ASCO: Is the PD-1 target behind Keytruda's small-cell miss? Merck exec says no

Merck is discussing the Keynote-604 results with regulators. (Merck)

Back in January, Merck said Keytruda—its anti-PD-1 therapy—had missed the mark in an area where two of its rivals had succeeded. Both those rivals are anti-PD-L1 treatments, so could that PD-1/PD-L1 difference be the reason? The New Jersey drugmaker doesn’t think so.

The idea that its PD-1 target might be behind Keytruda’s failure to help newly diagnosed, extensive-stage small cell lung cancer (SCLC) patients live longer is “a bit of a stretch,” Roy Baynes, M.D., Merck senior vice president and head of global clinical development, said.

“There’s no head-to-head data, and I don’t think it’s an answerable question,” he added.


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Analysts put forth the idea following Merck’s top-line data announcement, in which it revealed that Keytruda, paired with chemo, had failed to beat chemo alone at prolonging patients’ lives in the phase 3 Keynote-604 study. Its 20% improvement in overall survival didn’t meet the threshold for statistical significance.

At that time, Roche’s Tecentriq had already cut the risk of death by 30%, and AstraZeneca’s Imfinzi by 27% in their respective trials, both passing the significance bar.

Bristol Myers Squibb’s fellow PD-1 Opdivo, meanwhile, had failed to extend the lives of extensive-stage SCLC patients who had undergone an initial round of platinum-based chemo. And it fell short not only as monotherapy, but also in tandem with CTLA-4 drug Yervoy.

“The Keytruda miss lends credence to the argument that targeting the PD-L1 side of the PD-1/PD-L1 axis is more effective in settings characterized by low PD-L1 expression and poor patient fitness (like SCLC),” Leerink Partners analyst Daina Graybosch wrote in a January note to clients.

It hasn’t all been a bust for Keytruda in SCLC, though. Keytruda nailed the Keynote-604 study’s other primary endpoint, showing it could reduce the risk of disease progression or death by 25%, a figure in line with those Tecentriq and Imfinzi previously posted.

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And Keytruda already bears an approval later in SCLC treatment. Last June, the FDA cleared it as a monotherapy for patients who have failed platinum-based chemo and at least one other line of therapy. That go-ahead gave it a place beside Opdivo, its PD-1 rival, which already had a nod that setting.

Regulators based the green light on data from the phase 2 Keynote-158 and phase 1 Keynote-028 trials; between them, they showed that 19.3% of patients responded to Keytruda, and more than half of those who benefited from the drug continued to benefit for 18 months or longer.

“If you look at the effect sizes across all three trials, I think if you look at the totality of data, you might ask the question the other way around,” Baynes said when asked whether PD-L1 drugs had a small-cell advantage.

Either way, they have a sales opportunity Graybosch says Merck will miss out on. On its own, the progression-free survival win from the Keynote-604 study “is insufficient to support approval,” she wrote in January, adding that an overall survival win could have helped Keytruda add $269 million to $429 million to its U.S. sales haul in 2024.

Merck, for its part, has said it plans to discuss the results with regulators, but Baynes declined to comment on the nature of those conversations.