Keytruda fail 'small beans' for Merck, bigger riddle for immuno-oncology scorekeepers

Keytruda
Merck's Keytruda has scored two lung cancer approvals Bristol-Myers' Opdivo doesn't have, in previously untreated patients and in combination with chemotherapy.

The immunotherapy mystery deepens. Merck & Co.’s Keytruda missed its goal in a head and neck cancer trial—a goal that its closest rival, Bristol-Myer Squibb’s Opdivo, met last year.

The tables were turned last year, when Keytruda scored its win in previously untreated lung cancer patients and Opdivo didn’t.

Both drugs are PD-1 checkpoint inhibitors, with lists of indications that are all but identical except in lung cancer. But a series of differing study outcomes, between these two meds and among others in the same class, highlight just how much drugmakers still don’t know about these big-selling—and groundbreaking—therapies.

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“Up until yesterday, I would have told you that there are at least 2 different indications where Merck worked and others failed ... and perhaps Merck is just executing these trials much better,” Evercore ISI analyst Umer Raffat said in a Tuesday note, pointing out that Roche’s PD-L1 drug Tecentriq failed a phase 3 bladder cancer trial where Merck’s med succeeded.

“However, as of today, there appears to be no consistency in the inconsistency,” Raffat said. “Now Merck failed where Bristol-Myers worked.”

Meanwhile, just last month, the FDA put two Keytruda multiple myeloma trials on clinical hold and stopped dosing in a third, at least temporarily thwarting Merck’s hopes for pairing Keytruda with Celgene’s myeloma meds Revlimid and Pomalyst. Bristol-Myers and AstraZeneca, which sells PD-L1 Imfinzi, have their own myeloma trials going. Will those turn up different results? It’ll be months before we have that information.

RELATED: Trial deaths frustrate Merck's bid to pair Keytruda with Celgene's myeloma stars

All of this variability has cropped up despite the fact, as Bernstein analyst Tim Anderson wrote in a Monday note, “The vast majority of experts think that the various PD-1s all have the same clinical profile.” 

In the new trial data, following up on Keytruda’s conditional head and neck cancer approval last year, the Merck med failed to prove that it could extend patients’ lives. The miss was a “near miss,” analysts pointed out, just shy of statistical significance. And Merck says the FDA sees no reason to shift its stance on Keytruda in that cancer type, at least not yet.

As Leerink Partners analyst Seamus Fernandez told investors late Monday, “the company noted that the FDA remains comfortable with the drug's current accelerated approval in this indication despite the trial results.” Plus, Fernandez pointed out, “Keytruda appears to have another shot on goal for full approval ... as the Keynote-048 study in first-line patients could, if positive, serve as the confirmatory trial.”

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Bristol-Myers’ Opdivo already has that sort of data: Last fall, after its failure in first-line lung cancer, Opdivo put up head and neck cancer results showing that patients lived a median 7.5 months after treatment with Opdivo, compared with a median 5.1 months for patients treated with the trial investigators’ choice of therapies.

Bottom line, for Merck? Small beans, Anderson figures. In the first quarter, only 15% of Keytruda’s sales stemmed from head and neck cancer, Anderson pointed out, citing the company’s statistics. That share has been shrinking as Keytruda’s lung cancer business grows. 

“Overall, this is only a small setback. Almost hitting statistical significance, and FDA deciding to not take action on the basis of these results, is reassuring, and prescribers are subsequently not likely to materially change how they use the product because of this,” Anderson concluded.

RELATED: Merck's Keytruda speeds its I-O market-share grab as Bristol-Myers' Opdivo declines

Ironically enough, the fact that Opdivo succeeded in its trial—coupled with the forthcoming results in Keytruda’s first-line head and neck trial—may be a favorable influence on the FDA’s choice to leave Keytruda’s label as-is for now.  

So far, Roche’s Tecentriq is the only other PD-1/L1 med to fall short in a confirmatory trial, with top-line data unveiled in May. At the time, analysts figured the FDA would consider pulling the drug’s nod in bladder cancer. But in recent days, European officials backed Tecentriq for bladder cancer approval despite that phase 3 fail.

Bristol-Myers had its own announcement Monday; the company has asked the FDA to approve a new Opdivo dosing schedule—fixed at 480 mg, every four weeks. Together, the two immuno-oncology releases were “noteworthy in that they highlight how early we still are in the evolution of the I-O market,” Credit Suisse analyst Vamil Divan wrote in late-night note, “and how frequently there are interesting and surprising developments in the space as a result.”