Acceptance of an additional regulatory filing is normally a footnote. The exception to this rule is Merck & Co. (NYSE:MRK), whose market cap this morning gained an incredible $8bn on news that the FDA had accepted for review an application to use Keytruda plus chemotherapy in first-line lung cancer.
Then again, this is the first direct evidence of the group taking on Bristol-Myers Squibb (NYSE:BMY) in the combination setting. True, Merck was known to have been pursuing the chemo combo approach – it had tried and failed to get it listed in US compendia based on the uncontrolled Phase II Keynote-021 trial – but the market had until now assumed that it would wait for Phase III data before filing.
Bristol’s valuation lost $2.7bn this morning. Since Bristol’s Opdivo failed in the first-line setting, all the big immuno-oncology players have upped their game in a bid to take on Keytruda, which is approved first-line albeit only in PD-L1-high patients (Three imminent second chances in first-line lung cancer, January 5, 2017).
Stealing a march
Merck submitting Keynote-021 results for compendia listings last year was an attempt to steal a march on competitors, though when this failed, analysts had assumed that survival data from the controlled Keynote-189 trial, which does not end until September, would be needed.
This might still be the case – analysts accept that filing on Keynote-021 is an extremely risky strategy. Not only was this an uncontrolled trial, it failed to extend overall survival, though this could have been due to its crossover design; overall remission and progression-free survival were improved in the Keytruda arm.
Most importantly, however, Keynote-021 recruited all-comers, not just PD-L1-high patients, so an approval here would be a big coup for Merck. The group is seeking an accelerated approval based on the overall remission benefit, and this would presumably have to be confirmed later with survival data from Keynote-189.
The possible advantage, however, is huge: with an FDA action date of May 10, if approval is granted, it would put a Keytruda combo on the market before any of the competing combinations currently in Phase III. Quite a turnaround, then, from six months ago, when Opdivo plus Yervoy looked set to take the first-line NSCLC market by storm.
Of course, the likes of Bristol and AstraZeneca (NYSE:AZN) have the luxury of in-house immuno-oncology assets with which to combine their anti-PD-1/PD-L1s. Because of this, Merck has been limited to combining Keytruda either with chemo or with a rival’s drug.
The chemo setting specifically has been led by Roche (OTCQX:RHHBF) so far. The Swiss group has made chemotherapy the backbone of its Tecentriq combo strategy in first-line NSCLC, with the Phase III Impower-150 trial set to yield a progression-free survival result early this year.
Still, there is some controversy in this since chemo is typically thought of as being immunosuppressive, whereas checkpoint blockers need the tumor to be immunogenic to work.
At an immuno-oncology seminar at The Royal Society in London yesterday, Dr. Sergio Quezada, of the UCL Cancer Institute, summed the issue up neatly, suggesting that chemotherapy could elicit a “vaccine effect,” releasing antigens that would then become “visible to the immune system.”
The subsequent problem of the immune system kicking in and being downregulated could be overcome by using only a low dose of chemo or radiotherapy, he suggested.
At its JPMorgan presentation, Bristol said the Checkmate-026 trial of Opdivo versus chemo did yield “interesting data” that would be published this year. However, the group’s combo focus centers on Yervoy, and in particular on the Checkmate-568 and 227 trials.
It is now facing even stiffer competition from Merck, however, and at a JPMorgan breakout session yesterday, Merck executives did not mince their words, stating that the checkpoint space was now “all about winning in first-line lung cancer.” Investors just found out that they really do mean it.