The phase 3 KEYNOTE-598 study of pembrolizumab plus ipilimumab in a population of patients with metastatic non–small cell lung cancer has been discontinued for futility.
The phase 3 KEYNOTE-598 study of pembrolizumab (Keytruda) plus ipilimumab (Yervoy) in a population of patients with metastatic non–small cell lung cancer (NSCLC) has been discontinued for futility, Merck announced in a press release.1
The trial was evaluating the efficacy and safety of the immune checkpoint inhibitor with either ipilimumab or placebo as treatment of patients with metastatic NSCLC whose tumors express PD-L1 with a tumor proportion score (TPS) ≥50% and no EGFR or ALK aberrations. The trial was halted based on recommendations from an independent Data Monitoring Committee, who determined the benefit/risk profile of pembrolizumab plus ipilimumab did not support continuing the study.
“We conducted KEYNOTE-598 in order to explicitly explore whether combining our anti-PD-1 therapy, Keytruda, with ipilimumab provided additional benefits beyond treatment with Keytrudaalone in the metastatic non-small cell lung cancer setting,” said Roy Baynes, MD, PhD, senior vice president and head of Global Clinical Development, and chief medical officer, Merck Research Laboratories, in a statement. “It is very clear that in this study, the addition of ipilimumab did not add clinical benefit but did add toxicity. Keytruda monotherapy remains a standard of care for the treatment of certain patients with metastatic non-small cell lung cancer whose tumors express PD-L1.”
According to findings from an interim analysis, this combination demonstrated no incremental benefit compared with pembrolizumab monotherapy in terms of either overall survival or progression-free survival, which were the co-primary end points of the study, and the combination crossed futility boundaries.
The randomized, double-blind study included secondary end points o objective response rate, duration of response, and safety. Overall, 568 patients were enrolled and randomized 1:1 to receive either pembrolizumab with ipilimumab or pembrolizumab with placebo.
No new safety signals were observed for the pembrolizumab monotherapy, but the combination demonstrated a higher incidence of grade 3-5 adverse events (AEs), serious AEs, and AEs leading to either treatment discontinuation or death compared with the single agent.
The independent Data Monitoring Committee has recommended that patients discontinue treatment with ipilimumab with placebo. Data from the study will be submitted to be presented during an upcoming medical meeting, as well as communicated to regulatory agencies.
The use of an anti-PD-1 therapy in combination with ipilimumab has been approved for certain indications, such as the combination of nivolumab (Opdivo) plus ipilimumab for the frontline treatment of patients with metastatic or recurrent NSCLC and no EGFR or ALK genomic tumor aberrations in combination with 2 cycles of platinum-doublet chemotherapy, and for the frontline treatment of those with metastatic disease whose tumors express PD-L1(TPS ≥1%) with no EGFR or ALK abberations, but the studies for these approvals have not compared the combination directly with a single-agent anti-PD-1 therapy, for the most part.2
In NSCLC, pembrolizumab is approved under a number of indications from the FDA. These include in combination use with pemetrexed and platinum chemotherapy for the frontline treatment of patients with metastatic nonsquamous NSCLC without EGFR or ALK genomic aberrations, as well as in combination with carboplatin and either paclitaxel or paclitaxel protein-bound for the frontline treatment of patients with metastatic squamous disease.1
The immune checkpoint inhibitor is also indicated as a single agent for the treatment of those with metastatic NSCLC who express PD-L1 (TPS ≥1%) and harbor no EGFR or ALK aberrations, for stage III patients who are ineligible for surgical resection or definitive chemoradiation, or metastatic. It is also indicated for patients with metastatic NSCLC whose tumors express PD-L1 with TPS ≥1% and disease progression on or after prior platinum-based chemotherapy.
1. Merck announces keynote-598 trial evaluating keytruda (pembrolizumab) in combination with ipilimumab versus ketruda monotherapy in certain patients with metastatic non-small cell lung cancer to stop for futility and patients to discontinue. News Release. Merck. November 9, 2020. Accessed November 10, 2020. https://bit.ly/3ndvstQ
2. U.S. Food and Drug Administration Approves Opdivo® (nivolumab) + Yervoy® (ipilimumab) Combined with Limited Chemotherapy as First-Line Treatment of Metastatic or Recurrent Non-Small Cell Lung Cancer. News Release. Bristol Myers Squibb. May 26, 2020. Accessed November 10, 2020. https://bwnews.pr/2znmG9j