FDA Update

TON - January 2015 Vol 8 No 1 - FDA Approvals

Jakafi Gets New Indication for Use in Patients with Polycythemia Vera

The FDA approved ruxolitinib (Jakafi; Incyte Corporation) for the treatment of patients with polycythemia vera (PV) who have had an inadequate response to or are intolerant of hydroxyurea. The FDA approval was based on Protocol CINC424B2301, a multicenter, open-­label, active-control trial of 222 patients with PV whose disease was resistant to or who were intolerant of hydroxyurea. The composite end point was durable hemat­ocrit control and spleen volume reduction, and a durable hematocrit control that obviated the need for regular phlebotomy. Patients were randomized to ruxolitinib 10 mg twice daily (N = 110) or to best available care (N = 112).

Ruxolitinib was superior to best available therapy in durable hematocrit control and in spleen volume reduction at week 32 (21% vs 1%; P <.001) and at week 48 (19% vs 1%; P <.001), as well as in a relatively high rate (55%) of durable hematocrit control at week 48.

The most common hematologic adverse reactions (incidence >20%) through week 32 were thrombocytopenia and anemia. The most common nonhematologic adverse events (incidence >10%) were headache, abdominal pain, diarrhea, dizziness, fatigue, pruritus, dyspnea, and muscle spasms. Overall, 4% of patients discontinued therapy with ruxolitinib because of adverse events. (December 14, 2014)


Cyramza Approved in Combination with Docetaxel for Metastatic NSCLC

Ramucirumab (Cyramza; Eli Lilly) received a new indication for use in combination with docetaxel for the treatment of patients with metastatic non–small-cell lung cancer (NSCLC) whose disease is progressing with or after platinum-based chemotherapy. In patients with EGFR or ALK mutations, disease progression should be considered for treatment with an FDA-approved medication for these genetic mutations before administering ramucirumab. Earlier in the year, the FDA approved ramucirumab alone and in combination with paclitaxel for the treatment of patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma after disease progression while using first-line therapy.

The approval of ramucirumab in combination with docetaxel for patients with NSCLC was based on results of the multicenter, double-blind, placebo-­controlled study of 1253 patients with previously treated metastatic NSCLC that showed improved overall survival (OS). Patients were randomized to ramucirumab in combination with docetaxel on day 1 of a 21-day cycle (N = 628) or to placebo plus docetaxel (N = 625). The median OS was 10.5 months in the ramucirumab plus docetaxel arm and 9.1 months in the placebo plus docetaxel arm, a significant difference (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.75-0.98; P = .024). Progression-free survival (PFS) was also significantly longer with ramucirumab than with placebo (HR, 0.76; 95% CI, 0.68-0.86; P <.001).

Among 1245 patients who received at least 1 dose of ramucirumab plus docetaxel, the most frequent adverse reactions (incidence ≥30%) were neutropenia, fatigue/asthenia, and stomatitis/mucosal inflammation. The most common serious adverse reactions with the active combination were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). (December 12, 2014)


Cyramza plus Paclitaxel for Advanced Gastric Cancer After Chemotherapy

The FDA approved ramucirumab (Cyramza; Eli Lilly) in combination with paclitaxel for patients with advanced or metastatic gastric cancer or with GEJ adenocarcinoma whose cancer has progressed while receiving or after fluoropyrimidine- or platinum-containing chemotherapy. In April, ramucirumab was approved as monotherapy for advanced or metastatic gastric cancer or GEJ adenocarcinoma.

This new approval was based on the RAINBOW study, a phase 3 clinical trial that compared ramucirumab plus paclitaxel versus placebo plus paclitaxel. Ramucirumab plus paclitaxel significantly extended median OS at 9.6 months compared with 7.4 months (P = .017) with placebo plus paclitaxel. Furthermore, ramucirumab plus paclitaxel significantly delayed disease progression: the PFS was 4.4 months with the active combination versus 2.9 months (P <.001) with placebo plus paclitaxel. Overall, 28% of patients responded to ramucirumab plus paclitaxel versus 16% with placebo plus paclitaxel (P <.001).

The FDA approved this new therapy with a boxed warning regarding the risk for bleeding, including severe and sometimes fatal hemorrhaging. Ramucirumab injection should be permanently discontinued in patients with severe bleeding.

The most common adverse reactions in the trial with the active combination and ≥2% higher than in the placebo group were fatigue, neutropenia, diarrhea, and epistaxis. The most common serious adverse events with ramuciru­mab plus paclitaxel were neutro­penia (3.7%) and febrile neutropenia (2.4%); furthermore, 19% of patients receiving the active combination had to receive granulocyte colony-stimulating factors. (November 5, 2014)


Blincyto First Immunotherapy Approved for B-Cell Acute Lymphoblastic Leukemia

The FDA approved blinatumomab (Blincyto; Amgen) for the treatment of patients with relapsed or refractory Philadelphia chromosome (Ph)-negative precursor B-cell acute lymphoblastic leukemia (ALL), a rare and rapidly growing form of ALL. Blinatumomab is intended for use in patients with B-cell ALL. Blinatumomab is the first immunotherapy approved by the FDA for patients with leukemia. The drug acts as a connector between the CD19 protein (which is found on the surface of most B-cell lymphoblasts) and the CD3 protein found on T-cell lymphocytes, using the body’s T-cells to destroy the leukemia cells.

