Keytruda (pembrolizumab) in combination with Yervoy (ipilimumab) did not improve overall survival or progression-free survival, and instead added toxicity compared with Keytruda as monotherapy in the phase III KEYNOTE-598 study.
The phase III study evaluates Keytruda in combination with Yervoy compared with Keytruda monotherapy as first-line treatment in metastatic non-small cell lung cancer without EGFR or ALK genomic tumor aberrations and whose tumors express PD-L1 (tumor proportion score [TPS] ≥50%) .
Keytruda is sponsored by Merck, and Yervoy is sponsored by Bristol Myers Squibb.
The median OS was 21.4 months for patients randomized to Keytruda in combination with Yervoy versus 21.9 months for those randomized to Keytruda monotherapy (HR=1.08 [95% CI, 0.85-1.37]; p=0.74). Additionally, the median PFS was 8.2 months for patients in the combination arm versus 8.4 months for those in the Keytruda monotherapy arm (HR=1.06 [95% CI, 0.86-1.30]; p=0.72).
“In KEYNOTE-598, the addition of ipilimumab to Keytruda did not improve overall survival or progression-free survival, and patients who received the combination were more likely to experience serious side effects than those who received Keytruda monotherapy,” Michael Boyer, chief clinical officer and conjoint chair of thoracic oncology of Chris O’Brien Lifehouse, Camperdown, NSW, Australia, said in a statement.
These results were presented in the presidential symposium at the IASLC 2020 World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer on Jan. 29 and published in the Journal of Clinical Oncology.
The study was discontinued due to futility based on the recommendation of an independent data monitoring committee, which determined the benefit/risk profile of KEYTRUDA in combination with Yervoy did not support continuing the trial. The DMC also advised that patients in the study discontinue treatment with Yervoy/placebo.
KEYNOTE-598 (ClinicalTrials.gov, NCT03302234) is a randomized, double-blind, phase 3 trial designed to evaluate Keytruda in combination with Yervoy compared to Keytruda monotherapy as first-line treatment for patients with metastatic NSCLC without EGFR or ALK genomic tumor aberrations and whose tumors express PD-L1 (TPS ≥50%). The dual primary endpoints are OS and PFS. Secondary endpoints include objective response rate, duration of response and safety.
The study enrolled 568 patients who were randomized 1:1 to receive Keytruda (200 mg intravenously [IV] on Day 1 of each three-week cycle for up to 35 cycles) in combination with Yervoy (1 mg/kg IV on Day 1 of each six-week cycle for up to 18 cycles); or Keytruda (200 mg IV on Day 1 of each three-week cycle for up to 35 cycles) as monotherapy. Non-binding futility criteria for the study were based on restricted mean survival time (RMST), an alternative outcome measure estimated as the area under the survival curve through a fixed timepoint.
The pre-specified criteria were differences in RMST for Keytruda in combination with Yervoy and Keytruda monotherapy of ≤0.2 at the maximum observation time and ≤0.1 at 24 months of follow-up.
As of data cut-off, the median study follow-up was 20.6 months. Findings showed the median OS was 21.4 months for patients randomized to Keytruda in combination with Yervoy (n=284) versus 21.9 months for those randomized to Keytruda monotherapy (n=284) (HR=1.08 [95% CI, 0.85-1.37]; p=0.74).
The differences in RMST for Keytruda in combination with Yervoy and Keytruda monotherapy were -0.56 at the maximum observation time and -0.52 at 24 months, meeting the futility criteria for the trial and confirming the benefit/risk profile of the combination did not support continuing the study.
Additionally, the median PFS was 8.2 months for patients randomized to Keytruda in combination with Yervoy versus 8.4 months for those randomized to Keytruda monotherapy (HR=1.06 [95% CI, 0.86-1.30]; p=0.72). In both arms of the study, ORR was 45.4%; the median DOR was 16.1 months for patients randomized to Keytruda in combination with Yervoy versus 17.3 months for those randomized to Keytruda monotherapy.
