Clinical outcomes of immune checkpoint inhibitors in combination with tyrosine kinase inhibitors in metastatic MSS/pMMR colorectal cancer: A systematic review and meta-analysis.

Abstract

e15593 Background: Immune checkpoint inhibitors (ICIs) have limited efficacy in microsatellite-stable or mismatch repair-proficient (MSS/pMMR) metastatic colorectal cancer (CRC). Aberrant angiogenesis and an immunosuppressive tumor microenvironment contribute to resistance to immunotherapy in this population. Tyrosine kinase inhibitors (TKIs) may enhance antitumor immunity, providing a rationale for combination with ICIs. We conducted a systematic review & meta-analysis to evaluate efficacy and safety of TKI-ICI combinations in patients with MSS/pMMR metastatic CRC. Methods: A systematic search of PubMed, Embase, and Cochrane databases was done through December 2025 to identify studies reporting outcomes of ICI + TKI in CRC. Objective response rate (ORR) was defined as a combination of complete response and partial response, while disease control rate (DCR) was defined as a combination of ORR and stable disease. ORR, DCR, ≥ grade 3 treatment-associated adverse event rates (TRAEs), and median progression-free survival (PFS) were pooled using the random-effects model and inverse-variance methods to report effect size with its 95% CI. Results: A total of 13 clinical trials, comprising 1183 patients with metastatic MSS/pMMR CRC treated with ICI + TKI, were included. The mean age of the patients was 58.1 years, and 41% were women. ECOG performance status of 0 was present in 44.4% of the patients, and 65% of them had BRAF and/or RAS mutations. The pooled ORR was 11.6% (95% CI, 6.6-17.7) with substantial heterogeneity (I² = 84.4%). The pooled DCR was 62.8% (95% CI, 53-72.2), also with high heterogeneity (I² = 85.3%). Median PFS pooled across 13 studies was 3.45 months (95% CI, 2.78-4.13). Pooled rate of ≥ grade 3 TRAEs was 30.8%. Subgroup analysis by the type of TKI showed that studies using regorafenib had lower DCR and ORR (51.52% & 9.93%) when compared to studies using cabozantinib (87.07% & 26.01%) (p < 0.001). Meta-regression analyses, including ECOG 0 status, age, female sex, BRAF/RAS mutation, or presence of right-sided CRC, were not significantly associated with ORR or DCR. Conclusions: In this meta-analysis, outcomes with ICI+TKI in MSS/pMMR metastatic colorectal cancer were associated with modest objective responses and short median PFS, but a relatively high disease control rate. Cabozantinib+ICI showed better ORR and DCR when compared with regorafenib + ICI, although patient numbers were much lower in studies of the former. ORR & DCR stratified by the type of TKI administered. TKIs No. of Trials Total No. of MSS/pMMR participants ORR DCR Fruquintinib 2 118 15.4 [7.7 - 25.1] 80.8 [64.5 - 94.1] Zanzalitinib 1 451 3.5 [1.7 - 5.4] 53.7 [48.9 - 58.4] Regorafenib 7 327 9.9 [3.0 - 19.7] 51.5 [40.5 - 62.5] Cabozantinib 2 46 26.0 [13.9 - 40.1] 87.1 [75.2 - 95.8] Lenvatinib 1 241 10.4 [6.0 -14.3] - Overall 13 1183 11.62 [6.6 - 17.7] 62.8 [53.1 - 72.2]