Merck Reports Failures of Two Phase III Trials of Keytruda in Prostate Cancer and NSCLC, Disclosed in Recent IPO Filing

On February 28, MSD announced that two Phase III studies (KEYNOTE-641 and KEYNOTE-789) of the PD-1 inhibitor Pembrolizumab (Keytruda) did not meet their co-primary endpoints. The former study targeted metastatic castration-resistant prostate cancer, while the latter was for the treatment of tyrosine kinase inhibitor (TKI)-resistant, epidermal growth factor receptor (EGFR)-mutant metastatic non-squamous non-small cell lung cancer (NSCLC).

KEYNOTE-641 Study (NCT03834493) aims to evaluate the efficacy and safety of pembrolizumab combined with enzalutamide and androgen deprivation therapy (ADT) in treating patients with metastatic castration-resistant prostate cancer (mCRPC).

In the interim analysis, compared with the placebo group, the pembrolizumab group did not show improvement in the coprimary endpoints of radiographic progression-free survival (rPFS) or overall survival (OS), and crossed the prespecified OS futility boundary. Based on the recommendation of the independent data monitoring committee, MSD will terminate this study.

It is worth noting that this is not the first setback for the combination therapy of pembrolizumab with enzalutamide and ADT. On January 25, the Phase III KEYNOTE-991 study evaluating this combination for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) also failed to meet its primary endpoints of improving OS and rPFS. As a result, Merck & Co., Inc. decided to terminate the KEYNOTE-991 study.

KEYNOTE-789 Study (NCT03515837) aims to evaluate the efficacy and safety of pembrolizumab combined with pemetrexed and platinum-based chemotherapy in treating patients with metastatic non-squamous NSCLC who carry epidermal growth factor receptor (EGFR) genomic tumor mutations and have experienced disease progression after treatment with tyrosine kinase inhibitors (TKIs), including osimertinib.

In the final analysis of the study, compared with the pemetrexed and platinum chemotherapy group, the OS of patients receiving pembrolizumab plus pemetrexed and platinum chemotherapy improved, but according to the pre-specified statistical plan, these improvements were not statistically significant. In an earlier interim analysis, the pembrolizumab group also failed to show a statistically significant improvement in another co-primary endpoint—progression-free survival (PFS)—compared with chemotherapy alone.

In the KEYNOTE-641 and KEYNOTE-789 studies, the safety profile of pembrolizumab was consistent with that observed in previous studies, with no new safety signals identified.

"Throughout the clinical development of pembrolizumab, we have posed some challenging questions and worked hard to explore the potential of this breakthrough immunotherapy to help more patients," said Dr. Eliav Barr, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer of Merck Research Laboratories. "Science is rarely a straight line. While we are disappointed with these study results, we continue to advance research on pembrolizumab for many difficult-to-treat cancer types. We are extremely grateful to all the investigators and patients."

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