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Q-TWiST analysis for pembrolizumab plus chemotherapy versus chemotherapy as first-line treatment for patients with advanced esophageal cancer in the KEYNOTE-590 study
Background
In the phase 3 KEYNOTE-590 study (NCT03189719), first-line pembrolizumab plus chemotherapy provided statistically significant and clinically meaningful improvement in OS and PFS, maintained HRQoL, and was associated with a manageable safety profile versus chemotherapy in patients with locally advanced, unresectable or metastatic esophageal cancer or Siewert type 1 gastro-esophageal junction adenocarcinoma. The objective of this analysis was to assess Quality-adjusted Time Without Symptoms of disease progression or Toxicity of treatment (Q-TWiST) among patients receiving pembrolizumab + chemotherapy or chemotherapy in the KEYNOTE-590 study.
Methods
Q-TWiST analysis divided survival time into 3 health states: time with grade 3+ toxicity before disease progression or death (TOX), time without symptoms or toxicities before progression (TWiST), and time from disease progression (REL). Q-TWiST was calculated as the restricted mean time spent in each health state, weighted by a health-state utility for that particular state, combined. Average utility weights for each health state were based on the pooled EQ-5D health utility score using base case utility weights of Utility[TWiST], 1.0; Utility[TOX], 0.5; and Utility[REL], 0.5. Treatment difference 95% CIs were generated using the non-parametric bootstrapping method. Data are reported for all randomized patients and patients with PD-L1 combined positive score (CPS) ≥10. Relative gains in Q-TWiST of ≥10% and ≥15% have been established as “clinically important” and “clearly clinically important,” respectively, in the literature. Data cutoff, July 2, 2020.
Results
In all patients at month 33, patients receiving pembrolizumab + chemotherapy had a 1.51 month (95% CI, 0.10-2.95) longer restricted mean time in TWiST (5.95 vs 4.44 months), 1.59 month (95% CI, 0.76-2.43) longer restricted mean time in TOX (3.71 vs 2.12 months), and a 0.01 month (95% CI, -1.93-1.85) shorter restricted mean time in REL (6.16 vs 6.18 months) versus chemotherapy. For the restricted mean Q-TWIST in all patients, the difference between the pembrolizumab + chemotherapy and chemotherapy arms favored the pembrolizumab + chemotherapy arm by 2.30 months (95% CI, 1.27-3.40; 10.89 vs 8.59 months) at month 33, representing a 18.1% relative Q-TWiST gain. In patients with PD-L1 CPS ≥10, those receiving pembrolizumab + chemotherapy had a 2.24 month (95% CI, 0.08-4.44) longer restricted mean time in TWiST (6.35 vs 4.11 months), 2.16 month (95% CI, 0.82-3.52) longer restricted mean time in TOX (4.39 vs 2.23 months), and a 0.19 month (95% CI, -2.44-2.99) longer restricted mean time in REL (5.98 vs 5.80 months) versus chemotherapy. For the restricted mean Q-TWIST in patients with PD-L1 CPS ≥10, the difference between the pembrolizumab + chemotherapy and chemotherapy arms favored the pembrolizumab + chemotherapy arm by 3.41 months (95% CI, 1.92-4.84; 11.54 vs 8.13 months) at month 33, representing a 28.1% relative Q-TWiST gain.
Conclusions
Pembrolizumab + chemotherapy demonstrated clinically meaningful improvement in quality-adjusted survival based on Q-TWIST analyses compared with chemotherapy in patients with advanced esophageal cancer.
Clinical trial identification
ClinicalTrials.gov, NCT03189719.
Editorial acknowledgement
We thank Lin Wang for their contributions to this analysis. Medical writing and/or editorial assistance was provided by Obinna Ezeokoli, PhD and Lauren D’Angelo, PhD of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Legal entity responsible for the study
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Funding
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Disclosures
S. Shah: Full / Part-time employment: Merck. S. Joo: Shareholder / Stockholder / Stock options: MSD; Full / Part-time employment: MSD. A. Valderrama: Shareholder / Stockholder / Stock options: Merck; Full / Part-time employment: Merck. S. Zhang: Shareholder / Stockholder / Stock options: Merck; Full / Part-time employment: Merck. Y. Zhang: Full / Part-time employment: MSD Sharp & Dohme GmbH. P. Enzinger: Advisory / Consultancy: Arcus Biosciences, Astellas Pharma, AstraZeneca, Blueprint Medicines, Bristol Myers Squibb/Celgene, Celgene, Coherus Biosciences, Daiichi Sankyo, Five Prime Therapeutics, IDEAYA Biosciences, ISTARI Oncology, Legend Biotech, Lilly, loxo, Merck, Novartis, Ono Pharmaceutical, SERVIER, Taiho Pharmaceutical, Takeda, Turning Point Therapeutics, Xencor, Zymeworks. The author has declared no conflicts of interest.
