Merck Halts Phase III KEYNOTE-598 Trial of Keytruda Plus Yervoy in First-Line NSCLC Due to Lack of Efficacy and Increased Toxicity

Compiled by Hemingway

MSD announced on November 9 that it would discontinue the Phase 3 clinical trial KEYNOTE-598, which evaluated the combination of Keytruda and ipilimumab (Yervoy®) (“K+Y” dual immunotherapy) versus Keytruda monotherapy as a first-line treatment for metastatic non-small cell lung cancer (NSCLC) with PD-L1 expression (Tumor Proportion Score [TPS] ≥50%) and without EGFR or ALK genomic tumor aberrations.

At the recommendation of the independent Data Monitoring Committee (DMC), MSD voluntarily terminated the study, as the committee determined that the benefit/risk profile of the combination therapy did not support continuation of the trial.

In the interim analysis, compared with Keytruda monotherapy, the “K+Y” combination did not demonstrate additional patient benefit in terms of overall survival (OS) or progression-free survival (PFS) (the dual primary endpoints of this study), and crossed the futility boundary.

No new adverse events were observed with monotherapy; however, compared with Keytruda monotherapy, the combination of “K+Y” was associated with a higher incidence of Grade 3–5 adverse events (AEs), serious AEs, and AEs leading to discontinuation or death.

The initial rationale for the KEYNOTE-598 clinical trial was to investigate whether the combination of the anti-PD-1 therapeutic agent Keytruda and ipilimumab provided additional benefits beyond Keytruda monotherapy in metastatic non-small cell lung cancer. However, this study demonstrated that the addition of ipilimumab did not enhance clinical benefit but instead increased treatment-related toxicity.

Currently, approved combination therapies of anti-PD-1 treatment plus ipilimumab exist for certain indications; however, the studies supporting these approvals generally did not directly compare anti-PD-1 therapy with anti-PD-1 monotherapy. For example, the clinical trial for Bristol Myers Squibb’s recently EU-approved “O+Y” regimen as first-line treatment for NSCLC was conducted against chemotherapy. [Related reading:EU Approves Bristol Myers Squibb’s “Opdivo + Yervoy” Regimen as First-Line Treatment for NSCLC】

However, according to the Keytruda-related treatment regimens published by MSD, its lung cancer program is evaluating the role of Keytruda across various stages of disease and treatment modalities in more than 200 clinical trials involving over 10,000 patients.

KEYNOTE-598 (ClinicalTrials.gov, NCT03302234) is a randomized, double-blind, Phase III clinical trial evaluating the efficacy of Keytruda in combination with ipilimumab versus Keytruda monotherapy as first-line treatment for patients with metastatic non-small cell lung cancer (NSCLC) lacking EGFR or ALK genomic tumor aberrations and expressing PD-L1 (TPS ≥ 50%).

The clinical dual primary endpoints of this study were OS and PFS, and the secondary clinical endpoints included objective response rate, duration of response, and safety. A total of 568 patients were enrolled in the study and randomized (1:1) to receive the following treatment regimens:

Keytruda (200 mg intravenously on Day 1 of each 3-week cycle, for up to 35 cycles) in combination with ipilimumab (1 mg/kg intravenously on Day 1 of each 6-week cycle, for up to 18 cycles);

Keytruda (200 mg intravenously on Day 1 of each 3-week cycle, for up to 35 cycles) in combination with placebo (intravenously on Day 1 of each 6-week cycle, for up to 18 cycles).

Reference Source: Merck Announces KEYNOTE-598 Trial Evaluating KEYTRUDA® (pembrolizumab) in Combination With Ipilimumab Versus KEYTRUDA