Neoadjuvant Immunotherapy Shows Promise in pMMR/MSS Rectal Cancer

Combining neoadjuvant therapy with immunotherapy in patients with mismatched repair-proficient/microsatellite stable (pMMR/MSS) rectal cancer yielded high pathological and clinical response rates, excellent surgical outcomes, and a manageable safety profile, highlighting short-course chemoradiotherapy as a potentially superior approach, a study finds.

This systematic cohort study is published in the Journal of Cancer Research and Clinical Oncology.

High response rates, strong R0 resection, and low severe adverse events with neoadjuvant therapy plus immunotherapy were identified in a rectal cancer study. | Image credit: Aidman-stock.adobe.com

“This study presents the first systematic meta-analysis specifically focused on neoadjuvant immunotherapy in non-metastatic pMMR/MSS rectal cancer, integrating efficacy, safety, and treatment timing across diverse clinical cohorts,” wrote the researchers of the study.

pMMR/MSS nonmetastatic rectal cancer represents the majority of early-stage colorectal cancers and is characterized by proficient DNA mismatch repair and microsatellite stability.2 Unlike microsatellite instability-high tumors, which generally have a better prognosis, pMMR/MSS tumors are associated with a higher risk of recurrence and variable response to standard therapies, including adjuvant chemotherapy. Therefore, understanding the molecular features of pMMR/MSS tumors is critical for guiding treatment decisions, optimizing neoadjuvant strategies, and improving patient outcomes.

The study aimed to evaluate neoadjuvant therapy combined with immunotherapy in patients with pMMR/MSS nonmetastatic rectal cancer.1 Major databases, including PubMed, Web of Science, Cochrane Library, Embase, and conference proceedings from the American Society of Clinical Oncology and the European Society for Medical Oncology, were searched up to April 2025 for relevant studies.

Outcomes assessed included pathological complete response (pCR), major pathological response (MPR), clinical complete response (cCR), R0 resection, anal preservation rate, and incidence of adverse events. Subgroup analyses were conducted based on chemoradiotherapy regimen, neoadjuvant therapy protocol, and type of immune checkpoint inhibitor to explore potential sources of variation in treatment efficacy and safety.

The meta-analysis included 21 trial cohorts from 18 studies. The pooled pathological pCR rate was 35% (95% CI, 30%-40%), with an MPR of 58% (95% CI, 51%-64%) and a clinical cCR of 19% (95% CI, 11%-26%). Surgical outcomes were favorable, with an R0 resection rate of 99% (95% CI, 99%-100%) and an anal preservation rate of 84% (95% CI, 79%-90%).

Severe adverse events were infrequent, with grade 3 or greater immune-related events occurring in 1% of patients and surgery-related adverse events in 6%.

Subgroup analyses demonstrated that short-course chemoradiotherapy (SCRT) achieved higher pCR (46% vs 31%; P < .001) and MPR (66% vs 53%; P = .02) compared with long-course chemoradiotherapy, with a trend toward improved cCR (25% vs 15%; P = .08). Comparisons among neoadjuvant therapy protocols showed similar pCR rates across consolidation (36%), induction (34%), and concurrent (35%) strategies, while MPR rates varied significantly. Furthermore, efficacy was also comparable between monotherapy (pCR, 36%) and dual PD-1 plus CTLA-4 inhibitor therapy (pCR, 29%).

However, the researchers acknowledged this study had several limitations. This study was limited by mostly single-arm trials with small sample sizes, heterogeneity in protocols and patient selection, and a predominance of East Asian cohorts. Additionally, limited biomarker data restricted analysis of predictive factors, and high-quality randomized trials are needed to confirm these findings.

Despite these limitations, the researchers believe the study supports neoadjuvant therapy combined with immunotherapy in pMMR/MSS nonmetastatic rectal cancer, with high response rates, excellent R0 resection, favorable anal preservation, and a manageable safety profile.

“In summary, our study not only confirms the benefit of neoadjuvant therapy in improving local pathological response and surgical outcomes in rectal cancer but also strengthens the existing body of literature,” wrote the researchers. “Future studies should build on larger sample sizes and improved trial designs to further elucidate the molecular mechanisms behind the synergistic effects of radiotherapy combined with immunotherapy, ultimately providing more precise and individualized treatment options for rectal cancer patients.”

References

1. Li Y, Han C, Tang J. Efficacy and safety of neoadjuvant therapy combined with immunotherapy in MMR‑proficient/microsatellite stable non‑metastatic rectal cancer: a systematic review and meta‑analysis. J Cancer Res Clin Oncol. 2025;152(1):9. doi:10.1007/s00432-025-06387-4

2. Kawakami H, Zaanan A, Sinicrope FA. Implications of mismatch repair-deficient status on management of early-stage colorectal cancer. J Gastrointest Oncol. 2015;6(6):676-684. doi:10.3978/j.issn.2078-6891.2015.065