Merck’s Keytruda narrowly passes confirmatory liver cancer trial, but FDA’s murky fate awaits

After late-stage trial failure and FDA scrutiny, a conditional nod to liver cancer for Merck’s Keytruda hinged on a second confirmatory study — or at least that’s what it seemed. Now that the test has come back positive, the future of the indication remains uncertain.

Keytruda reduced the risk of death by 21% compared with placebo in patients with hepatocellular carcinoma in Asia who had previously received Bayer’s Nexavar or chemotherapy. Merck’s PD-1 inhibitor also beat placebo in shrinking tumors and preventing disease progression, data show present at the 2022 American Society of Clinical Oncology (ASCO) Symposium on Gastrointestinal Cancers.

The results come from the KEYNOTE-394 Phase 3 trial, which is expected to serve as a new confirmatory trial for accelerated approval of Keytruda in post-Nexavar liver cancer; a previous phase 3 called KEYNOTE-240 just missed its mark. But now the new findings themselves, plus the FDA’s seemingly shifting attitudes and a changing treatment landscape, are adding wrinkles to the indication’s validation.

First, a 21% reduction in the risk of death is hardly practice-changing evidence that would excite doctors, especially since Keytruda only extended the median lifespan of patients by 1.6 months. at 14.6 months. Nonetheless, Scot Ebbinghaus, MD, vice president of clinical research in oncology at Merck Research Laboratories, said Keytruda offers “an important breakthrough” for patients, giving them a second-line option when they inevitably progress after treatment with First line.

RELATED: Merck grabs lifeline for problematic Keytruda liver cancer approval with Asian trial win

Keytruda showed a similar 22% reduction in the risk of death in the global KEYNOTE-240 trial, which narrowly missed statistical significance. At an April meeting on fast-track approvals that failed in confirmatory trials, an FDA expert panel voted unanimously to keep the conditional liver cancer bookmark in place. second intention of Keytruda, pending the reading of this KEYNOTE-394 trial.

Despite the similarity in numbers, the new Asian trial achieved statistical significance, thanks to a sample size that was expanded after Merck noted that subsequent lines of treatment had muddied the analysis of life extension in KEYNOTE-240, Ebbinghaus said.

Ebbinghaus touted the similarity as a positive attribute: it shows Keytruda’s consistent therapeutic effect on different populations. However, in the Asian subgroup of KEYNOTE-240, Keytruda provided a remarkable reduction in the risk of death by 45% compared to placebo, with a median patient survival of 13.8 months versus 8.3 months, respectively.

The difference between the two Asian groups is a “puzzling finding that we can’t fully rationalize or explain,” Ebbinghaus said. How patients were managed and treated beyond the trial period could be one aspect of a complex issue, he said. KEYNOTE-394 takes place mainly in China.

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So the question is, will the FDA be satisfied with the statistical significance of Keytruda in these new data? Or is 20% overall survival not good enough in this trial, just as it was not good enough before? Ebbinghaus tends to believe it’s the first.

The FDA “cannot use a negative study as a confirmatory study,” he said. “It just puts them in a really bad spot if they started using near-accidental or negative studies.”

Because KEYNOTE-394 tested positive, the FDA will at least accept the data for review, Ebbinghaus said, as it provides a “substantial basis” for the FDA’s assessment of accelerated approval.

Meanwhile, the Asian nature of KEYNOTE-394 may add uncertainty to an FDA review. Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence, recently criticized developers of PD-1/L1 drugs developed in China for seeking US approvals based on trials conducted solely or primarily in China. .

Ebbinghaus argued that this Asian trial was part of a larger Keytruda program that was global in nature. In fact, KEYNOTE-394 was originally planned as part of KEYNOTE-240, but it was split off on its own after the listing was delayed in China. Now the two “nearly identical” trials – and the KEYNOTE-224 Phase 2 study that earned Keytruda its initial approval – are providing insight into the “totality of the data”, he said.

RELATED: Merck, Eisai’s Keytruda-Lenvima Combo Stuck in Liver Cancer After Roche’s First Green Light

Finally, the landscape for treating the liver with immuno-oncology agents is changing as PD-1/L1 developers shift their offerings toward earlier treatment. Even before FDA scrutiny, a combination of Roche’s PD-L1 inhibitor Tecentriq and VEGF inhibitor Avastin became the first immunotherapy regimen for untreated liver cancer patients previously in 2020.

Merck argued that some patients may not receive the Tecentriq combo as first-line therapy, leaving an opening for Keytruda as a second-line IO option. But at ASCO GI, AstraZeneca details a Phase 3 victory for its cocktail of PD-L1 inhibitor Imfinzi and experimental CTLA-4 inhibitor tremelimumab, which reduces the risk of death by 22% compared to Nexavar. If approved, the AZ combo would become an immunotherapy-only treatment that could further expand IO’s frontline reach.

Roche’s use of Tecentriq-Abraxane in metastatic triple-negative breast cancer could serve as a lesson to Merck. Roche withdrew the indication from the market in August, even though the FDA’s advisory committee had backed approval after a confirmatory trial failed. The reason? Keytruda had obtained a green light from the FDA in July for before and after surgery in a high-risk, early-stage disease.

Merck has its own frontline combo coming. A Phase 3 trial dubbed LEAP-002 from Keytruda and Lenvima in partnership with Eisai in newly diagnosed liver cancer is expected to read later this year. The FDA previously denied an application there, blaming Merck for a premature filing based on tumor shrinkage data from an early-stage study. Additionally, Ebbinghaus noted that a triplet regimen of quavonlimab, Keytruda, Lenvima, and Merck’s investigational CTLA-4 agent, is in the works. phase 2 trial.

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