Bristol-Myers Squibb pulls US filing seeking approval of Opdivo, Yervoy combination in first-line NSCLC

Bristol-Myers Squibb revealed Thursday alongside its fourth-quarter financial results that it withdrew a filing in the US seeking approval of Opdivo (nivolumab) plus low-dose Yervoy (ipilimumab) for the treatment of first-line advanced non-small-cell lung cancer (NSCLC) in patients with tumour mutational burden (TMB) of at least 10 mutations per megabase (mut/Mb). Shares in the company fell more than 3 percent on the news.

The FDA accepted the application for review in June last year, with the filing based on results from Part 1 of the Phase III CheckMate -227 study. The trial met its co-primary endpoint of progression-free survival, with data showing that the combination of the PD-1 inhibitor Opdivo and the CTLA-4 inhibitor Yervoy reduced the risk of progression or death by 42 percent versus chemotherapy.

However, in October last year, the agency extended its review of the application by three months after Bristol-Myers Squibb submitted an exploratory overall survival (OS) analysis from the study. At the time, the drugmaker indicated that in an updated descriptive analysis, the hazard ratio for OS with Opdivo plus low-dose Yervoy versus chemotherapy in patients with TMB of at least 10 mut/Mb was 0.77, while in patients with TMB of less than 10 mut/Mb, the hazard ratio was 0.78.

Bristol-Myers Squibb said Thursday that following recent discussions with the FDA, further evidence is needed on the relationship between TMB and PD-L1 to fully evaluate the impact of Opdivo plus Yervoy in this indication. The drugmaker indicated that the analysis will require final data from Part 1a of the Checkmate -227 study, which is expected to be available in the first-half of 2019. The company added that as the results "will not be available within the review cycle of the current application [we] decided to withdraw."

Commenting on the news, Credit Suisse analyst Vamil Divan said the withdrawn filing raises new questions about Bristol-Myers Squibb's overall strategy and approach in advanced lung cancer, although he noted that approval of Opdivo and Yervoy in this indication would not have had much near-term impact.

The decision by Bristol-Myers Squibb comes shortly after AstraZeneca reported results from the Phase III MYSTIC study suggesting that patients with high TMB may benefit more from treatment with the PD-L1 inhibitor Imfinzi (durvalumab) plus the anti-CTLA4 antibody tremelimumab. Data from the trial, which included previously-untreated patients with Stage IV NSCLC, showed that in those with 16 or more mut/Mb, OS was 16.5 months with Imfinzi plus tremelimumab versus 10.5 months with chemotherapy, with a HR of 0.62.

For related analysis, see ViewPoints: AstraZeneca looks at an alternative biomarker as it seeks diminishing returns from MYSTIC. See also, ViewPoints: More questions asked about Bristol-Myers Squibb’s strategy in NSCLC.

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