Q-TWiST analysis of pembrolizumab plus trastuzumab and chemotherapy for patients with metastatic HER2-positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma in the KEYNOTE-811 trial.

354 Background: In the phase 3 KEYNOTE-811 trial (NCT03615326), first-line pembrolizumab plus trastuzumab and chemotherapy (pembrolizumab group) statistically significantly improved PFS and OS versus placebo plus trastuzumab and chemotherapy (placebo group), with manageable safety, in patients with metastatic HER2-positive G/GEJ adenocarcinoma, while maintaining HRQoL, specifically in patients with PD-L1 combined positive score (CPS) ≥1 tumors. The objective of this analysis was to assess quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST) for patients treated in the KEYNOTE-811 trial. Methods: Q-TWiST is a measure of survival weighted by health states utility values. The analysis categorized survival time into 3 health states: time with grade ≥3 adverse events (toxicity [TOX]) and time without symptoms or toxicities (TWiST)—both before disease progression or death—and relapse (REL), defined as time from disease progression to death. Q-TWiST was calculated as the restricted mean survival time spent in each state, with a weighted health state utility for that state. Average utility weights were derived based on pooled EQ-5D-5L scores using the US mapping algorithm and standardized base case utility weights. Relative gains in Q-TWiST of ≥10% and ≥15% were “clinically important” and “clearly clinically important,” respectively, as reported in the literature. Treatment difference 95% CIs were generated using the nonparametric bootstrapping method. Data are reported for patients with PD-L1 CPS ≥1 tumors. The data cutoff date was March 20, 2024. Results: At the maximum follow-up of 63 months, patients in the pembrolizumab group had a 2.36-month (95% CI, −0.24 to 4.56) longer restricted mean time in TOX (6.98 vs 4.63 months), a 3.40-month (95% CI, −0.44 to 7.45) longer restricted mean time in TWiST (12.03 vs 8.62 months), and a 1.45-month (95% CI, −5.84 to 3.09) shorter restricted mean time in REL (8.87 vs 10.32 months) versus the placebo group. For the restricted mean Q-TWIST at month 63, based on the US mapping algorithm, the difference between the pembrolizumab and placebo groups favored the pembrolizumab group by 3.90 months (95% CI, 1.30 to 6.72), representing a 16.57% relative Q-TWiST gain. Based on the standardized base case utility weights, the difference also favored the pembrolizumab group by 3.86 months (95% CI, 1.47 to 6.67), representing a 16.38% relative Q-TWiST gain. Conclusions: Pembrolizumab plus trastuzumab and chemotherapy produced a clearly clinically important improvement in quality-adjusted survival time based on Q-TWiST analyses compared with placebo plus trastuzumab and chemotherapy in patients with previously untreated metastatic HER2-positive G/GEJ adenocarcinoma with PD-L1 CPS ≥1. Clinical trial information: NCT03615326 .