Abstract CT033: Avelumab combined with regorafenib in solid tumors with tertiary lymphoid structures: A phase 2 REGOMUNE trial cohort

Abstract Background: Mature tertiary lymphoid structures (mTLS) predict improved outcome in patients treated with immune checkpoint inhibitors (ICIs). However, a significant proportion of patients with TLS-positive tumors do not respond to ICI when used as a single agent and may therefore benefit from combination therapy. The multikinase inhibitor, regorafenib, deplete regulatory T cells, an immune population associated with resistance to ICI in TLS-positive tumors. We report the results of the PD-L1 inhibitor avelumab combined with regorafenib in patients with mTLS-positive advanced solid tumors. Methods: ‘Regomune’ is an open-label, multicenter phase II study assessing the combination of avelumab (10mg/kg IV every 14 days) with regorafenib (160 mg daily for 3 weeks in a 4-week cycle) in patients with advanced mTLS-positive solid tumors. The mTLS status was centrally assessed as previously described (Vanhersecke et al Nature Cancer 2021). All patients had confirmed progressive disease at inclusion, based on a central review of imaging. The primary efficacy endpoint was a 6-month non-progression rate using RECIST v1. 1 based on blinded central review. 29 assessable patients were deemed necessary, and to meet the primary endpoint, at least 8 patients needed to be progression-free at 6 months. Results: Between January 2021 and July 2022, 132 patients (5 centers) underwent mTLS screening. Of these, 55 (41. 7%) were identified as mTLS+, and 38 were included in the study. The top five histological subtypes were MSS colorectal cancer (15. 8%), sarcoma (13. 1%), oesogastric (10. 5%), biliary tract (7. 9%), and pancreatic cancer (7. 9%). The most frequent grade 3/4 adverse events were palmar-plantar erythrodysesthesia syndrome (23. 7%), maculo-papular rash (18. 4%), fatigue, and oral mucositis (7. 9% each). No treatment-related deaths were reported. Of the 34 patients assessed for efficacy, 16 (47%) showed tumor shrinkage, with 9 achieving a partial response (26. 7%) and 7 having stable disease (20. 6%). The median duration of response was 6 months. Twelve patients (comprising various tumor types including MSS colorectal cancer, small bowel carcinomas, biliary tract cancer, sarcomas, thyroid and gynecological tumors. ) were progression-free at 6 months, marking the study’s primary endpoint achievement. The median progression-free survival and overall survival were 3. 6 months and 8. 6 months, respectively. Spatial transcriptomics, multiplex immunofluorescence (IF) of tumor tissues, and comprehensive plasma proteomics analysis have collectively uncovered critical biomarkers that significantly determine both sensitivity and resistance to treatment. Conclusions: This is the first histology-agnostic clinical trial employing mTLS as a biomarker for patient selection for treatment with an immune checkpoint inhibitor-based regimen. Durable responses were recorded, even in cases typically resistant to immunotherapy, confirming the predictive value of mTLS. Trial Registration NCT03475953 Citation Format: Antoine Italiano, Sophie Cousin, Carine Bellera, Jean-Philippe Guegan, Jean-Philippe Metges, Antoine Adenis, Rastilav Bahleda, Philippe Cassier, Coralie Cantarel, Michele Kind, Jean Palussiere, Lucile Vanhersecke, Alban Bessede. Avelumab combined with regorafenib in solid tumors with tertiary lymphoid structures: A phase 2 REGOMUNE trial cohort abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr CT033.