [Taxol, Bristol-Myers Squibb] (Arm A: AC→T) either following (Arm B: AC→T→H) or starting concurrently with paclitaxel (Arm C: AC→T+H→H) for women with resected stage I-III invasive HER2-positive breast cancer. The trial demonstrated superior outcomes for patients with HER2-positive early-stage breast cancer receiving concurrent (with paclitaxel) and sequential trastuzumab over the arm in which patients received trastuzumab only sequentially, after the completion of chemotherapy.

It was already known from a previous report of this trial, and the NSABP B-31, that the addition of trastuzumab to anthracycline and taxane-containing chemotherapy reduces recurrence and death from HER2-positive early-stage breast cancer (N Engl J Med 2005; 353:1673-1684, PMID: 16236738).

In the most recent results from the NCCTG 9831 trial, disease-free survival (DFS) with 50% of planned events (recurrences) were analyzed for the 1,903 patients in arms “B” (sequential) and “C” (concurrent). Median follow-up was 5.3 years. There was a 4.4% reduction in the likelihood of recurrence favoring arm C (concurrent trastuzumab with paclitaxel) compared with arm B (sequential use of trastuzumab after chemotherapy; HR, 0.77; logrank P=0.0190). Given that the

than paclitaxel alone.

The SOLTI trial of capecitabine plus sorafenib reported by Baselga et al, demonstrated an improvement in the primary end point of PFS (6.4 vs. 4.1 months; P=0.006), but this combination of dose and schedule led to a 45% rate of grade 3 hand–foot syndrome (Figure 4). In this study, patients received capecitabine 1,000 mg/m2 for 14 of every 21 days and sorafenib 400 mg twice daily continuously or the same dose and schedule of capecitabine plus placebo.

The dose of capecitabine in this trial is lower than the approved dose of 1,250 mg/m2.

Although promise is demonstrated for sorafenibbased chemotherapy combinations based on these studies, additional study is needed to maximize efficacy and reduce toxicity.

Exemestane Versus Tamoxifen An update of the TEAM trial at a median follow-up of five years demonstrated a similar disease-free survival between five years of up-front exemestane (Aromasin, Pfizer) and tamoxifen followed by exemestane (total of five years), according to Rea et al (abstract 11). These data suggest that a sequencing strategy that includes both an aromatase inhibitor (AI) and tamoxifen may be a reasonable alternative to five years of an AI alone.

This study supports sequencing of these therapies for patients experiencing intolerable side effects or poor compliance related to cost.

The trial demonstrated superior outcomes for patients with HER2-positive early-stage breast cancer receiving concurrent (with paclitaxel) and sequential trastuzumab over the arm in which patients received trastuzumab only sequentially, after the completion of chemotherapy.

NSABP B-31 trial also employed concurrent use of trastuzumab plus paclitaxel, Dr. Perez showed the combined results of arm C with the NSABP experimental group, compared with both non–trastuzumab-containing arms (i.e., AC-T alone)—with three-year median follow-up, there was a 52% reduction in the annual odds of recurrence with the concurrent approach compared with not using trastuzumab (HR, 0.48; 95% CI, 0.41-0.57; P<0.00001). There was a 35% reduction in death as well (HR, 0.65; 95% CI, 0.51-0.84; P=0.0007).

Previous trials of weekly paclitaxel plus trastuzumab in HER2-positive MBC provided a foundation of data on the efficacy and cardiac safety of this approach from Seidman et al (J Clin Oncol 2001;19:2587-2595, PMID: 11352950, and J Clin Oncol 2008;26:1642-1649, PMID: 18375893). Indeed, despite temporary closure of accrual to arm C during the course of this trial, the incidence of significant cardiac events was 2.8% in arm B and 3.3% in arm C. The risk–benefit analysis, according to Dr. Perez, clearly favors the concurrent use of paclitaxel plus trastuzumab. Notably, this approach is being explored in an iteration of the current ALTTO trial. This trial is testing four treatment options: trastuzumab alone for 52 weeks; lapatinib alone for 52 weeks; trastuzumab for 12 weeks, followed by a six-week break, then lapatinib for 34 weeks; or lapatinib in combination with trastuzumab for 52 weeks.

Denosumab Bests Zoledronic Acid Results from a double-blind, randomized Phase III trial comparing denosumab (Prolia, Amgen) to zoledronic acid (Zometa, Novartis) for the prevention of skeletal-related events (SREs) in MBC reveal that denosumab is superior. It is anticipated that the results of this trial presented by Stopeck et al (abstract 22), when mature, will support an FDA application for drug approval for denosumab.

This large trial randomized 2,046 patients with MBC to receive either the RANK-ligand monoclonal antibody denosumab 120 mg subcutaneously every four weeks (with IV placebo) or IV zoledronate 4 mg every four weeks (with subcutaneous placebo) in a double-blinded fashion. The primary end point was time to first SRE; 45% of patients still Fluorodeoxyglucose positron remain on study. emission tomography image There was an 18% reduction in SREs assodepicting bone metastases in a patient with inflammatory breast ciated with the use of denosumab (HR, 0.82; cancer.

P=0.01). The median time to first SRE was 26.5 months for zoledronic acid; it has not yet been reached for denosumab. There were no differences in DFS or OS, or in the incidence of osteonecrosis of the jaw (denosumab, 2.0%; zoledronic acid, 1.4%) between groups. Whereas there were fewer acute reactions with denosumab (fever, chills and bone pain), overall there was no difference in the frequency of adverse events, serious or not, between groups.

BCIRG 006 Update The BCIRG 006 update provided by Slamon et al (abstract 62) was the third report for this still-unpublished important trial examining the use of trastuzumab with doxorubicin/cyclophosphamide and docetaxel [Taxotere, Sanofi-Aventis] (AC-DH) versus docetaxel/carboplatin (DCH) versus doxorubicin/cyclophosphamide and docetaxel alone. It represents a planned analysis after 650 events. The main results have not changed: Both trastuzumab-containing arms are significantly superior to the non–trastuzumab-containing arm in terms of both DFS and OS. The two arms are not statistically significantly different from each other with respect to these end points. One case of secondary acute leukemia was noted in each trastuzumab-containing arm. There were numerically more instances of congestive heart failure with AC-DH compared with DCH (21 vs. seven patients).

There were also numerically more deaths from breast cancer for patients on DCH compared with AC-DH. Indeed, the difference in the number of deaths attributable to MBC was greater for patients receiving DCH than for AC-DH, and this difference exceeded the difference in significant cardiac events, which are rarely fatal.

17

CLINICAL TRIALS

CLINICAL ONCOLOGY NEWS • FEBRUARY 2010

New Phase II and III Clinical Trials

Hematologic Malignancies

Solid Tumors

Trials added to the National Cancer Institute’s list of clinical trials in the 30 days prior to January 21, 2010. For eligibility criteria and additional information, visit www.cancer.gov/clinicaltrials, click on the advanced link and enter the protocol ID.

Supportive

18

Protocol Type

Age

Protocol ID

Trial Sites

Effects of Selected Vegetable and Herb Mix (SV) on Advanced Non-Small Cell Lung Cancer (NSCLC), Phase III

18 and over

SV-001

NY

Erlotinib and Chemotherapy for Patients With Stage IB-IIIA NSCLC With EGFR Mutations (ECON), Phase II

18 and over

07-103

NY

Study of Dichloroacetate in Patients With Previously Treated Metastatic Breast Cancer (MBC) or NSCLC, Phase II

18 and over

DCA Breast NSCLC

CA

Multi-Media Imagery Program for Breast Cancer Patients, Phase II

18 and over

MMR-117597

WA

Study of EZN-2208 in Patients With MBC, Phase II

18 and over

EZN-2208-03

AZ, CO, FL, IN, MN, MO, NC, NV, NY, OR, PA, SC, TX, VA

A Study of YM155 Plus Docetaxel in Subjects With HER2-Negative MBC, Phase II

18 and over

155-CL-36

OH

Trial of Amrubicin as Treatment for Patients With HER2-Negative MBC, Phase I/II

18 and over

SCRI BRE 161

FL, TX

Temozolomide Plus Bevacizumab in Patients With Metastatic Melanoma Involving the Central Nervous System, Phase II

18 to 90

MEL0107

FL

Clinical Trial of Purified Isoflavones in Prostate Cancer: Comparing Safety, Effectiveness, Phase II

30 to 80

MCC-15835

FL

CyberKnife Radiosurgery for Localized Prostatic Carcinoma, Phase II

18 and over

Virtual HDR CK Radiosurgery

CA

Ketoconazole and Dexamethasone in Prostate Cancer, Phase II

18 and over

CC # 09553

CA

Docetaxel, Androgen Deprivation and Proton Therapy for High-Risk Prostate Cancer, Phase II

18 and over

UFPTI 0703 - PR05

FL

A Study to Compare Tivozanib (AV-951) to Sorafenib in Subjects With Advanced Renal Cell Carcinoma, Phase III

18 and over

AV-951-09-301

FL

Interleukin-2, Aldesleukin and Entinostat for Kidney Cancer, Phase I/II

18 and over

RPCI I 145208

NY

PD 0332991 in Treating Patients With Refractory Solid Tumors, Phase II

18 and over

UPCC 03909

PA

Study of RAD001 in Soft Tissue Extremity and/or Retroperitoneal Sarcomas, Phase II

18 and over

MCC-15962

FL

A Study Evaluating STA-9090 in Patients With Metastatic and/or Unresectable Gastrointestinal Stromal Tumor, Phase II

18 and over

9090-05

MA

Trial of Sorafenib in Combination With Capecitabine for the Treatment of Patients With Measurable Hepatocellular Carcinoma, Phase II

18 and over

INST 0820

NM

A Trial Exploring the Efficacy of EMD 1201081 in Combination With Cetuximab in Second-Line Cetuximab-Naïve Subjects With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck, Phase II

18 and over

EMR 200068-006

IL, KY, MA, NY, PA

Capecitabine and Lapatinib Ditosylate in Treating Patients With Squamous Cell Cancer of the Head and Neck, Phase II

18 and over

UPCC 15309

PA

A Single-Arm Study Evaluating Carboplatin/Gemcitabine in Combination With BSI-201 in Patients With Platinum-Sensitive Recurrent Ovarian Cancer, Phase II

18 and over

20090207 and 20090208

MA

Radiation Therapy Sandwiched Between Paclitaxel and Carboplatin in Patients With High-risk Endometrial Cancer, Phase II

18 and over

MMC-08-03-060

NY

Multi-Media Imagery Program for Breast Cancer Patients, Phase II

18 and over

MMR-117597

WA

Mature B-Cell Lymphoma And Leukemia Study, Phase III

0 to 21

SJBC3

TN

Lenalidomide And Rituximab as Maintenance Therapy in Treating Patients With B-Cell Non-Hodgkin Lymphoma, Phase I/II

18 and over

CASE2409

OH

Lenalidomide as Maintenance Therapy After Combination Chemotherapy With or Without Rituximab and Stem Cell Transplant in Treating Patients With Persistent or Recurrent Non-Hodgkin Lymphoma That is Resistant to Chemotherapy, Phase I/II

19 and over

446-08

NE

5-Azacytidine With Lenalidomide in Patients With High-Risk Myelodysplastic Syndrome (MDS) and Acute Myelogenous Leukemia

Any age

2009-0467

TX

A Study of Withdrawal of Immunosuppression and Donor Lymphocyte Infusions Following Allogeneic Transplant for Pediatric Hematologic Malignancies, Phase II

6 months to 25 years

CC# 09082

CA

Study of 5-Fluoro-2-deoxycytidine With Tetrahydrouridine (FdCyd + THU) in Myeloid Leukemia and MDS, Phase II

18 and over

09045

CA

Rituximab in Preventing Acute Graft-Versus-Host Disease in Patients Undergoing a Donor Stem Cell Transplant for Hematologic Cancer, Phase II

19 to 75

083-09

NE

Curcumin for the Prevention of Radiation-induced Dermatitis in Breast Cancer Patients, Phase II

21 and over

URCC116

NY

Vitamin D3 and Early-Stage Prostate Cancer in Active Surveillance, Phase II

18 to 90

CTRF #P-06-068

SC

see CLINICAL TRIALS, page 25

APPROVED in combination with paclitaxel first line

First and only biologic for HER2-negative metastatic breast cancer Indication Avastin is indicated for the treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer in combination with paclitaxel.

