The Oncology Report Guide to Cancer Drugs and Devices in 2011

From an immunotherapy that improves melanoma survival to a device that zaps brain tumors, 2011 was a year of firsts from the FDA. This is our second annual guide to approvals of new cancer drugs, indications, and devices – along with a review of safety warnings and other actions affecting oncology practices.

(Click here for a PDF version of The Oncology Report Guide to Cancer Drugs and Devices in 2011.)

NEW DRUG APPROVALS

• Abiraterone acetate (Zytiga Tablets, Centocor Ortho Biotech, Inc.). An androgen suppressant that decreases testosterone production for use in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have received prior chemotherapy containing docetaxel. The fourth approval in late-stage prostate cancer since April 2010.

Basis: An international study of 1,195 men who had previously received chemotherapy containing docetaxel. Median overall survival was 14.8 months with abiraterone plus prednisone, vs. 10.9 months with prednisone alone.

© Aydin Mutlu/iStockphoto.com

• Asparaginase Erwinia chrysanthemi [Erwinaze for injection, EUSA Pharma (USA), Inc.] An asparagine-specific enzyme approved as a component of a multiagent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL) who developed hypersensitivity to E. coli-derived asparaginase. An orphan drug, it works by the same mechanism as the two previously approved treatments that block asparagine, a protein necessary for the proliferation of neoplastic cells.

Basis: In a single-arm, multicenter, open-label study of 58 patients, all 48 patients with available samples achieved threshold trough asparaginase levels shown to correlate with asparagine depletion and with serum levels that predict clinical efficacy.

• Brentuximab vedotin (Adcetris for injection, Seattle Genetics, Inc.). A CD30-directed antibody-drug conjugate for the treatment of Hodgkin’s lymphoma after failure of autologous stem cell transplant (ASCT) or at least two prior multiagent chemotherapy regimens in patients who are not ASCT candidates, and for the treatment of systemic anaplastic large cell lymphoma (ALCL) after failure of at least one prior multiagent chemotherapy regimen. The first new treatment approved for Hodgkin’s since 1977 and the first treatment approved for ALCL.

Basis: In a single-arm study of 102 patients treated with brentuximab, 73% had either a complete or partial response. In a similarly designed study of 58 patients with ALCL, 86% achieved a partial or complete response.

Addendum: An accelerated approval, based on clinical data suggesting that treatment resulted in significant responses; conversion to full approval is contingent on confirmation of benefits in follow-up studies. (In January 2012, the FDA added a warning about the risk of a rare brain infection to the label.)

• Crizotinib (Xalkori Capsules, Pfizer, Inc.). A kinase inhibitor for the treatment of locally advanced or metastatic non–small cell lung cancer (NSCLC) that express an abnormal anaplastic lymphoma kinase (ALK) gene, as detected by the Vysis ALK Break-Apart FISH Probe Kit (Abbott Molecular, Inc.), a companion diagnostic test approved at the same time.

Basis: In two single-arm studies of 255 patients with locally advanced or metastatic, ALK-positive NSCLC, most of whom had received prior chemotherapy, the overall response rate was 50% and 61%, with a median response duration of 42 and 48 weeks, respectively.

Addendum: An accelerated approval, so conversion to full approval is contingent on follow-up studies confirming clinical benefit.

• Deferiprone (Ferriprox Tablets, ApoPharma, Inc.). An oral iron chelator for the treatment of patients with transfusional iron overload due to thalassemia syndromes when current chelation therapy is inadequate.

Basis: A prospective pooled analysis of previously conducted studies of 236 patients (most had thalassemia syndromes) with transfusion-dependent iron overload, for which previous iron chelation therapy had failed or was considered inadequate because of poor tolerance. Within 1 year of starting treatment, 50% of the patients had at least a 20% decrease in serum ferritin levels.

Addendum: An accelerated approval. Safety and effectiveness not established for the treatment of transfusional iron overload due to other chronic anemias, including sickle cell disease. As a condition of approval, ApoPharma will conduct a study of safety and efficacy in patients with sickle cell disease and transfusional iron overload not adequately treated with available chelating agents.

• Hemacord (New York Blood Center). A hematopoietic progenitor cells–cord (HPC-C) preparation for allogenic hematopoietic stem cell transplantation. The first approval of a license for an umbilical cord blood therapy.

Basis: Safety and effectiveness data submitted to a public docket and data submitted in the license application demonstrating compliance with other regulatory requirements.

• Ipilimumab injection (Yervoy, Bristol-Myers Squibb). A human cytotoxic T-lymphocyte antigen (CTLA-4)-blocking antibody for the treatment of unresectable or metastatic melanoma. The first treatment proven to prolong survival in patients with metastatic melanoma.

Basis: An international study of 676 patients with previously treated unresectable stage III or IV melanoma whose disease had progressed, comparing ipilimumab plus an experimental tumor vaccine (gp100), gp100 alone, and ipilimumab alone. Median overall survival was 10 months among those who received ipilimumab with or without the vaccine, vs. 6 months among those who received the vaccine alone.

Addendum: Approved with a Risk Evaluation and Mitigation Strategy (REMS) program addressing life-threatening toxicity and deaths associated with ipilimumab in the study. Acts slowly, and some patients may have tumor progression before therapy becomes effective.

• Ruxolitinib (Jakafi oral tablets, Incyte Corp.). A Janus-associated kinase (JAK) inhibitor for the treatment of intermediate- or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis, and post–essential thrombocythemia myelofibrosis. An orphan drug that is the first treatment approved for the rare blood disease – and the first approved JAK inhibitor.

Basis: Two randomized controlled trials of 528 patients with intermediate- or high-risk myelofibrosis. In one study, 42% of those on ruxolitinib had more than at least a 35% reduction in spleen volume vs. 1% of those on placebo at 24 weeks, and nearly half of those on treatment had achieved at least a 50% reduction in myelofibrosis symptoms, vs. 5% of those on placebo. In the second study, 29% of those on ruxolitinib had at least a 35% reduction in spleen size, vs. none of those on best available therapy after 48 weeks.

