Patterns of progressive disease in patients with microsatellite instability-high (MSI-H) metastatic colorectal cancer treated with immune checkpoint inhibitor(s): Different entities requiring tailored management.

[BACKGROUND] We aimed to assess patterns of progressive disease (PD) in patients with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC) treated with immune checkpoint inhibitors (ICIs).

[METHODS] All patients with ICI(s)-treated dMMR/MSI-H mCRC were included in the prospective, single-center ImmunoMSI cohort at Saint-Antoine Hospital and retrospectively analyzed. PD, per iRECIST criteria, was classified as early-global PD (within 6 months), late-global PD (after 6 months), or oligo-PD (limited to <3 metastases (after 6 months), with other lesions remaining controlled). Survival outcomes were analyzed.

[RESULTS] Among the 212 included patients, 65 (31 %) experienced PD (68 % received anti-PD1 monotherapy, 32 % anti-PD1 + anti-CTLA4). Early-global PD occurred in 34 patients (52 %), late-global PD in 17 (28 %), and oligo-PD after 6 months in 13 (20 %). Patient characteristics were right-sided tumor (66 %), prior primary tumor surgery (82 %), prior chemotherapy (86 %), liver metastasis (49 %), peritoneal carcinomatosis (25 %), and ≥ 2 metastatic sites (58 %). With a median follow-up of 74.7 months and a median time to progression of 5.5 months, median overall survival was 7.8 months for early-global PD, 38.8 months for late-global PD, and 97.2 months for oligo-PD (p < 0.0001). Among oligoprogressors, nine received local treatment (surgery, stereotaxic radiotherapy, or cryotherapy), while five received systemic therapy, including three rechallenged with ICIs.

[CONCLUSION] PD under ICI(s) in dMMR/MSI-H mCRC follows distinct patterns, with overall survival < 1 year in case of early-PD. Oligo-PD accounts for half of secondary resistance and is associated with favorable survival, offering an opportunity for focal ablative therapies, and highlighting the need for personalized post-progression management.