Merck ends last Keytruda trial in aggressive prostate cancer campaign, takes separate hit in lung cancer

The last of four pivotal trials for Merck's Keytruda in prostate cancer has returned negative, ending a four-year expedition that endured repeated failures.

In a phase 3 trial, Keytruda, used on top of Astellas and Pfizer’s Xtandi and androgen deprivation therapy (ADT), didn’t add any survival benefit for metastatic castration-resistant prostate cancer (mCRPC) patients who hadn’t received prior chemo. The PD-1 inhibitor did not help stave off cancer progression, either.

Based on the observation, Merck decided to discontinue the study, coded Keynote-641, at the recommendation of an independent data monitoring committee, the company said Tuesday.

With that, Keytruda has failed in four phase 3 trials that comprised an aggressive prostate cancer program launched by Merck in 2019. Just last month, Merck called it quits on Keynote-991, which evaluated the Keytruda-Xtandi-ADT regimen in hormone-sensitive prostate cancer.

The other two failed trials, Keynote-921 and Keylynk-010, tested Keytruda in combination with chemotherapy and the AstraZeneca-partnered PARP inhibitor Lynparza, respectively.

Despite the setbacks, Scot Ebbinghaus, M.D., VP of clinical research at Merck Research Laboratories recently defended Merck’s decision to run the studies.

Merck launched the trials based on early signals from the phase 1/2 Keynote-365 trial. Merck “made the right decision to go into prostate cancer with a relatively aggressive approach given the data that we had, given the unmet need and given the overall success of the Keytruda program,” Ebbinghaus said a few days ago on the sidelines of the 2023 ASCO Genitourinary Cancers Symposium, where investigators presented detailed data from Keynote-921.

For now, the Keynote-365 trial is still looking at various combinations for Keytruda in prostate cancer and has yielded some promising data in neuroendocrine prostate cancer, Ebbinghaus noted.

Prostate cancer wasn’t the only field where Merck reported a setback for Keytruda on Tuesday. In Keytruda’s home turf, non-small cell lung cancer, pairing the PD-1 inhibitor with chemotherapy didn’t significantly prolong the lives of patients with nonsquamous EGFR-mutated tumors after progression on AstraZeneca’s Tagrisso. The finding came from the final analysis of the phase 3 Keynote-789 trial.

In 2018, this same Keytruda-chemo combo was famously linked to a 51% death risk reduction—and subsequently became a standard of care—in newly diagnosed nonsquamous NSCLC without actionable mutations. In NSCLC with EGFR or ALK mutations, targeted therapies like Tagrisso remain the go-to drugs. 

For this newer study, Merck tried to see if Keytruda could help patients who’ve progressed on an EGFR inhibitor. At a previous interim analysis, the Keytruda arm didn’t experience significantly longer progression-free survival. Now, in the final analysis, the regimen again showed an improvement in overall survival that failed to meet statistical significance.

Keytruda’s flop in EGFR-progressing NSCLC followed a similar result for Bristol Myers Squibb’s Opdivo. In the phase 3 CheckMate-722 trial conducted among patients with cancer progressing on one or two prior EGFR inhibitors, Opdivo plus chemo cut the risk of death by 18% over chemo alone and reduced the risk of progression or death by 25%. Both were positive trends that weren’t statistically significant.

Trial failures from Keytruda have become more frequent lately as Merck and its partners explore various combinations to expand the reach of the powerful PD-1 inhibitor. Other setbacks include misses in head and neck cancer and liver cancer.

“Science is rarely a straight line, and while we are disappointed in these study results, our research to investigate Keytruda in many difficult-to-treat types of cancer continues in earnest,” Eliav Barr, chief medical officer of Merck Research Laboratories, said in a statement Tuesday.