• Vandetanib (Caprelsa, AstraZeneca Pharmaceuticals LP). A kinase inhibitor for the treatment of symptomatic or progressive medullary thyroid cancer in adults with unresectable, locally advanced, or metastatic disease. The first drug approved for this rare cancer.

Basis: An international study of 331 patients with unresectable locally advanced or metastatic medullary thyroid cancer. Median progression-free survival was at least 22.6 months with vandetanib vs. 16.4 months among with placebo, a highly significant difference.

Addendum: Approved with a REMS addressing the risk of QT interval prolongation and a note that use in patients with indolent, asymptomatic, or slowly progressing disease "should be carefully considered" because of treatment-associated risks, as well as a boxed warning and a restricted distribution program.

• Vemurafenib (Zelboraf tablets, Hoffmann-LaRoche, Inc.). A BRAF inhibitor for the treatment of patients with unresectable or metastatic melanoma with the BRAF^V600E mutation, as detected by the cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems), a companion diagnostic test approved at the same time. The second therapy found to prolong survival in patients with melanoma.

Basis: A study of 675 treatment-naive patients with unresectable or metastatic melanoma, positive for the BRAF^V600E mutation. At the time of review, median survival was 7.9 months in a control group treated with dacarbazine, but had not been reached among those on vemurafenib. Median progression-free survival was 1.6 and 5.3 months, respectively.

Addendum: About half of melanoma patients have the BRAF mutation, and about half of them respond to vemurafenib. Approved with a medication guide to inform patients about the need for the diagnostic test and potential risks associated with treatment, including cutaneous squamous cell carcinoma. Roche and ipilimumab manufacturer Bristol-Meyers Squibb announced collaboration on a phase I/II study to determine whether combining the two agents is safe and effective in patients with BRAF mutations.

Photo courtesy Mela Sciences

NEW DEVICES

• MelaFind (Mela Sciences). A noninvasive melanoma detection device for use "on clinically atypical cutaneous pigmented lesions with one or more clinical or historical characteristics of melanoma, excluding those with a clinical diagnosis of melanoma or likely melanoma."

Basis: The road to approval was controversial, with a split vote from an advisory panel, a citizens petition submitted by the manufacturer, and an agreement between the agency and manufacturer on how the device would be used and by whom.

• NovoTTF-100A System (NovoTTF, Novocure). A portable, battery-powered device that delivers electrical fields to the brain as a treatment for adults with glioblastoma multiforme that has recurred after chemotherapy.

Basis: In a randomized study of 237 patients whose GBM had recurred after surgery, radiation, and chemotherapy, median overall survival was 6.3 months with the approximately 6-pound device and 6.4 months with best available chemotherapy. The agency cited evidence suggesting better quality of life without chemotherapy side effects.

NEW INDICATIONS

• Cetuximab (Erbitux, ImClone LLC, a wholly owned subsidiary of Eli Lilly & Co. and Bristol-Myers Squibb). The epidermal growth factor receptor (EGFR) antagonist in combination with platinum-based therapy plus 5-fluorouracil for the first-line treatment of recurrent locoregional and/or metastatic squamous cell carcinoma of the head and neck.

Basis: A multicenter non-U.S. study of 442 patients not suitable for potentially curative treatment with surgery or radiation. Mean overall survival was 10.1 months with cetuximab and chemotherapy (cisplatin or carboplatin and 5-fluorouracil), vs. 7.4 months with chemotherapy alone.

Addendum: Cetuximab available in the United States provides about 22% greater exposure than the European Union–approved cetuximab used in this study, but the study results, pharmacokinetic data, and other clinical trial data "establish the efficacy" of cetuximab at the dose recommended, according to the prescribing information.

• Denosumab (Prolia, Amgen, Inc.). The RANK ligand (RANKL) inhibitor to increase bone mass in patients at high risk for fracture when receiving androgen deprivation therapy (ADT) for nonmetastatic prostate cancer or adjuvant aromatase inhibitor (AI) therapy for breast cancer.

Basis: Two international, randomized, double-blind placebo-controlled studies. In one study of 1,468 men with nonmetastatic prostate cancer receiving ADT, lumbar spine bone mineral density (BMD) at 2 years was significantly higher with denosumab vs. placebo (6.7% difference). At 3 years of treatment, the incidence of new vertebral fractures was 1.5% with denosumab vs. 3.9% with placebo, a risk reduction of 62%. In a study of 252 postmenopausal women with breast cancer on AI treatment, BMD at the lumbar spine was significantly higher with denosumab vs. placebo after 12 months of treatment (5.5% difference).

Addendum: Denosumab was initially approved in 2010. It is marketed as Prolia for treating postmenopausal women with osteoporosis at high risk of fracture, and as Xgeva for preventing skeletal-related events in patients with bone metastases from solid tumors; Xgeva is administered more frequently and at a higher dose for the latter indication.

• Everolimus (Afinitor Tablets, Novartis Pharmaceuticals Corp.). The mammalian target of rapamycin (mTOR) inhibitor for progressive pancreatic neuroendocrine tumors (pNETs) that are unresectable, locally advanced, or metastatic. (Safety and effectiveness of everolimus for treating carcinoid tumors have not been established). The first new drug in about 30 years for the treatment of advanced pNET.

Basis: A randomized controlled study of 410 patients, all of whom also received best supportive care. Median progression-free survival was 11 months with everolimus, vs. 4.6 months with placebo. In an interim analysis, overall survival was not different between the two groups.

• Peg-interferon alfa-2b (Sylatron, Schering Corp.). An alpha interferon for the adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resection, including complete lymphadenectomy.

Basis: An open-label multicenter study of 1,256 patients. Median relapse-free survival was 34.8 months among those treated with peg-interferon alfa-2b, vs. 25.5 months with observation.

• Rituximab (Rituxan, Genentech, Inc.). The CD20-directed cytolytic antibody for maintenance therapy in people with previously untreated follicular, CD-20 positive, B-cell non-Hodgkin lymphoma who achieve a response to rituximab in combination with chemotherapy.