The effectiveness of Avastin in metastatic breast cancer is based on an improvement in progression free survival. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin.

Avastin is not indicated for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease.

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

Avastin plus paclitaxel in first-line HER2-negative MBC*

Provide more time without progression Boxed WARNINGS and additional important safety information Gastrointestinal (GI) perforation: Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls. The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies. Discontinue Avastin in patients with GI perforation Surgery and wound healing complications: The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound dehiscence requiring medical intervention Hemorrhage: Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6%. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood). Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention) Additional serious and sometimes fatal adverse events for which the incidence was increased in the Avastin-treated arm vs control included non-GI fistula formation (≤0.3%), arterial thromboembolic events (grade ≥3, 2.4%), and proteinuria including nephrotic syndrome (<1%). Additional serious adverse events for which the incidence was increased in the Avastin-treated arm vs control included hypertension (grade 3–4, 5%–18%) and reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%). Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients The most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions Grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E2100 increased by 20.5% in the Avastin plus paclitaxel vs paclitaxel groups. Grade 1–2 adverse events were not collected in Study E2100, and common adverse events of Avastin in combination with paclitaxel for metastatic breast cancer are not known. The most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E2100, which occurred at a higher absolute incidence (≥5%) in the Avastin plus paclitaxel vs paclitaxel groups, were sensory neuropathy (24% vs 18%), hypertension (16% vs 1%), and fatigue (11% vs 5%). The rate of CHF (defined as NCI-CTC grade 3–4) in the Avastin plus paclitaxel arm was 2.2% vs 0.3% in the control arm. Among patients receiving anthracyclines, the rate of CHF was 3.8% for Avastin-treated patients and 0.6% for patients receiving paclitaxel alone. Fatal adverse reactions occurred in 1.7% (6/363) of patients who received Avastin plus paclitaxel in Study E2100. Causes of death were GI perforation (2), myocardial infarction (2), and diarrhea/abdominal pain/weakness/hypotension (2) References: 1. Avastin Prescribing Information. Genentech, Inc. July 2009. 2. Data on file. Genentech, Inc. 3. Kirkwood BR, Sterne JAC. Essential Medical Statistics. 2nd ed. Malden, MA: Blackwell Science Ltd; 2003.

©2009 Genentech USA, Inc.

All rights reserved.

9046202

Printed in USA.

(10/09)

Significant PFS† benefit achieved Avastin is indicated for the treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer in combination with paclitaxel. The effectiveness of Avastin in metastatic breast cancer is based on an improvement in progression free survival. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. Avastin is not indicated for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease.

Median PFS1,2

Percentage Progression Free

100

11.3 vs 5.8 mo risk 52% Reduced of progression

80

(HR=0.48, P<0.0001)

60

Avastin + paclitaxel (n=368)

40

Paclitaxel (n=354)

20

0

6

12

18

24

30

36

Progression-free Survival (Months) *MBC=metastatic breast cancer. † Primary analysis of progression-free survival (PFS) was based on the retrospective blinded review of tumor data by an independent review facility.2

PFS nearly doubled vs paclitaxel alone —11.3 vs 5.8 months (HR=0.48, P<0.0001) (95% CI: 10.5, 13.3 vs 5.4, 8.2)1 On average during study follow-up, there was a 52% reduction in the risk of disease progression (HR=0.48, P<0.0001)1,3

Important treatment considerations—Dose modifications Discontinue Avastin in patients with GI perforations (GI perforations, fistula formation in the GI tract, intra-abdominal abscess), fistula formation involving an internal organ, wound dehiscence and wound healing complications requiring medical intervention, serious hemorrhage (ie, requiring medical intervention), severe ATE, hypertensive crisis or hypertensive encephalopathy, RPLS (symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae), and nephrotic syndrome. Temporarily suspend Avastin for at least 4 weeks prior to elective surgery, severe hypertension not controlled with medical management, moderate to severe proteinuria pending further evaluation, and severe infusion reactions. The safety of resumption of Avastin therapy in patients that experienced RPLS, ATE, and moderate to severe proteinuria is unknown.

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

www.avastin.com

AVASTIN® (bevacizumab) Solution for intravenous infusion Initial U.S. Approval: 2004 WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE Gastrointestinal Perforations The incidence of gastrointestinal perforation, some fatal, in Avastin-treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).]

Surgery and Wound Healing Complications The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), and Adverse Reactions (6.1).]

Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), and Adverse Reactions (6.1).]

1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.

1.2 Non-Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

1.3 Metastatic Breast Cancer (MBC) Avastin is indicated for the treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer in combination with paclitaxel.

The effectiveness of Avastin in MBC is based on an improvement in progression free survival. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. [See Clinical Studies (14.3).]

Avastin is not indicated for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease.

1.4 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease following prior therapy as a single agent.

The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. [See Clinical Studies (14.4).]

1.5 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).]

The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra-abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin.

Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).]

5.2 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).]

Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention.

The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half-life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).]

5.3 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%. [See Adverse Reactions (6.1).]

Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non-squamous non-small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone.

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin-treated patients (rate 1.2%, 95% CI 0.06%–5.93%).

Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage.

Do not administer Avastin to patients with recent history of hemoptysis of ≥1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).]

5.4 Non-Gastrointestinal Fistula Formation Serious and sometimes fatal non-gastrointestinal fistula formation involving tracheo-esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin-treated patients compared to controls. The incidence of non-gastrointestinal perforation was ≤0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy.

Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).]

5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.4% compared to 0.7% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, or age greater than 65 years. [See Use in Specific Populations (8.5).]

The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).]

5.6 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5-18%.

Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti-hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin-induced or -exacerbated hypertension after discontinuation of Avastin.

Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).]

5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of <0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days,although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).]

5.8 Proteinuria The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy.

Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy.

Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24-hour urine collection.

Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is <2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57).

[See Use in Specific Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).]

5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post-marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients.

Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).]

hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis.

Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).]

[See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

[See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

[See Dosage and Administration (2.4), Warnings and Precautions (5.4).]

[See Dosage and Administration (2.4), Warnings and Precautions (5.5).]

[See Dosage and Administration (2.4), Warnings and Precautions (5.6).]

[See Dosage and Administration (2.4), Warnings and Precautions (5.7).]

[See Dosage and Administration (2.4), Warnings and Precautions (5.8).]

The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal

6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data below reflect exposure to Avastin in 2661 patients with mCRC, non-squamous NSCLC, MBC, glioblastoma, or mRCC in controlled (Studies 1, 2, 4, 5, 6 and 9) or uncontrolled, single arm (Study 7) trials treated at the recommended dose and schedule for a median of 8 to 16 doses of Avastin.

[See Clinical Studies (14).] The population was aged 21-88 years (median 59), 46.0% male and 84.1% white.The population included 1089 first- and second-line mCRC patients who received a median of 11 doses of Avastin, 480 first-line metastatic NSCLC patients who received a median of 8 doses of Avastin, 592 MBC patients who had not received chemotherapy for metastatic disease received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin.

Surgery and Wound Healing Complications The incidence of post-operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy.Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding In Study 7, events of post-operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with and resolved without medical intervention. Grade 1 or 2 hemorrhagic gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

Venous Thromboembolic Events The incidence of Grade 3–4 venous thromboembolic events was higher in patients with mCRC or NSCLC receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone. The risk of developing a second subsequent thromboembolic event in mCRC patients receiving Avastin and chemotherapy was increased compared to patients receiving chemotherapy following a venous thromboembolic event. Among these patients, an additional The overall incidence of Grade 3–4 venous thromboembolic events in following Grade 3–4 venous thromboembolic events was higher in intra-abdominal venous thrombosis (10 vs. 5 patients).

Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients Study 4, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)].

In Study 7, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3-5 infection was 10%.

Proteinuria Grade 3-4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4 and 9. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 9, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 9). [See Warnings and Precautions (5.8).]

Congestive Heart Failure The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied.

Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double-blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks.

All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life-threatening (Grade 3–4) adverse events, which occurred at a higher incidence (≥ 2%) in patients receiving presented in Table 1.

SOLID TUMORS Breast

Alcohol Ups Breast Cancer Recurrence Risk AVASTIN® (bevacizumab) Table 1 NCI-CTC Grade 3−4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 2%] Avastin vs. Control)

NCI-CTC Grade 3-4 Events Asthenia Abdominal Pain Pain Cardiovascular Hypertension Deep Vein Thrombosis Intra-Abdominal Thrombosis Syncope Digestive Diarrhea Constipation Hemic/Lymphatic Leukopenia Neutropeniaa a

Arm 1

Arm 2

(n = 396) 74%

(n = 392) 87%

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

37% 21%

Central laboratories were collected on Days 1 and 21 of each cycle.

Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.

Grade 1–4 adverse events which occurred at a higher incidence (≥ 5%) in placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who Table 2 NCI-CTC Grade 1-4 Adverse Events in Study 1 Arm 1

Arm 2

Arm 3

(n = 98)

(n = 102)

(n = 109)

55% 55% 19%

61% 61% 26%

62% 50% 26%

14% 7% 3%

23% 15% 9%

34% 7% 6%

47% 30% 29% 18% 15% 6%

52% 43% 40% 32% 24% 24%

47% 35% 29% 30% 17% 19%

2% 1%

7% 6%

4% 1%

Pain Abdominal Pain Headache Cardiovascular Hypertension Hypotension Deep Vein Thrombosis Digestive Vomiting Anorexia Constipation Stomatitis Dyspepsia GI Hemorrhage Dry Mouth Colitis Hemic/Lymphatic Thrombocytopenia Nervous Dizziness Respiratory Upper Respiratory Infection Epistaxis Dyspnea Voice Alteration Skin/Appendages Alopecia Skin Ulcer Special Senses Taste Disorder Urogenital Proteinuria

0%

5%

5%

20%

26%

19%

39% 10% 15% 2%

47% 35% 26% 9%

40% 32% 25% 6%

26% 1%

32% 6%

6% 6%

9%

14%

21%

24%

36%

36%

Avastin in Combination with FOLFOX4 in Second-line mCRC Only Grade 3-5 non-hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events) occurring at 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under-estimate the true adverse event rates due to the reporting mechanisms used in Study 2.

