The landscape of colorectal cancer (CRC) treatment is evolving, with neoadjuvant immunotherapy emerging as a promising strategy, particularly for patients with mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) tumors. These tumors, characterized by a high mutational burden, are more susceptible to immune checkpoint inhibitors. Recent studies are focusing on optimizing the use of neoadjuvant immunotherapy to improve pathological response rates, reduce recurrence, and potentially avoid radical surgery.
Immunotherapy in dMMR/MSI-H Colorectal Cancer
Neoadjuvant immunotherapy has demonstrated remarkable efficacy in dMMR/MSI-H CRC. Studies have shown high rates of pathological complete response (pCR) and major pathological response (MPR) with neoadjuvant PD-1 blockade. For instance, the NEOPRISM-CRC trial (NCT04977378) is evaluating neoadjuvant pembrolizumab in high-risk stage II or III dMMR/MSI-H CRC, stratified by tumor mutation burden (TMB). Similarly, a phase Ib study (NCT04165772) explored the combination of IBI310 (anti-CTLA-4 antibody) plus sintilimab (anti-PD-1 antibody) in MSI-H/dMMR CRC, demonstrating promising results.
One notable study published in the New England Journal of Medicine demonstrated that neoadjuvant immunotherapy in locally advanced mismatch repair-deficient colon cancer led to significant tumor regression and, in some cases, complete pathological response, potentially sparing patients from extensive surgery.
Biomarkers for Predicting Response
Identifying predictive biomarkers is crucial for personalizing neoadjuvant immunotherapy. TMB, PD-L1 expression, and immune cell infiltration are being investigated as potential markers. A study in Annals of Oncology found that TMB is predictive of response to immune checkpoint inhibitors in MSI-high metastatic CRC. However, the optimal TMB cutoff and its correlation with clinical outcomes are still under investigation. PD-L1 expression, while commonly assessed, has shown variable predictive value in CRC. Some studies suggest that high PD-L1 expression correlates with increased immune infiltration and better response to anti-PD-1/PD-L1 therapy, while others have found no significant association.
Novel Immunotherapy Combinations
For patients with mismatch repair-proficient (pMMR) or microsatellite stable (MSS) CRC, which are typically less responsive to single-agent immunotherapy, combination strategies are being explored. The combination of botensilimab, an Fc-enhanced CTLA-4 antibody, plus balstilimab, a PD-1 inhibitor, has shown encouraging results in relapsed/refractory MSS metastatic CRC. The NEST-1 trial (NCT05275474) is evaluating this combination in resectable MMR proficient and deficient colorectal cancer.
Neoadjuvant Immunotherapy in Rectal Cancer
Locally advanced rectal cancer presents a unique challenge, and neoadjuvant chemoradiotherapy (CRT) is the standard of care. However, the addition of immunotherapy to CRT is being investigated to improve outcomes and potentially increase organ preservation rates. The TORCH trial (NCT03942585) is a randomized phase II trial evaluating immunotherapy-based total neoadjuvant therapy for proficient mismatch repair or microsatellite stable locally advanced rectal cancer. Another study (NCT03424605) is exploring preoperative chemoradiotherapy plus nivolumab before surgery in patients with microsatellite stable and microsatellite instability-high locally advanced rectal cancer.
Challenges and Future Directions
While neoadjuvant immunotherapy holds great promise, several challenges remain. Predicting which patients will respond to therapy and managing immune-related adverse events (irAEs) are critical. Biomarkers that can accurately predict response and identify patients at risk for irAEs are needed. Additionally, optimizing the timing and duration of neoadjuvant immunotherapy, as well as identifying the best combination strategies, are areas of ongoing research.
Neoadjuvant clinical trials provide a unique opportunity for cancer drug discovery. By studying the changes in the tumor microenvironment and immune response during neoadjuvant therapy, researchers can gain valuable insights into the mechanisms of action of immunotherapies and identify new therapeutic targets.