Basis: An international study of 1,217 previously untreated patients with advanced follicular lymphoma; it randomized 1,018 patients who had a complete or partial response with rituximab and chemotherapy. Maintenance treatment with rituximab reduced the risk of progression by 46% compared with observation only.

• Sunitinib (Sutent Capsules, Pfizer, Inc.). A kinase inhibitor for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNETs) in patients with unresectable, locally advanced, or metastatic disease; it was approved soon after everolimus for this indication.

Basis: A randomized controlled study of 171 patients with unresectable, locally advanced or well-differentiated pNET; treatment with somatostatin analogues was allowed. Median progression-free survival was 10.2 months with sunitinib, vs. 5.4 months with placebo.

WARNINGS AND LABEL CHANGES

• Bevacizumab (Avastin, Genentech, Inc.). Revised prescribing information includes the risk of ovarian failure in premenopausal women treated with bevacizumab and chemotherapy; postmarketing reports of osteonecrosis of the jaw in patients treated with bevacizumab but not bisphosphonates; and information from a clinical trial about the risk of venous thromboembolic events and bleeding in patients receiving anticoagulation therapy after a first VTE event while receiving bevacizumab.

• Dasatinib (Sprycel, Bristol-Myers Squibb). Information on increased risk for pulmonary arterial hypertension added to prescribing information.

• Fentanyl. A classwide risk management program approved for all transmucosal immediate-release fentanyl formulations.

• IV methotrexate and proton pump inhibitors (PPIs). A warning added to the methotrexate label advises caution when high-dose methotrexate is administered to patients taking a PPI, because concomitant administration may result in elevated and prolonged serum levels of methotrexate and/or its metabolite hydroxymethotrexate, with possible toxic effects.

• Lenalidomide (Revlimid, Celgene). Advisory informed the public that the FDA is monitoring the risk of secondary cancers in patients treated for myelodysplastic syndromes or multiple myeloma.

• Ondansetron (Zofran, GlaxoSmithKline, and generic formulations). Following a review of information on the risk of QT prolongation, label now recommends ECG monitoring in patients who are treated with ondansetron and have an electrolyte abnormality, congestive heart failure, or bradyarrhythmias; and in patients taking other medications that prolong the QT interval – who are at an increased risk of developing torsades de pointes. Label recommends against use in patients with congenital long QT syndrome. Safety review ongoing.

• Opioids. Draft issued for opioid prescriber education program, as part of the Risk Evaluation and Mitigation Strategy (REMS) now in place for brand-name and generic long-acting and extended-release opioids.

• Pioglitazone. Bladder cancer warning risk added to the label for type 2 diabetes drug marketed as Actos (or in combination with metformin as Actoplus Met, and with glimepiride as Duetact).

• Romiplostim (Nplate for subcutaneous injection, Amgen, Inc.) and eltrombopag (Promacta tablets, GlaxoSmithKline LLC). Elements of the REMS for the two thrombopoietin receptor agonists were dropped, including the restricted distribution program that required health care professionals, hospitals, and patients to be enrolled in order to prescribe, dispense, or receive these drugs. Clinicians no longer need to file periodic safety forms for their patients on these treatments.

• Tumor necrosis factor (TNF) blockers. Manufacturers asked to report cases of malignancies in children, adolescents, and adults aged 30 years and younger treated with TNF blockers and to conduct in-depth follow-up of them.

OTHER ACTIONS

• Bevacizumab (Avastin, Genentech, Inc.). FDA Commissioner Margaret Hamburg withdrew bevacizumab’s indication in metastatic breast cancer. She cited a lack of data establishing benefit and serious risks associated with treatment. The decision followed a July hearing, where the Oncologic Drugs Advisory Committee unanimously voted that the indication be withdrawn despite emotional testimony from patients who said they benefited from the monoclonal antibody.

• Drug shortages. A new rule requires some manufacturers to give early warning of shortages. The agency also held a workshop on the crisis and is working to avert and/or resolve shortages.

• Office of Oncology Products. Many New Drug Applications, Biologic License Applications, and Investigational New Drug Applications for cancer drugs are being reassigned to new review divisions as part of a reorganization.

From an immunotherapy that improves melanoma survival to a device that zaps brain tumors, 2011 was a year of firsts from the FDA. This is our second annual guide to approvals of new cancer drugs, indications, and devices – along with a review of safety warnings and other actions affecting oncology practices.

(Click here for a PDF version of The Oncology Report Guide to Cancer Drugs and Devices in 2011.)

NEW DRUG APPROVALS

• Abiraterone acetate (Zytiga Tablets, Centocor Ortho Biotech, Inc.). An androgen suppressant that decreases testosterone production for use in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have received prior chemotherapy containing docetaxel. The fourth approval in late-stage prostate cancer since April 2010.

Basis: An international study of 1,195 men who had previously received chemotherapy containing docetaxel. Median overall survival was 14.8 months with abiraterone plus prednisone, vs. 10.9 months with prednisone alone.

© Aydin Mutlu/iStockphoto.com

• Asparaginase Erwinia chrysanthemi [Erwinaze for injection, EUSA Pharma (USA), Inc.] An asparagine-specific enzyme approved as a component of a multiagent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL) who developed hypersensitivity to E. coli-derived asparaginase. An orphan drug, it works by the same mechanism as the two previously approved treatments that block asparagine, a protein necessary for the proliferation of neoplastic cells.

Basis: In a single-arm, multicenter, open-label study of 58 patients, all 48 patients with available samples achieved threshold trough asparaginase levels shown to correlate with asparagine depletion and with serum levels that predict clinical efficacy.

• Brentuximab vedotin (Adcetris for injection, Seattle Genetics, Inc.). A CD30-directed antibody-drug conjugate for the treatment of Hodgkin’s lymphoma after failure of autologous stem cell transplant (ASCT) or at least two prior multiagent chemotherapy regimens in patients who are not ASCT candidates, and for the treatment of systemic anaplastic large cell lymphoma (ALCL) after failure of at least one prior multiagent chemotherapy regimen. The first new treatment approved for Hodgkin’s since 1977 and the first treatment approved for ALCL.

