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Merck’s Keytruda, on a losing streak, fails in once FDA-rejected liver cancer use and prostate cancer—again

Add two more failures to Merck & Co.’s recent string of Keytruda trial readouts. The once seemingly untouchable immuno-oncology agent appears to have hit a snag in its indication expansion efforts.

The combination of Keytruda and Eisai-partnered Lenvima failed in newly diagnosed liver cancer, Merck said Wednesday. The pair didn’t significantly extend patients’ lives, nor did it substantially stall tumor progression or death compared with Lenvima monotherapy in the phase 3 Leap-002 trial.

In hindsight, the failure makes FDA’s previous decision to reject that Keytruda-Lenvima use look all the more reasonable. In rebuffing that application back in 2020, the FDA blasted Merck for filing prematurely based on tumor shrinkage data.

The latest Keytruda-Lenvima flop means Roche’s Tecentriq, used alongside Avastin, can continue to enjoy immuno-oncology dominance in frontline liver cancer. But it could have broader implications than a frontline nod.

As a monotherapy, Keytruda bears an accelerated approval in liver cancer that’s been treated with Bayer’s Nexavar. But that indication came into question after the confirmatory phase 3 Keynote-240 trial narrowly missed its mark.

Despite that result, an FDA advisory committee last year voted to keep Keytruda’s second-line liver cancer indication in place, pending additional trial readouts. Then in September 2021, Merck found that Keytruda hit its goal in the Keynote-394 study in Asian patients, which could serve as the drug’s new confirmatory trial. But the PD-1 inhibitor only cut the risk of death by 21% over placebo in previously treated hepatocellular carcinoma patients in that Asia-only trial.

The FDA has yet to turn Keytruda’s second-line liver cancer accelerated approval into a full nod. If the agency still hasn’t made up its mind after Keynote-394, then the latest Leap-002 study in the front-line setting probably isn’t going to help Merck secure the indication. On a slightly positive note, Merck did note that patients on Lenvima monotherapy in Leap-002 lived longer than those observed in previous trials.

In a separate piece of bad news on Wednesday, Merck said the addition of Keytruda to chemotherapy failed to extend lives or stave off disease advances in patients with metastatic castration-resistant prostate cancer (mCRPC).

Merck cited positive trends for improvement on the two primary endpoints of overall survival and radiographic progression-free survival, but they didn’t meet the statistical significance bar.

This marks Keytruda’s second pivotal mCRPC flop in recent months. In March, Merck said a combination of Keytruda and AstraZeneca-partnered Lynparza couldn’t outdo Johnson & Johnson’s Zytiga or Astellas and Pfizer’s Xtandi in mCRPC patients who had previously got one of the anti-androgen therapies.

Meanwhile, Keytruda is undergoing other mCRPC trials. Merck is pairing Keytruda with Xtandi in the phase 3 Keynote-641 trial, which currently bears a primary completion date in November 2023, according to

Separately, the phase 3 Keynote-991 trial is adding Keytruda to Xtandi and androgen deprivation therapy in patients with metastatic hormone-sensitive prostate cancer.