Merck Discontinues Trials of Pembrolizumab in Prostate Cancer, Non–Small Cell Lung Cancer

Merck has announced the discontinuation of the KEYNOTE-641 and -789 trials investigating pembrolizumab (Keytruda) in patients with metastatic castration-resistant prostate cancer (mCRPC) as well as metastatic nonsquamous non–small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR)-genomic tumor mutations.

The phase 3 KEYNOTE-641 trial was evaluating pembrolizumab in combination with enzalutamide and androgen deprivation therapy (ADT) for patients with mCRPC. At an interim analysis, the treatment regimen did not demonstrate an improvement in radiographic progression-free survival (rPFS) or overall survival (OS), the trial’s dual primary endpoints, compared to placebo plus enzalutamide and ADT. The trial also crossed a pre-specified futility boundary for OS.

mCRPC is the second most common cancer in male patients globally and has a significant mortality rate. Development in the prostate cancer space is largely driven by androgens, including testosterone.

Approximately 10% to 20% of patients with prostate cancer are estimated to develop CRPC within 5 years, with at least 84% of these patients presenting with metastases at the time of CRPC diagnosis. Among those with no metastases at CRPC diagnosis, 33% are likely to develop metastases within 2 years.

Similarly, the phase 3 KEYNOTE-789 trial evaluating pembrolizumab in combination with pemetrexed plus platinum-based chemotherapy did not meet its dual primary endpoint of OS for patients with metastatic NSCLC with EGFR-genomic tumor mutations who have previously progressed on a tyrosine kinase inhibitor (TKI), including osimertinib. At the final analysis, there was an improvement in OS for patients who received pembrolizumab plus pemetrexed with platinum-based chemotherapy compared to pemetrexed with platinum-based chemotherapy. However, these results did not meet statistical significance per the pre-specified statistical plan.

At an earlier interim analysis, the trial’s other dual primary endpoint, PFS, was tested and showed an improvement in the pembrolizumab arm compared to chemotherapy alone, but these results did not reach statistical significance.

Lung cancer is the leading cause of cancer deaths worldwide, with more than 2.2 million new cases and 1.8 million deaths globally in 2020. NSCLC is the most common type of lung cancer, accounting for approximately 81% of all cases. Among those, between 10% and 15% have EGFR mutations in the United States and Europe and up to 40% to 50% in Asia.

In the United States, the 5-year OS rate for patients diagnosed with lung cancer is 25%, which is a 21% improvement over the past 5 years. Improved survival rates are due, in part, to earlier detection and screening, reduction in smoking, advances in diagnostic and surgical procedures, and the introduction of new therapies.

“Throughout the clinical development of Keytruda, 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 and chief medical officer at Merck Research Laboratories, in a press release. “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. We are extremely grateful to all the investigators and patients for their participation in these studies.”

REFERENCE

Merck Provides Update on Phase 3 Trials KEYNOTE-641 and KEYNOTE-789. News release. Merck; February 28, 2023. Accessed March 9, 2023. https://www.merck.com/news/merck-provides-update-on-phase-3-trials-keynote-641-and-keynote-789/