Basis: In a single-arm study of 102 patients treated with brentuximab, 73% had either a complete or partial response. In a similarly designed study of 58 patients with ALCL, 86% achieved a partial or complete response.

Addendum: An accelerated approval, based on clinical data suggesting that treatment resulted in significant responses; conversion to full approval is contingent on confirmation of benefits in follow-up studies. (In January 2012, the FDA added a warning about the risk of a rare brain infection to the label.)

• Crizotinib (Xalkori Capsules, Pfizer, Inc.). A kinase inhibitor for the treatment of locally advanced or metastatic non–small cell lung cancer (NSCLC) that express an abnormal anaplastic lymphoma kinase (ALK) gene, as detected by the Vysis ALK Break-Apart FISH Probe Kit (Abbott Molecular, Inc.), a companion diagnostic test approved at the same time.

Basis: In two single-arm studies of 255 patients with locally advanced or metastatic, ALK-positive NSCLC, most of whom had received prior chemotherapy, the overall response rate was 50% and 61%, with a median response duration of 42 and 48 weeks, respectively.

Addendum: An accelerated approval, so conversion to full approval is contingent on follow-up studies confirming clinical benefit.

• Deferiprone (Ferriprox Tablets, ApoPharma, Inc.). An oral iron chelator for the treatment of patients with transfusional iron overload due to thalassemia syndromes when current chelation therapy is inadequate.

Basis: A prospective pooled analysis of previously conducted studies of 236 patients (most had thalassemia syndromes) with transfusion-dependent iron overload, for which previous iron chelation therapy had failed or was considered inadequate because of poor tolerance. Within 1 year of starting treatment, 50% of the patients had at least a 20% decrease in serum ferritin levels.

Addendum: An accelerated approval. Safety and effectiveness not established for the treatment of transfusional iron overload due to other chronic anemias, including sickle cell disease. As a condition of approval, ApoPharma will conduct a study of safety and efficacy in patients with sickle cell disease and transfusional iron overload not adequately treated with available chelating agents.

• Hemacord (New York Blood Center). A hematopoietic progenitor cells–cord (HPC-C) preparation for allogenic hematopoietic stem cell transplantation. The first approval of a license for an umbilical cord blood therapy.

Basis: Safety and effectiveness data submitted to a public docket and data submitted in the license application demonstrating compliance with other regulatory requirements.

• Ipilimumab injection (Yervoy, Bristol-Myers Squibb). A human cytotoxic T-lymphocyte antigen (CTLA-4)-blocking antibody for the treatment of unresectable or metastatic melanoma. The first treatment proven to prolong survival in patients with metastatic melanoma.

Basis: An international study of 676 patients with previously treated unresectable stage III or IV melanoma whose disease had progressed, comparing ipilimumab plus an experimental tumor vaccine (gp100), gp100 alone, and ipilimumab alone. Median overall survival was 10 months among those who received ipilimumab with or without the vaccine, vs. 6 months among those who received the vaccine alone.

Addendum: Approved with a Risk Evaluation and Mitigation Strategy (REMS) program addressing life-threatening toxicity and deaths associated with ipilimumab in the study. Acts slowly, and some patients may have tumor progression before therapy becomes effective.

• Ruxolitinib (Jakafi oral tablets, Incyte Corp.). A Janus-associated kinase (JAK) inhibitor for the treatment of intermediate- or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis, and post–essential thrombocythemia myelofibrosis. An orphan drug that is the first treatment approved for the rare blood disease – and the first approved JAK inhibitor.

Basis: Two randomized controlled trials of 528 patients with intermediate- or high-risk myelofibrosis. In one study, 42% of those on ruxolitinib had more than at least a 35% reduction in spleen volume vs. 1% of those on placebo at 24 weeks, and nearly half of those on treatment had achieved at least a 50% reduction in myelofibrosis symptoms, vs. 5% of those on placebo. In the second study, 29% of those on ruxolitinib had at least a 35% reduction in spleen size, vs. none of those on best available therapy after 48 weeks.

• Vandetanib (Caprelsa, AstraZeneca Pharmaceuticals LP). A kinase inhibitor for the treatment of symptomatic or progressive medullary thyroid cancer in adults with unresectable, locally advanced, or metastatic disease. The first drug approved for this rare cancer.

Basis: An international study of 331 patients with unresectable locally advanced or metastatic medullary thyroid cancer. Median progression-free survival was at least 22.6 months with vandetanib vs. 16.4 months among with placebo, a highly significant difference.

Addendum: Approved with a REMS addressing the risk of QT interval prolongation and a note that use in patients with indolent, asymptomatic, or slowly progressing disease "should be carefully considered" because of treatment-associated risks, as well as a boxed warning and a restricted distribution program.

• Vemurafenib (Zelboraf tablets, Hoffmann-LaRoche, Inc.). A BRAF inhibitor for the treatment of patients with unresectable or metastatic melanoma with the BRAF^V600E mutation, as detected by the cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems), a companion diagnostic test approved at the same time. The second therapy found to prolong survival in patients with melanoma.

Basis: A study of 675 treatment-naive patients with unresectable or metastatic melanoma, positive for the BRAF^V600E mutation. At the time of review, median survival was 7.9 months in a control group treated with dacarbazine, but had not been reached among those on vemurafenib. Median progression-free survival was 1.6 and 5.3 months, respectively.

Addendum: About half of melanoma patients have the BRAF mutation, and about half of them respond to vemurafenib. Approved with a medication guide to inform patients about the need for the diagnostic test and potential risks associated with treatment, including cutaneous squamous cell carcinoma. Roche and ipilimumab manufacturer Bristol-Meyers Squibb announced collaboration on a phase I/II study to determine whether combining the two agents is safe and effective in patients with BRAF mutations.

Photo courtesy Mela Sciences

NEW DEVICES

• MelaFind (Mela Sciences). A noninvasive melanoma detection device for use "on clinically atypical cutaneous pigmented lesions with one or more clinical or historical characteristics of melanoma, excluding those with a clinical diagnosis of melanoma or likely melanoma."