Unresectable Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Only Grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events were collected in Study 4. Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/ pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%).

Metastatic Breast Cancer (MBC) Only Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events were collected in Study 5. Grade 3–4 adverse events occurring at a higher incidence (≥2%) in 363 patients receiving paclitaxel plus Avastin compared with 348 patients receiving paclitaxel alone were sensory neuropathy (24% vs. 18%), hypertension (16% vs. 1%), fatigue (11% vs. 5%), infection without neutropenia (9% vs. 5%), neutrophils (6% vs.

3%), vomiting (6% vs. 2%), diarrhea (5% vs. 1%), bone pain (4% vs. 2%), headache (4% vs. 1%), nausea (4% vs. 1%), cerebrovascular ischemia (3% vs. 0%), dehydration (3% vs. 1%), infection with unknown ANC (3% vs. 0.3%), rash/desquamation (3% vs.

0.3%) and proteinuria (3% vs. 0%).

Sensory neuropathy,hypertension,and fatigue were reported at a ≥ 5% higher absolute incidence in the paclitaxel plus Avastin arm compared with the paclitaxel alone arm. plus Avastin. Causes of death were gastrointestinal perforation (2), myocardial infarction (2), diarrhea/abdominal, and pain/weakness/hypotension (2).

Avastin is not approved for use in combination with capecitabine or for use in second or third line treatment of MBC.The data below are presented to provide information on the overall safety profile of Avastin in women with breast cancer since Study 6 is the only randomized, controlled study in which all adverse events were collected for all

AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

patients. All patients in Study 6 received prior anthracycline and taxane therapy in the adjuvant setting or for metastatic disease.Grade 1– 4 events which occurred at a higher incidence (≥5%) in patients receiving capecitabine plus Avastin compared to the capecitabine alone arm are presented in Table 3.

Table 3 NCI-CTC Grade 1−4 Adverse Events in Study 6 (Occurring at Higher Incidence [≥5%] in Capecitabine + Avastin vs. Capecitabine Alone)

may be influenced by several factors, including sample handling, timing of

Asthenia Headache Pain Cardiovascular Hypertension Digestive Stomatitis Metabolic/Nutrition Musculoskeletal Myalgia Respiratory Dyspnea Epistaxis Skin/Appendages Exfoliative dermatitis Urogenital Albuminuria

Capecitabine (n = 215)

Capecitabine + Avastin (n = 229)

47% 13% 25%

57% 33% 31%

2%

24%

19%

25%

8%

14%

18% 1%

27% 16%

75%

84%

7%

22%

Glioblastoma All adverse events were collected in 163 patients enrolled in Study 7 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan.Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone.

In patients receiving Avastin alone (N=84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%).Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection.

In patients receiving Avastin alone or Avastin plus irinotecan (N=163), the incidence of Avastin-related adverse events (Grade 1–4) were bleeding/ hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound-healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%).The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound-healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%).

Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 9. Grade 3–5 adverse events occurring at a higher incidence (≥ 2%) in 337 patients receiving α) plus Avastin compared to 304 patients receiving α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma).

Grade 1–5 adverse events occurring at a higher incidence (≥ 5%) in patients receiving α α plus placebo arm are presented in Table 4.

Table 4 NCI-CTC Grades 1−5 Adverse Events in Study 9 α α + Placebo) Preferred term* Gastrointestinal disorders Diarrhea General disorders and administration site conditions

α (n = 304) 16%

α + Avastin (n = 337)

7 DRUG INTERACTIONS A drug interaction study was performed in which irinotecan was results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38.

In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin.

However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0.

In Study 9, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no studies of bevacizumab in pregnant women. Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab resulted in teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).]

Human IgG is known to cross the placental barrier; therefore, bevacizumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Because of the observed teratogenic effects of known inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus.

8.3 Nursing Mothers It is not known whether Avastin is secreted in human milk, but human IgG is excreted in human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half-life of the bevacizumab (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).]

8.4 Pediatric Use The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established.

Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose-related and were partially reversible upon cessation of treatment.

8.5 Geriatric Use In Study 1, severe adverse events that occurred at a higher incidence (≥ 2%) in patients aged ≥65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure,diarrhea,constipation,anorexia,leukopenia,anemia,dehydration,hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients.

21%

Investigations Metabolism and nutrition disorders Anorexia Musculoskeletal and connective tissue disorders Myalgia Back pain Nervous system disorders Headache Renal and urinary disorders Proteinuria Respiratory, thoracic and mediastinal disorders Epistaxis Dysphonia Vascular disorders Hypertension

reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading.

6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Avastin. 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.

Body as a Whole: Polyserositis Cardiovascular: Pulmonary hypertension, RPLS Digestive: Intestinal necrosis, mesenteric venous occlusion, anastomotic ulceration Hemic and lymphatic: Pancytopenia Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia

31%

36%

14% 6%

19% 12%

16%

24%

3%

20%

4% 0%

27% 5%

9%

28%

*Adverse events were encoded using MedDRA, Version 10.1.

The following adverse events were reported at a 5-fold greater incidence in the α α alone and not represented in Table 4: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1).

6.2 Immunogenicity As with all therapeutic proteins,there is a potential for immunogenicity.The incidence of antibody development in patients receiving Avastin has not been adequately determined because the assay sensitivity was inadequate to reliably detect lower titers. Enzyme-linked immunosorbent assays (ELISAs) were performed on sera from approximately 500 patients treated with Avastin, primarily in combination with chemotherapy. High titer human anti-Avastin antibodies were not detected.

Immunogenicity data are highly dependent on the sensitivity and specificity of the assay.Additionally,the observed incidence of antibody positivity in an assay

greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue.

In Study 4, patients aged ≥ 65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).]

In Study 5, there were insufficient numbers of patients ≥ 65 years old to determine whether the overall adverse events profile was different in the elderly as compared with younger patients.

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

In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥65 years and 1127 patients <65 years of age.The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years (8.5% vs.

2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).]

10 OVERDOSAGE The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

Manufactured by: Genentech, Inc. 94080-4990

7453214 4835706 © 2009 Genentech, Inc

M

oderate to heavy consumption of alcoholic beverages (at least three to four drinks per week) is associated with a 34% increase in the risk for breast cancer recurrence, according to a study presented at the San Antonio Breast Cancer Symposium (abstract 17). Increased risk was greater among women who were postmenopausal, had estrogen receptornegative tumors or were overweight.

“Women previously diagnosed with breast cancer should consider limiting their consumption of alcohol to less than three drinks per week,” said Marilyn L. Kwan, PhD, staff scientist in the Division of Research at Kaiser Permanente, Oakland, Calif., who presented the study.

Previous studies have shown that consumption of alcohol is associated with an increased risk for breast cancer, but few studies have examined its role in breast cancer survival. To remedy this, investigators examined the impact of alcohol on breast cancer recurrence and mortality in the LACE (Life After Cancer Epidemiology) study. LACE is a prospective cohort study of 1,897 breast cancer survivors diagnosed with early-stage invasive breast cancer between 1997 and 2000. The researchers recruited participants from the Kaiser Permanente Northern California Cancer Registry. Wine, beer and liquor consumption was documented via questionnaire. Participants provided information on health outcomes, including recurrence of breast cancer, which was then verified by their medical records.

After eight years of follow-up, there were 349 breast cancer recurrences and 332 deaths. Compared with little (no more than 0.5 g/d) or no alcohol consumption, consuming at least 6 g per day was associated with an increased risk for recurrence (hazard ratio [HR], 1.34; 95% confidence interval [CI], 1.00-1.82).

Among drinkers (50% of the study population), wine was the most popular choice of alcohol (90%), followed by liquor (43%) and beer (36%). Risk for overall death also was increased among moderate and heavy drinkers (HR, 1.51; 95% CI, 1.00-2.28) compared with nondrinkers.

Researchers not involved in the study urged caution in drawing conclusions.

“Although this was a large prospective cohort study, the conclusions from this epidemiologic study may be confounded by the other activities that these women may have participated in. In this study, compared to nondrinkers, women who drank alcohol were younger, predominantly white, had more education, were of normal weight and were more likely to be former or current smokers.

These and other confounding factors may have impacted these results,” said Maura Dickler, MD, an attending physician in the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center.

“Although these kinds of studies try to control for these factors, it is impossible to control for all of them. Therefore, we are careful to counsel women that these results are not conclusive, but moderation in everything is important.”

23

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • FEBRUARY 2010

Breast

SECOND LINE continued from page 1

Dr. Brufsky discussed the results from the RIBBON-2 trial at the recent San Antonio Breast Cancer Symposium (SABCS; abstract 42). Currently, subsequent chemotherapy or hormone therapy is the only FDA-approved option for second-line treatment of advanced human epidermal growth factor receptor 2 (HER2)-negative breast cancer.

Study Details RIBBON-2 included 684 women with MBC that progressed on first-line chemotherapy. Women were randomized 2:1 to receive either chemotherapy plus bevacizumab or chemotherapy alone and were treated until disease progression. Women received chemotherapy of the investigators’ choice—44% received a taxane, 23% received gemcitabine (Gemzar, Eli Lilly), 21% received capecitabine (Xeloda, Roche) and 12% received vinorelbine.

Treatment arms were well balanced for demographic and disease characteristics. Median age was 55 years. A slight imbalance was observed for patients with triple-negative breast cancer (estrogen receptor-negative, progesterone receptor-negative, and HER2-negative): 20% in the chemotherapy arm and 24% in the bevacizumab-containing arm.

For the primary end point of PFS, the addition of bevacizumab achieved a highly statistically significant 22% improvement (P=0.0072) from a median of 5.1 months with chemotherapy alone to 7.2 months with the addition of bevacizumab (Figure).

An exploratory analysis that looked at PFS results according to type of chemotherapy received suggested that the choice of chemotherapy matters.

“As a class, there was a benefit with taxanes and with capecitabine. Patients on gemcitabine or vinorelbine did not appear to benefit from the addition of bevacizumab. But this was a preliminary analysis in very small numbers of patients,” Dr. Brufsky said.

Response rates were also much higher with the addition of bevacizumab. Overall response rates were 39.5% with the combination therapy versus 29.6% with chemotherapy alone. No difference in overall survival was seen in this interim analysis. Only 57% of the patients have died.

