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

BACKGROUND

Subgroup 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.

METHODS

We 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.

RESULTS

One 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).

CONCLUSIONS

Overall 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.

Informations de copyright

© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Déclaration de conflit d'intérêts

Competing interests: RC has received personal fees from AstraZeneca, Bristol-Myers Squibb, Exeliom Biosciences, Enterome Bioscience, MSD Oncology, Mylan Medical, Pierre Fabre, Servier and non-financial support from Amgen, Bristol-Myers Squibb, Mylan Medical and Servier outside the submitted work. SJK reports consulting/advisory role with Astellas, Merck, BMS, Servier, Sanofi-Aventis, Novartis, Mersana, Exact Sciences, Natera, Coherus Biosciences, Daiichi-Sankyo, AstraZeneca, Pfizer, and Eli Lilly. SJK reports equity in Turning Point Therapeutics, and Nuvalent Therapeutics. SBM received consulting fees from Natera, Bicara, Novartis, Basilea, Elevation Oncology, and Daiichi Sankyo. LF reported receiving personal honoraria as invited speaker from Incyte, BMS, Lilly; research funding (to Institution) from MSD, BMS, AstraZeneca, Incyte, BeiGene, Astellas, Daiichi Sankyo, Roche; participation in advisory board for MSD, AstraZeneca, Incyte, Taiho, Servier, Daiichi Sankyo, Lilly. AK reports receiving honoraria (lecture fee) from Lilly, Bristol-Myers Squibb, Ono Pharmaceutical, Merck Pharmaceutical, Taiho Pharmaceutical, Daiichi Sankyo; receiving personal fees for advisory roles from Merck Pharmaceutical, Zymeworks; and receiving research funding from AstraZeneca, outside the submitted work. SL reports roles as consultant or advisor for Amgen, AstraZeneca, Bristol-Myers Squibb, Daiichi-Sankyo, Incyte, Lilly, Merck Serono, MSD, Servier, and reports research funding from Amgen, Astellas, AstraZeneca, Bayer, BMS Daichii Sankyo, Hutchinson, Incyte, Merck Serono, Mirati, MSD, Pfizer, Roche. She is part of speakers’ bureau of Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Lilly, Merck Serono, Pierre Fabre, Roche, Servier. KS reports receiving personal fees for advisory roles from Lilly, Bristol-Myers Squibb, Takeda, Pfizer, Ono Pharmaceutical, Merck Pharmaceutical, Taiho Pharmaceutical,Astellas, Novartis, AbbVie, GlaxoSmithKline, Daiichi Sankyo, Amgen, Boehringer Ingelheim, Guardant Health Japan,and Janssen; receiving honoraria (lecture fee) from Takeda, Bristol-Myers Squibb and Janssen; and receiving research funding from Astellas, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Chugai, Merck Pharmaceutical, Medi Science, Eisai and Amgen, outside the submitted work. TA reports attending advisory board meetings and receiving consulting fees from Aptitude Health, AstraZeneca, Astellas, Bristol-Myers Squibb, Gritstone Oncology, GamaMabs Pharma Sa, Gilead, GlaxoSmithKline, Merck & Co. Inc., Nordic Oncology, Pierre Fabre, Seagen, Servier and Transgène; honoraria from AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Merck & Co. Inc., Pierre Fabre, Roche, Sanofi Seagen and Servier; and support for meetings from Merck & Co. Inc. and Servier. FP reported receiving grants from BMS, Incyte, and AstraZeneca and personal fees from BMS, MSD, AstraZeneca, Amgen, Merck Serono, Eli Lilly & Company, Pierre Fabre, Servier, Bayer, and Organon outside the submitted work. JC received grants or contracts from Merck and Brooklyn Immunotherapeutics; consulting fees from Lilly, Merck, AstraZeneca, Foundation Medicine, Daiichi Sankyo, Amgen, Bristol-Myers Squibb, Astellas, Turning Point Therapeutics, Silverback Therapeutics, Novartis, Coherus Biosciences, Geneos, Roche, Guardant Health; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Merck, Bristol-Myers Squibb and disclose Participation on a Data Safety Monitoring Board or Advisory Board of Yiviva and Daiichi-Sankyo; disclose other financial or non-financial interests (employment) from Amgen. No other competing interests to disclose.