Neoadjuvant Immunotherapy Achieves Up to 100% Response in Mismatch Repair-Deficient Colorectal Cancer
This JAMA Oncology review synthesizes multiple phase 2 trials showing that neoadjuvant immune checkpoint inhibitors achieve 60-100% complete clinical and pathological response rates in localized dMMR colorectal cancer, with low severe toxicity. Deficient mismatch repair status serves as the pivotal predictive biomarker, making MSI/MMR testing the gateway diagnostic for this potential paradigm shift toward organ preservation. Labs performing MMR immunohistochemistry and MSI testing are now directly influencing surgical versus immunotherapy treatment decisions.
The original study
Neoadjuvant Immune Checkpoint Inhibitor Therapy for Localized Deficient Mismatch Repair Colorectal Cancer: A Review.
- Authors
- Emiloju OE, Sinicrope FA
- Journal
- JAMA oncology
- Type
- Review, Journal Article
- PMID
- 37676680
Original abstract
IMPORTANCE: Colorectal cancers (CRCs) with deficient DNA mismatch repair (dMMR) account for 15% of all CRCs. Deficient MMR is a predictive biomarker associated with responsiveness to immune checkpoint inhibitors (ICIs) in solid tumors, including CRC. The remarkable effectiveness of ICIs in metastatic CRC has led to their evaluation in the neoadjuvant and adjuvant treatment of localized disease. OBSERVATIONS: Multiple prospective phase 2 studies in limited numbers of patients with localized dMMR CRC demonstrate high complete clinical and pathological response rates (60%-100%) to neoadjuvant ICIs, with low rates of grade 3 or higher ICI-related toxic effects. Given the median follow-up of 12 to 25 months in these studies, longer-term monitoring is needed to determine the durability of response and to ensure that oncologic outcomes are not compromised in patients undergoing nonoperative management. Neoadjuvant ICI therapy is especially attractive for patients with rectal cancer given the significant morbidity that accompanies pelvic irradiation and total mesorectal excision. Ongoing and planned prospective phase 2 trials will provide further data on important issues, including optimal neoadjuvant treatment duration, ICI monotherapy vs combination, and the need for adjuvant ICI therapy. CONCLUSIONS AND RELEVANCE: While this review found that early results of neoadjuvant immunotherapy for localized dMMR CRC show high rates of major and complete pathological response, longer-term follow-up data are needed to ensure that oncologic outcomes are not compromised and are ideally improved. Neoadjuvant ICI therapy in localized dMMR CRC represents a potential paradigm shift with implications for organ preservation.