BACKGROUND: Treatment strategies for metastatic colorectal cancer (mCRC) patients with unresectable liver metastases include systemic therapy and local ablative treatments (LATs). While immunotherapy outcomes in patients with microsatellite stable mCRC have been disappointing, LATs may induce local immune activation and potentially prime the tumour microenvironment for a systemic immunotherapy response. This study investigates the combination of partial liver ablation with tremelimumab and durvalumab to induce responses in unablated liver metastases.

PATIENTS AND METHODS: This was a multicentre, single-arm phase II study. Eligible patients had unresectable, liver-predominant mCRC with at least stable disease following 3-6 months of first- or second-line chemotherapy. Liver metastases had to be amenable to partial LAT, either radiofrequency ablation (RFA) or stereotactic body radiotherapy (SBRT). At least two liver metastases, or one liver metastasis and one extrahepatic lesion, were required to remain untreated. Patients received tremelimumab and durvalumab for four cycles, followed by durvalumab administered every 4 weeks. RFA or SBRT was carried out during the first treatment cycle. The primary endpoint was the overall response rate of untreated lesions. Secondary endpoints were safety and progression-free survival (PFS).

RESULTS: A total of 23 patients were enrolled from 6 centres across 4 countries, of whom 20 received protocol treatment. In the per-protocol population, 12 patients were treated with RFA and 8 with SBRT. The median duration of immunotherapy treatment was 85 days from the first to the last dose. No patients demonstrated an objective response in any of the untreated metastases. The best overall response was stable disease in 9 (42.9%) patients. The median PFS was 2.2 months (95% confidence interval 1.8-3.6). At a median follow-up of 17.1 months, 55% of patients had died. The study was closed for futility at the first planned interim analysis.

CONCLUSIONS: In this phase II trial, the combination of immunotherapy with partial LAT did not elicit any responses in locally untreated liver metastases in patients with mCRC. Further strategies are required to enhance the efficacy of immunotherapy in this clinical setting.