Bristol-Myers Squibb's nivolumab, Yervoy combination improves survival in melanoma study

Bristol-Myers Squibb reported Monday follow-up results from a Phase Ib study demonstrating that patients with advanced melanoma given the experimental PD-1 immune checkpoint inhibitor nivolumab in combination with Yervoy (ipilimumab) had improved survival at one and two years. Study investigator Mario Sznol remarked that "just a few years ago, median survival for patients diagnosed with advanced melanoma was as little as a year or less...so it's truly remarkable that we're seeing a median survival over three years in this trial."

In Study-004, 127 patients with advanced melanoma were treated with nivolumab and Yervoy in combination or sequentially. In the concurrent group, which consisted of 53 patients, subjects received nivolumab and Yervoy every three weeks for four doses, followed by nivolumab alone every three weeks for four doses. Bristol-Myers Squibb noted that the concurrent combination regimen treatment was subsequently continued every 12 weeks for up to eight doses.

Results, which were presented at the ASCO annual meeting, showed that in the concurrent group, tumour shrinkage occurred in 42 percent of patients, while the one- and two-year overall survival (OS) rates were 85 percent and 79 percent, respectively. The company indicated that for the 17 patients who received the nivolumab and Yervoy doses being studied in the ongoing Phase II and Phase III CheckMate-069 and -067 trials, the one-year OS rate was 94 percent and the two-year OS rate was 88 percent. Michael Giordano, head of development, Oncology & Immunology at Bristol-Myers Squibb, noted "these results are the most advanced data set to date evaluating the potential of combining immune checkpoint inhibitors."

The drugmaker said that no new safety signals were noted in the study. Grade 3-4 treatment-related adverse events were observed in 62 percent of patients in the concurrent group, while 23 percent of patients discontinued treatment due to adverse events. The most common adverse events were asymptomatic elevations in lipase, AST and ALT levels, although one patient died as a result of fatal multi-organ failure following an initial event of colitis. "These toxicities really are manageable in the clinic," stated Sznol, adding "if you're getting 79 percent overall survival at two years, the side effects are clearly worth it."

Bristol-Myers Squibb is conducting a number of studies of nivolumab, both as monotherapy or in combination with other therapies, including potentially registrational trials in melanoma, non-small-cell lung cancer (NSCLC) and renal cell carcinoma. Last year, the FDA granted fast track designation for nivolumab in these three indications, while the agency recently granted the drug breakthrough therapy status for the treatment of certain patients with Hodgkin lymphoma. The company expects to complete an FDA filing for the therapy by the end of this year in NSCLC.

Yervoy was approved by the FDA for the treatment of advanced melanoma in March 2011, and the therapy was cleared by regulatory authorities in the EU and Australia later that year. Analysts at Cowen & Co. project annual sales of about $2 billion for the drug by 2020. Separately on Monday, Bristol-Myers Squibb reported that Yervoy was associated with significantly improved recurrence-free survival versus placebo in a Phase III study of patients with stage 3 melanoma who are at high risk of recurrence following complete surgical resection.

Other companies developing anti-PD-1 and anti-PDL-1 drugs include AstraZeneca, Roche and Merck & Co., with the latter reporting Monday positive results from a Phase Ib study for pembrolizumab, also known as MK-3475, in patients with advanced melanoma and also those with PD-L1-positive, advanced NSCLC.

For related analysis, read ViewPoints: New data indicates key role for biomarkers in immuno-oncology development race, FirstWord Lists: A revolution in cancer – a launch calendar for key immuno-oncology indications and Physician Views Poll Results: First-to-market status for Merck & Co.'s MK-3475 in melanoma could open substantial opportunity for off-label front-line usage.

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