Browsing by Author "Castro, Hugo R."

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    Association of Tumor Mutational Burden with Efficacy of Pembrolizumab plus Chemotherapy as First-Line Therapy for Gastric Cancer in the Phase III KEYNOTE-062 Study
    (2022) Lee, Keun-Wook; Van Cutsem, Eric; Bang, Yung-Jue; Fuchs, Charles S.; Kudaba, Iveta; Garrido, Marcelo; Chung, Hyun Cheol; Lee, Jeeyun; Castro, Hugo R.; Chao, Joseph; Wainberg, Zev A.; Cao, Z. Alexander; Aurora-Garg, Deepti; Kobie, Julie; Cristescu, Razvan; Bhagia, Pooja; Shah, Sukrut; Tabernero, Josep; Shitara, Kohei; Wyrwicz, Lucjan
    Purpose: This prespecified exploratory analysis evaluated the association between tumor mutational burden (TMB) status and outcomes of first-line pembrolizumab+chemotherapy versus chemotherapy in KEYNOTE-062. Patients and Methods: In patients with advanced gastric cancer and evaluable TMB data, we evaluated the association between TMB (continuous variable; square root scale) assessed with FoundationOne CDx and clinical outcomes [objective response rate (ORR), progression-free survival (PFS), and overall survival (OS)] using logistic (ORR) and Cox proportional hazards (PFS, OS) regression models. Clinical utility of TMB was assessed using the prespecified cutoff of 10 mut/Mb. Results: TMB data were available for 306 of 763 patients (40.1%; pembrolizumab, 107; pembrolizumab+chemotherapy, 100; chemotherapy, 99). TMB was significantly associated with clinical outcomes in patients treated with pembrolizumab and pembrolizumab+chemotherapy (ORR, PFS, and OS; all P < 0.05) but not with chemotherapy (all P > 0.05). The overall prevalence of TMB >= 10 mut/Mb was 16% across treatment groups; 44% of patients who had TMB >= 10 mut/Mb had high microsatellite instability (MSI-H) tumors. Improved clinical outcomes (ORR, PFS, and OS) were observed in pembrolizumab-treated patients (pembrolizumab monotherapy and pembrolizumab+ chemotherapy) with TMB >= 10 mut/Mb. When the analysis was limited to the non-MS I-H subgroup, both the positive association between clinical outcomes with pembrolizumab or pembrolizumab+chemotherapy and TMB as a continuous variable and the clinical utility of pembrolizumab (with or without chemotherapy) versus chemotherapy by TMB cutoff were attenuated. Conclusions: This exploratory analysis of KEYNOTE-062 suggests an association between TMB and clinical efficacy with first -line pembrolizumab-based therapy in patients with advanced gas-tric/gastroesophageal junction adenocarcinoma. However, after the exclusion of patients with MSI-H tumors, the clinical utility of TMB was attenuated.