NEW DRUG APPROVALS
• Cabazitaxel (Jevtana Injection, Sanofi-Aventis). A microtubule inhibitor for use in combination with prednisone for metastatic, hormone-refractory prostate cancer previously treated with a docetaxel (Taxotere)–containing regimen.
Basis: Median survival was 15.1 months with cabazitaxel vs. 12.7 months with mitoxantrone (both combined with 10 mg of prednisone a day) in a randomized, open-label study of 755 patients.
Dosage: 25 mg/m2 administered every 3 weeks over 1 hour in an intravenous infusion; requires premedication with an antihistamine, corticosteroid, and H2 antagonist.
• Denosumab (Xgeva, Amgen). A monoclonal antibody targeting the RANKL (receptor-activated nuclear factor–kappaB) ligand, for prevention of skeletal-related events (SREs) in patients with bone metastases from solid tumors. It is specifically not indicated for multiple myeloma. Also approved for postmenopausal women with osteoporosis at a high risk of fracture (marketed as Prolia for this indication).
Basis: Three randomized studies of 5,700 patients found denosumab superior to zoledronic acid (Zometa) in preventing SREs in patients with breast or hormone-refractory prostate cancer. Median time to an SRE had not been reached in breast cancer, but was 26 months with zoledronic acid; it was 21 months vs. 17 months in prostate cancer.
Dosage: 120 mg subcutaneously every 4 weeks.
Addendum: Amgen launched a patient-assistance program because of the drug’s cost.
• Eribulin mesylate (Halaven Injection, Eisai). A nontaxane microtubule inhibitor for patients with metastatic breast cancer previously treated with at least two chemotherapeutic regimens. Previous treatment should include an anthracycline and a taxane in either the adjuvant or metastatic setting.
Basis: In an international, open-label, randomized study of 762 patients, median overall survival was 13.1 months with eribulin vs. 10.6 months with a single-agent therapy chosen by the patients’ physicians.
Dosage: 1.4 mg/m2 administered intravenously on days 1 and 8 of a 21-day cycle.
• Sipuleucel-T (Provenge, Dendreon). An autologous immunotherapy for asymptomatic or minimally symptomatic metastatic, castrate-resistant prostate cancer. It is the first vaccine approved for cancer therapy.
Basis: In a randomized double-blind, study of 512 men, median overall survival was 25.8 months with sipuleucel-T vs. 21.7 months with placebo at a median follow-up of 3 years.
Dosage: Three infusions administered at approximately 2-week intervals.
Addendum: Ongoing controversies surround cost, access, and coverage; the one-time cost is about $93,000 and manufacturing capacity was limited initially. A Centers for Medicare and Medicaid Services advisory committee said that the existing clinical data support sipuleucel-T’s approved use, but cannot be "generalizable" to off-label uses. The committee met as part of a national coverage analysis scheduled for release by March 3, 2011.
NEW INDICATIONS
• Dasatinib (Sprycel, Bristol Myers Squibb). Approved for newly diagnosed Philadelphia chromosome–positive chronic myeloid leukemia in chronic phase in adults.
Basis: In a randomized, open-label study of 519 patients, the rate of confirmed complete cytogenetic response at 12 months was 77% with dasatinib vs. 66% with imatinib.
Dosage: 100 mg orally once daily.
Addendum: As a condition of accelerated approval, the manufacturer must collect long-term efficacy and safety data confirming the drug’s benefit.
• Erlotinib (Tarceva, OSI Pharmaceuticals). Approved for maintenance treatment of locally advanced or metastatic non–small cell lung cancer in patients whose disease has not progressed after four cycles of platinum-based, first-line chemotherapy. The FDA’s Oncology Drugs Advisory Committee (ODAC) had voted 12-1 against a maintenance indication, citing the modest effect in the submitted study and the fact that only one trial supported the indication.
Basis: In a randomized, double-blind study of 889 patients, median progression-free survival was 2.8 months with erlotinib vs. 2.6 months with placebo, a statistically significant difference that represented a 29% reduced risk of progression.
Dosage: 150 mg daily (tablet formulation).
• Everolimus (Afinitor, Novartis). Approved for subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis in patients who need therapy but are not candidates for surgical resection.
Basis: A study of 28 patients found that after 6 months of treatment, 9 patients (32%) had at least a 50% reduction in the volume of their largest SEGA tumor.
Dosage: Starting dose based on body surface area* (tablet formulation)
• HPV Vaccine (Gardasil [Human Papillomavirus Quadrivalent (Types 6, 11, 16, and 18) Vaccine, Recombinant], Merck). Approved for the prevention of anal intraepithelial neoplasia (AIN) grades 1, 2, and 3 caused by HPV types included in the vaccine in young men and women aged 9-26 years, and the prevention of anal cancer caused by HPV types 16 and 18 in young men and women aged 9-26 years.
Basis: In a randomized, controlled study of men who identified themselves as having sex with men, vaccination was 78% effective in the prevention of HPV-16– and HPV-18–related AIN. These data were used to support approval in women "because anal cancer is the same disease in both males and females."
Dosage: Three separate IM injections, with the second and third doses at 2 and 6 months after the first dose.
