FDA News – September 2016

September 2016, Vol 6, No 9 - FDA News


In This Article




First Extended-Release Serotonin Receptor Antagonist Approved for the Prevention of CINV

On August 10, 2016, the FDA approved granisetron extended-release (Sustol; Heron Therapeutics) injection, the first extended-release 5-hydroxytryptamine (5-HT3) receptor antagonist, in combination with other antiemetic drugs in adults, for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy or anthracycline and cyclophosphamide combination chemotherapy regimens.

This long-acting formulation of granisetron is delivered through the Biochronomer polymer-based technology that allows the drug to remain in the body at therapeutic levels for at least 5 days, during the acute and delayed phases of chemotherapy-induced nausea and vomiting (CINV).

“Despite advances in the management of CINV, up to half of patients receiving chemotherapy can still experience CINV, with delayed CINV being particularly challenging to control. In our experience, other 5-HT3 receptor antagonists, including palonosetron, are generally effective for 48 hours or less. Sustol, due to its extended-release profile, represents a novel option that can protect patients from CINV for a full 5 days,” said Ralph V. Boccia, MD, FACP, Medical Director, Center for Cancer and Blood Disorders, in a press release.

The approval was based on 2 large clinical trials that evaluated granisetron’s efficacy and safety in the acute and delayed phases of CINV in more than 2000 patients with cancer. The primary end point was the complete response rate, which was defined as no emetic episodes and no use of rescue medications. In one trial, 200 patients who received granisetron extended-release after moderately emetogenic chemotherapy, 166 (83%) patients had a complete response in the acute phase of CINV, and 137 (69%) had a complete response in the delayed phase. And of 171 patients who received granisetron extended-release after anthracycline plus cyclophosphamide, 120 (70%) patients had complete response in the acute phase of CINV, and 85 (50%) patients had a complete response in the delayed phase of CINV.

The most common (≥3%) adverse reactions are injection-site reactions, constipation, fatigue, headache, diarrhea, abdominal pain, insomnia, dyspepsia, dizziness, asthenia, and gastroesophageal reflux.

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Keytruda Receives New Indication for Head and Neck Squamous-Cell Carcinoma

On August 5, 2016, the FDA approved a new indication for pembrolizumab (Keytruda; Merck) for the treatment of patients with recurrent or metastatic head and neck squamous-cell carcinoma (SCC) that progressed during or after platinum-containing chemotherapy. This approval was done under the FDA’s priority review process.

Pembrolizumab was first approved in September 2014 for the treatment of unresectable or metastatic melanoma. In October 2015, pembroliz­umab received a new indication for the treatment of patients with metastatic non–small-cell lung cancer.

This latest accelerated approval of pembrolizumab was based on the results of an international, multicenter, nonrandomized, open-label, multicohort study involving 174 patients with recurrent or metastatic head and neck SCC that progressed during or after platinum-based chemotherapy. The patients received intravenous pembrolizumab 10 mg/kg every 2 weeks or 200 mg every 3 weeks. The primary end point was the objective response rate.

The objective response rate was 16%, and the median duration of response had not been reached at the time of analysis (range, 2.4-27.7 months). Of the 28 patients with head and neck SCC whose disease responded to pembrolizumab, 82% had responses lasting 6 months or longer.

The most common (≥20%) adverse reactions reported in patients who received pembrolizumab included fatigue, decreased appetite, and dyspnea. The most common (≥2%) serious adverse events observed with pembrolizumab included pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. Clinically significant immune-mediated adverse reactions included pneumonitis, colitis, hepatitis, adrenal insufficiency, diabetes mellitus, skin toxicity, myositis, and thyroid disorders.

The clinical trial KEYNOTE 040, an ongoing, multicenter, randomized clinical trial in patients with recurrent or metastatic head and neck SCC, has a primary end point of overall survival, and will help determine whether pembrolizumab is superior over standard therapy.

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Cabometyx Approved for Patients with Advanced Renal-Cell Carcinoma

On April 25, 2016, the FDA approved cabozantinib (Cabometyx; Exelixis), a tyrosine kinase inhibitor, for the treatment of patients with advanced renal-cell carcinoma who had received antiangiogenic therapy. The FDA granted this approval under its fast track and priority review designations.

The approval was based on 1 randomized clinical trial of patients with advanced renal-cell carcinoma who had previously received antiangiogenic therapy and were randomized to oral cabozantinib 60 mg daily (N = 330) or to everolimus 10 mg orally once daily (N = 328). The primary end point was progression-free survival (PFS) in the first 375 randomized patients.

The median PFS in this group was 7.4 months with cabozantinib and 3.8 months with everolimus (P <.001). The median overall survival in the full study population was 21.4 months with cabozantinib and 16.5 months with everolimus. The response rates were 17% and 3%, respectively.

The safety of cabozantinib was evaluated in 331 patients. The most common adverse reactions included diarrhea, fatigue, nausea, decreased appetite, palmar-plantar erythrodys­esthesia syndrome, hypertension, vomiting, weight loss, and constipation. In addition, 60% of patients receiving cabozantinib had ≥1 dose reductions. Serious adverse events were reported in 40% of patients, and included abdominal pain, pleur­al effusion, diarrhea, and nausea. The recommended dose for cabozantinib is 60 mg orally daily.

Cabozantinib received a breakthrough therapy designation from the FDA in August 2015.

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