MSI-H/dMMR is considered the first predictive marker of efficacy for ICIs with tissue/site-agnostic approval. However, around 39% of cases are refractory and no additional biomarker has been identified. We explored the prognostic value of pretreatment LIPI in MSI-H/dMMR patients (pts) treated with ICI, particularly to identify the fast-progressors (FP).
Multicenter retrospective study of pts with metastatic MSI-H/dMMR tumors treated with ICIs from Apr2014 to May2019. Biological and clinical data were collected; LIPI was calculated based on dNLR [neutrophils/leucocytes-neutrophils]>3 + LDH>Upper Limit of Normality (ULN), as reported. LIPI groups were: good (0 factor), intermediate (interm.; one factor) and poor (2 factors). Primary endpoint was overall survival (OS), including the FP (OS < 3 months); secondary endpoints were progression free survival (PFS).
A total of 151 pts were treated, mainly female (59%), median age of 64y, with performance status (PS) >1 (68%), and sporadic dMMR status (68%). ICI was the 1st or 2nd line in 59%. The most frequent tumors types were gastrointestinal (66%) and gynecological (22%). LIPI groups were distributed as follows: good n=67 (47%), interm. n=62 (43%), poor n=14 (10%). The median (m) follow up was 32 months (m.). 24m OS rates were 71.1%, 54.2% and 14.3% for good, interm and poor risk groups, respectively (P<0.0001). After adjustment on tumor site, metastatic sites and PS, LIPI remains independently associated with OS (HR poor: 3.2, 95%CI:1.3-7.9, P=0.03). Overall, the FP rate was 16%; up to 35.7% in poor LIPI group vs. 7.5% in good LIPI (P=0.02). The odds ratio for FP event among the poor group was 6.9 [95%CI: 1.7-28.6; P=0.01]. Overall, mPFS was 10.5m. (7.1-35.1); by LIPI groups: 20.9m. (8.4-NR) for good, 9.9m. (2.8-NR) for interm. and 2.3m. (1.8-NR) for the poor group (P<0.0001).
LIPI identifies dMMR pts that do not benefit from ICI treatment, particularly the fast-progressors. It should be included as stratification factor for future trials.
Legal entity responsible for the study
Has not received any funding.
E. Auclin: Travel/Accommodation/Expenses: Mundipharma; Honoraria (self): Sanofi Genzymes. J. Taieb: Honoraria (self): Merck, Roche, Amgen, Lilly, Sanofi, Samsung, MSD, Servier, Celgene, Pierre Fabre; Advisory/Consultancy: Roche, Merck KGaA, Amgen, Lilly, MSD, Servier, Pierre Fabre, Sanofi, Samsung; Speaker Bureau/Expert testimony: Servier, Amgen, Roche, Sanofi, Merck, Lilly, Pierre Fabre. B. Besse: Research grant/Funding (institution): Abbvie, Amgen, AstraZeneca, BeiGene, Blueprint Medicines, BMS, Boehringer Ingelheim, Celgene, Cristal Therapeutics, Daiichi-Sankyo, Eli Lilly, GSK, Ignyta, IPSEN, Inivata, Janssen, Merck KGaA, MSD, Nektar, Onxeo, OSE immunotherapeutics, Pfizer, Pharma Mar. C. Massard: Advisory/Consultancy: Amgen, Astellas, AstraZeneca, Bayer, BeiGene, BMS, Celgene, Debiopharm, Genentech, Ipsen, Janssen, Lilly, MedImmune, MSD, Novartis, Pfizer, Roche, Sanofi, Orion. L. Mezquita: Research grant/Funding (self): Bristol Myers Squibb, Boehringer Ingelheim, Amgen; Advisory/Consultancy: Roche Diagnostics, Takeda; Honoraria (self): Bristol Myers Squibb, Tecnofarma, Roche; Travel/Accommodation/Expenses: Roche; Non-remunerated activity/ies: AstraZeneca. A. Hollebecque: Advisory/Consultancy: Gritstone Oncology, Eisai Co., Ltd., Amgen, Servier and Merck Serono. All other authors have declared no conflicts of interest.