Phase II Single Arm Study of Durvalumab and Tremelimumab with Concurrent Radiotherapy in Patients with Mismatch Repair Proficient Metastatic Colorectal Cancer.

Purpose: Immune checkpoint inhibition (ICI) alone is not active in mismatch repair-proficient (MMR-P) metastatic colorectal cancer (mCRC), nor does radiotherapy (RT) alone result in objective systemic benefit. However, combined RT plus ICI can induce systemic anti-tumor immunity in pre-clinical and clinical models. Experimental Design: In this single-center, phase II study, patients with chemotherapy-refractory MMR-P mCRC received durvalumab 1500 mg plus tremelimumab 75 mg every 4 weeks plus RT. The primary endpoint was objective response rate (ORR) in non-irradiated lesions. Treatment and efficacy were correlated with peripheral immune cell profiles. Results: We enrolled 24 patients, and report outcomes after a median follow up of 21.8 (range: 15.9 to 26.3) months. The ORR was 8.3% (2 patients) (95% confidence interval [CI], 1.0% to 27.0%). The median progression-free survival was 1.8 (95% CI, 1.7 to 1.9) months, median overall survival was 11.4 (95% CI, 10.1 to 17.4) months. Twenty five percent of patients (n=6) had treatment-related grade 3-4 adverse events. We observed increased circulating CD8+ T lymphocyte activation, differentiation, and proliferation in patients with objective response. Conclusion: This combination of RT plus ICI study did not meet the prespecified end point criteria to be considered worthwhile for further study. However, rare instances of systemic immune augmentation and regression in non-irradiated lesions were observed (an abscopal response). Combination durvalumab and tremelimumab plus RT is feasible in MMR-P mCRC with a manageable safety profile. Further studies of novel immunotherapy combinations, and identification of biomarkers predictive of abscopal response are warranted.