Neoadjuvant Immunotherapy and Organ-sparing Treatment in Patients With Stage I-III dMMR Colon Cancer

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

The RESET C2 trial aims to introduce organ sparing treatment or watch-and-wait (WW) to patients with localized deficient mismatch repair (dMMR) colon cancer through use of neoadjuvant pembrolizumab. Patients will be divided into four treatment arms based on their surgical and oncologic risks. Each arm provides different intensity neoadjuvant immunotherapy regimens. Patients with complete response at disease restaging procedures will be offered non-operative management, whereas those with non-complete response will proceed to surgery ± adjuvant chemotherapy as standard of care. A WW protocol with regular disease surveillance continues over survivorship. If there is recurrence, surgery and/or appropriate oncologic therapy will be offered determined by multi-disciplinary teams. This is a national, non-randomised, investigator-initiated trial including patients from 13 hospitals across Denmark. The rationale, design, and clinical response metrics are derived from the RESET C study (NCT05662527) showing efficacy, safety and feasibility of neoadjuvant pembrolizumab in this cohort.

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.

Inclusion Criteria:

1. Age ≥ 18 years
2. Written informed consent
3. Clinical UICC stage I-III dMMR colon carcinoma
4. Indication for elective curative-intent surgery
5. ECOG status 0-2

Exclusion Criteria:

1. Patients deemed to be non-surgical candidates by MDT
2. Patients with a need for emergent surgery due to tumour obstruction
3. Contraindications to pembrolizumab, including allergy and hypersensitivity reactions, assessed by the study investigator(s)
4. Any serious or uncontrolled medical disorder, including other malignant disease, that may increase the risk associated with participation or drug administration.
5. Patients with colonic stents

Additional Circumstances:

In the following circumstances, eligibility will be individually verified:

• Synchronous colonic tumours (may be included if other lesions are biopsy-verified with dMMR status)
• Concurrent tumours (e.g., patients with prostate cancer may be included if this does not hinder their other cancer treatment or assessments of efficacy)

In the following circumstance patients may be excluded from the PROMs outcomes:

• Danish language skills insufficient to answer PROMs
• Unable to use eBoks