Colon Cancer Awareness Month

M

arch is National Colorectal Cancer Awareness Month. Are you looking for educational materials to provide to your patients or do you want to get involved?

Materials on colon cancer can be found at www.preventcancer.org/ or the Web site of the Colon Cancer Alliance (CCA), www.ccalliance. org/news_events_dress-in-blue.html. The CCA once again is involved in the Dress in Blue Campaign, which has been held annually since 2006.

Chemotherapy Chemotherapy plus bevacizumab

‘These results are clinically meaningful. We have few options for second-line chemotherapy in metastatic disease.’

—Adam Brufsky, MD

“A difference in overall survival may emerge with longer follow-up,” Dr. Brufsky said. “We now know that bevacizumab is clearly beneficial as first-line and as second-line therapy. We are interested in a study of continuous bevacizumab in metastatic breast cancer, the so-called RIBBON-3 trial.”

Toxicity with bevacizumab was consistent with previous experience in MBC and other tumor types.

No new toxicity signals emerged.

Dissecting the Data Edith Perez, MD, director of the Breast Cancer Program at Mayo Clinic in Jacksonville, Fla., who was not involved with the study, said that a previous study in second-line therapy of MBC showed no benefit for the addition of bevacizumab to capecitabine.

“It is an important finding that bevacizumab plus several options of chemotherapy improved PFS in patients who did not get it as first-line,” Dr. Perez commented. She said that bevacizumab plus chemotherapy should be considered for patients with metastatic breast cancer who did not get the drug first-line.

8 6

Months

24

P=0.0072

7.2

5.1

4 2 0

Figure. Comparison of progression-free survival.

in PFS for the addition of bevacizumab to capecitabine in women with advanced breast cancer that had progressed on an anthracycline and a taxane (J Clin Oncol 2005;23:792-795, PMID: 15681523). Secondly, none of the trials to date with bevacizumab plus chemotherapy in breast cancer has demonstrated significant improvements in overall survival. These issues, coupled with the difficult-to-manage side effects of hypertension and blood clots, raise concern that the addition of bevacizumab may provide only modest, transient benefits for patients with metastatic breast cancer, Dr. Michaud suggested.

“Further, recent preclinical data indicate that tumors

‘Recent preclinical data indicate that tumors relapsing while on antiangiogenic therapies appear to be more invasive, which may be one reason why the addition of bevacizumab has not had a positive effect on [overall] survival.’

—Laura Boehnke Michaud, PharmD, BCOP, FASHP

When asked whether the cost of bevacizumab was worth an extra 2.1 months of PFS, Dr. Brufsky acknowledged that cost is an issue. “When we compare trial results, 2.1 months is a mean. There are patients who do much better at one end of the curve.

We want to identify characteristics that predict better response,” he commented.

Maura Dickler, MD, attending physician in the Breast Cancer Medicine Service at Memorial SloanKettering Cancer Center, New York City, pointed out that the updated AVADO study also presented at SABCS showed that the addition of bevacizumab to docetaxel as first-line therapy in patients with MBC improved PFS and overall response rate, but at 25 months, no difference in overall survival was seen.

She agreed with Dr. Perez’s conclusion. “Based on results from these two studies, clinicians may consider bevacizumab in combination with their choice of chemotherapy for patients with metastatic breast cancer in either the first-line or second-line setting,” Dr. Dickler said.

Laura Boehnke Michaud, PharmD, BCOP, FASHP, manager of clinical pharmacy services at M.D. Anderson Cancer Center in Houston, said the results of RIBBON-2 “confuse the picture” of how to manage patients with advanced cancer and MBC. A previous large randomized Phase 3 trial found no advantage

relapsing while on antiangiogenic therapies appear to be more invasive, which may be one reason why the addition of bevacizumab has not had a positive effect on [overall] survival. These data, of course, need to be confirmed in clinical trials, but bring to light significant concerns with this agent,” she said.

“Everyone is grappling with how to apply results of RIBBON-2 and to decide what is in the best interest of patients,” Dr. Michaud added. “My concern is about giving a clearly toxic drug to potentially compromised patients that does not extend survival. The drug is going to be studied as maintenance therapy in this population, which is also of concern, but should be systematically studied.”

Dr. Michaud also stated that the decision to add bevacizumab should be individualized and discussed fully with each appropriate patient, including mention of all the concerns she cited.

The bottom line is that bevacizumab has difficultto-manage toxicities, does not prolong overall survival and is also expensive. Dr. Michaud is not convinced that this drug should be used second-line, as in the RIBBON-2 trial. “However, each patient should be presented with the available information and given the opportunity to decline or accept the therapy.”

—Alice Goodman

CLINICAL TRIALS

CLINICAL ONCOLOGY NEWS • FEBRUARY 2010

Supportive Care

Continued from page 18

Protocol Type

Age

Protocol ID

Trial Sites

NicVAX/Placebo as an Aid for Smoking Cessation, Phase III

18 to 65

Nabi-4514

CA, FL, ID, KY, MA, MD, NC, NY, OR, VA, WA

Contingency Management and Pharmacotherapy for Smoking Cessation, Phase II

18 and over

08-035-3

CT

Behavioral Exercise Intervention for Smoking Cessation, Phase II

18 to 65

0603-01

RI

Do Treatments for Smoking Cessation Affect Alcohol Drinking? Study 2: Do Varenicline (Chantix) and Bupropion (Zyban) Change Alcohol Drinking? Phase II

21 and over

HIC0702002391

CT

Varenicline for Smoking Cessation in Heavy Drinking Smokers, Phase II

18 to 75

NIAAA-O’MalleyP50AA15632-2009

CT

D-Cycloserine

18 to 65

1728

MA

Enhancement of Exposure-Based CBT for Smoking Cessation

ECO MOVEMENT continued from page 13

Given the premium on most “green” consumer products, ecologically friendly hospitals might seem to cost more to build than conventional facilities. But that’s not necessarily the case.

Alan R. Bell, director of design and construction for Seton Network Facilities, said the 500,000-sq ft Dell cost $130 million, or $260 per square foot.

In current dollars, the project would cost $318 per square foot—well within the range of what hospital buildings now cost without environmentally kind details. “I’ve talked to some of my contractor friends, and they said that for a ‘normal’ hospital, right now, it would be between $310 and $325 per square foot,” Mr. Bell said.

The last three years have seen a monumental shift toward construction vendors and suppliers with green products, he added. This, in turn, has driven down the cost of many products. “It gives them a competitive advantage,” he said. “If you can get green carpet or a regular carpet, and they’re the same cost, you’ll get green carpet.”

Culturing Change Increasing access to daylight is not the only thing that hospitals are doing to reduce their energy consumption and lighten their ecological tread (see page 27). Steps can be taken to reduce waste by adopting reusable products or even starting a composting program. Some hospital landscaping incorporates fruit trees and vegetable gardens to produce natural foods for their cafeterias. Mr. Shinn cited a hospital in Florida that captures condensate from its air conditioning system to be used in its cooling tower.

But challenges remain.

“We knew this was about market transformation, about culture change,” Mr. Smith explained. “Before sustainable design came along, before the Green Guide, before anything, it was just ‘this is the way we do business.’ To change see ECO MOVEMENT, page 27

25

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • FEBRUARY 2010

CML Imatinib

Nilotinib 300 mg bid

Nilotinib 400 mg bid

35

NILOTINIB continued from page 7

31

31

in the two nilotinib arms (Figure).

Edema and weight gain were also more common in the imatinib arm, although overall rates were low. The most common type of edema was peripheral (any grade), reported in 14% of patients taking imatinib and 5% taking either dose of nilotinib. Grade 3 and 4 laboratory abnormalities were also observed at a low frequency overall. Although grade 3 or 4 total bilirubin elevations were more common with nilotinib than imatinib (4% and 8% vs. <1%) and lipase abnormalities were more common with nilotinib (6% in either arm vs. 3% with imatinib), there was one discontinuation for nilotinib and one for imatinib due to pancreatitis. No clinically significant QTc abnormalities were observed in any group.

Nearly 30% of the patients enrolled in this study were in a high Sokal risk classification, with the remaining patients relatively evenly divided between low and intermediate risks. When rates of MMR were stratified by Sokal risk, nilotinib was consistently more effective in all risk groups. Regardless of therapy, the study supported other evidence that patients with a better response, characterized by CCyR, are less likely to progress in CML. The researchers said the greater efficacy of nilotinib can be attributed to a greater specificity for the molecular target, producing a greater likelihood of an MMR. This response predicts protection from

% of Patients

26

30 26

24

25

21

20

21

20 14

14

15

12

11 7

10

8 6

9

8

7 5

0 Nausea

Muscle spasm

follow-up that continues to show meaningful clinical differences, such as risk for progression, beyond the surrogate end points,” Dr. Stone said. “These are strong findings that do predict nilotinib has the potential to emerge as the better first-line agent, but we are not there yet.”

Diarrhea

Vomiting

Rash

Headache

Figure. Comparison rates of nonhematologic side effects.

‘The story is complicated, and it is not clear that this study has generated the type of data that warrants an immediate change in practice.’

—Richard M. Stone, MD progression, which was more common for imatinib by the end of the study (4% vs. <1% for either nilotinib dose).

“We know that despite excellent results we can achieve with imatinib, progression can still occur in a small proportion of patients, and progression is associated with a poor outcome,” Dr. Saglio said. Based on these results, nilotinib further reduces the risk for progression relative to imatinib.

More Data Needed Asked to comment on the study, Richard M. Stone, MD, director of the Adult Leukemia Program at Dana-Farber Cancer Institute, in Boston, characterized the results as “encouraging,” but he

did not agree with the conclusion that the study establishes nilotinib as the new standard of care in CML. He noted that nilotinib has only demonstrated superiority on the surrogate markers of MMR and CCyR. Although the responses of both parameters likely predict a decreased risk for disease progression, patients who take somewhat longer to attain the desired end points may still do well. According to Dr. Stone, the decreased rate of progression to AP disease was the most compelling finding in favor of nilotinib over imatinib.

“The story is complicated, and it is not clear that this study has generated the type of data that warrants an immediate change in practice. We need longer

Hem/Onc Pharmacist Urges Caution Asked for his comment, Casey B. Williams, PharmD, hematology/oncology clinical coordinator and residency director, Kansas University Medical Center, Kansas City, concurred with Dr. Stone.

“I am also not convinced that this data warrants an immediate change in practice. We have at least eight years of follow-up information to go on with imatinib from the IRIS trial and the results have been quite impressive. Overall survival is approximately 85% with imatinib, and actually climbs to around 93% when only CML-related deaths and those prior to stem cell transplant are considered,” Dr. Williams reported.

From the pharmacy perspective, one variable of interest is price. Dr. Williams noted that nilotinib “is a lot more expensive than imatinib,” but these results may change pricing for both imatinib and nilotinib. Pricing strategies are particularly difficult to predict because the same pharmaceutical company, Novartis, markets both drugs. In any event, Dr. Williams characterized nilotinib as “a promising alternative to imatinib as a first-line agent,” but “I am not ready to change my practice just yet.”

