FDA Approves Ixabepilone for the Treatment of Advanced Breast Cancer

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Title: FDA Approves Ixabepilone for the Treatment of Advanced Breast Cancer
URL: http://www.pslgroup.com/dg/215F7E.htm
Doctor's Guide
October 18, 2007

PRINCETON, NJ -- October 18, 2007 -- Bristol-Myers Squibb Company announced today that the U.S. Food and Drug Administration (FDA) has granted approval of Ixempra(TM) (ixabepilone) as monotherapy for the treatment of patients with metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine.

The FDA has also granted approval of Ixempra in combination with capecitabine for the treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline, and a taxane, or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated. Ixempra is a microtubule inhibitor belonging to a class of antineoplastic agents, the epothilones. Bristol-Myers Squibb anticipates that Ixempra will be available within days.

"Previously, patients with aggressive metastatic or locally advanced breast cancer no longer responding to currently available chemotherapies had limited treatment options," said Linda Vahdat, MD, Associate Professor of Clinical Medicine and Associate Attending Physician, New York-Presbyterian Hospital/Weill Cornell Medical Center. "The approval of Ixempra means that we now have an important new option for patients with metastatic breast cancer who have rapidly progressed through currently approved chemotherapies."

"Bristol-Myers Squibb has a rich history in oncology spanning more than 40 years, and we are extremely proud that Ixempra has been approved as it is a significant addition to the Bristol-Myers Squibb oncology portfolio and addresses a serious unmet medical need in the treatment of patients with metastatic or locally advanced breast cancer," said Elliott Sigal, M.D., Ph.D., Executive Vice President, Chief Scientific Officer and President, Research and Development, Bristol-Myers Squibb.

Registrational Trials

The FDA reviewed the efficacy and safety of Ixempra based on the analysis of two multi-center, multinational trials that included 878 patients and evaluated Ixempra either as a monotherapy or in combination with capecitabine in patients with metastatic or locally advanced breast cancer.

(Phase II, Monotherapy Trial: -081) The single-arm Phase II trial evaluated the efficacy and safety of Ixempra as a monotherapy. This study enrolled 126 patients with metastatic or locally advanced breast cancer resistant to three prior therapies (an anthracycline, a taxane and capecitabine). Resistance was defined as disease progression while on therapy in the metastatic setting (defined as progression while on treatment or within eight weeks of last dose) or recurrence within six months of the last dose in the adjuvant or neoadjuvant setting (only for anthracycline and taxane). HER2 positive patients must also have progressed during or after discontinuation of trastuzumab. The primary endpoint was objective response rate, which is an assessment of tumor shrinkage in response to treatment. Results determined by an independent radiology review (IRR) showed an objective partial response of 12.4% (95% CI, 6.9-19.9) in 113 response-evaluable patients.

Treatment-related non-hematological adverse events (greater than or equal to 20%) included: peripheral sensory neuropathy 62% (Grade 3/4: 14%), fatigue/asthenia 56% (Grade 3/4: 13%), myalgia/arthralgia 49% (Grade 3/4: 8%), alopecia 48% (Grade 3/4: 0%), nausea 42% (Grade 3/4: 2%), stomatitis/mucositis 29% (Grade 3/4: 6%), vomiting 29% (Grade 3/4: 1%), diarrhea 22% (Grade 3/4: 1%), and musculoskeletal pain 20% (Grade 3/4: 3%). Treatment-related hematological adverse events (greater than or equal to 20%) included: neutropenia (Grade 3/4: 54%) and leukopenia (Grade 3/4: 49%).

(Phase 3, Combination Trial: -046) The randomized phase 3 trial evaluated the efficacy and safety of Ixempra in combination with capecitabine in comparison with capecitabine as monotherapy. This trial included 752 patients who were previously treated with anthracyclines and taxanes, and whose tumors had demonstrated prior resistance to these therapies. Anthracycline resistance is defined as progression while on therapy or within six months in the adjuvant setting, or three months in the metastatic setting. Taxane resistance is defined as progression while on therapy or within 12 months in the adjuvant setting or four months in the metastatic setting. Evaluation of the primary endpoint demonstrated that Ixempra in combination with capecitabine resulted in a statistically significant improvement in progression-free survival compared to capecitabine monotherapy - median 5.7 (95% CI, 4.8-6.7) vs. 4.1 months (95% CI, 3.1-4.3); P<0.0001, Hazard ratio=0.69 (95% CI, 0.58-0.83).

Treatment-related non-hematological adverse events (greater than or equal to 20%) reported in patients treated with Ixempra in combination with capecitabine included: peripheral sensory neuropathy 65% (Grade 3/4: 21%), palmar-plantar erythrodysesthesia (hand-foot) syndrome 64% (Grade 3/4: 18%), fatigue/asthenia 60% (Grade 3/4: 16%), nausea 53% (Grade 3/4: 3%), diarrhea 44% (Grade 3/4: 6%), vomiting 39% (Grade 3/4: 4%), myalgia/arthralgia 39% (Grade 3/4: 8%), anorexia 34% (Grade 3/4: 3%), stomatitis/mucositis 31% (Grade 3/4: 4%), alopecia 31% (Grade 3/4: 0%), abdominal pain 24% (Grade 3/4: 2%), nail disorder 24% (Grade 3/4: 2%), musculoskeletal pain 23% (Grade 3/4: 2%), and constipation 22% (Grade 3/4: 0%). Treatment-related hematological adverse events (greater than or equal to 20%) reported in patients treated with Ixempra in combination with capecitabine included: neutropenia (Grade 3/4: 68%) and leukopenia (Grade 3/4: 57%).

Comparative treatment-related non-hematological adverse events reported in patients treated with capecitabine alone included: peripheral sensory neuropathy 16% (Grade 3/4: 0%), palmar-plantar erythrodysesthesia (hand-foot syndrome) 63% (Grade 3/4: 17%), fatigue/asthenia 29% (Grade 3/4: 4%), nausea 40% (Grade 3/4: 2%), diarrhea 39% (Grade 3/4: 9%), vomiting 24% (Grade 3/4: 2%), myalgia/arthralgia 5% (Grade 3/4: <1%), anorexia 15% (Grade 3/4: 1%), stomatitis/mucositis 20% (Grade 3/4: 3%), alopecia 3% (Grade 3/4: 0%), abdominal pain 14% (Grade 3/4: 1%), nail disorder 10% (Grade 3/4: <1%), musculoskeletal pain 5% (Grade 3/4: 0%), and constipation 6% (Grade 3/4: <1%). Treatment-related hematological adverse events of Grade 3/4 severity reported in patients treated with capecitabine alone included: neutropenia 11% and leukopenia 6%.

SOURCE: Bristol-Myers Squibb Company

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