Neoadjuvant Pembrolizumab for Stage I-III dMMR Colon Cancer: A Phase II Organ-Sparing Study

The primary objective is to determine the proportion of patients achieving clinical complete response (cCR) at the end of pembrolizumab therapy in individuals with localized dMMR colon cancer. Secondary objectives assess overall survival, disease‑free survival, the rate of complete response and major pathologic response in patients who proceed to surgery, adverse events associated with pembrolizumab, surgery‑related adverse events, endoscopy‑related adverse events, healthcare utilisation, quality of life, and the efficacy of prehabilitation.

The trial enrolled adult patients (age ≥ 18 years) of both sexes diagnosed with localized dMMR colon cancer at clinical UICC stage I‑III who were candidates for elective curative‑intent surgery. The sponsor did not provide the total number of participants, and no specific lifestyle requirements such as diet, physical activity, or habit restrictions were reported. Selection was based on meeting the principal inclusion criteria, which required a confirmed diagnosis of dMMR colon adenocarcinoma, eligibility for curative surgery, and provision of written informed consent; general health status was limited to individuals without contraindicating conditions, as implied by the exclusion of those not suitable for surgery.

The study is a phase II, national, multicentre, personalized trial evaluating 400 mg intravenous pembrolizumab in patients with localized dMMR colon cancer (clinical UICC stage I‑III) who are candidates for curative‑intent surgery. After written informed consent, participants undergo a screening visit to confirm eligibility, followed by a baseline visit where the first infusion is administered. Subsequent treatment visits occur at regular intervals for additional pembrolizumab infusions, with clinical assessments, endoscopic examinations, and contrast‑enhanced CT imaging performed to evaluate local response and detect metastatic disease. Patients achieving a clinical complete response may enter a watch‑and‑wait pathway, while those proceeding to surgery have postoperative follow‑up visits to assess surgical complications, pathological response, and functional outcomes. Quality‑of‑life questionnaires and prehabilitation assessments are collected at predefined time points during treatment and at 3, 6, 12, 24, and 60 months after definitive therapy. The overall participant involvement extends from the screening visit through a final end‑of‑study visit up to 36 months post‑inclusion, encompassing all safety and efficacy evaluations. Early termination may occur due to disease progression, unacceptable adverse events, withdrawal of consent, or significant protocol deviations.

The investigational product is KEYTRUDA 25 mg/mL concentrate for solution for infusion, which contains the monoclonal antibody pembrolizumab. Each administered dose consists of 400 mg, delivered as an intravenous infusion of the solution for infusion according to the study dosing schedule.

Dosing is performed per protocol, with the specified 400‑mg dose prepared in accordance with the manufacturer’s instructions and infused over the designated period. Administration details are recorded in the source data verification log, and participant compliance is monitored by confirming completion of each infusion and documenting any deviations.

Efficacy is primarily evaluated by the proportion of participants achieving a clinical complete response, defined as the presence of a local response on endoscopy combined with the absence of metastatic disease on CT imaging at the reassessment performed at the end of pembrolizumab treatment.

Secondary efficacy assessments include overall survival and disease‑free survival, measured from the date of inclusion to 36 months post‑inclusion, and pathological response rates in surgical patients, classified as complete pathological response (Mandard Tumour Grade Regression 1) or major pathologic response (Mandard Tumour Grade Regression 1 or 2). Additional efficacy outcomes are captured using validated patient‑reported outcome instruments—EORTC QLQ‑C30, EORTC QLQ‑CR29, the Colon Cancer Dysfunction Score, EQ‑5D‑5L, FACIT‑Fatigue, the Fear of Cancer Recurrence Short Form, and the Quality of Recovery‑15 questionnaire—administered before treatment, during treatment, and at 3, 6, 12, 24 and 60 months after definitive therapy. Functional prehabilitation efficacy is assessed through serial measurements of the 6‑minute walk test, Sit‑to‑Stand test, hand‑grip strength, BORG Scale, G8 frailty score, and NPAQ‑Short, performed at enrolment, after each immunotherapy cycle, and at 3 months post‑definitive treatment.