—Ted Bosworth

Are Imatinib’s Days as the Drug of Choice for CML Over?

Richard Stone, MD Director of the Adult Leukemia Program Dana-Farber Cancer Institute Professor of Medicine, Harvard Medical School Boston, Massachusetts

A

late-breaking abstract (LBA1) that generated much interest at the recent American Society of Hematology (ASH) meeting was the presentation of the randomized up-front trial comparing nilotinib (Tasigna, Novartis) with imatinib (Gleevec, Novartis). The study provides evidence that nilotinib could replace imatinib as the drug of choice for CML. At the ASH annual meeting in 1999, also held in New Orleans, the world heard about the exciting results with the tyrosine kinase inhibitor imatinib in patients with CML. This drug seemed to be the first “magic bullet” in cancer: Virtually all patients with chronic-phase CML achieved hematologic remission. A subsequent critical study, the IRIS (International Randomized study

of Interferon versus ST1571) trial, randomized patients with newly diagnosed CML to either imatinib 400 mg per day or interferon/ara-C, which was the standard when IRIS was initiated. The striking and durable results in favor of imatinib have been updated at the last few ASH meetings, including at this year’s meeting. Studies show the agent has good tolerability relative to the control arm and results in a high cumulative rate of cytogenetic remissions (approximately 80%) and a low rate of progression to advanced-phase CML. This trial has led to the standard use of imatinib 400 mg per day in patients newly diagnosed with chronic-phase CML. It is difficult to imagine how better results could be achieved. Nonetheless, at least one-third of patients discontinue therapy with imatinib because of a lack of response, disease progression or toxicity. Two new, more potent BCR-ABL inhibitors—dasatinib (Sprycel, Bristol-Myers Squibb) and nilotinib (Tasigna, Novartis)—have been shown to be effective in patients with CML who

are intolerant or resistant to imatinib.

Given the ability of a drug like nilotinib to inhibit BCR-ABL potently and inhibit secondary imatinib-resistant mutations in BCR-ABL, it was thought that nilotinib might be superior in the up-front setting. Previously, several Phase II trials demonstrated a rapid reduction in the disease burden measured by quantitative polymerase chain reaction (qPCR) testing for the BCR-ABL fusion mRNA. The results presented by Saglio et al (LBA1) were from a study in which 846 patients with newly diagnosed CML were randomized to either 300-mg twice daily (bid) of nilotinib, 400-mg bid of nilotinib or the standard oncedaily 400 mg dose of imatinib. Nilotinib was at least as well tolerated as imatinib.

The primary end point of major molecular response (3 log reduction in BCRABL transcript by qPCR from baseline) at one year was reachable more often in those randomized to nilotinib (44% in the 300 mg arm and 43% in the 400 mg arm) compared with those randomized to imatinib (22%). One-year cytogenetic

responses also were more prominent in the nilotinib groups (79% vs. 65%). Perhaps the most striking finding was a small but significant reduction in the patients who progressed to advanced-phase CML during the first year. The latter finding was the only clear-cut clinical benefit that can be ascertained in the brief follow-up period of this study. Given these results, it becomes an open question as to whether patients newly diagnosed with CML could or should receive imatinib or whether practitioners should “switch” to nilotinib. The results of this trial must be considered preliminary and longer follow-up is needed before firm answers to this question can be rendered. But, this trial does suggest that a good prognosis for those diagnosed with chronic-phase CML may be getting even better in the future.

POLICY & MANAGEMENT

CLINICAL ONCOLOGY NEWS • FEBRUARY 2010

Sustainable Practices

Energy Diets Help Cut Waste

H

continued from page 25

In addition to reducing demand for resources, some hospitals have begun tackling the power problem from the other end of the plug: generation. The Veterans Affairs hospital in Ann Arbor, Mich., is one of a handful of facilities to mount a turbine on its roof in an effort to produce at least some of its annual energy needs, which amount to about 22 million kWh. Hospital administrators also plan to install solar panels to complement the 16-ft tall turbine, and to reap savings from more efficient air conditioning systems and other technologies.

A consortium of Pennsylvania hospitals recently announced that it would begin buying roughly onethird of its electricity directly from a major wind farm in Bucks County.

The deal could save the individual institutions millions of dollars over the coming decade.

the culture of a health care institution or to transform the way we design and deliver architecture, is huge.”

‘Fight It With Science’ Some hospitals, municipalities and patients have questions about the safety of sustainable design. One area where this has been true is infection control.

“There are the regulatory systems—it’s not only getting the hospital leadership on board, there is the local municipality

National Cancer Institute

ospitals are notorious consumers of energy, sucking power for heat, lights, hot water, laundry and other aspects of daily operation.

All that adds up to an average of 27.5 kWh of electricity, and another 110 cu ft of natural gas—or $3.71 per square foot in 2005 prices, according to the Healthcare Environmental Resource Center, an information clearinghouse. But energy diets can help. A 150,000-sq ft hospital that slashes its power use by 20% can save more than $111,000 per year on its energy bill.

ECO MOVEMENT

that will be impacted by their design decisions,” Ms. Dilwali said.

“You have to fight it with science,” Mr. Shinn suggested. “A doctor is a scientist, a nurse has scientific training.

If you can show them that a practice has no infection control compromises, then you have a chance.”

Advocates admit that the hospital that creates more energy than it uses, that creates more clean water than it pollutes, that heals the planet as well as people, and that is truly restorative remains a goal, not a reality. But work

on the new guide is moving forward: Volunteer committees are being formed to write the new toolkit. Clinicians are welcome to contact the Green Guide if they are interested in assisting.

Ms. Guenther added that clinicians can also change their own hospitals. “If you are an anesthesiologist and can’t stand the waste in your operating suite, join your hospital’s green team. If you don’t have one, create one.

You can make a difference.”

—David Jakubiak

Committed to Cancer Research

CCR Clinical Trials at NIH

A

re you looking for more options for your patients? NCI’s Center for Cancer Research (CCR) conducts more than 150 clinical trials at the National Institutes of Health (NIH) in Bethesda, Md. In the state-ofthe-art NIH Clinical Center, the latest innovations in medicine are put into practice every day.

CCR is currently conducting trials for many types of cancer including: • Prostate Cancer • Lung Cancer/Thymoma • Lymphoma • Pediatric Sarcoma • Kidney Cancer • Brain Cancer

To learn whether your patients may be eligible, visit

bethesdatrials.cancer.gov or call 1-888-NCI-1937 (1-888-624-1937)

27

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • FEBRUARY 2010

Multiple Myeloma

continued from page 1

Not least of their attributes, “these novel bortezomib-based schemes appear to overcome the poor prognosis of high-risk cytogenetics,” said MariaVictoria Mateos, MD, PhD, Hospital Universitario Salamanca, in Salamanca, Spain. Presenting the results at the annual meeting of the American Society of Hematology (ASH; abstract 3), Dr. Mateos said that survival data so far have been almost identical between highand low-risk patients. Importantly for a patient population in which the goal is to prolong survival rather than eradicate cancer, both the induction and maintenance regimens were well tolerated.

Previous data from a trial called VISTA (N Engl J Med 2008;359:906-917, PMID: 18753647) are credited with establishing VMP as the standard of care in patients with newly diagnosed MM who are ineligible for high-dose chemotherapy with curative intent.

In VISTA, the addition of bortezomib extended the time to progression (TTP) by almost eight months (P<0.001) compared with melphalan and prednisone (MP) alone. Many of the investigators who participated in the VISTA trial were also involved in the more recent study.

20

100 17

VTP VMP

15 11 10 5 0

Complete Response, %

NEW STANDARD

Pts Discontinuing Therapy, %

28

Patients receiving VT maintenance Patients receiving VP maintenance

80 60

59

55

40 20 0

Figure 1. Comparison of patients discontinuing therapy because of side effects.

Figure 2. Comparison of patients with MM achieving a CR or near CR.

VMP, bortezomib, melphalan and prednisone; VTP, bortezomib, thalidomide and prednisone

CR, complete response; MM, multiple myeloma; VP, bortezomib and prednisone; VT, bortezomib and thalidomide

‘These novel bortezomib-based schemes appear to overcome the poor prognosis of high-risk cytogenetics.’

—Maria-Victoria Mateos, MD, PhD

Complex Study In the somewhat more complex recent study, 260 patients over the age of 65 with newly diagnosed MM were randomized to VMP or to the same regimen with thalidomide substituted for melphalan (VTP). Both therapies were administered in six, six-week cycles.

Unlike the VISTA trial, in which patients received eight doses of bortezomib for the initial five of the nine-week cycles (and weekly thereafter), bortezomib was administered weekly after the first cycle in this study.

After completing the six cycles of treatment, patients were randomized a second time. They received maintenance therapy with either bortezomib and thalidomide (VT) or bortezomib and prednisone (VP).

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Thalidomide (50 mg) and prednisone (50 mg) were administered daily. The 1.3 mg/m2 dose of bortezomib, which was the same dose used in the induction regimen, was administered on days 1, 4, 8 and 11 of an every-three-month cycle. The maintenance regimen was continued for up to three years.

The primary objective of the induction portion, which compared the rates of objective response, was to identify whether the immunomodulator melphalan or the alkylating agent thalidomide was a better partner for VP. The primary objective of the maintenance portion of the study, which compared CR rates, was to evaluate whether the depth of response from induction could be improved with maintenance. PFS, tolerability and overall safety were important secondary objectives.

Highly Active Both induction regimens were highly active, producing objective response rates of 80% for VMP and 81% for VTP, which did not differ significantly. However, the side-effect profiles were different, with more neutropenia (39% vs. 22%; P=0.008) and more thrombocytopenia (27% vs. 12%; P=0.001) for VMP, but more cardiac events (8% vs. 0; P=0.001) for VTP. Discontinuations due to serious side effects were significantly more common for VTP (17% vs. 11%; P=0.03) (Figure 1).

In 178 patients who entered and could be evaluated in the maintenance portion of the study, a CR or near CR was achieved in 59% of those on VT maintenance and 55% of those on VP maintenance, which was nearly a doubling of the CR rates achieved at the end of induction in either treatment arm (Figure 2).

Both maintenance regimens were well tolerated with very modest differences in the types of side effects.

Only 5% of those on VP and 7% of those on VT discontinued therapy because of side effects.

One of the most remarkable findings of both the induction and maintenance portions of the study was

a 29% CR rate in patients with the cytogenetic abnormalities of t(4;14), t(4;16) and del 17p. This was actually greater, although not significantly so, than the 23% CR rate in patients with normal cytogenetics. Similarly, the rate of immunofixation-negative complete response (CRIF–) after initiating maintenance therapy was relatively high and not significantly different in patients with abnormal versus normal cytogenetics (38% vs. 42%, respectively).

