CombiCoR-Vax trial: study protocol for a phase II, single-arm, multicenter trial of sequential pembrolizumab plus dendritic cell vaccine followed by trifluridine/tipiracil and bevacizumab in refractory microsatellite-stable metastatic colorectal cancer.

BACKGROUND: Metastatic colorectal cancer (mCRC) remains an incurable disease with a poor prognosis. Recently, the global phase 3 SUNLIGHT study demonstrated that adding bevacizumab to trifluridine/tipiracil (FTD/TPI) in refractory disease significantly improves overall survival (OS). As a result, this combination is set to become the new standard of care for refractory mCRC. Immune checkpoint inhibitors (ICIs), including Pembrolizumab, have shown excellent results in mCRC patients with mismatch-repair deficiency (dMMR) or high microsatellite instability (MSI-H) mCRC. Additionally, recent trials evaluating both concomitant and sequential chemoimmunotherapy in mismatch-repair-proficient (pMMR) and microsatellite-stable (MSS) mCRC have yielded promising outcomes. Dendritic cell (DC) vaccines, though historically limited in effectiveness, show potential when combined with ICIs. Preliminary studies suggest they enhance chemotherapy response while maintaining favorable safety profiles. These evidences support the exploration of immunotherapy and FTD/TPI plus Bevacizumab in pMMR/MSS mCRC patients.

METHODS: This is a single-arm, open-label, multicenter, phase 2 clinical trial evaluating the clinical and immunological activity of an innovative approach combining induction immunotherapy (Pembrolizumab plus DC vaccine) followed by maintenance chemotherapy (FTD/TPI plus Bevacizumab) in patients with refractory MSS/pMMR mCRC. The primary endpoint is the objective response rate (ORR). Secondary endpoints include progression-free survival (PFS), safety, and overall survival (OS).

DISCUSSION: This study explores a novel sequential immunochemotherapy approach combining a DC-based vaccine with anti-PD-1 immunotherapy and standard chemotherapy in patients with refractory pMMR/MSS mCRC. By integrating cellular immunotherapy without omitting the current standard of care (FTD/TPI plus bevacizumab), the trial aims to enhance treatment efficacy in a setting traditionally resistant to immunological strategies. To the best of our knowledge, this is the only ongoing trial investigating this therapeutic combination in this specific patient population.

TRIAL REGISTRATION: This study, acronym CombiCoR-Vax, has been registered on clinicaltrials.gov registry with identifier NCT06522919, on July 9, 2024.