Neoadjuvant Immunotherapy and Organ-sparing Treatment in Patients With Stage I-III dMMR Colon Cancer: A National, Multicentre, Personalised, Phase II Study (RESET C2)

Organ preservation in colorectal cancer has been pioneered in rectal cancer populations, where watch-and-wait (WW) strategies emerged from total neoadjuvant therapy. RESET C2 aims to brings this same treatment paradigm to colon cancer (CC). Despite improvements in surgical outcomes for CC over time, the risk of relapse and disproportionate complications in frail patients remain core challenges. Avoidance of surgery to limit these risks is attractive from a safety perspective but WW approaches have not been validated as curative and oncologically safe in a CC population. The subgroup of patients with CC and deficient mismatch repair (dMMR) proteins are ideal candidates for investigation as they demonstrate marked sensitivity to immunotherapy, which has the capacity to induce complete responses in a substantial proportion. The question of how this can be best leveraged for maximum benefit in a real-world setting remains to be answered.

In this study, 152 eligible participants will be recruited nationwide across 13 participating sites in Denmark. Following enrolment, clinicians will assign a surgical risk category using a composite of the American society of anaesthesiology (ASA) score and Eastern Cooperative Oncology Group performance status (ECOG). This input is combined with cancer stage data to allocate patients to one of four treatment arms. Depending on allocation, participants will receive between one to three consecutive cycles of up-front 4mg/kg pembrolizumab (max. 400mg) every six weeks. This is followed by a disease re-evaluation step, involving colonoscopy and contrast CT imaging. Colonoscopy is used to determine local disease response, and cross-sectional CT is used to confirm absence of distant disease. Participants with clinical complete response (cCR) will be eligible for WW, and those with non-cCR will be offered additional pembrolizumab before a second/final re-evaluation. Any patients with cCR at the final re-evaluation will be eligible for WW and those with non-cCR will be offered surgery. Quality of life (QoL) and late effects will be captured via patient reported outcome measures (PROMs) which will be distributed after enrolment, during immunotherapy, and at designated timepoints across survivorship. A separate cohort of 250 CC patients who undergo surgery without neoadjuvant treatment will complete identical PROMs and act as a comparator group after surgical treatment. Final analysis will compare QoL and late effects in patients who are allocated to WW (cCR), with those who receive neoadjuvant treatment and proceed to surgery (non-cCR), and finally those who proceed directly to surgery (matched cohort).

Across all treatment arms, enrolled patients will be offered multi-disciplinary prehabilitation. These functional, exercise, and nutrition interventions are graded in intensity and dependent on patient frailty and disease-factors. This forms the backbone of standard-of-care nationally for colorectal cancer patients and is implemented across all participating sites.