Despite similar efficacy of the different regimens in the two phases of the study, VMP/VT, which produced a 60% improvement in PFS (P=0.008) compared with VTP/ VP was identified as the preferred sequence. This relative advantage is likely to have been driven by the lower discontinuation rate on VMP than on VTP during induction and by the greater PFS on VT than on VP during maintenance (not yet reached on VT and 23 months on VP [P=0.05]).

According to Donna M. Weber, MD, associate professor in the Department of Lymphoma and Myeloma at the University of Texas M.D. Anderson Cancer Center, Houston, this trial is the first large randomized study to investigate the value of maintenance therapy in previously untreated, elderly MM patients who did not proceed to stem cell transplantation (SCT). She suggested that the study “heralds a new era” in the effort to identify how to improve regimens in patients who are not candidates for SCT. In particular, she was impressed with the apparent ability of bortezomib to eliminate the disadvantage of certain abnormal cytogenetics. Similar to studies that tested other regimens in this patient population, the new study is limited in that it did not demonstrate an overall survival advantage. The PFS data, however, are encouraging, Dr. Weber said, and an overall survival benefit may become more apparent as the data mature.

—Ted Bosworth

PRN

CLINICAL ONCOLOGY NEWS • FEBRUARY 2010

Around the Water Cooler Pediatric Oncologist To Lead ASCO Michael P. Link, MD, a leader in the field of pediatric oncology, has been elected president of the American Society of Clinical Oncology (ASCO) for a oneyear term beginning Michael P. Link, MD in June 2011. He will be the first pediatric oncologist to take the reins as president of ASCO. Dr. Link currently serves as the Lydia J. Lee Professor of pediatric hematology/ oncology at Stanford University School of Medicine and director of the Bass Center for Cancer and Blood Diseases at the Lucile Salter Packard Children’s Hospital at Stanford, Calif. He joined the faculty of Stanford University in 1979 after completing his residency and fellowship at Children’s Hospital and the Dana-Farber Cancer Institute in Boston.

His research interests include the biology and management of non-Hodgkin’s lymphoma and Hodgkin’s.

Clinicians Receive Awards The American Association for Cancer Research and the International Association for the Study of Lung Cancer has honored Paul A. Bunn Jr., MD, for his leadership in lung cancer research at the first Molecular Origins of Lung Cancer conference. Dr. Bunn is professor of medicine and the James Dudley chair in cancer research at the University of Colorado, Denver. Dr. Bunn’s studies have set standards for the treatment of lung cancer, shed light on the natural history of the disease and identified biomarkers of prognosis and therapy selection.

Paul A. Bunn Jr., MD, receives award.

“Dr. Bunn has been an inspiration to physicians and scientists working in the field of lung cancer. He deserves this award for everything that he has contributed to this important field past, present and future,” said conference co-chairperson Roy Herbst, MD, PhD, chief of the section of thoracic medical oncology at The University of Texas M.D. Anderson Cancer Center, in Houston.

The American Society for Radiation Oncology (ASTRO) has selected Theodore Lawrence, MD, PhD, and William Shipley, MD, as its 2009 Gold Medal

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

recipients. The Gold Medal is the society’s highest honor. It is presented annually to a member who has made outstanding contributions to the field of radiation oncology, through his or her research, clinical care, teaching and service.

Dr. Shipley is chair of the genitourinary oncology unit at Massachusetts General Hospital and the Andres Soriano Professor of radiation oncology at Harvard Medical School. Dr. Lawrence is an Isadore Lampe professor of radiation oncology, chair of the Department of Radiation

Oncology and a professor in the Department of Environmental Health, School of Public Health at the University of Michigan, in Ann Arbor. “ D r. L aw r e n c e and Dr. Shipley have been outstand- William ing contributors Shipley, MD to the society and to the field of radiation oncology as a

whole,” said Patricia Eifel, MD, chairman of ASTRO. “It is an honor and a personal pleasure for me to be able to present them with the Gold Medal this year in recognition of their distinguished careers and dedication to the specialty.”

Multidisciplinary Cancer Programs Multiplying Seeking to offer patients convenience as well as a better understanding of see PROGRAMS, page 31

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PRN

CLINICAL ONCOLOGY NEWS • FEBRUARY 2010

Communication

Open Body Language: Optimizing Your Nonverbal Communication Our words convey what we are thinking, but our eye contact, gestures, facial expressions and tone of voice express what we are feeling in any given situation.

W

hether you are speaking in a clinical setting, delivering a formal presentation to a group of your peers or discussing medical findings with a patient, there may be a significant difference between what you say and how others hear you. This difference arises from how your nonverbal communication—your “body language”—is interpreted. Most people are largely unaware of how others view them and what messages their body language projects.

The power of body language is illustrated by the emotional response it elicits from listeners. Feelings drive our reactions in virtually every situation, including when we are listening to someone present information. A listener’s interpretation of nonverbal cues can either strengthen or undermine the overall impact of the speaker’s information. The listener will receive mixed messages when the speaker’s

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gestures are not in alignment with verbal content.

In an ideal world, we would be able to control every nonverbal message we transmit when speaking. Although this level of control may not be possible, increasing our understanding of the signs and signals we exhibit while speaking will strengthen our awareness of what we communicate to others. The best way to improve nonverbal communication is to learn open body language, which is characterized by four main components: direct eye focus, open body posture, open and purposeful hand gestures and a favorably expressive voice.

The key feature of open body language is eye contact. The ability to connect with the audience is enhanced if you slow the shift of your gaze to incorporate the time it takes to impart complete, discrete ideas. This technique

Part 2 of a 3-Part Series Be sure to watch for more articles on effective communication skills in future issues: PART 3: “The Other Side of a Two-Way Street: Active Listening Is Essential for Conversation”

helps regulate the flow of information.

Slower-paced eye movement gives the audience an impression of confidence, interest, credibility and sincerity. Conversely, poor eye contact, such as scanning the audience or staring at only one spot, projects an image of nervousness, deception and tension.

To provide a strong base for effective communication, adopt an overall open body posture. This communicates a sense of authority while also projecting approachability, confidence and comfort. An open body posture features: • keeping movement away from the body’s vertical center line; • placing your feet hip-distance apart with your weight equally distributed; • keeping your hands open and down at

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hat do music and medicine have in common? To be good at either, you have to be an improviser. Both disciplines place improvisational skill on a pedestal, acknowledging that thinking on one’s feet is a vital element of how one practices the art of medicine and music.

This wonderful compilation showcases the great musical skills of those in medicine: practitioners who, in addition to devoting their life to the healing power of medicine, have also devoted themselves to the great art of creating music.

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It is widely understood that music has healing powers. Listen to the great music on this compilation CD to be inspired by these great artists and heal what ails you.

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PRN

CLINICAL ONCOLOGY NEWS • FEBRUARY 2010

Communication

your sides; • relaxing your shoulders; and • leaning forward slightly.

The ability to connect with your listeners, capture their attention and facilitate their understanding strengthens with the use of open and purposeful hand gestures. Hand gestures act as a visual aid that can demonstrate the size of an incision, the shape of a medical device or even the distance among stages of disease development; they also can subtly express emotion about the topic under discussion. Failure to use gestures gives the impression that you are stiff, uncomfortable and anxious.

Poor eye contact, such as scanning the audience or staring at only one spot, projects an image of nervousness, deception and tension.

The qualities of your voice as you deliver your presentation also greatly affect how the audience perceives

the spoken information. The sound and timbre projected by your voice will convey how you feel about the information being shared. By controlling the speed, volume, tone, pitch and energy of your voice, you can alter the way the audience interprets and understands your messages.

Regardless of whether the information being communicated is a complicated clinical discussion or a simple conversation, it is important to understand what nonverbal messages reveal.

When our words have one meaning but our body language conveys another, our intended message suffers. By

GEMZAR姞 (GEMCITABINE HCl) FOR INJECTION

PROGRAMS continued from page 29

their diagnosis, Saint Barnabas Medical Center in Livingston, N.J., has started a multidisciplinary breast cancer program. By allowing patients to meet with their breast surgeon, radiation oncologist and medical oncologist at the same time, the center hopes

From left: Raquel Wagman, MD, radiation oncologist; M. Michele Blackwood, MD, breast surgeon; and Delia Radovich, MD, medical oncologist.

to develop individualized cancer treatments and improved communication between patients and providers. “This practice is about addressing the needs of our community in a manner that is efficient and convenient for them,” said M. Michele Blackwood, MD, director of Breast Health and Disease Management at Saint Barnabas.

Physicians involved in the program are Dr. Blackwood, a breast surgeon; Delia Radovich, MD, a medical oncologist; and Raquel Wagman, MD, a radiation oncologist.

BRIEF SUMMARY (OVARIAN). For complete safety please consult the package insert for complete prescribing information.

INDICATION AND USAGE: THERAPEUTIC INDICATION—Ovarian Cancer—Gemzar in combination with carboplatin is indicated for the treatment of patients with advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy.

CLINICAL STUDIES: Ovarian Cancer—Gemzar was studied in a randomized Phase 3 study of 356 patients with advanced ovarian cancer that had relapsed at least 6 months after first-line platinum-based therapy.

Patients were randomized to receive either Gemzar 1000 mg/m2 on Days 1 and 8 of a 21-day cycle and carboplatin AUC 4 administered after Gemzar on Day 1 of each cycle or single-agent carboplatin AUC 5 administered on Day 1 of each 21-day cycle as the control arm. The primary endpoint of this study was progression free survival (PFS).

The addition of Gemzar to carboplatin resulted in statistically significant improvement in PFS and overall response rate. Approximately 75% of patients in each arm received poststudy chemotherapy. Only 13 of 120 patients with documented poststudy chemotherapy regimen in the carboplatin arm received Gemzar after progression. There was not a significant difference in overall survival between arms.

CONTRAINDICATION: Gemzar is contraindicated in those patients with a known hypersensitivity to the drug (see Allergic under ADVERSE REACTIONS).

WARNINGS: Caution—Prolongation of the infusion time beyond 60 minutes and more frequent than weekly dosing have been shown to increase toxicity (see CLINICAL STUDIES in the full Prescribing Information).

Hematology—Gemzar y can suppress bone marrow function as manifested by leukopenia, thrombocytopenia, and anemia (see ADVERSE REACTIONS), and myelosuppression is usually the dose-limiting toxicity.

Patients should be monitored for myelosuppression during therapy. See DOSAGE AND ADMINISTRATION in the full Prescribing Information for recommended dose adjustments.

Pulmonary—Pulmonary toxicity has been reported with the use of Gemzar. In cases of severe lung toxicity, Gemzar therapy should be discontinued immediately and appropriate supportive care measures instituted (see Pulmonary under Single-Agent Use and under Post-marketing experience in ADVERSE REACTIONS in the full Prescribing Information).

Renal—Hemolytic Uremic Syndrome (HUS) and/or renal failure have been reported following one or more doses of Gemzar. Renal failure leading to death or requiring dialysis, despite discontinuation of therapy, has been rarely reported. The majority of the cases of renal failure leading to death were due to HUS (see Renal under Single-Agent Use and under Post-marketing experience in ADVERSE REACTIONS in the full Prescribing Information).