Basis: The road to approval was controversial, with a split vote from an advisory panel, a citizens petition submitted by the manufacturer, and an agreement between the agency and manufacturer on how the device would be used and by whom.

• NovoTTF-100A System (NovoTTF, Novocure). A portable, battery-powered device that delivers electrical fields to the brain as a treatment for adults with glioblastoma multiforme that has recurred after chemotherapy.

Basis: In a randomized study of 237 patients whose GBM had recurred after surgery, radiation, and chemotherapy, median overall survival was 6.3 months with the approximately 6-pound device and 6.4 months with best available chemotherapy. The agency cited evidence suggesting better quality of life without chemotherapy side effects.

NEW INDICATIONS

• Cetuximab (Erbitux, ImClone LLC, a wholly owned subsidiary of Eli Lilly & Co. and Bristol-Myers Squibb). The epidermal growth factor receptor (EGFR) antagonist in combination with platinum-based therapy plus 5-fluorouracil for the first-line treatment of recurrent locoregional and/or metastatic squamous cell carcinoma of the head and neck.

Basis: A multicenter non-U.S. study of 442 patients not suitable for potentially curative treatment with surgery or radiation. Mean overall survival was 10.1 months with cetuximab and chemotherapy (cisplatin or carboplatin and 5-fluorouracil), vs. 7.4 months with chemotherapy alone.

Addendum: Cetuximab available in the United States provides about 22% greater exposure than the European Union–approved cetuximab used in this study, but the study results, pharmacokinetic data, and other clinical trial data "establish the efficacy" of cetuximab at the dose recommended, according to the prescribing information.

• Denosumab (Prolia, Amgen, Inc.). The RANK ligand (RANKL) inhibitor to increase bone mass in patients at high risk for fracture when receiving androgen deprivation therapy (ADT) for nonmetastatic prostate cancer or adjuvant aromatase inhibitor (AI) therapy for breast cancer.

Basis: Two international, randomized, double-blind placebo-controlled studies. In one study of 1,468 men with nonmetastatic prostate cancer receiving ADT, lumbar spine bone mineral density (BMD) at 2 years was significantly higher with denosumab vs. placebo (6.7% difference). At 3 years of treatment, the incidence of new vertebral fractures was 1.5% with denosumab vs. 3.9% with placebo, a risk reduction of 62%. In a study of 252 postmenopausal women with breast cancer on AI treatment, BMD at the lumbar spine was significantly higher with denosumab vs. placebo after 12 months of treatment (5.5% difference).

Addendum: Denosumab was initially approved in 2010. It is marketed as Prolia for treating postmenopausal women with osteoporosis at high risk of fracture, and as Xgeva for preventing skeletal-related events in patients with bone metastases from solid tumors; Xgeva is administered more frequently and at a higher dose for the latter indication.

• Everolimus (Afinitor Tablets, Novartis Pharmaceuticals Corp.). The mammalian target of rapamycin (mTOR) inhibitor for progressive pancreatic neuroendocrine tumors (pNETs) that are unresectable, locally advanced, or metastatic. (Safety and effectiveness of everolimus for treating carcinoid tumors have not been established). The first new drug in about 30 years for the treatment of advanced pNET.

Basis: A randomized controlled study of 410 patients, all of whom also received best supportive care. Median progression-free survival was 11 months with everolimus, vs. 4.6 months with placebo. In an interim analysis, overall survival was not different between the two groups.

• Peg-interferon alfa-2b (Sylatron, Schering Corp.). An alpha interferon for the adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resection, including complete lymphadenectomy.

Basis: An open-label multicenter study of 1,256 patients. Median relapse-free survival was 34.8 months among those treated with peg-interferon alfa-2b, vs. 25.5 months with observation.

• Rituximab (Rituxan, Genentech, Inc.). The CD20-directed cytolytic antibody for maintenance therapy in people with previously untreated follicular, CD-20 positive, B-cell non-Hodgkin lymphoma who achieve a response to rituximab in combination with chemotherapy.

Basis: An international study of 1,217 previously untreated patients with advanced follicular lymphoma; it randomized 1,018 patients who had a complete or partial response with rituximab and chemotherapy. Maintenance treatment with rituximab reduced the risk of progression by 46% compared with observation only.

• Sunitinib (Sutent Capsules, Pfizer, Inc.). A kinase inhibitor for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNETs) in patients with unresectable, locally advanced, or metastatic disease; it was approved soon after everolimus for this indication.

Basis: A randomized controlled study of 171 patients with unresectable, locally advanced or well-differentiated pNET; treatment with somatostatin analogues was allowed. Median progression-free survival was 10.2 months with sunitinib, vs. 5.4 months with placebo.

WARNINGS AND LABEL CHANGES

• Bevacizumab (Avastin, Genentech, Inc.). Revised prescribing information includes the risk of ovarian failure in premenopausal women treated with bevacizumab and chemotherapy; postmarketing reports of osteonecrosis of the jaw in patients treated with bevacizumab but not bisphosphonates; and information from a clinical trial about the risk of venous thromboembolic events and bleeding in patients receiving anticoagulation therapy after a first VTE event while receiving bevacizumab.

• Dasatinib (Sprycel, Bristol-Myers Squibb). Information on increased risk for pulmonary arterial hypertension added to prescribing information.

• Fentanyl. A classwide risk management program approved for all transmucosal immediate-release fentanyl formulations.

• IV methotrexate and proton pump inhibitors (PPIs). A warning added to the methotrexate label advises caution when high-dose methotrexate is administered to patients taking a PPI, because concomitant administration may result in elevated and prolonged serum levels of methotrexate and/or its metabolite hydroxymethotrexate, with possible toxic effects.

• Lenalidomide (Revlimid, Celgene). Advisory informed the public that the FDA is monitoring the risk of secondary cancers in patients treated for myelodysplastic syndromes or multiple myeloma.

