Outcomes and a prognostic classifier in 130 patients with microsatellite instability-high metastatic gastric cancer receiving PD-1 blockade

Subgroup analyses of randomized trials suggest superiority of immune checkpoint inhibitor(ICI)-based therapy over chemotherapy in patients with mismatch-repair deficient (dMMR) or microsatellite instability(MSI)-high advanced gastric or gastroesophageal junction adenocarcinoma. However, these subgroups are small and studies examining prognostic features within larger cohorts of MSI-high patients are lacking.

We conducted an international cohort study at 9 tertiary cancer centers and collected baseline clinico-pathological features of patients with dMMR/MSI-high metastatic or unresectable gastric cancer treated with anti-PD-1-based therapies in any line. The logs10 of the hazard ratio (HR) of the variables independently associated with overall survival (OS) obtained from the multivariable model were used to derive the weighting factors of a prognostic score. Coefficient estimates were normalized by dividing by the smallest one and rounding the resulting ratios to the nearest integer value.

One hundred and thirty patients were included. One-hundred and sixteen patients (89%) received anti-PD-1 monotherapy, whereas 8 (6%) and 6 (5%) received combinations with chemotherapy or an anti-CTLA-4 agent, respectively. Thirty-two (25%) patients received ICIs in the first-line setting and 98 (75%) in later treatment lines. At a median follow-up of 25.1 months, the median progression-free survival (PFS) was 30.3 months (95%CI: 20.4-NA) and 2-year PFS rate of 56% (95%CI: 48-66). Median OS was of 62.5 months (95%CI: 28.4-NA) and 2-year OS rate was 63% (95%CI: 55-73). Among the 103 RECIST-evaluable patients, objective response rate was 66% and disease control rate 87%. In the multivariable models, ECOG PS of 1 or 2, non-resected primary tumor, presence of bone metastases and malignant ascites were independently associated with poorer PFS and OS. These 4 readily-available clinical variables were used to build a three-category (ie, good, intermediate and poor risk) prognostic score. Compared to patients with good risk, patients with intermediate risk score had numerically inferior PFS and OS (2-year PFS rate: 54.3% vs 74.5%; HR 1.90, 95%CI: 0.99-3.66; 2-year OS rate: 66.8% vs 81.2%; HR 1.86, 95%CI: 0.87-3.98), whereas patients with poor risk score had significantly inferior PFS and OS (2-year PFS rate: 10.6%; HR 9.65, 95%CI: 4.67-19.92; 2-year OS rate: 13.3%; HR 11.93, 95%CI: 5.42-26.23).

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.

The authors.

Has not received any funding.

S. Klempner: Advisory / Consultancy: Astellas, BMS, Daichi Sankyo, Eli Lilly, Merck, AstraZeneca, Novartis, Servier, Mersana, Natera, Pieris, sanofi-aventis, Exact Sciences; Shareholder / Stockholder / Stock options: Turning Point Therapeutics, MBrace Therapeutics. S. Maron: Advisory / Consultancy: Amgen, Novartis, Elevation Oncology; Research grant / Funding (institution): Guardant Health; Travel / Accommodation / Expenses: Astra Zeneca. A. Kawazoe: Honoraria (self): TAIHO PHARMACEUTICAL CO., LTD., Eli Lilly , DAIICHI SANKYO COMPANY, LIMITED; Advisory / Consultancy: Zymeworks , Merck & Co.; Research grant / Funding (institution): Merck & Co. K. Shitara: Honoraria (self): Takeda, Bristol-Myers Squibb, Janssen; Advisory / Consultancy: Eli Lilly and Company; Bristol Myers Squibb; Takeda; Pfizer, Ono Pharmaceutical; Merck Pharmaceutical; Taiho Pharmaceutical; Astellas; Novartis, AbbVie; GlaxoSmithKline; Daiichi Sankyo; Amgen; Boehringer Ingelheim; Guardant Health Japan; Janssen; Research grant / Funding (institution): Astellas; Ono Pharmaceutical; Daiichi Sankyo; , Taiho Pharmaceutical; Chugai; Merck Pharmaceutical, Medi Science; Eisai; Amgen. T. André: Honoraria (self): Amgen, AstraZeneca, Bristol-Myers Squibb, Gritstone Oncology, GlaxoSmithKline, Kaleido Biosciences, Merck & Co., Inc., Pierre Fabre, Roche, Sanofi, Servier , Seagen; Advisory / Consultancy: Astellas Pharma, BMS, Gritstone Oncology, Transgène, Seagen, Merck & Co., Inc, Aptitude Health, Gilead, Sevier; Research grant / Funding (institution): BMS, Seagen, GSK; Travel / Accommodation / Expenses: BMS, Merck & Co., Inc; Non-remunerated activity/iesA: President of ARCAD foundation. All other authors have declared no conflicts of interest.