Phase III study results presented Sunday at the ASCO annual meeting and published in the NEJM suggest that the combination of Bristol-Myers Squibb's PD-1 inhibitor Opdivo (nivolumab) plus its CTLA-4 inhibitor Yervoy (ipilimumab) significantly extended progression-free survival (PFS) in patients with advanced melanoma, compared with either drug alone. Lead author Jedd Wolchok said "we're very encouraged that the initial observations about the efficacy of this combination held up in this large Phase III trial," adding that the findings also indicate "that patients with a specific tumour marker appear to benefit the most from the combination treatment, whereas other patients may do just as well with [Opdivo] alone."
In the study, investigators randomly assigned 945 patients with metastatic melanoma who were previously untreated for the disease to receive Opdivo, Yervoy or a combination of the two immunotherapies. Results showed that 58 percent of patients who received Opdivo plus Yervoy achieved an objective response, measured as a significant reduction tumour size, compared to 44 percent on Opdivo alone and 19 percent on Yervoy alone. Participants in the combined-therapy arm also lived a median duration of 11.5 months before either dying or experiencing disease progression, versus 6.9 months and 2.9 months for those who received Opdivo or Yervoy, respectively.
Further, in patients whose tumour cells had a higher expression of PD-L1, median PFS was around 14 months, regardless of whether Opdivo was administered alone or in combination with Yervoy, and 3.9 months for Yervoy alone. However, among patients with low PD-L1 expression, the combination treatment resulted in a median PFS of 11.2 months, versus 5.3 months for Opdivo alone and 2.8 months for Yervoy alone. Michael Giordano, Bristol-Myers Squibb's head of oncology development, said "we believe it will probably become important for patients to be tested" for PD-L1 in order to guide treatment decisions.
Meanwhile, results showed that higher-grade adverse events were reported for about 55 percent of patients in the combination-treatment arm, causing about one-third of them to stop the regimen. Approximately 16 percent of patients administered Opdivo alone and 27 percent of those receiving Yervoy monotherapy experienced side effects, with nearly 8 percent and 15 percent of patients discontinuing, respectively. Wolchok suggested that most of the side effects could be mitigated by use of steroids and other therapies, noting there were no treatment-related deaths among participants taking the combination.
The results follow the recent release of data from the 142-patient Phase II CheckMate-069 study, showing that the combination of Opdivo and Yervoy led to higher objective response rates versus Yervoy monotherapy in patients with BRAF wild-type tumours. For related analysis, see ViewPoints: Bristol-Myers Squibb ups the stakes with combination melanoma play.
Opdivo, which costs about $150 000 if used for a year, became the first PD-1 inhibitor available anywhere in the world following its launch in Japan last September. The drug has since gained accelerated approval by the FDA for the treatment of melanoma, while its indication was expanded in March to include the treatment of advanced squamous non-small-cell lung cancer in select patients.
Bernstein Research estimates that Opdivo and Yervoy will generate $6.5 billion in combined annual revenues by 2020.
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