42-04 FDA Expands Opdivo-Yervoy Label with Accelerated Approval

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FDA Expands Opdivo-Yervoy Label with Accelerated Approval

FDA granted accelerated approval to a combination of Opdivo (nivolumab) and Yervoy (ipilimumab) for the treatment of patients with BRAF V600 wild-type and BRAF V600 mutation-positive unresectable or metastatic melanoma.

This approval expands the original indication for the Opdivo-Yervoy regimen for the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma to include patients regardless of BRAF mutational status, based on data from the phase III CheckMate-067 trial, in which PFS and overall survival were co-primary endpoints. Opdivo is sponsored by Bristol-Myers Squibb.

FDA also expanded the use of Opdivo as a single-agent to include previously untreated BRAF mutation-positive advanced melanoma patients. The use of Opdivo as a single-agent in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma is approved under accelerated approval based on progression-free survival. Opdivo was approved by the FDA in November 2015, for use in previously untreated patients with BRAF V600 wild-type unresectable or metastatic melanoma.

CheckMate-067 is a double-blind, randomized study that evaluated the Opdivo-Yervoy regimen or Opdivo monotherapy vs. Yervoy monotherapy in patients with previously untreated advanced melanoma.

The trial evaluated previously untreated patients, including both BRAF V600 mutant and wild-type advanced melanoma, and enrolled 945 patients who were randomized to receive the combination regimen (Opdivo 1 mg/kg plus Yervoy 3 mg/kg every 3 weeks for 4 doses followed by Opdivo 3 mg/kg every 2 weeks thereafter; n=314), Opdivo monotherapy (Opdivo 3 mg/kg every 2 weeks; n=316) or Yervoy monotherapy (Yervoy 3 mg/kg every 3 weeks for 4 doses followed by placebo every 2 weeks; n=315).

Patients were treated until progression or unacceptable toxic effects. The median duration of exposure was 2.8 months (range: 1 day to 18.8 months) for patients in the combination arm with a median of four doses (range: 1 to 39 for Opdivo; 1 to 4 for Yervoy), and 6.6 months (range: 1 day to 17.3 months) duration for the Opdivo monotherapy arm with a median of 15 doses (range: 1 to 38). The co-primary endpoints were PFS and OS; the study is ongoing and patients continue to be followed for OS.

Results from the trial demonstrated a statistically significant improvement in PFS in patients with advanced melanoma treated with the combination regimen (p<0.0001) and with Opdivo as a single-agent (p<0.0001) vs. Yervoy monotherapy.

Median PFS was 11.5 months (95% CI: 8.9-16.7) for the combination regimen and 6.9 months (95% CI: 4.3-9.5) for Opdivo monotherapy, compared to 2.9 months (95% CI: 2.8-3.4) for Yervoy alone.

The Opdivo-Yervoy regimen demonstrated a 58 percent reduction in the risk of disease progression vs. Yervoy (HR: 0.42; 95% CI: 0.34-0.51; p<0.0001), while Opdivo monotherapy demonstrated a 43 percent risk reduction vs. Yervoy monotherapy (HR: 0.57; 95% CI: 0.47-0.69; p<0.0001).

Opdivo is associated with immune-mediated: pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, rash, encephalitis, other adverse reactions; infusion reactions; and embryofetal toxicity.

FDA approved Halaven (eribulin mesylate) Injection for the treatment of patients with unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen, following priority review.

The approval was based on the results of a phase III trial, Study 309, which demonstrated that previously treated liposarcoma patients who received Halaven (n=71) experienced a median overall survival of 15.6 months compared with 8.4 months for those who received dacarbazine (n=72) (HR 0.51; 95% CI: 0.35-0.75), making it the first single agent to demonstrate an OS benefit in this stage of the disease, according to the drug’s sponsor, Eisai.

Median progression-free survival, the trial’s secondary endpoint, was longer in patients with liposarcoma treated with Halaven than in those who received dacarbazine (2.9 vs. 1.7 months; HR 0.52; 95% CI: 0.35-0.78).

The adverse events seen in Study 309 were consistent with the known profile of Halaven. Serious side effects from treatment with Halaven may include neutropenia, peripheral neuropathy, embryo-fetal toxicity and QT prolongation.

First in the halichondrin class, Halaven is a microtubule dynamics inhibitor with a distinct binding profile.

Halaven is a synthetic analog of halichondrin B, a natural product that was isolated from the marine sponge Halichondria okadai. Based on in vitro studies, Halaven exerts its effect via a tubulin-based antimitotic mechanism, ultimately leading to apoptotic cell death after prolonged and irreversible mitotic blockage.

Halaven was first approved in the U.S. in November 2010 for patients with metastatic breast cancer who have received at least two chemotherapeutic regimens for the treatment of metastatic disease. Halaven was granted an FDA Orphan Drug Designation for soft tissue sarcoma in May 2012.

FDA approved Zepatier (elbasvir and grazoprevir) for the treatment of adult patients with chronic hepatitis C virus genotype 1 or 4 infection, with or without ribavirin, following priority review.

Zepatier is a once-daily combination tablet containing the NS5A inhibitor elbasvir (50 mg) and the NS3/4A protease inhibitor grazoprevir (100 mg). The FDA previously granted two Breakthrough Therapy designations to Zepatier, for the treatment of chronic HCV GT1 infection in patients with end stage renal disease on hemodialysis, and for the treatment of patients with chronic HCV GT4 infection.

Across multiple clinical studies, Zepatier achieved high rates of sustained virologic response ranging from 94 to 97 percent in GT1-infected patients, and 97 to 100 percent in GT4-infected patients, according to Merck, the therapy’s sponsor. Sustained virologic response is defined as HCV RNA levels measuring less than the lower limit of quantification at 12 weeks after the cessation of treatment.

Zepatier was approved with a treatment duration of 12 or 16 weeks, depending on HCV genotype, prior treatment history and, for patients with GT1a infection, the presence of certain baseline NS5A polymorphisms. A 12-week, once-daily regimen is recommended for the vast majority of patients for whom Zepatier is indicated.

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