Pembrolizumab Misses Survival End Points in mCRPC/NSCLC


The phase 3 KEYNOTE-641 of pembrolizumab, enzalutamide, and androgen deprivation therapy has been discontinued, and overall survival rates in the phase KEYNOTE-789 study of pembrolizumab, pemetrexed, platinum-based chemotherapy did not meet statistical significance.

Data from 2 phase 3 studies evaluating pembrolizumab, KEYNOTE-641 (NCT03834493) and KEYNOTE-789 (NCT03515837) failed to meet their primary end points, according to Merck.1 As a result, the KEYNOTE-641 trial will be discontinued based on the recommendation of an independent Data Monitoring Committee. The KEYNOTE-789 trial will continue.1

The phase 3 KEYNOTE-641 trial evaluated the combination of pembrolizumab (Keytruda), enzalutamide (Xtandi), and androgen deprivation therapy (ADT) in patients with metastatic castration-resistant prostate cancer (mCRPC). At an interim analysis, the trial failed to demonstrate an improvement in either of its dual primary end points of radiographic progression-free survival (rPFS) or overall survival (OS) compared withplacebo plus enzalutamide and ADT.

Investigators on the phase 3 KEYNOTE-789 trial of pembrolizumab plus pemetrexed and platinum-based chemotherapy also reported that the study did not meet its dual primary end point of OS in patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with epidermal growth factor receptor (EGFR)-genomic tumor mutations, who previously had progressed on a tyrosine kinase inhibitor (TKI), including osimertinib.

“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,” said Eliav Barr, MD, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. “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.”

While the final analysis of KEYNOTE-789 revealed an improvement in OS among patients administered pembrolizumab plus pemetrexed and platinum-based chemotherapy vs pemetrexed with platinum-based chemotherapy, these data did not meet statistical significance per the pre-specified statistical plan.

An earlier interim analysis of the trial also showed that the other dual primary end point of progression-free survival (PFS) showed an improvement among patients administered pembrolizumab vs placebo, but the results did not reach statistical significance.

Both the KEYNOTE-641 and KEYNOTE-789 study showed a consistent safety profile of pembrolizumab to what have been previously reported in studies. Additionally, no new safety signals were identified.

In KEYNOTE-641, patients administered the combination with pembrolizumab had a higher incidence of grade 3-5 adverse events (AEs) and serious AEs compared with patients administered the control.

KEYNOTE-641 was a randomized, double-blind phase 3 trial assessing the combination of pembrolizumab with enzalutamide and ADT vs placebo in place of pembrolizumab for the treatment of an estimated 1,240 patients with mCRPC. Patients had not received chemotherapy for mCRPC, and were abiraterone-naïve, intolerant to, or had progressed on abiraterone acetate.2

Patients aged 18 years and older were randomized to receive intravenous (IV) pembrolizumab at a dose of 200 mg every 3 weeks for up to 2 years in addition to plus enzalutamide at 160 mg daily, or placebo plus enzalutamide.

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

In the randomized, double-blind, phase 3 KEYNOTE-789 trial, pembrolizumab plus pemetrexed and platinum-based chemotherapy was evaluated compared with pemetrexed plus platinum-based chemotherapy for the treatment of patients with TKI-resistant, EGFR-mutated metastatic, nonsquamous NSCLC.3

Patients were aged 18 years and older, required to have previously had disease progression following treatment with TKI therapy, and either had a T790M-negative mutation tumorsT790M-positive mutation tumors with prior exposure to osimertinib, or first-line osimertinib failure regardless of T790M mutation status.

A total of 492 patients were randomized to receive either IV pembrolizumab 200 mg on day 1 of each 3-week cycle for up to 35 cycles plus IV pemetrexed 500 mg/m2 every 3 weeks with no restrictions on the number of cycles, and platinum chemotherapy via IV infusion every 3 weeks for 4 cycles or the same regimen with placebo instead of pembrolizumab.

Investigators evaluated the primary end points of OS and PFS and the secondary end points of ORR, DOR and safety.

According to the press release, further results from each study will be shared at future scientific congresses.1

Merck provides update on phase 3 trials KEYNOTE-641 and KEYNOTE-789. News release. Merck. February 28, 2023. Accessed March 1, 2023.
Study of pembrolizumab (MK-3475) plus enzalutamide versus placebo plus enzalutamide in participants with metastatic castration-resistant prostate cancer (mCRPC) (MK-3475-641/KEYNOTE-641). Updated November 23, 2022. Accessed March 1, 2023.
Study of pemetrexed + platinum chemotherapy with or without pembrolizumab (MK-3475) in adults with tyrosine kinase inhibitor- (TKI)-resistant epidermal growth factor receptor- (EGFR)-mutated metastatic non-squamous non-small cell lung cancer (NSCLC) (MK-3475-789/KEYNOTE-789. Updated August 19, 2022. Accessed March 1, 2023.
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