Journal Article

Outcomes and a prognostic classifier in patients with microsatellite instability-high metastatic gastric cancer receiving PD-1 blockade

Randon, Giovanni, Klempner, Samuel J, Kawazoe, Akihito, Manca, Paolo, Cowzer, Darren, Shitara, Kohei, Nasca, Vincenzo, Genovesi, Virginia, Salati, Massimiliano, Chao, Joseph, Aoki, Yu, Provenzano, Leonardo, Ferrari Bravo, Walter, Ambrosini, Margherita, Pietrantonio, Filippo, Lonardi, Sara, André, Thierry, Fornaro, Lorenzo, Maron, Steven B, Cerantola, Riccardo, Ghelardi, Filippo, Zhu, Valerie, Cohen, Romain

2023

Overview

BackgroundSubgroup analyses of randomized trials suggest the superiority of immune checkpoint inhibitor-based therapy over chemotherapy in patients with mismatch-repair deficient (dMMR) and/or microsatellite instability-high (MSI-high) advanced gastric or gastroesophageal junction adenocarcinoma. However, these subgroups are small and studies examining prognostic features within dMMR/MSI-high patients are lacking.MethodsWe conducted an international cohort study at tertiary cancer centers and collected baseline clinicopathologic features of patients with dMMR/MSI-high metastatic or unresectable gastric cancer treated with anti-programmed cell death protein-1 (PD-1)-based therapies. The adjusted HRs of variables significantly associated with overall survival (OS) were used to develop a prognostic score.ResultsOne hundred and thirty patients were included. At a median follow-up of 25.1 months, the median progression-free survival (PFS) was 30.3 months (95% CI: 20.4 to NA) and 2-year PFS rate was 56% (95% CI: 48% to 66%). Median OS was of 62.5 months (95% CI: 28.4 to NA) and 2-year OS rate was 63% (95% CI: 55% to 73%). Among the 103 Response Evaluation Criteria in Solid Tumors-evaluable patients, objective response rate was 66% and disease control rate 87% across lines of therapy. In the multivariable models, Eastern Cooperative Oncology Group Performance Status of 1 or 2, non-resected primary tumor, presence of bone metastases and malignant ascites were independently associated with poorer PFS and OS. These four clinical variables were used to build a three-category (ie, good, intermediate, and poor risk) prognostic score. Compared with patients with good risk, patients with intermediate risk score had numerically inferior PFS and OS (2-year PFS rate: 54.3% versus 74.5%, HR 1.90, 95% CI: 0.99 to 3.66; 2-year OS rate: 66.8% versus 81.2%, HR 1.86, 95% CI: 0.87 to 3.98), whereas patients with poor risk score had significantly inferior PFS and OS (2-year PFS rate: 10.6%, HR 9.65, 95% CI: 4.67 to 19.92; 2-year OS rate: 13.3%, HR 11.93, 95% CI: 5.42 to 26.23).ConclusionsOverall outcomes with anti-PD-1-based therapies are favorable in MSI-high gastroesophageal adenocarcinomas. However, within this overall favorable subgroup a more accurate prognostication using baseline clinical characteristics might identify patients at higher risk of rapid disease progression who may deserve intensified immunotherapy combination strategies.

• Publisher: BMJ Publishing Group Ltd,BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Adenocarcinoma / Apoptosis / Ascites / Biomarkers / Cancer / Cancer therapies / Cell death / Chemotherapy / Clinical trials / Clinical/Translational Cancer Immunotherapy / Cohort Studies / CTLA-4 antigen / Cytotoxicity / Disease control / Gastric cancer / gastrointestinal neoplasms / Humans / Immune checkpoint inhibitors / Immunotherapy / Lymphocytes / Metastasis / Microsatellite Instability / Oncology / Patients / Population / Prognosis / programmed cell death 1 receptor / Proteins / Response rates / Stomach Neoplasms - drug therapy / Stomach Neoplasms - genetics / Survival analysis / tumor biomarkers / Tumors