Effect of one or two cycles of dual immunotherapy with nivolumab and ipilimumab in patients with mismatch repair-deficient rectal cancer (RESET-R): interim results from a multicentre, single-arm, phase 2 trial

BACKGROUND: Mismatch repair-deficient (dMMR) tumours are highly sensitive to immune checkpoint blockade in the metastatic setting. Previous trials showed near-universal pathological responses after short-course dual immune checkpoint inhibition in patients with early-stage dMMR colon cancer, and high clinical complete response rates after 6 months of single-agent PD-1 blockade in patients with dMMR rectal cancer. We aimed to evaluate the activity and safety of a short duration of preoperative nivolumab and ipilimumab in patients with early or locally advanced dMMR rectal cancer.

METHODS: In the RESET-R trial, a multicentre, single-arm, phase 2 trial conducted in two hospitals in Denmark, we enrolled patients aged 18 years or older with histologically confirmed stage I-III dMMR rectal adenocarcinoma, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no previous systemic or local therapy for rectal cancer. Patients received one cycle of nivolumab (3 mg/kg intravenously on days 1 and 15) and ipilimumab (1 mg/kg intravenously on day 1). Patients with definite tumour regression but without clinical complete response at day 43 received a second cycle (nivolumab 3 mg/kg intravenously on days 50 and 65 and ipilimumab 1 mg/kg intravenously on day 50). The primary endpoint was the proportion of patients with a clinical complete response at day 93, defined as no visible or palpable tumour on rectal digital examination, endoscopy, and MRI. In patients with digital and endoscopic complete response, and with non-complete response on MRI, the absence of viable tumour cells in a representative biopsy was also classified as clinical complete response. Patients who had a clinical complete response were recommended to proceed with a watch-and-wait strategy without surgery. Analyses were done in the intention-to-treat population. The study was designed as a Simon two-stage trial, with an analysis for futility after enrolment of 19 participants. The study was to continue to enrol an additional 20 participants if six or more of the initial 19 participants had a clinical complete response, and the regimen would be deemed worthy of further investigation if 16 participants of the total 39 had a clinical complete response. An early interim analysis (and dissemination of the findings) was approved by the trial protocol committee when it became apparent that this measure of success had been met after enrolment of the first 16 participants. The trial is registered with EU Clinical Trials (2022-500646-14-00); the study is ongoing and continues to enrol patients.

FINDINGS: Between Feb 1, 2023, and Oct 28, 2025, 16 patients (nine [56%] male, seven [44%] female) were enrolled. Four (25%) patients had stage I tumours, two (13%) had stage II tumours, and ten (63%) had stage III tumours. All patients received at least one cycle of nivolumab and ipilimumab. By day 93, all 16 patients (100·0% [95% CI 79·4-100·0]) had a clinical complete response: 11 (68·7% [41·3-89·0]) patients after one cycle and five (31·3% [11·0-58·7]) after two cycles. No patient received chemoradiotherapy or underwent surgery, and no patients had progression or recurrence during follow-up (median 16 months [IQR 9-18]). Grade 3 immune-related adverse events occurred in three (19%) patients (infusion-related reaction, hypophysitis, and serous retinal detachment). No grade 4 or grade 5 toxicities, serious treatment-related adverse events, treatment discontinuations, or treatment-related deaths were reported.

INTERPRETATION: All participants in this trial of short-course dual immune checkpoint blockade for dMMR rectal cancer had a clinical complete response with manageable toxicity, allowing them to proceed to a watch-and-wait strategy without surgery. Longer follow-up and completion of enrolment are needed to confirm the durability of these effects and the safety of an organ-preserving strategy.

FUNDING: The Danish Comprehensive Cancer Center-ctDNA Research Center, the NEYE Foundation, the Aage and Johanne Louis-Hansen Foundation, and the Eva and Henry Frænkel Memorial Foundation.