Pembrolizumab Misses Mark in mCRPC, EGFR-Mutant NSCLC Trials


In both the KEYNOTE-641 and KEYNOTE-789 trials, pembrolizumab, in addition to standard therapies, did not improve survival outcomes in their target populations.

Pembrolizumab missed its primary radiographic progression-free survival (rPFS) and overall survival (OS) end points when added to enzalutamide (Xtandi) and androgen deprivation therapy (ADT) and assessed in patients with metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 KEYNOTE-641 trial (NCT03834493).

Similarly, in the phase 3 KEYNOTE-789 trial (NCT03515837), the addition of pembrolizumab to pemetrexed and platinum-based chemotherapy failed to show a statistically significant improvement in OS vs chemotherapy alone in patients with metastatic nonsquamous non–small cell lung cancer (NSCLC) harboring EGFR mutations who have progressed on therapy with a TKI, including osimertinib (Tagrisso).

Merck has decided to discontinue the KEYNOTE-641 trial based on a recommendation from an independent data monitoring committee. The company will inform study investigators of the decision and encourages patients enrolled in the study to discuss treatment with their physician.

In both trials, the safety profile of pembrolizumab was consistent with data from prior studies, and no new safety signals were identified. In KEYNOTE-641, the combination incurred a higher incidence of grade 3 to 5 adverse effects (AEs) and serious AEs compared with the control arm. Results will be shared at upcoming medical meetings.

“Throughout the clinical development of [pembrolizumab], we have asked the tough questions in an effort to fully explore the potential of this breakthrough immunotherapy and determine how we could help as many patients as possible,” Eliav Barr, MD, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, said in a press release. “Science is rarely a straight line, and while we are disappointed in these study results, our research to investigate [pembrolizumab] in many difficult-to-treat types of cancer continues in earnest. We are extremely grateful to all the investigators and patients for their participation in these studies.”

The randomized, double-blind, phase 3 KEYNOTE-641 trial enrolled patients with mCRPC who have not received chemotherapy for mCRPC, are abiraterone acetate (Zytiga)–naïve or are intolerant to or progressed on abiraterone acetate. Approximately 1,240 patients were randomly assigned to receive 200 mg of intravenous (IV) pembrolizumab every 3 weeks for up to 2 years plus 160 mg of enzalutamide daily, or placebo plus enzalutamide.

The primary end points of the trial were OS and rPFS per Prostate Cancer Working Group-modified RECIST v1.1 criteria as assessed by blinded independent central review. Secondary end points include objective response rate (ORR), duration of response (DOR), and safety.

The randomized, double-blind, phase 3 KEYNOTE-789 trial enrolled patients with EGFR-mutated metastatic nonsquamous NSCLC who had disease progression per RECIST v1.1 criteria following treatment with TKI therapy. Patients had to have either EGFR T790M–negative mutation tumors; EGFR T790M–positive mutation tumors with prior exposure to osimertinib; or progressive disease on frontline osimertinib regardless of EGFR T790M mutation status.

The study enrolled 492 patients who were randomly assigned to receive 200 mg of IV pembrolizumab on day 1 of every 3-week cycle for up to 35 cycles, 500 mg/m2 of IV pemetrexed every 3 weeks as tolerated, plus IV carboplatin with an area under the curve of 5 every 3 weeks for 4 cycles, or 75 mg/m2 of IV cisplatin every 3 weeks for 4 cycles; or placebo administered as IV saline on day 1 of every 3-week cycle for up to 35 cycles, 500 mg/m2 of IV pemetrexed every 3 weeks as tolerated, plus the same dose and schedule of platinum chemotherapy as in the experimental arm.

The primary end points of the study were OS and PFS. Secondary end points included ORR, DOR, and safety.


Merck provides update on phase 3 trials KEYNOTE-641 and KEYNOTE-789. News release. Merck. February 28, 2023. Accessed February 28, 2023.

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