Evaluation of the combination of regorafenib + avelumab in patients with HPV-associated cancer: The phase II REGOMUNE study.

2517 Background: HPV-associated malignancies—including cervical, anal, head and neck, and penile cancers—form a biologically distinct group with limited responsiveness to immune checkpoint inhibitors (ICP) in monotherapy. Combining anti-angiogenic agents with immunotherapy may enhance efficacy by reshaping the tumor microenvironment. REGOMUNE explores this rationale by evaluating regorafenib plus avelumab association. Methods: REGOMUNE is a French multicenter, open-label, phase II trial assessing the combination of regorafenib (160 mg daily for 3 weeks of a 4-week cycle) and avelumab (10 mg/kg biweekly) in patients with advanced/metastatic HPV-driven solid tumors. The primary endpoint is the 6-month disease control rate (DCR) per RECIST 1.1 after central review. Secondary endpoints include overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Correlative studies will analyze baseline tumor samples to identify biomarkers of response. An exact single stage design was used testing 10% vs 25% DCR (5% type 1 error rate and 80% power), requiring ≥ 8 patients with disease control at 6 months among 40 patients to demonstrate efficacy. Results: From March 2023 and to February 2024, 44 patients were enrolled across 6 centers. Median age was 62 (range :33-80). Median follow-up was 18.3 months (95% CI : 14.9-21.1). Median number of prior treatment lines was 2 (range :0-7). Anal (41%) and cervical (32%) cancers were the predominant primary sites, with squamous cell carcinoma representing 70.5% of cases. Among 33 evaluable patients for efficacy, the 6-month DCR was 45.5% (N = 15) [90% CI : 30.5-61.1], with 12 (36.4%) partial response, 11 (33.3%) stable disease, and 10 (30.3%) progressions. Median PFS was 5.3 months (95% CI: [3.0 – 7.3]). Median OS was 15.0 months (95% CI [7.2 – 21.6]). Treatment modifications due to adverse events occurred in 33/42 (78.6%) patients. Common grade 3/4 adverse events included palmar-plantar eryhtrodysesthesia syndrome (11.9%), diarrhea (9.5%) and fatigue (7.1%). One treatment-related death was reported. Conclusions: REGOMUNE is the first phase II trial to demonstrate a clinically meaningful efficacy signal surpassing historical CPI outcomes as monotherapy with an anti-angiogenic plus immune CPI combination in patients with HPV-positive tumors. Biomarker analyses are ongoing to identify predictive signatures associated with the durable responses observed in this cohort. Clinical trial information: NCT03475953 .