Combination therapies are emerging as a promising strategy to enhance the effectiveness of immunotherapy for patients with mismatch repair-proficient/microsatellite stable (pMMR/MSS) metastatic colorectal cancer (mCRC). These patients, who constitute the majority of mCRC cases, typically do not respond well to single-agent immune checkpoint inhibitors (ICIs). Researchers are exploring various combinations, including multi-target tyrosine kinase inhibitors (TKIs), chemotherapy, radiotherapy, and novel immunotherapeutic agents, to overcome resistance and improve outcomes.
ICIs Combined with Multi-Target Tyrosine Kinase Inhibitors
Multi-target TKIs, such as regorafenib, lenvatinib and fruquintinib, have demonstrated the ability to modulate the tumor microenvironment and enhance the effects of ICIs. These TKIs target various receptor tyrosine kinases, including VEGFR, PDGFR and FGFR, which play critical roles in angiogenesis and tumor growth. By inhibiting these kinases, TKIs can normalize tumor blood vessels, reduce immunosuppressive cells, and increase the infiltration of immune cells into the tumor microenvironment, potentially converting "cold tumors" into "hot tumors" that are more responsive to immunotherapy.
The REGONIVO study, a Phase Ib trial, showed a 33.3% objective response rate (ORR) and a median progression-free survival (PFS) of 7.9 months in pMMR/MSS colorectal cancer patients treated with regorafenib and nivolumab. However, a subsequent North American Phase II study failed to replicate these results, with an ORR of only 7.1% and a median PFS of 1.8 months. These conflicting results suggest that patient selection and specific biomarkers may play a crucial role in determining the efficacy of this combination.
Other studies have explored the combination of regorafenib with avelumab (REGOMUNE study) and toripalimab (REGOTORI study), as well as lenvatinib with pembrolizumab (LEAP-005 study). While these studies have shown some encouraging results, with ORRs ranging from 7% to 27% and median overall survival (OS) from 7.5 to 15.5 months, larger, randomized controlled trials are needed to confirm these findings.
Combination Therapy with Two ICIs
Dual ICI regimens, such as anti-PD-(L)1 combined with anti-CTLA-4 therapy, are also being investigated to overcome resistance to single-agent ICIs. CTLA-4 inhibitors block the inhibitory signal transduction of CTLA-4, promoting T cell activation, while PD-(L)1 inhibitors remove the inhibition of the PD-1/PD-L1 interaction, enhancing T cell killing of tumor cells. The combination of these two approaches can synergistically promote anti-tumor immune responses.
The CCTG CO.26 randomized Phase II trial evaluated the combination of durvalumab and tremelimumab in patients with advanced refractory colorectal cancer. The study met its primary endpoint, with a median OS increase from 4.1 months in the best supportive care group to 6.6 months in the dual immunotherapy group. However, the incidence of grade 3 or 4 adverse events also increased significantly.
ICIs Combined with Chemotherapy
Chemotherapy-induced tumor cell death can promote the release and presentation of tumor antigens, increasing tumor immunogenicity and improving the activity of CD8+ T lymphocytes. Therefore, combining ICIs with cytotoxic chemotherapy may enhance efficacy. The METIMMOX study evaluated the efficacy of short-course repeat sequential oxaliplatin-based chemotherapy (FLOX) combined with nivolumab in first-line treatment of MSS mCRC. The ORR rates in the combined immunotherapy group and chemotherapy group were 48% and 23%, respectively, indicating that immunotherapy combined with chemotherapy could improve the chances of immunotherapy response for patients. However, the difference in median PFS between the two groups was not significant.
Biomarkers for Predicting the Efficacy of ICIs in pMMR/MSS Colorectal Cancer
Identifying biomarkers to predict the efficacy of ICIs in MSS colorectal cancer is crucial for enabling more patients to benefit from immunotherapy. Several biomarkers are currently being studied, including tumor mutational burden (TMB), mutations of polymerase ε and polymerase δ (POLE/POLD1), PD-L1 expression, tumor-infiltrating lymphocytes (TILs), and gut microbiome.
High TMB has been associated with greater immunogenicity and enhanced anti-tumor activity of immunotherapy. In the REGONIVO study, pMMR/MSS colorectal cancer patients with high TMB were more likely to benefit from regorafenib combined with nivolumab. POLE/POLD1 mutations, which are associated with high TMB, have also been shown to predict the efficacy of ICIs in various solid tumors. However, the role of TMB in MSS mCRC has not been definitively established, and there is currently no optimal mCRC-specific TMB cutoff to predict the benefit of ICIs-based treatment strategies.
While PD-L1 expression has an important predictive role in other gastrointestinal tumors, there is no evidence to date that PD-L1 expression can be used as a predictive biomarker in pMMR/MSS mCRC patients. TILs, particularly CD8+ T lymphocytes, have been correlated with prognosis in colorectal cancer and may also predict the efficacy of ICIs. Gut microbiota composition has also been shown to influence the response to ICIs in various cancers, including colorectal cancer.
Future Directions
Combination therapies are showing promise in improving the efficacy of immunotherapy for patients with pMMR/MSS mCRC. Further research is needed to identify the optimal combinations, patient selection criteria, and predictive biomarkers to maximize the benefits of immunotherapy in this challenging patient population. Precision therapy based on molecular typing will likely become the premise and basis of future clinical practice and research design.
