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Neoadjuvant Immunotherapy in Localized dMMR/MSI-H Colon Cancer: A Systematic Review of Pathological Response and
Rathin Gosavi1,2,3, Baxter Smith4, Hanumant Chouhan2
1Department of Surgery (School of Clinical Sciences at Monash Health), Monash University, Melbourne, VIC, Australia.
Background:
Neoadjuvant immune checkpoint inhibition is increasingly being investigated in localized mismatch repair-deficient or microsatellite instability-high (dMMR/MSI-H) colon cancer, but evidence remains immature and often combined with broader cohorts.
Methods:
We reviewed prospective interventional studies of neoadjuvant immune checkpoint inhibition in adults with localized, non-metastatic dMMR/MSI-H colon cancer. The Ovid MEDLINE, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov databases and reference lists were searched to 12 June 2026. Studies were eligible when colon-specific pathological response outcomes were reported or extractable. Primary outcomes were pathological complete response (pCR) and major pathological response (MPR). Secondary outcomes included surgical feasibility, R0 resection, delay, morbidity, adverse events, recurrence, and survival.
Results:
Six studies were included: NICHE, NICHE-2, NICHE-3, RESET-C, IMHOTEP, and IBI310/sintilimab. pCR ranged from 44 to 78.4% and MPR from 57 to 95%, varying by regimen, denominator, and definition. NICHE-based dual-checkpoint studies reported pCR rates of 60-68% and MPR rates of 92-95%. Pembrolizumab-based studies reported pCR rates of 44-62.7%. The only randomized comparative study favored CTLA-4 plus programmed cell death protein-1 blockade over programmed cell death protein-1 blockade alone. Most patients proceeded to colectomy, with high R0 resection rates where reported. Severe treatment-related or immune-related adverse events occurred, including rare grade 5 events. Follow-up ranged from 8.1 to 26 months; recurrence was uncommon and survival outcomes immature.
Conclusions:
Neoadjuvant immune checkpoint inhibition demonstrates substantial pathological activity and apparent surgical feasibility in selected localized dMMR/MSI-H colon cancer. Longer follow-up and comparative trials are needed to define regimen, timing, patient selection, and durable oncological benefit.
Insights
Neoadjuvant immune checkpoint inhibitors show promise for localized dMMR/MSI-H colon cancer, achieving high pathological response rates. Further research is needed to optimize treatment and confirm long-term benefits.
Area of Science:
- Oncology
- Immunotherapy
- Gastrointestinal Cancer Research
Background:
- Neoadjuvant immune checkpoint inhibition (ICI) is under investigation for localized mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) colon cancer.
- Existing evidence is limited and often aggregates data across diverse patient cohorts.
Purpose of the Study:
- To systematically review prospective studies evaluating neoadjuvant ICI in localized, non-metastatic dMMR/MSI-H colon cancer.
- To assess pathological response rates, surgical outcomes, and safety profiles of neoadjuvant ICI regimens.
Main Methods:
- A comprehensive literature search of Ovid MEDLINE, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov was conducted up to June 12, 2026.
- Included studies reported or allowed extraction of colon-specific pathological response outcomes, focusing on pathological complete response (pCR) and major pathological response (MPR).
- Secondary outcomes included surgical feasibility, R0 resection rates, treatment delays, morbidity, adverse events, recurrence, and survival.
Main Results:
- Six studies (NICHE, NICHE-2, NICHE-3, RESET-C, IMHOTEP, IBI310/sintilimab) met the inclusion criteria.
- Pathological complete response (pCR) rates ranged from 44% to 78.4%, and major pathological response (MPR) rates ranged from 57% to 95%, varying by regimen and definition.
- Dual-checkpoint inhibition (CTLA-4 plus PD-1) showed higher pCR (60-68%) and MPR (92-95%) compared to PD-1 blockade alone (44-62.7% pCR).
- Most patients underwent colectomy with high R0 resection rates; severe adverse events were reported, including rare grade 5 events.
- Follow-up was limited (8.1-26 months), with uncommon recurrence and immature survival data.
Conclusions:
- Neoadjuvant ICI demonstrates significant pathological activity and surgical feasibility in select patients with localized dMMR/MSI-H colon cancer.
- Further long-term follow-up and comparative trials are essential to define optimal regimens, timing, patient selection, and durable oncological outcomes.
