Analysis of quality-adjusted survival time without symptoms or toxicity for pembrolizumab plus chemotherapy as treatment for previously untreated participants with advanced or metastatic esophageal cancer.

[BACKGROUND] Results of the KEYNOTE-590 trial showed that first-line pembrolizumab plus chemotherapy significantly improved overall and progression-free survival versus chemotherapy alone, and the safety profile was manageable for participants with previously untreated advanced or metastatic esophageal cancer. Using the quality-adjusted time without symptoms or toxicity (Q-TWiST) method of analysis, we assessed the benefit/risk profile of pembrolizumab plus chemotherapy.

[METHODS] Using data from the KEYNOTE-590 study, we partitioned participant survival time into three health states: time living with all-cause grade ≥ 3 adverse events (AEs) before disease progression (PD; TOX), time before start of PD or death without grade ≥ 3 AEs (TWiST), and time from the start of PD to death or the censoring date (REL). We calculated Q-TWiST by summing the restricted mean time spent in each health state weighted by health state utilities estimated using the EuroQol 5-Dimension, 5-Level quality-of-life questionnaire (EQ-5D-5L). The relative gain in quality-adjusted survival time was defined as the Q-TWiST difference divided by the survival time from chemotherapy alone. A relative gain of > 10% is considered “clinically important,” and a relative gain of > 15% is considered “clearly clinically important.” This analysis was primarily focused on clinical significance rather than statistical significance due to the nature of the Q-TWiST analyses. No prespecified formal hypothesis testing was performed, and hence, there was no adjustment for multiplicity.

[RESULTS] At a maximum follow-up of 30 months, Q-TWiST was 2.23 months longer with pembrolizumab plus chemotherapy versus chemotherapy alone for all randomly assigned participants and was clearly clinically important, with a relative Q-TWiST gain of 17.86%. In all three subpopulations, including participants with esophageal squamous cell carcinoma (ESCC), programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥ 10, and ESCC PD-L1 CPS ≥ 10, Q-TWiST gain with pembrolizumab plus chemotherapy versus chemotherapy was 2.29 to 3.87 months, equivalent to a relative Q-TWiST gain of 18.12% to 33.47%, which are all clearly clinically important.

[CONCLUSIONS] Although this analysis is limited by missing data and short follow-up time, pembrolizumab plus chemotherapy provided clinically meaningful and substantial benefit in quality-adjusted survival by Q-TWiST analysis versus chemotherapy alone in participants with advanced esophageal cancer.

[TRIAL REGISTRATION] Trial registration for KEYNOTE-590 ClinicalTrials.gov, NCT03189719 (date of registration: June 14, 2017).

[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1007/s11136-025-04109-4.