Phase II Single-arm Study of Durvalumab and Tremelimumab with Concurrent Radiotherapy in Patients with Mismatch Repair–proficient Metastatic Colorectal Cancer

Abstract

Purpose: Immune checkpoint inhibition (ICI) alone is not active in mismatch repair–proficient (MMR-P) metastatic colorectal cancer (mCRC), nor does radiotherapy alone result in objective systemic benefit. However, combined radiotherapy plus ICI can induce systemic antitumor immunity in preclinical and clinical models. Patients and Methods: In this single-center, phase II study, patients with chemotherapy-refractory MMR-P mCRC received durvalumab 1,500 mg plus tremelimumab 75 mg every 4 weeks plus radiotherapy. The primary endpoint was objective response rate (ORR) in nonirradiated 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: 15.9–26.3) months. The ORR was 8.3% (2 patients) [95% confidence interval (CI), 1.0–27.0]. The median progression-free survival was 1.8 (95% CI, 1.7–1.9) months, median overall survival was 11.4 (95% CI, 10.1–17.4) 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. Conclusions: This combination of radiotherapy plus ICI study did not meet the prespecified endpoint criteria to be considered worthwhile for further study. However, rare instances of systemic immune augmentation and regression in nonirradiated lesions were observed (an abscopal response). Combination durvalumab and tremelimumab plus radiotherapy 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.

Induction chemoimmunotherapy followed by CD8+ immune cell-based patient selection for chemotherapy-free radioimmunotherapy in locally advanced head and neck cancer

“…Only three small phase I–II trials combined durvalumab/tremelimumab combination and stereotactic radiotherapy in different metastatic tumors so far and reported no safety problems. 36–38 Similarly, no severe radiotherapy-related toxicity as soft-tissue necrosis or ulcers was detected in the CheckRad-CD8 trial. The frequency of typical radiotherapy-related head and neck treatment toxicity as dysphagia, stomatitis or dermatitis was lower than in the previous trial in this indication (PacCis-RCT) of the same study group.…”

Durvalumab Plus Tremelimumab in Solid Tumors: A Systematic Review

“…The electronic search identified 267 articles; after exclusion of duplicates, irrelevant articles, reviews, and papers not in English or with missing data, 19 articles were finally included for revision [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32]. Figure 1 depicts a flowchart describing the details of the document screening process, while Table 1 reports the principal details of the articles finally selected.…”

“…Recently, Segal et al performed a single-center phase II study including 24 patients with chemotherapy-refractory with mismatch repair (MMR)-proficient metastatic CRC treated with durvalumab plus tremelimumab plus radiotherapy (Table 4 ) [ 24 ]. In this study, the ORR was 8.3% (95% CI 1.0–27.0), the median PFS was 1.8 (95% CI 1.7–1.9) months, and the median OS was 11.4 (95% CI 10.1–17.4) months.…”

Combined Treatment with Immunotherapy-Based Strategies for MSS Metastatic Colorectal Cancer

“…Nonetheless, combined radiotherapy with durvalumab and tremelimumab led to shrinkage of distant, nonirradiated tumors in MSS mCRC, with manageable safety. Plus, a heightened CD8 + T-cell activation, differentiation and proliferation was noted in patients with objective response [ 21 ]. In another phase II trial evaluating radiotherapy with ipilimumab and nivolumab, the combined treatment led to shrinkage of nonirradiated distant tumors with an ORR of 12.5% [ 22 ].…”