Suffice to say, the year has not started well for Bristol-Myers Squibb. The company announced late on Thursday that it no longer plans to file an accelerated approval with the FDA for the combination of Opdivo and Yervoy in previously untreated non-small-cell lung cancer (NSCLC). This announcement follows recent confirmation that the FDA accepted Merck & Co.'s filing for the combination of Keytruda plus chemotherapy in first-line patients irrespective of PD-L1 status; a much earlier-than-expected filing on Merck's part (JP Morgan 2017: Stealing their thunder? – Merck & Co. does it again).
Bristol-Myers Squibb's announcement affords Merck considerable momentum in the likelihood of it dominating the first-line NSCLC market in the near term, while simultaneously casting doubt on the merits of a PD-1/CTLA-4 inhibitor combination in this setting (doubts that will persist, no doubt, thanks to the lack of details in Bristol-Myers Squibb's press release beyond confirmation it will not pursue accelerated approval based 'on a review of data available at this time'). At the close on Thursday, Merck's share price had risen 4.7 percent, while Bristol-Myers Squibb's closed down 5 percent.
Merck has already secured approval of Keytruda as a first-line monotherapy treatment in patients whose tumours have PD-L1 expression level of 50 percent or more and labelling could be expanded to include combination use with chemotherapy in all eligible first-line patients (i.e. irrespective of PD-L1 status) by May, if the company's recently confirmed regulatory filing is successful.
At the very least, notes Bernstein analyst Tim Anderson, Merck should be in a position to refile once its Phase III Keynote-189 delivers top-line data later this year (anticipated in the fourth quarter). By comparison, it now looks unlikely that Bristol-Myers Squibb will be able to file its Opdivo/Yervoy combination until 2018 at the earliest. Particularly if it secures FDA approval for the Keytruda/chemotherapy combination by May, Merck will have a considerable opportunity to establish Keytruda as the leading PD-(L)1 inhibitor in the first-line NSCLC market, adds Anderson.
For other companies competing in this race, Bristol-Myers Squibb's announcement will also be deemed broadly positive, as both Roche and AstraZeneca have pivotal-stage PD-L1-anchored combination studies set to read out later this year; Roche is assessing the combination of its PD-L1 inhibitor Tecentriq with chemotherapy, while AstraZeneca is assessing the combination of its PD-L1 inhibitor durvalumab with the CTLA-4 inhibitor tremelimumab and as a monotherapy in higher-expressing PD-L1 patients.
Furthermore, AstraZeneca's decision to modify its MYSTIC study – details of which were shared earlier this week – looks increasingly astute. Greater emphasis has been put on establishing durvalumab as a monotherapy, although the timing of this study change, widely considered to be a hedge on AstraZeneca's part, could raise concerns about the viability of using PD-(L)1 plus CTLA4 inhibitor combinations in NSCLC. Initial read out from the MYSTIC study, expected in mid-2017, will provide further clarity. In morning trading on Friday, AstraZeneca shares were down as much as 2 percent, although Deutsche Bank analysts were quick to argue it had always been unlikley that Bristol-Myers Squibb could file early based on non-randomised, Phase II data.
More cautiously, Leerink analyst Seamus Fernandez noted "if Merck and Roche's Phase III chemotherapy trials are both successful and IO plus IO combinations fail to impress, this would leave very little room for either Bristol-Myers Squibb or AstraZeneca to differentiate themselves in the first-line NSCLC market." Fernandez caveats this would be "particularly surprising and disappointing," in the wake of recent discussions with key opinion leaders; sentiment that echoes FirstWord's own interactions with experts in the field.
Bristol-Myers Squibb's shareholders will be hoping this latest setback is a case of mismanaged expectation and a high regulatory bar rather than any indication of a second major clinical setback for its immuno-oncology pipeline. The company had, for the previous few months, been indicating that an accelerated approval for the Opdivo/Yervoy combination was feasible, albeit if this assertion appeared to run contrary to trial readout timelines. Merck, on the other hand, continues to show that actions speak louder than words.
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