A Phase II Study of Nivolumab and Ipilimumab with Radiation Therapy in Patients with Metastatic, Microsatellite Stable Colorectal Cancer

Abstract

Purpose: Immune checkpoint inhibitors (ICIs) have significantly altered the natural history of microsatellite instability high (MSI-H) colorectal cancer (mCRC). For microsatellite stable (MSS) refractory mCRC, ICIs recently demonstrated efficacy signals in patients without liver metastases. This study evaluated combined radiation therapy (RT) and ICI therapy in MSS mCRC. Patients and Methods: This multi-institution, open-label, single arm Phase II study, enrolled patients with MSS mCRC previously treated with oxaliplatin, 5-fluorouracil, and irinotecan. Patients received combined RT and nivolumab/ipilimumab. The primary endpoint was the objective response rate (ORR) for unirradiated lesions. Secondary endpoints included the disease control rate (DCR) for unirradiated lesions, DCR and ORR of irradiated lesions, treatment-related adverse event (AE) rates, progression-free survival (PFS), and overall survival (OS). Results: Among 30 patients treated, the confirmed ORR was 10.0%. DCR was 33.3% and ORR was 10.0% in unirradiated lesions, and in irradiated lesions ORR was 13.3% and DCR 83.3%. In 8 patients without active liver metastases, ORR was 25.0% (95% CI, 3.2-65.1%) whereas in 22 patients with liver metastases ORR was 4.6% (95% CI, 0.1-22.8%). Median PFS was 2.4 months at median follow up of 19.8 months. The median OS of the cohort was 12.8 months (95% CI 6.8-17.9 months). Treatment was tolerable and only 10% of patients experienced grade 4 toxicity, which in all cases was lymphopenia. Conclusions: The combination of immune-modulating, non-ablative doses of radiation therapy with ipilimumab and nivolumab has selective clinical activity in refractory MSS CRC, with responses concentrated primarily in patients without active liver metastases.