Two Phase 3 Pembrolizumab Trials Show Lack of Benefit in Prostate/Lung Cancer

Two phase 3 trials assessing the benefit of pembrolizumab (Keytruda) combination therapies in metastatic castration-resistant prostate cancer (mCRPC) and metastatic non-squamous non–small cell lung cancer (NSCLC) demonstrated a lack of efficacy, according to a press release published by Merck.

The safety profile of pembrolizumab in KEYNOTE-641 and KEYNOTE-789 was consistent with previous findings, and no new safety signals were identified.

The first trial, the phase 3 KEYNOTE-641 study (NCT03834493), was discontinued because the experimental combination of pembrolizumab (Keytruda) plus enzalutamide (Xtandi) and androgen deprivation therapy (ADT) did not improve radiographic progression-free survival (rPFS) in patients with mCRPC. Moreover, the pre-specified futility boundary for overall survival (OS) was crossed.

Additionally, data from the phase 3 KEYNOTE-789 trial (NCT03515837), assessing pembrolizumab plus pemetrexed and platinum-based chemotherapy in metastatic non-squamous NSCLC, indicated that the regimen yielded a non-statistically significant OS benefit by pre-specified statistical plan in the final analysis.

“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, and chief medical officer at Merck Research Laboratories, said in the 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.”

The randomized, double-blind KEYNOTE-641 trial evaluated pembrolizumab vs placebo in patients with mCRPC who had not received prior therapy for the disease, and who were naïve, intolerant to, or who progressed on abiraterone (Zytiga). Secondary end points in the trial included objective response rate (ORR), duration of response (DOR), and the toxicity profile.

KEYNOTE-641 had an estimated enrollment of 1240 patients who were randomly assigned to receive either intravenous pembrolizumab at 200 mg every 3 weeks for up to 2 years plus enzalutamide at 160 mg daily, or placebo plus the same dose of enzalutamide.

The recommendation for discontinuation came from the study’s independent data monitoring committee. Study investigators have been informed of the decision and patients have been instructed to speak with their physician regarding treatment.

KEYNOTE-789 is a randomized, double-blind trial comparing pembrolizumab plus pemetrexed and platinum-based chemotherapy vs the same chemotherapy backbone for Tyrosine kinase inhibitor (TKI)–resistant, EGFR-mutated, metastatic, non-squamous NSCLC.

The trial assessed a total of 492 patients who experienced disease progression following prior treatment with a TKI and who had either T790M mutation–negative tumors or T790M mutation–positive tumors with prior exposure to osimertinib (Tagrisso), or for whom prior frontline treatment with osimertinib had failed regardless of T790M mutation status.

The experimental regimen in KEYNOTE-789 consisted of intravenous pembrolizumab at 200 mg on the first day of each 3-week cycle for up to 35 cycles, intravenous pemetrexed at 500 mg/m² every 3 weeks for an unrestricted number of cycles, and platinum chemotherapy consisting of either intravenous carboplatin at a dose of Area Under the Curve (AUC) 5 or cisplatin at 75 mg/m² every 3 weeks for 4 cycles. The control regimen substituted saline for pembrolizumab as a placebo and otherwise matched the experimental regimen.

Additional data from an earlier interim analysis highlighted an improvement in progression-free survival among those who received the pembrolizumab regimen vs placebo, although it was not statistically significant.

The safety profile of pembrolizumab in both trials was consistent with previous findings, and no new safety signals were identified. The experimental arm in KEYNOTE-641 experienced more frequent grade 3 to 5 adverse effects (AEs) vs the control arm. Merck also announced that more detailed findings will be shared during future medical conferences.

Reference

Merck provides update on phase 3 trials KEYNOTE-641 and KEYNOTE-789. News Release. Merck. February 28, 2023. Accessed February 28, 2023. https://bit.ly/3J2BKu1