• Ondansetron (Zofran, GlaxoSmithKline, and generic formulations). Following a review of information on the risk of QT prolongation, label now recommends ECG monitoring in patients who are treated with ondansetron and have an electrolyte abnormality, congestive heart failure, or bradyarrhythmias; and in patients taking other medications that prolong the QT interval – who are at an increased risk of developing torsades de pointes. Label recommends against use in patients with congenital long QT syndrome. Safety review ongoing.

• Opioids. Draft issued for opioid prescriber education program, as part of the Risk Evaluation and Mitigation Strategy (REMS) now in place for brand-name and generic long-acting and extended-release opioids.

• Pioglitazone. Bladder cancer warning risk added to the label for type 2 diabetes drug marketed as Actos (or in combination with metformin as Actoplus Met, and with glimepiride as Duetact).

• Romiplostim (Nplate for subcutaneous injection, Amgen, Inc.) and eltrombopag (Promacta tablets, GlaxoSmithKline LLC). Elements of the REMS for the two thrombopoietin receptor agonists were dropped, including the restricted distribution program that required health care professionals, hospitals, and patients to be enrolled in order to prescribe, dispense, or receive these drugs. Clinicians no longer need to file periodic safety forms for their patients on these treatments.

• Tumor necrosis factor (TNF) blockers. Manufacturers asked to report cases of malignancies in children, adolescents, and adults aged 30 years and younger treated with TNF blockers and to conduct in-depth follow-up of them.

OTHER ACTIONS

• Bevacizumab (Avastin, Genentech, Inc.). FDA Commissioner Margaret Hamburg withdrew bevacizumab’s indication in metastatic breast cancer. She cited a lack of data establishing benefit and serious risks associated with treatment. The decision followed a July hearing, where the Oncologic Drugs Advisory Committee unanimously voted that the indication be withdrawn despite emotional testimony from patients who said they benefited from the monoclonal antibody.

• Drug shortages. A new rule requires some manufacturers to give early warning of shortages. The agency also held a workshop on the crisis and is working to avert and/or resolve shortages.

• Office of Oncology Products. Many New Drug Applications, Biologic License Applications, and Investigational New Drug Applications for cancer drugs are being reassigned to new review divisions as part of a reorganization.

From an immunotherapy that improves melanoma survival to a device that zaps brain tumors, 2011 was a year of firsts from the FDA. This is our second annual guide to approvals of new cancer drugs, indications, and devices – along with a review of safety warnings and other actions affecting oncology practices.

(Click here for a PDF version of The Oncology Report Guide to Cancer Drugs and Devices in 2011.)

NEW DRUG APPROVALS

• Abiraterone acetate (Zytiga Tablets, Centocor Ortho Biotech, Inc.). An androgen suppressant that decreases testosterone production for use in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have received prior chemotherapy containing docetaxel. The fourth approval in late-stage prostate cancer since April 2010.

Basis: An international study of 1,195 men who had previously received chemotherapy containing docetaxel. Median overall survival was 14.8 months with abiraterone plus prednisone, vs. 10.9 months with prednisone alone.

© Aydin Mutlu/iStockphoto.com

• Asparaginase Erwinia chrysanthemi [Erwinaze for injection, EUSA Pharma (USA), Inc.] An asparagine-specific enzyme approved as a component of a multiagent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL) who developed hypersensitivity to E. coli-derived asparaginase. An orphan drug, it works by the same mechanism as the two previously approved treatments that block asparagine, a protein necessary for the proliferation of neoplastic cells.

Basis: In a single-arm, multicenter, open-label study of 58 patients, all 48 patients with available samples achieved threshold trough asparaginase levels shown to correlate with asparagine depletion and with serum levels that predict clinical efficacy.

• Brentuximab vedotin (Adcetris for injection, Seattle Genetics, Inc.). A CD30-directed antibody-drug conjugate for the treatment of Hodgkin’s lymphoma after failure of autologous stem cell transplant (ASCT) or at least two prior multiagent chemotherapy regimens in patients who are not ASCT candidates, and for the treatment of systemic anaplastic large cell lymphoma (ALCL) after failure of at least one prior multiagent chemotherapy regimen. The first new treatment approved for Hodgkin’s since 1977 and the first treatment approved for ALCL.

Basis: In a single-arm study of 102 patients treated with brentuximab, 73% had either a complete or partial response. In a similarly designed study of 58 patients with ALCL, 86% achieved a partial or complete response.

Addendum: An accelerated approval, based on clinical data suggesting that treatment resulted in significant responses; conversion to full approval is contingent on confirmation of benefits in follow-up studies. (In January 2012, the FDA added a warning about the risk of a rare brain infection to the label.)

• Crizotinib (Xalkori Capsules, Pfizer, Inc.). A kinase inhibitor for the treatment of locally advanced or metastatic non–small cell lung cancer (NSCLC) that express an abnormal anaplastic lymphoma kinase (ALK) gene, as detected by the Vysis ALK Break-Apart FISH Probe Kit (Abbott Molecular, Inc.), a companion diagnostic test approved at the same time.

Basis: In two single-arm studies of 255 patients with locally advanced or metastatic, ALK-positive NSCLC, most of whom had received prior chemotherapy, the overall response rate was 50% and 61%, with a median response duration of 42 and 48 weeks, respectively.

Addendum: An accelerated approval, so conversion to full approval is contingent on follow-up studies confirming clinical benefit.

• Deferiprone (Ferriprox Tablets, ApoPharma, Inc.). An oral iron chelator for the treatment of patients with transfusional iron overload due to thalassemia syndromes when current chelation therapy is inadequate.

Basis: A prospective pooled analysis of previously conducted studies of 236 patients (most had thalassemia syndromes) with transfusion-dependent iron overload, for which previous iron chelation therapy had failed or was considered inadequate because of poor tolerance. Within 1 year of starting treatment, 50% of the patients had at least a 20% decrease in serum ferritin levels.

Addendum: An accelerated approval. Safety and effectiveness not established for the treatment of transfusional iron overload due to other chronic anemias, including sickle cell disease. As a condition of approval, ApoPharma will conduct a study of safety and efficacy in patients with sickle cell disease and transfusional iron overload not adequately treated with available chelating agents.