The FDA had initially granted this drug a breakthrough therapy designation, and applied its priority review and accelerated approval program to approve the drug 5 months ahead of the scheduled date. Blinatumomab has an orphan drug designation. The FDA is now requiring the manufacturer to conduct a new clinical trial to show a survival benefit with blinatumomab in patients with relapsed or refractory Ph-negative precursor B-cell ALL.

The approval was based on the safety and efficacy of blinatumomab in a clinical trial of 185 adults with Ph-negative relapsed or refractory precursor B-cell ALL. All patients received an infusion of blinatumomab for at least 4 weeks. The results showed a 32% complete remission rate lasting approximately 6.7 months. The trial was not designed to show improvement in survival.

Blinatumomab is associated with significant risks, including cytokine release syndrome, encephalopathy, and nervous system adverse events. The most common side effects reported were pyrexia, headache, peripheral edema, febrile neutropenia, nausea, hypokalemia, fatigue, constipation, diarrhea, and tremor.

Blinatumomab was approved with a Risk Evaluation and Mitigation Strategy (REMS) program to inform healthcare providers about the serious risks associated with this medication. The product information also carries a boxed warning to alert providers of the risks and serious side effects associated with the use of blinatumomab. (December 3, 2014)


Avastin plus Chemotherapy for Platinum-Resistant Gynecologic Cancers

The FDA approved a new indication for bevacizumab solution (Avastin; Genentech) to be used in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan for the treatment of patients with platinum-resistant, recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer.

The approval is based on the results of the AURELIA study, an international, randomized trial with investigator-assessed PFS. AURELIA compared bevacizumab plus chemotherapy versus chemotherapy alone. Overall, 179 patients were randomized to bevaciz­umab plus chemotherapy and 182 patients received chemotherapy alone with 1 of the 3 chemotherapies.
Treatment continued until disease progression, unacceptable toxicity, and/or consent withdrawal. All the patients had received ≤2 previous chemotherapy regimens, had ECOG performance status of 0 to 2, and had disease recurrence within <6 months of the platinum-based therapy.

Bevacizumab plus chemotherapy had a significant PFS improvement compared with chemotherapy alone (HR, 0.38; 95% CI, 0.30-0.49; P <.001), with a median PFS of 6.8 months versus 3.4 months, respectively; however, the OS was not significantly different, with a median OS of 16.6 months versus 13.3 months, respectively (HR, 0.89; 95% CI, 0.69-1.14).

The most common adverse reactions (≥15%) with bevacizumab plus chemotherapy were neutropenia, peripheral sensory neuropathy, and hypertension. Gastrointestinal perforations were reported in 1.7% of patients who received bevacizumab. (November 14, 2014)


FDA Approves Nivolumab for Advanced Melanoma

The US Food and Drug Administration (FDA) recently approved nivolu­mab (Opdivo; Bristol-Myers Squibb Company), a human programmed death receptor-1 blocking antibody, for the treatment of patients with unresectable or metastatic melanoma that no longer responds to ipilimumab. The drug was also approved for the treatment of patients with melanoma with a BRAF V600 mutation that no longer responds to ipilimumab and BRAF inhibitor therapy.

The FDA accelerated its approval of nivolumab based on interim data from the CheckMate 037 phase 3 trial showing a 32% (N = 38) objective response rate (ORR) in the first 120 patients who received the drug. This response lasted for >6 months in approximately one third of the patients. The 32% ORR (95% confidence interval, 23, 41) was based on data from 4 patients (3%) who achieved a complete response and 34 patients (28%) who achieved a partial response.

Efficacy of the drug was evaluated during a planned, interim, single-arm analysis of data from the phase 3, randomized, open-label CheckMate 037 trial. A total of 268 patients received the 3-mg/kg intravenous dose every 2 weeks; patients in the comparator arm (N = 102) received an investigator’s choice of chemotherapy: single-agent dacarbazine or a combination of carboplatin plus paclitaxel. The primary objectives in this trial are ORR and overall survival. The study is ongoing but no longer recruiting patients.

The most common adverse reaction reported among patients receiving the study drug was rash (21%). Grade 3/4 adverse reactions occurred in 42% of the patients receiving the study drug. The most frequent of these—reported in 2% to <5% of patients receiving the study drug—were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase.

The FDA granted breakthrough therapy designation, priority review, and orphan product designation for nivolumab because (1) preliminary clinical evidence demonstrated that the drug may offer a substantial improvement over available therapies; (2) the drug has the potential to be a significant improvement in safety or effectiveness in the treatment of a serious condition; and (3) the drug is intended to treat a rare disease, respectively.

“Opdivo is the seventh new melanoma drug approved by the FDA since 2011,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “The continued development and approval of novel therapies based on our increasing understanding of tumor immunology and molecular pathways are changing the treatment paradigm for serious and life-threatening diseases.” (December 22, 2014)

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Last modified: May 21, 2015