Crossing survival curves of KEYNOTE-177 illustrate the rationale behind combining immune checkpoint inhibition with chemotherapy

We commend Luis A Diaz Jr and colleagues 1 Diaz Jr, LA Shiu K-K Kim T-W et al. Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study. Lancet Oncol. 2022; (published online April 12.)https://doi.org/10.1016/S1470-2045(22)00197-8 Summary Full Text Full Text PDF PubMed Scopus (150) Google Scholar for using restricted mean survival time, a robust, non-parametric alternative method to quantify an effect size when conducting a time-to-event analysis, on the KEYNOTE-177 trial. The restricted mean survival time difference is the area bounded by two Kaplan-Meier curves, and reflects the absolute gain, or loss, in survival. 2 Bomze D Azoulay D Meirson T Immunotherapy with programmed cell death 1 vs programmed cell death ligand 1 inhibitors in patients with cancer. JAMA Oncol. 2020; 6: 1114-1115 Crossref PubMed Scopus (7) Google Scholar The authors report that the restricted mean survival time for overall survival after 36 months of follow-up was 26·6 months in the pembrolizumab group and 25·0 months in the chemotherapy group—a difference of 1·6 months. To further analyse the restricted mean survival time difference at distinct timepoints, we reconstructed individual-level survival data from the Kaplan-Meier curves in figure 2 of Diaz and colleagues’ paper 1 Diaz Jr, LA Shiu K-K Kim T-W et al. Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study. Lancet Oncol. 2022; (published online April 12.)https://doi.org/10.1016/S1470-2045(22)00197-8 Summary Full Text Full Text PDF PubMed Scopus (150) Google Scholar (figure). Health-related quality of life in patients with microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer treated with first-line pembrolizumab versus chemotherapy (KEYNOTE-177): an open-label, randomised, phase 3 trialPembrolizumab monotherapy led to clinically meaningful improvements in HRQOL compared with chemotherapy in patients with previously untreated microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. These data, along with the previously reported clinical benefits, support pembrolizumab as a first-line treatment option for this population. Full-Text PDF Crossing survival curves of KEYNOTE-177 illustrate the rationale behind combining immune checkpoint inhibition with chemotherapy – Authors' replyIn their letter, David Bomze and colleagues note that the restricted mean survival time provides an alternative approach to quantify treatment effect, and they estimate that 21% of patients included in KEYNOTE-177 had inferior overall survival with first-line pembrolizumab compared with first-line chemotherapy. We believe that these data highlight the need to investigate the molecular underpinnings of PD-1 resistance, and how best to overcome this resistance. Full-Text PDF