Regorafenib-Avelumab Combination in Patients with Microsatellite Stable Colorectal Cancer (REGOMUNE): A Single-arm, Open-label, Phase II Trial

Abstract

Purpose: Regorafenib is synergistic with immune checkpoint inhibition in colorectal cancer preclinical models.Patients and Methods: This was a single-arm, multicentric phase II trial. Regorafenib was given 3 weeks on/1 week off, 160 mg every day; avelumab 10 mg/kg i.v. was given every 2 weeks, beginning at cycle 1, day 15 until progression or unacceptable toxicity. The primary endpoint was the confirmed objective response rate under treatment, as per RECIST 1.1. The secondary endpoints included a 1-year nonprogression rate, progression-free survival (PFS), and overall survival (OS), safety and biomarkers studies performed on sequential tumor samples obtained at baseline and at cycle 2 day 1.Results: Forty-eight patients were enrolled in four centers. Fortythree were assessable for efficacy after central radiological review. Best response was stable disease for 23 patients (53.5%) and progressive disease for 17 patients (39.5%). The median PFS and OS were 3.6 months [95% confidence interval (CI), 1.8-5.4] and 10.8 months (95% CI, 5.9-NA), respectively. The most common grade 3 or 4 adverse events were palmar-plantar erythrodysesthesia syndrome (n ¼ 14, 30%), hypertension (n ¼ 11, 23%), and diarrhea (n ¼ 6, 13%). High baseline infiltration by tumor-associated macrophages was significantly associated with adverse PFS (1.8 vs. 3.7 months; P ¼ 0.002) and OS (3.7 months vs. not reached; P ¼ 0.002). Increased tumor infiltration by CD8 þ T cells at cycle 2, day 1 as compared with baseline was significantly associated with better outcome.Conclusions: The combination of regorafenib þ avelumab mobilizes antitumor immunity in a subset of patients with microsatellite stable colorectal cancer. Computational pathology through quantification of immune cell infiltration may improve patient selection for further studies investigating this approach.

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

“…Although there were no responses, 23 patients presented stable disease (54%), with a median PFS of 3.6 months (95% CI 1.8–5.4), and a median OS of 10.8 months (95% CI 5.9–NA). Increased tumor infiltration by CD8 + T cells at cycle 2 was associated with better outcomes [ 20 ].…”

Advances and new frontiers for immunotherapy in colorectal cancer: Setting the stage for neoadjuvant success?

“…High baseline infiltration by TAMs was significantly associated with adverse PFS, whereas increased tumor infiltration by CD8 + T cells from baseline was significantly associated with a better outcome. 107 Inhibition of mitogen/extracellular signal regulated kinase (MEK), a downstream effector of the RAS-MAPK pathway, was found to result in upregulation of PD-L1 and have synergistic effects with the PD-1 inhibitor in preclinical models. 108,109 However, the result of the IMBLAZE370 trial studying the effect of cobimetinib did not meet its primary endpoint of improved OS with atezolizumab plus cobimetinib or atezolizumab versus regorafenib.…”

Combination Immunotherapies to Overcome Intrinsic Resistance to Checkpoint Blockade in Microsatellite Stable Colorectal Cancer

“…However, they reported that the ORR was 0%, with intolerable toxicities. Unlike the previous two trials that targeted PD-1, an anti-PD-L1 (avelumab) was combined with regorafenib in a phase II REGOMUNE trial [ 96 ]. They reported that the best response was stable disease in 53.5% of patients, whereas there was no objective response in patients with MSS/pMMR mCRC.…”