Patterns of immunotherapy use in dMMR/MSI-H metastatic CRC.
Authors: Hayley Lemisch, Li Zhang, Jill Hasler, Efrat Dotan, Vanessa Wookey
Journal: Journal of Clinical Oncology (2025)

3557 Background: Immune checkpoint inhibitors (ICI) are more effective in mismatch repair deficient/microsatellite instability high (dMMR/MSI-H) metastatic colorectal cancers (mCRC) compared to chemotherapy (chemo). However, real-world data and patterns of use are limited. We evaluated real-world ICI use in mCRC after FDA approval in 2017 and approval as first-line (1L) therapy in 2020, and the impact on survival. Methods: We used the nationwide Flatiron Health electronic health record (EHR) derived de-identified database to determine patterns of ICI usage in patients diagnosed with dMMR/MSI-H mCRC since 2013. Trends in ICI use were estimated with the Cochran-Armitage test, while real-world time to next treatment (rwTTNT), progression free survival (rwPFS), and overall survival (OS) between ICI vs chemo only groups were estimated with Kaplan Meier curves and log-rank test. Multivariate Cox Proportional-Hazards Models were fitted to adjust for potential cofounding variables (ie sex, performance status (ECOG) and treatment). Hazard ratios, p-values and 95% confidence intervals are presented. Proportional hazards assumptions were tested for violations. Results: Of 41,431 patients diagnosed with mCRC since 2013, 1,707 were dMMR/MSI-H and received therapy; thus were included in the analyses. Mean age was 66 years, 925 (54%) were female, and 884 (52%) had de novo mCRC. BRAF and RAS mutations were detected in 604 (35%) and 372 (22%) patients, respectively. Of 1,707 eligible patients, 573 (34%) received 1L ICI and 1,116 (66%) received 1L chemo. Of those who received 1L ICI, 480 (43%) received a single ICI and 56 (5%) received dual ICI. There was a linear increase in the proportion of ICI-based treatments used over time in both the 1L and second line (2L). With a median follow-up of 38.2 months (mo); median OS for patients who received 1L chemo was 25.9 mo vs 51.6 mo with 1L ICI (HR 0.62, p &lt; 0.0001, 95% CI 0.52-0.73). Presence of a BRAF mutation was associated with worse OS (median OS 44.4 mo, 95% CI 31.2-61.1) vs. no BRAF mutation (median OS not reached (NR), 95% CI 51.6-NR) in patients receiving 1L ICI (p = 0.0046). The presence of a RAS mutation was not significantly associated with OS. Median rwTTNT after 1L ICI was 31.8 mo (95% CI 23.7-50.2), compared to patients whose first ICI was in the 2L (21.9 mo [95% CI 12.9-36.8]) or third line (3L) (9.5 mo [95% CI 5.7-18.0]) (p = 0.0041). Median rwPFS for first receipt of ICI in the 1L was 18.1 mo (95% CI 13.2-30.1) compared to first receipt in 2L (8.3 mo [95% CI 6.5-14.5]) or 3L (4.8 mo [95% CI 4.0-13.7]) (p = 0.0032). Conclusions: There was a linear increase in the proportion of patients with dMMR/MSI-H mCRC treated with ICI, associated with FDA approvals in 2017 and 2020. Male gender and presence of a BRAF mutation in patients receiving 1L ICI and receipt of 1L chemo were inversely associated with OS. Receipt of ICI in earlier treatment lines was associated with increased rwPFS and rwTTNT. Patients with dMMR/MSI-H mCRC benefit from receiving early ICI.