Merck's Keytruda misses key mark in small cell lung cancer trial, dashing big expansion hopes

Keytruda
Merck & Co. rolled out mixed results for Keytruda in small cell lung cancer, jeopardizing its case for a potential FDA green light. (Merck & Co.)

Merck & Co.’s Keytruda may be the star in non-small cell lung cancer, but in another form of the lung disease, it has registered a rare clinical miss that will hurt its hopes for a key market expansion.

Keytruda, used in tandem with chemo for newly diagnosed extensive-stage small cell lung cancer (SCLC), failed to significantly outdo chemo alone at prolonging patients’ lives in a phase 3 trial, Merck said Monday.

The PD-1 inhibitor did demonstrate improvement in overall survival, but the 20% reduction in the risk of death didn’t meet the statistical significance bar.

The combo also hit the Keynote-604 trial’s co-primary endpoint, showing it could cut the risk of cancer progression or death by 25%. However, “this alone is insufficient to support approval,” SVB Leerink analyst Daina Graybosch said in an investor note, especially as rival meds—Roche’s Tecentriq and AstraZeneca’s Imfinzi—have pulled off overall survival wins.

Although SCLC accounts for only about 10% to 15% of all lung cancer cases—making it a much smaller indication than NSCLC—it represented “one of the largest metastatic market opportunities remaining for Keytruda to penetrate,” Graybosch said. By her calculation, had Keynote-604 been successful, Keytruda could have rung in another $269 million to $429 million in 2024 U.S. sales.

Keytruda’s progression-free survival data look competitive against those two PD-L1 drugs, though. In the IMpower133 study that landed Roche the first immuno-oncology nod in first-line SCLC, a pairing of Tecentriq and chemo pared down the risk of disease worsening or death by 23% versus solo chemo. The Imfinzi-chemo cocktail lowered that same risk by 22% in the Caspian trial. Thanks to that win, an application for Imfinzi’s use in frontline SCLC has been put under FDA priority review, with a decision expected soon.

RELATED: AstraZeneca wins speedy FDA review for Imfinzi to challenge Roche in small cell lung cancer

But the Merck drug missed the mark on life extension, the gold standard for evaluating a cancer therapy’s efficacy. In contrast, Tecentriq cut the risk of death by 30% and Imfinzi by 27% in their separate trials, both higher than the 20% Keytruda posted.

Still, instead of calling it quits, Merck said it plans to discuss the mixed results with regulatory authorities and will present them at an upcoming medical meeting.

“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),” Graybosch said in the Monday note. Previously, Bristol-Myers Squibb’s PD-1 inhibitor Opdivo, both by itself and in combination with CTLA4 drug Yervoy, failed to extend the lives of extensive-stage SCLC patients who had undergone an initial round of platinum-based chemotherapy.

Graybosch views topline data from the Keynote-355 trial in previously untreated triple-negative breast cancer as the next major catalyst for Keytruda. A combination of Tecentriq and chemo Abraxane in March nabbed the first immunotherapy go-ahead in that disease.

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