• Lapatinib (Tykerb, GlaxoSmithKline). Approved, in combination with letrozole (Femara Novartis), for postmenopausal women with hormone receptor–positive metastatic breast cancer that overexpresses the HER2 receptor and for which hormonal therapy is indicated.
Basis: Median progression-free survival was more than twofold longer with the all-oral combination of these two agents at 35.4 weeks vs. 13 weeks with letrozole alone in a phase III trial.
Dosage: 1,500 mg (six tablets) orally with letrozole 2.5 mg, both daily.
Addendum: As a condition of accelerated approval, the manufacturer must provide follow-up data to verify clinical benefit.
• Nilotinib (Tasigna, Novartis). Approved for newly diagnosed Philadelphia chromosome–positive chronic myeloid leukemia in chronic phase in adults.
Basis: In a randomized, open-label study of 846 patients, 43%-44% of those treated with nilotinib had a major molecular response vs. 22% of those randomized to imatinib (Gleevec).
Dosage: 300 mg orally twice daily.
Addendum: As a condition of accelerated approval, the manufacturer must collect long-term efficacy and safety data confirming the drug’s benefit.
• Rituximab (Rituxan, Genentech). Approved, in combination with fludarabine and cyclophosphamide (R-FC), for previously untreated and previously treated chronic lymphocytic leukemia.
Basis: Median progression-free survival was 39.8 months with R-FC vs. 31.5 months with FC in one study of 817 previously untreated patients. In a study of 552 patients with relapsed or refractory CLL, it was 26.7 months with R-FC vs. 21.7 months with FC.
Dosage: 375 mg/m2 on the day prior to FC chemotherapy in the first 28-day cycle, and then 500 mg/m2 on day 1 of cycles 2-6.
• Trastuzumab (Herceptin, Genentech). Approved, with cisplatin and a fluoropyrimidine (capecitabine or 5fluorouracil), for HER2-overexpressing metastatic gastric or gastroesophageal-junction adenocarcinoma in patients not previously treated for metastatic disease. This is the first indication for trastuzumab in an HER2-expressing cancer other than breast cancer.
Basis: An international, multicenter, open-label, randomized clinical study of 594 patients showed a significant improvement in median overall survival of 2.5 months with trastuzumab plus chemotherapy, compared with chemotherapy alone.
Dosage: An initial dose of 8 mg/kg administered in an IV infusion over 90 minutes, followed by 6 mg/kg over 30-90 minutes IV infusion every 3 weeks.
OTHER ACTIONS
• Erythropoiesis-stimulating agents (ESAs). A new REMS (Risk Evaluation and Mitigation Strategy) program mandates that health care providers be certified in order to prescribe these. The FDA acted after studies associated ESAs with shorter survival in cancer patients.
• Finasteride (Proscar, Merck) and dutasteride (Avodart, GlaxoSmithKline) failed to win ODAC support as chemopreventive agents for reducing the risk of prostate cancer.
• Fulvestrant (Faslodex) had its approved dose increased to 500 mg IM in the treatment of estrogen receptor–positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy.
• Gemtuzumab ozogamicin (Mylotarg) was voluntarily removed from the market by Pfizer at the FDA’s request after a phase III trial raised new concerns about its safety and clinical benefit in acute myeloid leukemia.
PENDING
• Bevacizumab (Avastin, Genentech) may lose accelerated approval in combination with paclitaxel (Taxol) as a first-line treatment for metastatic HER2-negative breast cancer. ODAC recommended and FDA moved to rescind because follow-up studies failed to confirm progression-free survival benefits. Genentech has appealed and requested a public hearing.
• Ipilimumab (Bristol-Myers Squibb) is the first agent to improve metastatic melanoma survival in a phase III trial. After granting fast-track status, the FDA is taking more time in reviewing a biologics license application. ODAC has scheduled and cancelled two meetings to discuss the immunotherapy, and the manufacturer said that it has submitted additional data at the agency’s request. A decision is due by March 26.
• Omacetaxine mepusuccinate (ChemGenex) is under review for chronic myeloid leukemia with the T315I mutation that does not respond to any approved treatments for CML. ODAC voted 7-1 that cancer therapies targeting specific genetic mutations (such as T315I) could be required to have corresponding validated diagnostic tests before consideration.
• Pegylated interferon alfa-2b (Pegintron, Schering-Plough) is under review as adjuvant treatment of stage III malignant melanoma after complete lymphadenectomy; the manufacturer announced that the FDA has requested more information.
• Pixantrone dimaleate (Cell Therapeutics) will undergo an additional study in non-Hodgkin’s lymphoma. ODAC unanimously voted that the submitted data lacked the robustness necessary to support approval as a single-agent treatment for patients who have received at least two prior lines of therapy.
• Vandetanib (AstraZeneca) is under review for medullary thyroid cancer. ODAC voted that the risk-benefit profile was acceptable for at least some patients with the disease, but that postmarketing evaluation of alternative dosing should be required, and that some restrictive language should describe toxicity concerns. A decision is due by April 7.
*An incorrect dosage was reported for everolimus and the error has been corrected.