The phase 3 KEYNOTE-598 trial evaluating the dual immunotherapy combination comprised of pembrolizumab and ipilimumab as frontline treatment in patients with metastatic non–small cell lung cancer who have a PD-L1 tumor proportion score of 50% or greater and do not harbor any EGFR or ALK aberrations has been discontinued.
The phase 3 KEYNOTE-598 trial (NCT03302234) evaluating the dual immunotherapy combination comprised of pembrolizumab (Keytruda) and ipilimumab (Yervoy) as frontline treatment in patients with metastatic non–small cell lung cancer (NSCLC) who have a PD-L1 tumor proportion score (TPS) of 50% or greater and do not harbor any EGFR or ALK aberrations has been discontinued.1
The decision follows a recommendation from an independent Data Monitoring Committee (DMC) which concluded that the benefit/risk profile of the regimen did not support continuance of the trial. Results from an interim analysis demonstrated that pembrolizumab/ipilimumab did not lead to an incremental benefit in overall survival (OS) or progression-free survival (PFS) over single-agent pembrolizumab; the data were reported to cross futility boundaries.
Moreover, although no new safety signals were reported with pembrolizumab alone, the combination was found to have a higher incidence of grade 3 to 5 toxicities, serious effects, adverse effects (AEs) that led to either treatment discontinuation or death.
The DMC has advised the patients currently enrolled to the study stop treatment with ipilimumab plus placebo. Merck announced that data from KEYNOTE-598 will be submitted for presentation at an upcoming medical meeting; the findings will also be shared with regulatory agencies.
“We conducted KEYNOTE-598 in order to explicitly explore whether combining our anti–PD-1 therapy, [pembrolizumab], with ipilimumab provided additional benefits beyond treatment with [pembrolizumab] alone in the metastatic NSCLC setting,” Roy Barnes, MD, PhD, senior vice president, head of global clinical development, and chief medical officer at Merck Research Laboratories, stated in a press release. “It is very clear that in this study, the addition of ipilimumab did not add clinical benefit but did add toxicity. [Pembrolizumab] monotherapy remains a standard of care for the treatment of certain patients with metastatic NSCLC whose tumors express PD-L1.”
In the randomized, double-blind phase 3 trial, investigators examined the efficacy of frontline pembrolizumab in combination with either ipilimumab or placebo in patients with metastatic NSCLC who had a PD-L1 TPS of 50% or greater without any EGFR or ALK aberrations.
To be eligible for participation, patients had to have a histologically or cytologically confirmed diagnosis of stage IV metastatic NSCLC, have measurable disease in accordance with RECIST v1.1 criteria, have an ECOG performance status of either 0 or 1, and a life expectancy of over 3 months, among others.2 If patients received previous systemic chemotherapy or other targeted or biologic antineoplastic therapy for their stage IV metastatic disease, had a tumor harboring EGFR activating mutation or ALK translocation, received previous PD-1, PD-L1, or PD-L1 inhibition, or had prior radiotherapy within 2 weeks of study start, they were excluded.
The coprimary end points of the trial were OS and PFS. Key secondary end points included objective response rate, duration of response, time to true deterioration, incidence of AEs, incidence of treatment discontinuation, and change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Global Health Status/Quality of Life Scale score.
A total of 568 patients were enrolled to the trial and they were randomized 1:1 to receive intravenous (IV) pembrolizumab at a dose of 200 mg on day 1 of each 3-week cycle for up to 35 cycles plus IV ipilimumab at a dose of 1 mg/kg on day 1 of each 6-week cycle for up to 18 cycles, or pembrolizumab in combination with placebo at the same dose and schedule.
Although the combination of a PD-1 inhibitor and ipilimumab has previously received regulatory approval for certain indications, studies that have supported these decisions have largely not directly compared the combination with single-agent PD-1 inhibition, according to Merck.
However, in the phase 3 CheckMate-915 trial (NCT03068455), investigators did compare ipilimumab in combination with nivolumab (Opdivo) in patients with resected stage IIIB/C/D or stage IV melanoma. Results showed that the combination failed to significantly improve recurrence-free survival when used as an adjuvant treatment.3 The trial did not meet its coprimary end points in the all-comer population, nor in those with a PD-L1 TPS of less than 1%.4