Background: Treatment for patients (pts) with metastatic colorectal cancer (mCRC) with unresectable liver metastases (mets) is usually chemotherapy (CT) +/- local ablative treatments. Immunotherapy (IO) effect is disappointing in mCRC with pMMR status so testing strategies to promote immune activation is key. Previous studies show that local ablative treatments may induce local immune activation and prime for IO response. Methods: This multi-center non-randomised early phase II study aims to test whether local liver therapy in combination with durvalumab and tremelimumab (durv/trem) will lead to immune response in liver metastases untreated locally. Eligible pts had non-resectable liver predominant mCRC and at least stable disease following 3-6 months first- or second line CT. Liver mets were amenable to radiofrequency ablation (RFA) or stereotactic radiotherapy (SBRT) allowing a total ablated volume of at least 25 cm3. At least 2 measurable liver or 1 liver and 1 extrahepatic lesions were left untreated locally. Tremelimumab 75 mg and durvalumab 1500 mg were given for 4 cycles followed by durvalumab 1500 mg every 4 weeks. During cycle 1, RFA and SBRT were performed concurrently.Primary endpoint was ORR per iRECIST in lesions untreated locally; secondary endpoints included feasibility and safety and progression free survival (PFS). According to an optimal Simon’s two-stage design to reject a ORR ≤ 10% with power of 90% under a ORR of 25% using a one-sided alpha of 5%, the study should be early stopped if there were ≤2 responses among the 21 first patients enrolled in the per protocol (PP) population (stage I) while ≥ 11 responses among 66 patients were needed to declare success. Results: Between March 2019 and March 2021, 23 pts were recruited from 6 centers in 4 countries; 21 pts started protocol treatment; 13 pts were treated with RFA; 8 pts with SBRT but 1 pt was ineligible out of 21. In the PP population (20 pts), median age was 57. Response to previous systemic CT was PR (75%) and SD (25%). No pt had prior surgery or local treatment to the liver. 60% had limited extra-hepatic disease (up to 2 sites). Median treatment duration was 85.0 days; all 20 pts received planned local ablative treatment. At best response assessment, 0% of patients had a CR or PR, 45% had SD and 55% PD. Median PFS was 2.2 months (95% CI: 1.8-3.6). At a median follow up of 11 months, 55% of pts had died. The study was closed due to futility. In patients treated with RFA + durv/trem, 30.8% had grade 3 toxicity; for SBRT +durv/trem it was 50%. Conclusions: In this phase II trial, combining IO with local ablative therapy in liver predominant mCRC did not result in responses in lesions untreated locally. Further strategies are required to improve IO response in this clinical setting. Clinical trial information: 2017-001375-22.