• Hemacord (New York Blood Center). A hematopoietic progenitor cells–cord (HPC-C) preparation for allogenic hematopoietic stem cell transplantation. The first approval of a license for an umbilical cord blood therapy.

Basis: Safety and effectiveness data submitted to a public docket and data submitted in the license application demonstrating compliance with other regulatory requirements.

• Ipilimumab injection (Yervoy, Bristol-Myers Squibb). A human cytotoxic T-lymphocyte antigen (CTLA-4)-blocking antibody for the treatment of unresectable or metastatic melanoma. The first treatment proven to prolong survival in patients with metastatic melanoma.

Basis: An international study of 676 patients with previously treated unresectable stage III or IV melanoma whose disease had progressed, comparing ipilimumab plus an experimental tumor vaccine (gp100), gp100 alone, and ipilimumab alone. Median overall survival was 10 months among those who received ipilimumab with or without the vaccine, vs. 6 months among those who received the vaccine alone.

Addendum: Approved with a Risk Evaluation and Mitigation Strategy (REMS) program addressing life-threatening toxicity and deaths associated with ipilimumab in the study. Acts slowly, and some patients may have tumor progression before therapy becomes effective.

• Ruxolitinib (Jakafi oral tablets, Incyte Corp.). A Janus-associated kinase (JAK) inhibitor for the treatment of intermediate- or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis, and post–essential thrombocythemia myelofibrosis. An orphan drug that is the first treatment approved for the rare blood disease – and the first approved JAK inhibitor.

Basis: Two randomized controlled trials of 528 patients with intermediate- or high-risk myelofibrosis. In one study, 42% of those on ruxolitinib had more than at least a 35% reduction in spleen volume vs. 1% of those on placebo at 24 weeks, and nearly half of those on treatment had achieved at least a 50% reduction in myelofibrosis symptoms, vs. 5% of those on placebo. In the second study, 29% of those on ruxolitinib had at least a 35% reduction in spleen size, vs. none of those on best available therapy after 48 weeks.

• Vandetanib (Caprelsa, AstraZeneca Pharmaceuticals LP). A kinase inhibitor for the treatment of symptomatic or progressive medullary thyroid cancer in adults with unresectable, locally advanced, or metastatic disease. The first drug approved for this rare cancer.

Basis: An international study of 331 patients with unresectable locally advanced or metastatic medullary thyroid cancer. Median progression-free survival was at least 22.6 months with vandetanib vs. 16.4 months among with placebo, a highly significant difference.

Addendum: Approved with a REMS addressing the risk of QT interval prolongation and a note that use in patients with indolent, asymptomatic, or slowly progressing disease "should be carefully considered" because of treatment-associated risks, as well as a boxed warning and a restricted distribution program.

• Vemurafenib (Zelboraf tablets, Hoffmann-LaRoche, Inc.). A BRAF inhibitor for the treatment of patients with unresectable or metastatic melanoma with the BRAF^V600E mutation, as detected by the cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems), a companion diagnostic test approved at the same time. The second therapy found to prolong survival in patients with melanoma.

Basis: A study of 675 treatment-naive patients with unresectable or metastatic melanoma, positive for the BRAF^V600E mutation. At the time of review, median survival was 7.9 months in a control group treated with dacarbazine, but had not been reached among those on vemurafenib. Median progression-free survival was 1.6 and 5.3 months, respectively.

Addendum: About half of melanoma patients have the BRAF mutation, and about half of them respond to vemurafenib. Approved with a medication guide to inform patients about the need for the diagnostic test and potential risks associated with treatment, including cutaneous squamous cell carcinoma. Roche and ipilimumab manufacturer Bristol-Meyers Squibb announced collaboration on a phase I/II study to determine whether combining the two agents is safe and effective in patients with BRAF mutations.

Photo courtesy Mela Sciences

NEW DEVICES

• MelaFind (Mela Sciences). A noninvasive melanoma detection device for use "on clinically atypical cutaneous pigmented lesions with one or more clinical or historical characteristics of melanoma, excluding those with a clinical diagnosis of melanoma or likely melanoma."

Basis: The road to approval was controversial, with a split vote from an advisory panel, a citizens petition submitted by the manufacturer, and an agreement between the agency and manufacturer on how the device would be used and by whom.

• NovoTTF-100A System (NovoTTF, Novocure). A portable, battery-powered device that delivers electrical fields to the brain as a treatment for adults with glioblastoma multiforme that has recurred after chemotherapy.

Basis: In a randomized study of 237 patients whose GBM had recurred after surgery, radiation, and chemotherapy, median overall survival was 6.3 months with the approximately 6-pound device and 6.4 months with best available chemotherapy. The agency cited evidence suggesting better quality of life without chemotherapy side effects.

NEW INDICATIONS

• Cetuximab (Erbitux, ImClone LLC, a wholly owned subsidiary of Eli Lilly & Co. and Bristol-Myers Squibb). The epidermal growth factor receptor (EGFR) antagonist in combination with platinum-based therapy plus 5-fluorouracil for the first-line treatment of recurrent locoregional and/or metastatic squamous cell carcinoma of the head and neck.

Basis: A multicenter non-U.S. study of 442 patients not suitable for potentially curative treatment with surgery or radiation. Mean overall survival was 10.1 months with cetuximab and chemotherapy (cisplatin or carboplatin and 5-fluorouracil), vs. 7.4 months with chemotherapy alone.

Addendum: Cetuximab available in the United States provides about 22% greater exposure than the European Union–approved cetuximab used in this study, but the study results, pharmacokinetic data, and other clinical trial data "establish the efficacy" of cetuximab at the dose recommended, according to the prescribing information.

• Denosumab (Prolia, Amgen, Inc.). The RANK ligand (RANKL) inhibitor to increase bone mass in patients at high risk for fracture when receiving androgen deprivation therapy (ADT) for nonmetastatic prostate cancer or adjuvant aromatase inhibitor (AI) therapy for breast cancer.