Hepatic—Serious hepatotoxicity, including liver failure and death, has been reported very rarely in patients receiving Gemzar alone or in combination with other potentially hepatotoxic drugs (see Hepatic under Single-Agent Use and under Post-marketing experience in ADVERSE REACTIONS in the full Prescribing Information).

Pregnancy—Pregnancy y Category D. Gemzar can cause fetal harm when administered to a pregnant woman.

Gemcitabine is embryotoxic causing fetal malformations (cleft palate, incomplete ossification) at doses of 1.5 mg/kg/day in mice (about 1/200 the recommended human dose on a mg/m2 basis). Gemcitabine is fetotoxic causing fetal malformations (fused pulmonary artery, absence of gall bladder) at doses of 0.1 mg/kg/day in rabbits (about 1/600 the recommended human dose on a mg/m2 basis). Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. There are no studies of Gemzar in pregnant women. If Gemzar is used during pregnancy, or if the patient becomes pregnant while taking Gemzar, the patient should be apprised of the potential hazard to the fetus.

PRECAUTIONS: General—Patients receiving therapy with Gemzar should be monitored closely by a physician experienced in the use of cancer chemotherapeutic agents. Most adverse events are reversible and do not need to result in discontinuation, although doses may need to be withheld or reduced. There was a greater tendency in women, especially older women, not to proceed to the next cycle.

Laboratory Tests—Patients receiving Gemzar should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet count. Suspension or modification of therapy should be considered when marrow suppression is detected (see DOSAGE AND ADMINISTRATION in the full Prescribing Information).

Laboratory evaluation of renal and hepatic function should be performed prior to initiation of therapy and periodically thereafter (see WARNINGS).

Carcinogenesis, Mutagenesis, Impairment of Fertility—Long-term animal studies to evaluate the carcinogenic potential of Gemzar have not been conducted. Gemcitabine induced forward mutations in vitro in a mouse lymphoma (L5178Y) assay and was clastogenic in an in vivo mouse micronucleus assay.

Gemcitabine was negative when tested using the Ames, in vivo sister chromatid exchange, and in vitro chromosomal aberration assays, and did not cause unscheduled DNA synthesis in vitroo. Gemcitabine IP doses of 0.5 mg/kg/day (about 1/700 the human dose on a mg/m2 basis) in male mice had an effect on fertility with moderate to severe hypospermatogenesis, decreased fertility, and decreased implantations. In female mice, fertility was not affected but maternal toxicities were observed at 1.5 mg/kg/day IV (about 1/200 the human dose on a mg/m2 basis) and fetotoxicity or embryolethality was observed at 0.25 mg/kg/day IV (about 1/1300 the human dose on a mg/m2 basis).

Pregnancy—Category D. See WARNINGS. Nursing Mothers—It is not known whether Gemzar 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 from Gemzar in nursing infants, the mother should be warned and 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 and the potential risk to the infant.

Elderly Patients—Gemzar clearance is affected by age (see CLINICAL PHARMACOLOGY in the full Prescribing Information). There is no evidence, however, that unusual dose adjustments (i.e., other than those already recommended in DOSAGE AND ADMINISTRATION section in the full Prescribing Information) are necessary in patients over 65, and in general, adverse reaction rates in the single-agent safety database of 979 patients were similar in patients above and below 65. Grade 3/4 thrombocytopenia was more common in the elderly.

Gender—Gemzar clearance is affected by gender (see CLINICAL PHARMACOLOGY in the full Prescribing Information). In the single-agent safety database (N=979 patients), however, there is no evidence that unusual dose adjustments (i.e., other than those already recommended in DOSAGE AND ADMINISTRATION section in the full Prescribing Information) are necessary in women. In general, in single-agent studies of Gemzar, adverse reaction rates were similar in men and women, but women, especially older women, were more likely not to proceed to a subsequent cycle and to experience Grade 3/4 neutropenia and thrombocytopenia.

Pediatric Patients—The effectiveness of Gemzar in pediatric patients has not been demonstrated. Gemzar was evaluated in a Phase 1 trial in pediatric patients with refractory leukemia and determined that the maximum tolerated dose was 10 mg/m2/min for 360 minutes three times weekly followed by a one-week rest period. Gemzar was also evaluated in a Phase 2 trial in patients with relapsed acute lymphoblastic leukemia (22 patients) and acute myelogenous leukemia (10 patients) using 10 mg/m2/min for 360 minutes three times weekly followed by a one week rest period. Toxicities observed included bone marrow suppression, febrile neutropenia, elevation of serum transaminases, nausea, and rash/desquamation, which were similar to those reported in adults. No meaningful clinical activity was observed in this Phase 2 trial.

Patients with Renal or Hepatic Impairment—Gemzar should be used with caution in patients with preexisting renal impairment or hepatic insufficiency as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations. Administration of Gemzar in patients with concurrent liver metastases or a preexisting medical history of hepatitis, alcoholism, or liver cirrhosis may lead to exacerbation of the underlying hepatic insufficiency.

GEMZAR姞 (GEMCITABINE HCl) FOR INJECTION

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consciously using direct eye focus, open body posture, open and purposeful hand gestures and a favorably expressive voice to reinforce your words, you will increase the impact of your communication and decrease the likelihood of miscommunication.

—Dalli Simmons Dalli Simmons, certified school psychologist, is a consultant at Exec|Comm LLC, a New York City-based communications consulting firm, where she coaches medical professionals, scientists and senior-level executives in a wide array of communication skills. She can be reached at dsimmons@exec-comm.com.

Drug Interactions—No specific drug interaction studies have been conducted. For information on the pharmacokinetics of Gemzar and cisplatin in combination, see Drug Interactions under CLINICAL PHARMACOLOGY. Radiation Therapy—A pattern of tissue injury typically associated with radiation toxicity has been reported in association with concurrent and non-concurrent use of Gemzar.

Non-concurrent (given >7 days apart)—Analysis of the data does not indicate enhanced toxicity when Gemzar is administered more than 7 days before or after radiation, other than radiation recall. Data suggest that Gemzar can be started after the acute effects of radiation have resolved or at least one week after radiation.

Concurrent (given together or ≤7 days apart)—Preclinical and clinical studies have shown that Gemzar has radiosensitizing activity. Toxicity associated with this multimodality therapy is dependent on many different factors, including dose of Gemzar, frequency of Gemzar administration, dose of radiation, radiotherapy planning technique, the target tissue, and target volume. In a single trial, where Gemzar at a dose of 1000 mg/m2 was administered concurrently for up to 6 consecutive weeks with therapeutic thoracic radiation to patients with non-small cell lung cancer, significant toxicity in the form of severe, and potentially life-threatening mucositis, especially esophagitis and pneumonitis was observed, particularly in patients receiving large volumes of radiotherapy [median treatment volumes 4795 cm3]. Subsequent studies have been reported and suggest that Gemzar administered at lower doses with concurrent radiotherapy has predictable and less severe toxicity. However, the optimum regimen for safe administration of Gemzar with therapeutic doses of radiation has not yet been determined in all tumor types.

ADVERSE REACTIONS: Combination Use in Ovarian Cancer—In the Gemzar plus carboplatin versus carboplatin study, dose reductions occurred with 10.4% of Gemzar injections and 1.8% of carboplatin injections on the combination arm, versus 3.8% on the carboplatin alone arm. On the combination arm, 13.7% of Gemzar doses were omitted and 0.2% of carboplatin doses were omitted, compared to 0% of carboplatin doses on the carboplatin alone arm. There were no differences in discontinuations due to adverse events between arms (10.9% versus 9.8%, respectively).

Table 1 presents the adverse events (all grades) occurring in ≥10% of patients in the ovarian cancer study.

Table 1: Adverse Events From Comparative Trial of Gemzar Plus Carboplatin Versus Single-Agent Carboplatin in Ovarian Cancera CTC Grades (% incidence) Gemzar plus Carboplatin (N=175) Carboplatin (N=174) All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Laboratory b Hematologic Neutropenia 90 42 29 58 11 1 Anemia 86 22 6 75 9 2 Leukopenia 86 48 5 70 6 <1 Thrombocytopenia 78 30 5 57 10 1 38 15 RBC Transfusions c Platelet Transfusions c 9 3 Non-laboratory b Nausea 69 6 0 61 3 0 Alopecia 49 0 0 17 0 0 Vomiting 46 6 0 36 2 <1 Constipation 42 6 1 37 3 0 Fatigue 40 3 <1 32 5 0 Neuropathy-sensory 29 1 0 27 2 0 Diarrhea 25 3 0 14 <1 0 Stomatitis/pharyngitis 22 <1 0 13 0 0 Anorexia 16 1 0 13 0 0 a Grade based on Common Toxicity Criteria (CTC) Version 2.0 (all grades ≥10%). b Regardless of causality. c Percent of patients receiving transfusions. Transfusions are not CTC-graded events. Blood transfusions included both packed red blood cells and whole blood.

In addition to blood product transfusions as listed in Table 1, myelosuppression was also managed with hematopoetic agents. These agents were administered more frequently with combination therapy than with monotherapy (granulocyte growth factors: 23.6% and 10.1%, respectively; erythropoetic agents: 7.3% and 3.9%, respectively).

The following are the clinically relevant adverse events, regardless of causality, that occurred in >1% and <10% (all grades) of patients on either arm. In parentheses are the incidences of Grade 3 and 4 adverse events (Gemzar plus carboplatin versus carboplatin): AST or ALT elevation (0 versus 1.2%), dyspnea (3.4% versus 2.9%), febrile neutropenia (1.1% versus 0), hemorrhagic event (2.3% versus 1.1%), hypersensitivity reaction (2.3% versus 2.9%), motor neuropathy (1.1% versus 0.6%), and rash/desquamation (0.6% versus 0).

No differences in the incidence of laboratory and non-laboratory events were observed in patients 65 years or older, as compared to patients younger than 65.

Post-marketing experience—The following adverse events have been identified during post-approval use of Gemzar. These events have occurred after Gemzar single-agent use and Gemzar in combination with other cytotoxic agents. Decisions to include these events are based on the seriousness of the event, frequency of reporting, or potential causal connection to Gemzar.

Cardiovascular—Congestive heart failure and myocardial infarction have been reported very rarely with the use of Gemzar. Arrhythmias, predominantly supraventricular in nature, have been reported very rarely.

Vascular Disorders—Clinical signs of peripheral vasculitis and gangrene have been reported very rarely.

Skin—Cellulitis and non-serious injection site reactions in the absence of extravasation have been rarely reported. Severe skin reactions, including desquamation and bullous skin eruptions, have been reported very rarely.

Hepatic—Increased liver function tests including elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase, and bilirubin levels have been reported rarely. Serious hepatotoxicity including liver failure and death has been reported very rarely in patients receiving Gemzar alone or in combination with other potentially hepatotoxic drugs.

