FDA News – January 2017

January 2017, Vol 7, No 1 - FDA Approvals, News & Updates

In This Article

Rubraca Approved for Advanced Ovarian Cancer with BRCA Mutations

On December 19, 2016, the FDA accelerated the approval of rucaparib (Rubraca; Clovis Oncology) for the treatment of women with BRCA mutation (germline and/or somatic) associated with advanced ovarian cancer who received ≥2 regimens of chemotherapy. The drug was reviewed by the FDA under its priority review program and has also received a breakthrough designation status. Rucaparib is a PARP inhibitor that blocks cancer cells growth and may slow or stop the development of the tumor.

“Today’s approval is another example of the trend we are seeing in developing targeted agents….Women with these gene abnormalities who have tried at least two chemotherapy treatments for their ovarian cancer now have an additional treatment option,” said Richard Pazdur, MD, Director of the FDA’s Office of Hematology and Oncology Products.

On the same day, the FDA approved the FoundationFocus CDxBRCA, a companion diagnostic test manufactured by Foundation Medicine that should be used with rucaparib to select patients who are most likely to benefit from rucaparib therapy.

The safety and efficacy of rucaparib were evaluated in 2 single-arm clinical trials involving 106 patients with BRCA mutation–positive advanced ovarian cancer who received ≥2 chemotherapy regimens. The primary end points were the objective response rate and the duration of response.

The use of the companion diagnostic test showed that 96% of patients had the BRCA mutation. Overall, 54% of the patients who received rucaparib had complete or partial shrinkage of their tumors that lasted a median of 9.2 months.

The common side effects reported with rucaparib include nausea, fatigue, anemia, abdominal pain, dysgeusia, constipation, decreased appetite, diarrhea, thrombocytopenia, and dyspnea. Rucaparib therapy has also been linked to the risk for myelodysplastic syndrome, acute myeloid leukemia, and fetal harm.

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Avastin Approved for Platinum-Sensitive Ovarian Cancer

On December 6, 2016, the FDA approved bevacizumab (Avastin; Genentech) for use in combination with carboplatin and paclitaxel or carboplatin and gemcitabine for the treatment of women with platinum-sensitive ovarian cancer (recurrent epithelial ovarian cancer, fallopian tube, or primary peritoneal cancer). Platinum sensitivity is defined as disease relapse occurring ≥6 months after the last treatment with platinum-based chemotherapy.

This approval of bevacizumab was based on 2 randomized, controlled, phase 3 clinical trials. In the GOG-0213 trial, the overall survival was 42.6 months with bevacizumab plus chemotherapy compared with 37.3 months with chemotherapy alone, and the progression-­free survival (PFS) was 13.8 months versus 10.4 months, respectively.

In the OCEANS study, the PFS was 12.4 months with bevacizumab plus chemotherapy compared with 8.4 months with chemotherapy plus placebo (P <.001). The secondary end point of overall survival was not significantly improved with the addition of bevacizumab to chemotherapy.

The most common adverse events in both studies included hypertension, fatigue, febrile neutropenia, proteinuria, pain, low platelet count, and headache. These adverse events were consistent with those in previous clinical trials of bevacizumab.

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Darzalex Approved for Use in Combination with Standard Regimen for Multiple Myeloma

On November 21, 2016, the FDA approved daratumu­mab (Darzalex; Janssen Biotech) in combination with lenalidomide (Revlimid) and dexamethasone, or with bortezomib (Velcade) and dexamethasone, for patients with multiple myeloma.

This new indication was based on 2 randomized, open-label clinical trials. The POLLUX clinical trial involved 569 patients with multiple myeloma who received ≥1 previous lines of therapy. Patients were randomized to receive daratumumab plus lenalidomide and dexamethasone or lenalidomide plus dexamethasone alone.

The results demonstrated a 63% reduction in the risk for disease progression or death in patients who received the 3-drug combination with daratumumab. The median progression-free survival (PFS) was 18.4 months in the control group and had not been reached in the daratumu­mab combination therapy group (hazard ratio [HR], 0.37; P <.001).

In the CASTOR clinical trial, the combination of daratumumab plus bortezomib and dexamethasone was compared with bortezomib plus dexamethasone alone. The study demonstrated a 61% reduction in the risk for disease progression or death for patients who received the daratumumab combination therapy compared with bortezomib plus dexamethasone alone. The estimated median PFS was not reached in patients who received daratumumab plus bortezomib and dexamethasone and was 7.2 months in patients who received bortezomib and dexamethasone alone (HR, 0.39; P <.001).

The most common (≥20%) adverse events in the POLLUX study were infusion reactions, diarrhea, nausea, fatigue, pyrexia, upper respiratory tract infection, muscle spasm, cough, and dyspnea. The most common (≥20%) adverse events in the CASTOR trial were infusion reactions, diarrhea, peripheral edema, peripheral neuropathy, and upper respiratory tract infection. Neutropenia and thrombocytopenia have been added to the warnings and precautions section of daratumumab.

“With Darzalex, we have a potential new backbone therapy, which has shown pronounced efficacy as either a single agent or in combination with standard of care regimens. The addition of Darzalex also significantly improved progression-free survival in combination with two of the most widely used treatment classes, making it a versatile option for patients who have received at least one prior therapy,” said Meletios A. Dimopoulos, MD, Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Alexandra General Hospital, Athens, Greece, a daratumumab clinical trial investigator, in a press release for the manufacturer.

Daratumumab was approved in November 2015 as a monotherapy for the treatment of patients with multiple myeloma who received at least 3 lines of therapy.

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Opdivo Now Approved for Head and Neck Squamous-Cell Carcinoma

On November 10, 2016, the FDA approved nivolumab (Opdivo; Bristol-Myers Squibb) for the treatment of patients with recurrent or metastatic squamous-cell carcinoma of the head and neck that has progressed during or after 6 months of platinum-based chemotherapy.

This new indication for nivolu­mab was based on data from the CheckMate 141 clinical trial, an international, multicenter, open-label study involving 361 patients with recurrent or metastatic squamous-cell carcinoma of the head and neck that progressed during or after platinum-based chemotherapy.

Patients were randomized to intravenous (IV) nivolumab 3 mg/kg every 2 weeks or IV cetuximab (Erbitux) 400 mg/m2 once, followed by IV cetuximab 250 mg/m2 weekly; IV methotrexate 40 mg/m2 weekly; or IV docetaxel 30 mg/m2 weekly, until disease progression or until unacceptable toxicity.

The CheckMate-141 clinical trial demonstrated a significant and clinically meaningful improvement in overall survival in patients who received nivolumab. The median overall survival was 7.5 months with nivolumab versus 5.1 months with cetuximab, metho­trexate, or doce­taxel (hazard ratio, 0.7; P = .0101).

Serious adverse reactions occurred in 49% of patients who received nivolu­mab. The most frequent (≥2%) serious events were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. The most common (≥10%) adverse reactions with nivolumab included cough and dyspnea.

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