Basis: Two international, randomized, double-blind placebo-controlled studies. In one study of 1,468 men with nonmetastatic prostate cancer receiving ADT, lumbar spine bone mineral density (BMD) at 2 years was significantly higher with denosumab vs. placebo (6.7% difference). At 3 years of treatment, the incidence of new vertebral fractures was 1.5% with denosumab vs. 3.9% with placebo, a risk reduction of 62%. In a study of 252 postmenopausal women with breast cancer on AI treatment, BMD at the lumbar spine was significantly higher with denosumab vs. placebo after 12 months of treatment (5.5% difference).

Addendum: Denosumab was initially approved in 2010. It is marketed as Prolia for treating postmenopausal women with osteoporosis at high risk of fracture, and as Xgeva for preventing skeletal-related events in patients with bone metastases from solid tumors; Xgeva is administered more frequently and at a higher dose for the latter indication.

• Everolimus (Afinitor Tablets, Novartis Pharmaceuticals Corp.). The mammalian target of rapamycin (mTOR) inhibitor for progressive pancreatic neuroendocrine tumors (pNETs) that are unresectable, locally advanced, or metastatic. (Safety and effectiveness of everolimus for treating carcinoid tumors have not been established). The first new drug in about 30 years for the treatment of advanced pNET.

Basis: A randomized controlled study of 410 patients, all of whom also received best supportive care. Median progression-free survival was 11 months with everolimus, vs. 4.6 months with placebo. In an interim analysis, overall survival was not different between the two groups.

• Peg-interferon alfa-2b (Sylatron, Schering Corp.). An alpha interferon for the adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resection, including complete lymphadenectomy.

Basis: An open-label multicenter study of 1,256 patients. Median relapse-free survival was 34.8 months among those treated with peg-interferon alfa-2b, vs. 25.5 months with observation.

• Rituximab (Rituxan, Genentech, Inc.). The CD20-directed cytolytic antibody for maintenance therapy in people with previously untreated follicular, CD-20 positive, B-cell non-Hodgkin lymphoma who achieve a response to rituximab in combination with chemotherapy.

Basis: An international study of 1,217 previously untreated patients with advanced follicular lymphoma; it randomized 1,018 patients who had a complete or partial response with rituximab and chemotherapy. Maintenance treatment with rituximab reduced the risk of progression by 46% compared with observation only.

• Sunitinib (Sutent Capsules, Pfizer, Inc.). A kinase inhibitor for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNETs) in patients with unresectable, locally advanced, or metastatic disease; it was approved soon after everolimus for this indication.

Basis: A randomized controlled study of 171 patients with unresectable, locally advanced or well-differentiated pNET; treatment with somatostatin analogues was allowed. Median progression-free survival was 10.2 months with sunitinib, vs. 5.4 months with placebo.

WARNINGS AND LABEL CHANGES

• Bevacizumab (Avastin, Genentech, Inc.). Revised prescribing information includes the risk of ovarian failure in premenopausal women treated with bevacizumab and chemotherapy; postmarketing reports of osteonecrosis of the jaw in patients treated with bevacizumab but not bisphosphonates; and information from a clinical trial about the risk of venous thromboembolic events and bleeding in patients receiving anticoagulation therapy after a first VTE event while receiving bevacizumab.

• Dasatinib (Sprycel, Bristol-Myers Squibb). Information on increased risk for pulmonary arterial hypertension added to prescribing information.

• Fentanyl. A classwide risk management program approved for all transmucosal immediate-release fentanyl formulations.

• IV methotrexate and proton pump inhibitors (PPIs). A warning added to the methotrexate label advises caution when high-dose methotrexate is administered to patients taking a PPI, because concomitant administration may result in elevated and prolonged serum levels of methotrexate and/or its metabolite hydroxymethotrexate, with possible toxic effects.

• Lenalidomide (Revlimid, Celgene). Advisory informed the public that the FDA is monitoring the risk of secondary cancers in patients treated for myelodysplastic syndromes or multiple myeloma.

• Ondansetron (Zofran, GlaxoSmithKline, and generic formulations). Following a review of information on the risk of QT prolongation, label now recommends ECG monitoring in patients who are treated with ondansetron and have an electrolyte abnormality, congestive heart failure, or bradyarrhythmias; and in patients taking other medications that prolong the QT interval – who are at an increased risk of developing torsades de pointes. Label recommends against use in patients with congenital long QT syndrome. Safety review ongoing.

• Opioids. Draft issued for opioid prescriber education program, as part of the Risk Evaluation and Mitigation Strategy (REMS) now in place for brand-name and generic long-acting and extended-release opioids.

• Pioglitazone. Bladder cancer warning risk added to the label for type 2 diabetes drug marketed as Actos (or in combination with metformin as Actoplus Met, and with glimepiride as Duetact).

• Romiplostim (Nplate for subcutaneous injection, Amgen, Inc.) and eltrombopag (Promacta tablets, GlaxoSmithKline LLC). Elements of the REMS for the two thrombopoietin receptor agonists were dropped, including the restricted distribution program that required health care professionals, hospitals, and patients to be enrolled in order to prescribe, dispense, or receive these drugs. Clinicians no longer need to file periodic safety forms for their patients on these treatments.

• Tumor necrosis factor (TNF) blockers. Manufacturers asked to report cases of malignancies in children, adolescents, and adults aged 30 years and younger treated with TNF blockers and to conduct in-depth follow-up of them.

OTHER ACTIONS

• Bevacizumab (Avastin, Genentech, Inc.). FDA Commissioner Margaret Hamburg withdrew bevacizumab’s indication in metastatic breast cancer. She cited a lack of data establishing benefit and serious risks associated with treatment. The decision followed a July hearing, where the Oncologic Drugs Advisory Committee unanimously voted that the indication be withdrawn despite emotional testimony from patients who said they benefited from the monoclonal antibody.

• Drug shortages. A new rule requires some manufacturers to give early warning of shortages. The agency also held a workshop on the crisis and is working to avert and/or resolve shortages.

• Office of Oncology Products. Many New Drug Applications, Biologic License Applications, and Investigational New Drug Applications for cancer drugs are being reassigned to new review divisions as part of a reorganization.