Updated quality-adjusted time without symptoms or toxicity (Q-TWiST) analysis of nivolumab plus chemotherapy versus chemotherapy alone as first-line (1L) treatment for advanced gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma (GC/GEJC/EAC): 4-year (yr) follow-up from CheckMate 649 (CM 649).
Authors: Lin Daniel , Quan Wenying , Garretson Marné , Chirikov Viktor , Chen Clara , Singh Prianka , Davis Catherine , Sugarman Ryan 
Published: June 2024

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Background: Q-TWiST analysis is an established methodology combining efficacy, safety, and quality of life (QoL) data into a single metric. Previous analyses among all randomized CM 649 patients with a minimum of 12 months’ follow-up demonstrated that nivolumab plus chemotherapy (NIVO+chemo) yielded a mean Q-TWiST gain of 1.8 (95% CI 0.9-2.7) months, representing an improved 12.8% relative gain, compared with chemo alone (Lin et al, 2023). An updated Q-TWiST analysis using 4-yr follow-up trial data may further inform treatment decisions for patients and providers regarding the long-term benefit of 1L NIVO+chemo in advanced GC/GEJC/EAC. Methods: Overall survival (OS) was partitioned into 3 mutually exclusive health states: time with grade 3/4 toxicity after randomization and before progression (TOX), time without symptoms of disease progression or toxicity (TWiST), and time from relapse or progression until death (ie, relapse, REL). Q-TWiST was calculated as the average time spent in each state, weighted by state-specific QoL utility (u, ranging from 0 to 1), assuming a base case u(TOX)=0.5, u(REL)=0.5, u(TWiST)=1. In sensitivity analysis (SA), utility values derived from the trial’s treatment-specific UK EQ-5D-3L scores reported during each state were instead used. Relative Q-TWiST gains were calculated by dividing the NIVO+chemo Q-TWiST difference versus chemo by the mean chemo group OS where gains ≥ 10% or ≥ 15% were considered “clinically important” or “clearly clinically important” (1). Results: With a minimum of 48 months of follow-up (and maximum of 66 months), patients on NIVO+chemo had a mean Q-TWiST gain of 3.4 months (1.8-5.1) compared with chemo alone, translating to a 20.5% relative Q-TWiST gain. In SA, using the trial’s treatment-specific EQ-5D-3L utility values resulted in an even greater mean Q-TWiST gain of 3.8 months (2.5-5.3) and 23% relative gain. Both base case and SA results were clearly clinically important. Relative gain benefit of NIVO+chemo (15.7%) remained clearly clinically important after broadening the analysis to include grade 2 adverse events, as well. Conclusions: This updated Q-TWiST analysis using 4-yr follow-up CM 649 data among all randomized patients demonstrates the clearly clinically important long-term benefit of NIVO+chemo versus chemo in advanced GC/GEJC/EAC. Compared with the originally published Q-TWiST findings with 12 months of follow-up, this update highlights that both the absolute and relative Q-TWiST gains in favor of NIVO+chemo are almost double with longer observed follow-up. These findings continue to support the use of 1LNIVO+chemo in advanced GC/GEJC/EAC. 1. Solem et al, 2018. Clinical trial information: NCT02872116 .