Pulmonary—Parenchymal toxicity, including interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome (ARDS), has been reported rarely following one or more doses of Gemzar administered to patients with various malignancies. Some patients experienced the onset of pulmonary symptoms up to 2 weeks after the last Gemzar dose. Respiratory failure and death occurred very rarely in some patients despite discontinuation of therapy.

Renal—Hemolytic-Uremic Syndrome (HUS) and/or renal failure have been reported following one or more doses of Gemzar. Renal failure leading to death or requiring dialysis, despite discontinuation of therapy, has been rarely reported. The majority of the cases of renal failure leading to death were due to HUS. Injury, Poisoning, and Procedural Complications — Radiation recall reactions have been reported (see Radiation Therapy under PRECAUTIONS).

Dosage and administration: Gemzar is for intravenous use only. Please consult full prescribing information for complete dosage and administration guidelines.

Literature revised May 7, 2007 PV 4067 AMP

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Eli Lilly and Company Indianapolis, IN 46285, USA Copyright © 1996, 2007, Eli Lilly and Company. All rights reserved.

GEMZAR姞 (GEMCITABINE HCl) FOR INJECTION

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31

GEMZAR/carboplatin is one option for 2nd-line treatment of your patients with platinum-sensitive* advanced ovarian cancer.

Myelosuppression is usually the dose-limiting toxicity with GEMZAR therapy.

G MZ GE ZAR in co omb m inat inat in a iio on wi w th car a bo bopl plattin pl n iiss iin ndi d ca cate ed fo or th t e tr t eaatm t en entt of pattie ient ntss wi nt w th th adv d aan nce ed o ovvvar a iaan ca ar c nc n er thaat haas rre elaaps psed ed d aatt le easst 6 mo mont ntths h aft fter er er co omp m le etiion on of p pllattin i um u -b bassed ed the eraapyy.

Myel My ellossu e up ppr p es essi siion o is us usua uallllly th ua he do ose se-l -lim -l im mittin ng to oxi x ci city tty y wiitth GE GEMZ EMZ MZAR AR the era r py. py y.

Overall response rate (%)†

Median progression-free survival (months) GEMZAR plus Carboplatin

95% Cl (8.0-9.7) (N=178)

Carboplatin 95% Cl (5.2-7.1) (N=178)

0

2

4

(p=0.0038)

GEMZAR plus Carboplatin (N=178)

8.6

Carboplatin (N=178)

5.8 6

8

(p=0.0016)

10

0%

10%

47.2%

30.9% 20%

30%

40%

50%

pat atie iieent nts ar aree de defi f ne fi ned aass pat ned atie ientts wh w o de d ve velo loop di d se seaasse pr prog o rreess og ssiioon ≥6 m moont n hs hs afftteerr rec e ei eivi ving firrst vi ving st-l -lin -l inee pl in plat atin inum in um m-b -bas asseed d ch heemo m th t errap py.

Inve In vest ve s iggat st a or o -rrevvie i we wed. d d.

* Plat Pllat a inum in num m-ssen nsiiti tive ve †

The Th e ov o erral a l su surrvviv ival a dif al i fe f rre enc n e be betw tw wee en GE GEMZ EMZAR MZ ZAR AR/c / ar /c a bo bop pllaattin (18 (1 18 8.0 0 mon onth th ths) hs) vs ca carb rb bop pla lati tin ti n (1 (17.

7 3 mo 7. mont nths nt hs) hs s) waas no ot si sign gnif nif i iccan antt (p=0 0.8 897 977) 7.

7) Se S ele ecctt IImp mpor mp orta or t ntt Saffe etty In nfo orm mattio on GEMZ GE EMZ M AR R ssho ho oul uld d no ot b be ea adm dm min inis isste ered re ed to t pat a ie en ntts wi w th h kno own w hyp hyp yperse yper erse er s ns n itiv ittivvity itty to thi hs drrug. ug g. In nfu usi sion on tim mes es of G GE EMZ ZAR A llon o ger on ge er th than an n 60 mi m nu n te t s an nd m mo ore e fre requ qu q uen entt th han n week we ekly ek lyy dos osin ing in g have ha ave e bee een n sh s ow own wn to o inc n re r asse to oxi xici c ttyy. Pu ci Pulm lmon on nar aryy to oxi x ci c tyy has a been een ee re epo p rt rted ed.. In ed n casses of se eve ere e lun u g to toxi xiici xici c ttyy, GE EMZ M AR AR the hera ra apyy ssho ho oul u d be be dis isco sco cont n in nt nu ue ed im mme m di d attel eya an nd ap ppr prop opri op rriiatte su supp por orti tive ti ve ccar ve arre me are meas a ur u ess iins nssti n t tu ute t d. d Hem e ol o yt y icc U emic Ur em micc Syn y drrome om me (H HUS US) S) an a d/ d/or o ren enal faiilu l re r havve be een n rep e or o te ted fo olll ow o in ng on o e or o mo ore ed dos osses o es of GEMZ GEMZ GE MZAR A . Re AR Rena n l fa f ilur ilur u e le eadin ad din i g to d dea e th ea h or re equ uir i in ng di dial a ys al y iss, de d sp pit ie d sccon di nti t nuat nu uat a io i n of o the h ra apyy, ha h s be been en rarre elly re epo port rted rt e . Th ed he ma majo j rriityy o jo off th the ca the ase sess of o r na re nall fa faililur illur ure le lead ad din ing g to o de ea ath h were erre du due e to o HUS S. Se Seri r ou ri o s he h pa ato toto toxi to x ci c tyy, in incl clud ud u din din i g lilive verr fa ve failili ur ure re an and de eat ath, h, has bee h, e n re r po p rrtted d ver eryy ra are elyy iin n pa p ti t en entss rrec e eiivi ec ving ng g GEM E ZA AR allon one or o iin n co c mbin mb bin na attio on wi with t oth th ther e potten er nti tial ally al llyy hep e at a ot otoxxicc dru r gs g . GE GEMZ MZAR is MZAR Prreg P reg e n na anc n y Ca Cate t go gory ry D D.. G GE EMZ MZAR A can AR n cau ause s fet se e al har arm w wh hen n ad dm min inis isste ere r d to t a pr preg eg gn na ant wo om man a . Usse ca c ut u io i n in patie atiie at entts wi with h pre re-e - xi -e xist ssttiin ng re en na al im al mpa airrm me ent orr hep e atticc iins n uffi ns uffi uf fici c en ci ncyy. Ad A mi mini niisttra n attiion n of GE GEMZ MZ ZAR A ma ayy exa exa ace cerb erb batte un u de erl r yyiing he epa p ti ticc in nsu suff f ic ff icie ie enc n yy.. T The he optim ptim pt imum u reg um egimen im men n for o saf afe a ad dm miini nist s ra st ati t on o of GE EMZ MZAR ZAR with wi t the th erra ap pe eut utic iicc dos osess of ra radi diiattio diat on ha as no n t ye et be been en n det e errmiin ne ed iin na allll tum u orr typ pes e .

G MZ GE ZAR R hass ra ad dio ose ens nsit itiz it izzin ng ac a ti t vi v ttyy and d ra ad dia iati tion ti on n reccal all re reac a ti ac t on ns ha have ve bee e n re epo port rted ed d. Itt is not no ot kn know o n wh ow whet etthe e h r GE GEMZ MZ ZA AR R or itts me meta eta abo b lilite tess ar te are e exxcr cret etted e e in in GEMZ EM AR A ®

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huma hu ma an mi m lk. lk. Th T e ef effe fect fe cttivven e esss off GE EM MZAR ZA AR in in ped dia iatr trric i pat atie ie entts ha hass not no ot be b en de d emo ons nstr trat a ed at ed.. T Th he to toxi x ci xi citi t es ti e of GE GEMZ M AR A obsser e vve ed in n ped e iatr iatr ia tric ic pattie entts we were re e ssim im milla arr to o tho ose e rrep e o ep orrte t d in n adu d ltts. s GEM MZA AR cl clea ea ara anc nce e iiss aff ffec eccte e ed by b age as we elll as ge gend end derr.

Pati Pa t en ti nts rec ecei eiivi e ving ng g tthe hera he r py ra p witth GE GEMZ GEMZ M AR A sho oul uld d be be mo on nitor itored it orred e clo ose s lyy b byy a ph phys yyssicia iccia an e p ex pe erriien e ce ed in i the e use e of ca c nccer e che emoth moth mo her erap ap pe eu utiic ag gen ents nts t.

A br Ab b ev evia ia ate ed Ad Adve ve ersse Ev ven ents tss (% in inci c de ci enc n e e)) Th T he mo ost sev e er e e adve ad dvve ers rse e ev even en nts t (Gr Grad dess 3/4 / ) wi with t GEMZA EM MZA AR pl p us us car arbo opl p at a in n vver e su er suss c rb ca bop opla la ati tn a allon one, e rres e, esspe pect cttivvel e y, y for o the e tre eattme ent n of pa patiien e ts wiitth ad a va v nc n ed d ova vari r an a c nc ca ncer er werre ne er neut uttro ope peni niia (7 71 vs 12 2)); th hro r mb mboc ocyt ytop yt op penia eniia en a (35 vs 11 1); leu e ko ope p ni nia a (5 53 vss 7); an a nem e ia a ((28 28 vs 11 28 1); nau ause ea (6 ( vs 3) 3 ; vo vomi miiti m ting ng (6 (6 vs v 3 3); );; an nd d co on nsttipat ip pat a io ion (7 7 vs 3) 3). ). T Th he m mo ostt com co comm mm mon on adv d er erse sse e eve v nt n s (a alll Gra ades) de es) wer e e ne n ut utro ro ope p ni n a (9 90 vs v 5 58) 8)); le euk uko op pen enia ia a ((86 86 8 6 vs 70 7 ); ) an nem mia a (86 86 vs 7 75 5); th hrrom om mbo bo ocy cyto ytope to ope p niia (7 (78 vvss 57)); RB RBC tr RBC tran an nsf s us u ion io on (3 38 vvss 15) 5 ; al a op opec eccia a (4 49 vs v 1 17) 7)); ne eur urop op pat a hy h /s /sen e sso en oryy (2 29 9 vs 27 7); ) na au use ea (69 (6 69 vs vs 61) 1 ; fa fati t gue ti gu ue (4 40 vs v 32)); vo omi miti tiing (4 46 vs v 36)); di d ar arrh rhea a (2 25 5 vs 14 4); ); and n con con o st stip ipat attio a on (4 42 vss 37).

7)).

Fo For or a ad dd diitiion onal al saf al a etty in info f rm rmat attio ion, n,, ple n easse se see e Br B ie ief Su Summ mm mar ary y of o Pre esc scri ribi ri ribi bing ng g IIn nfo form mat atio io on on o ad djjac a en ent pa page ge.

For mo Fo ore r inf n or orma rma m tiion o abo boutt ccan an nce cer tr t ea e tm men e t wi with th GEM E ZA AR, R viissit sitt GE GEMZ MZAR AR AR.c R.ccom o .