Abstract 512P
Background
Despite high response rates and durable response with ICI, many patients (pts) with deficient MMR (dMMR) tumours are refractory to ICI and identifying predictive markers to ICI response remains an unmet need.
Methods
We conducted a retrospective, single centre study evaluating pts with dMMR GI tumours treated with ICI. We described baseline characteristics for colorectal cancer (CRC) and non CRC pts. Progression free survival (PFS) and overall survival (OS) were compared in the overall study population and in both cohorts. We assessed for MMR protein loss, Lynch Syndrome (LS), presence of liver metastasis (LM) and neutrophil-to-lymphocyte ratio after 8 weeks of ICI (NLR8). Kaplan-Meier, log-rank and Cox regression were performed.
Results
Eighty-eight pts treated with ICI between 2016 and 2023 were included. Among those, 76.1% had CRC. In the CRC cohort, 37.3% were metastatic at diagnosis. LM was observed in 35.9% of pts. 11.9% had LS. Loss of MLH1 and PMS2 was demonstrated in 46 pts. In the non CRC cohort, 42.3% of pts had synchronous metastases; none had LS. Concurrent loss of MLH1 and PMS2 was found in 8 pts. The difference in OS and PFS was not significant between the 2 cohorts (p = 0.083 and p = 0.19 respectively). In the overall population, median PFS was 72.4 months for pts with loss of MLH1 vs 20.9 months in MLH1 proficient (p = 0.0083). Median OS was 101.9 and 48.6 months respectively (p = 0.12). Univariate analysis showed loss of MLH1 and low NLR8 were associated with improved PFS, as well as with better OS for the latter. Multivariate analysis in the overall population including cancer type, MMR protein loss, LM and NLR8 confirmed loss of MLH1 was associated with improved PFS compared to PMS2 only loss (HR: 0.32, 95%CI 0.11, 0.87, p=0.025). NLR8 was independently associated with PFS and OS outcomes [(PFS HR: 1.11, 95%CI 1.04, 1.19, p=0.001) (OS HR: 1.17, 95%C: 1.07, 1.28, p=0.001)].
Conclusions
Our analysis suggests loss of MLH1 correlates with improved PFS while raised NLR8 is associated with worse PFS and OS, which could be used as novel prognostic/predictive biomarkers. Correlation of MMR protein loss and ICI response needs further investigations in larger studies across other dMMR tumours.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
D. Cunningham: Financial Interests, Other: Research funding Clovis, Eli Lilly, 4SC, Leap, Roche. N. Starling: Financial Interests, Personal, Advisory Board: GSK, Novartis, MSD Oncology, Servier, AstraZeneca, Pfizer, Gilead Sciences, Seagen, Janssen, Takeda, Moderna, BMS; Financial Interests, Personal, Invited Speaker: Eli Lilly, Pierre Fabre, Amgen, Merck Serono, Novartis, MSD Oncology, GSK, Servier, Seagen, BMS, AstraZeneca, Astellas; Financial Interests, Institutional, Research Grant, Sept 2017 (24m) Paid to institution research: Merck; Financial Interests, Institutional, Research Grant, Nov 2017 (48m) - Paid to institution research fund: AstraZeneca; Financial Interests, Institutional, Research Grant, Jan 2018 - Paid to institution research fund: Pfizer; Financial Interests, Institutional, Research Grant, July 2018 (36m) Paid to institution research fund: BMS; Financial Interests, Institutional, Research Grant, June 2022 - Paid to institution research fund: Guardant; Financial Interests, Institutional, Research Grant, August 2023 - Paid to institution research fund: Gilead; Non-Financial Interests, Advisory Role, Ad Board uncompensated: Guardant. S. Rao: Financial Interests, Personal, Advisory Board: Hoopika, Bayer, BeiGene, AstraZeneca, Merck Serono, Seagen, Servier; Financial Interests, Personal, Expert Testimony: Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Merck Serono, Servier, Bayer; Financial Interests, Personal, Other, travel: Servier. C. Fribbens: Financial Interests, Personal, Sponsor/Funding: Novartis. I. Chau: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Eli Lilly, MSD, Roche, Merck Serono, AstraZeneca, OncXerna, Astella, Incyte, GSK, Sotio, Daiichi Sankyo, Eisai, Taiho, Seagen, Turning Point Therapeutics, Novartis, Takeda, Elevation Oncology; Financial Interests, Personal, Invited Speaker: Eisai, Eli Lilly, Servier, Roche; Financial Interests, Institutional, Invited Speaker: Cilag-Janssen, Eli Lilly. All other authors have declared no conflicts of interest.