In a prespecified interim analysis of phase III KEYNOTE-355 study, the addition of pembrolizumab to chemotherapy resulted in longer progression-free survival (PFS) than chemotherapy alone among patients with advanced triple-negative breast cancer (TNBC) whose tumours expressed programmed death ligand 1 (PD-L1) with a combined positive score (CPS) of 10 or more. The results of the protocol-specified final analysis show that pembrolizumab plus chemotherapy also result in significantly longer overall survival (OS) than chemotherapy alone in this patient subgroup, providing further support that a CPS of 10 or more is an appropriate criterion to define the population of patients with advanced TNBC who would be expected to derive benefit from adding pembrolizumab to chemotherapy. The findings from the final study analysis are published by Dr. Javier Cortes of the International Breast Cancer Center, Pangaea Oncology, Quironsalud Group in Barcelona and the Faculty of Biomedical and Health Sciences, Department of Medicine, Universidad Europea de Madrid in Madrid, Spain and KEYNOTE-355 study investigators in 21 July 2022 issue of The New England Journal of Medicine.
The authors wrote in the study background that chemotherapy for advanced TNBC results in suboptimal antitumour response rates and short OS and response durations. New therapeutic strategies to improve outcomes are needed. Pembrolizumab monotherapy has shown durable antitumour activity in advanced TNBC, particularly as first-line treatment, with improved clinical responses observed among patients with higher PD-L1 expression.
The phase III KEYNOTE-355 study examined whether the addition of pembrolizumab would enhance the antitumour activity of chemotherapy, including taxanes and a non-taxane platinum-based regimen, in patients with previously untreated locally recurrent inoperable or metastatic TNBC. In the latest article, the study team present the results of the protocol-specified final analysis, which assessed OS among patients treated with pembrolizumab plus chemotherapy as compared with those who received placebo plus chemotherapy.
The study team randomly assigned patients with previously untreated locally recurrent inoperable or metastatic TNBC in a 2:1 ratio to receive pembrolizumab 200 mg every 3 weeks plus the investigator’s choice of chemotherapy (nanoparticle albumin-bound paclitaxel, paclitaxel, or gemcitabine–carboplatin) or placebo plus chemotherapy. The study primary endpoints were PFS which was reported previously and OS among patients whose tumours expressed PD-L1 with a CPS of 10 or more (the CPS-10 subgroup), among patients whose tumours expressed PD-L1 with a CPS of 1 or more (the CPS-1 subgroup), and in the intention-to-treat (ITT) population. Safety was also assessed.
In total, 847 patients underwent randomisation with 566 being assigned to the pembrolizumab–chemotherapy arm and 281 to the placebo–chemotherapy arm. The median follow-up was 44.1 months. In the CPS-10 subgroup, the median OS was 23.0 months in the pembrolizumab–chemotherapy arm and 16.1 months in the placebo–chemotherapy arm (hazard ratio [HR] for death 0.73, 95% confidence interval [CI] 0.55 to 0.95; two-sided p = 0.0185) with criterion for significance met. In the CPS-1 subgroup, the median OS was 17.6 and 16.0 months in the two arms (HR 0.86, 95% CI 0.72 to 1.04; two-sided p = 0.1125) which was not significant, and in the ITT population, the median OS was 17.2 and 15.5 months (HR 0.89, 95% CI 0.76 to 1.05, significance was not tested).
The results of an exploratory analysis of OS according to additional CPS cut-offs showed a consistent benefit with the addition of pembrolizumab among patients whose tumours expressed PD-L1 with a CPS of 10 to 19 and among those whose tumours expressed PD-L1 with a CPS of 20 or more. The authors commented that this finding provides further support that a CPS of 10 or more is an appropriate criterion to define the population of patients with advanced TNBC who would be expected to derive benefit from pembrolizumab plus chemotherapy.
Adverse events of grade 3, 4, or 5 that were related to the study regimen occurred in 68.1% of the patients in the pembrolizumab–chemotherapy arm and in 66.9% in the placebo–chemotherapy arm, including death in 0.4% of the patients in the pembrolizumab–chemotherapy arm and in no patients in the placebo–chemotherapy arm. As in the interim analysis, the higher incidence of immune-mediated adverse events in the pembrolizumab–chemotherapy arm than in the placebo–chemotherapy arm was primarily driven by hypothyroidism and hyperthyroidism. Overall, these events were generally low grade and were manageable with dose interruptions and appropriate use of supportive care.
In an accompanied editorial, Prof. Xavier Pivot of the Institute of Cancerology Strasbourg in Strasbourg, France called pembrolizumab as a breakthrough treatment for patients with advanced TNBC. The KEYNOTE-355 results confirm the relationship between PD-L1 expression and the activity of pembrolizumab in preclinical and clinical studies, a finding that completes the bench-to-bedside cycle. Prof. Pivot stated that other immunotherapies will emerge, but pembrolizumab will remain the first treatment that showed prolong OS in the treatment of a subgroup of women with advanced TNBC. However, to provide patients with the greatest access to pembrolizumab, there is a need to optimise the duration of use early in the course of disease and to anticipate the actions that will be needed to address the cost issues.
The KEYNOTE-355 study was funded by Merck Sharp and Dohme.
