Evaluation of the combination of regorafenib + avelumab in patients with non-small cell lung cancer without oncogenic addiction: The phase II REGOMUNE study.

Abstract

8549 Background: Combining anti-angiogenic agents with immune checkpoint inhibitors (ICI) in NSCLC has a strong biological rational. This strategy may enhance antitumor immunity by downregulating PD-1/PD-L1 expression, increasing TIL infiltration, and reducing immunosuppressive Tregs and MDSCs, potentially resensitizing patients to ICI therapy. Methods: This phase II, single-arm, multicentric trial evaluated the combination of regorafenib (160 mg daily, 3 weeks on/1 week off) and avelumab (10 mg/kg Q2W) in advanced/metastatic NSCLC patients without EGFR/ALK/ROS1 alterations. Eligible patients were previously treated with anti-PD(L)1 inhibitors for ≥4 months and had received ≤2 prior systemic lines. The primary endpoint was the 6-month progression-free rate (PFR6) per RECIST 1.1. Secondary endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Correlative studies analyzed baseline tumor samples to identify biomarkers of response. A Simon’s two-stage design was used, requiring ≥13 non-progressions among 43 patients to demonstrate efficacy. Results: Between February 2021 and April 2024, 46 patients were enrolled across four centers (median age: 63, range: 41-88). Median follow-up was 13.4 months. Most patients (94%) had prior platinum-based chemotherapy. Dose adjustments for regorafenib were required in 78.3% of patients due to adverse events. Common grade 3/4 toxicities included erythroderma (15.2%) and oral mucositis/palmar-plantar erythrodysesthesia (13% each). No treatment-related deaths occurred. Among 34 evaluable patients, PFR6 was 35.3% (90% CI: 21.8-50.8), with 6 (17.6%) achieving partial responses and 16 (47.1%) having stable disease. The median duration of the response was 20.3 months (95% CI: 5.1-22.0). Median PFS was 3.7 months (95% CI: 1.9-8.7), and median OS was 25.5 months (95% CI: 8.7-NR). Conclusions: The combination of avelumab and regorafenib demonstrated the ability to resensitize a subset of anti-PD(L)1-exposed NSCLC patients to immune checkpoint inhibition, leading to durable responses and a promising 6-month PFR. Biomarker analyses will also be presented, providing insights into predictors of response. Clinical trial information: NCT03475953 .