A US Food and Drug Administration (FDA)-requested, unplanned, interim analyses of 2 randomized phase 3 trials that evaluated the safety and efficacy of adding the programmed cell death-1 (PD-1) inhibitor pembrolizumab to standard-of-care therapy for either previously untreated, transplant-ineligible patients with multiple myeloma or those with relapsed/refractory disease resulted in the early termination of both studies. The results of the interim analyses were published in separate reports in Lancet Haematology.1,2
In the open-label multicenter KEYNOTE-185 study (ClinicalTrials.gov Identifier: NCT02579863), 301 treatment-naïve patients had been randomly assigned 1:1 to receive either pembrolizumab plus lenalidomide and dexamethasone or lenalidomide/dexamethasone alone. Median patient age was 74 years in both study arms and all patients had Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
With a median follow-up of 6.6 months at the time of the interim analysis, median progression-free survival (PFS), the primary endpoint of the study, had not been reached in either study arm. However, 6 treatment-related deaths attributed to cardiac arrest, cardiac failure, myocarditis, large intestine perforation, pneumonia, or pulmonary embolism were reported in patients receiving treatment with the immune checkpoint inhibitor. In contrast, only 2 patient deaths — due to upper gastrointestinal hemorrhage and respiratory failure — occurred in patients receiving lenalidomide/dexamethasone alone. The rates of serious adverse events were 54% and 39% in the experimental and control arms, respectively,
In the open-label multicenter KEYNOTE-183 study (ClinicalTrials.gov Identifier: NCT02576977), 249 patients had been randomly assigned 1:1 to receive pomalidomide and dexamethasone with or without pembrolizumab at the time of the interim analysis. The co-primary endpoints of the study were PFS and overall survival (OS).
All study patients had received prior treatment with a least 2 lines of therapy (excluding pomalidomide), and had an ECOG performance status of 0 or 1. The median follow-up was 8.1 months, and the median patient age was 65 years in the pembrolizumab-containing arm, and 67 years for those receiving pomalidomide/dexamethasone alone.
Although no treatment-related deaths occurred in the pomalidomide/dexamethasone arm alone, 4 patient deaths were attributed to treatment of pembrolizumab-containing therapy, and in 2 cases, these were associated with myocarditis and Stevens-Johnsons syndrome. The serious adverse event rate was 63% and 46% in patients receiving treatment with and without the immune checkpoint inhibitor, respectively.
Estimated rates of 6-month PFS were 48% for patients receiving pembrolizumab-containing therapy, and 60% for those treated with pomalidomide/dexamethasone alone. Corresponding estimates of 6-month OS rates were 82% and 90%.
Following the findings of early mortality in these analyses that were not specified in the clinical trial protocols, a data monitoring committee halted enrollment in both studies, and the studies were subsequently terminated by the FDA.
- Usmani SZ, Schjesvold F, Oriol A, et al. Pembrolizumab plus lenalidomide and dexamethasone for patients with treatment-naive multiple myeloma (KEYNOTE-185): a randomised, open-label, phase 3 trial [published online July 18, 2019]. Lancet Haematol. doi: 10.1016/S2352-3026(19)30109-7
- Mateos MV, Blacklock H, Schjesvold F, et al. Pembrolizumab plus pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma (KEYNOTE-183): a randomised, open-label, phase 3 trial. Lancet Haematol. doi: 10.1016/S2352-3026(19)30110-3
This article originally appeared on Oncology Nurse Advisor