REGOMUNE: A phase II study of regorafenib plus avelumab in solid tumors—Results of the non-MSI-H metastatic colorectal cancer (mCRC) cohort.
Sophie Cousin, Carine Bellera, Jean‐Philippe Guégan, Carlos Gomez‐Roca, Jean‐Philippe Metges, Antoine Adenis, Simon Pernot, Coralie Cantarel, Michèle Kind, Maud Toulmonde, Kévin Bourcier, Isabelle Soubeyran, Alban Bessede, Antoîne Italiano
Abstract
4019 Background: Regorafenib (R) has been shown to modulate anti-tumor immunity by different mechanisms including reduction of tumor-associated macrophages (TAMs). Synergy between R and anti–PD-1/PD-L1 antibodies has been shown in pre-clinical models. Methods: This is a single-arm open-label multicentric phase II trial assessing the efficacy and safety of R (160 mg QD 3weeks/4) + Avelumab (A) (10 mg/kg every 2 weeks) combination in non MSI-H mCRC patients (pts). The primary endpoint was the confirmed objective response rate, based on central review according to RECIST 1.1. Secondary endpoints included: 1-year progression free survival (PFS), 1-year overall survival (OS), and Safety using NCI-CTCAE v5.0. Correlative studies were planned from pts tumor samples obtained at baseline and C2D1. Results: Between Nov. 2018 and Oct. 2019, 48 pts were enrolled in 4 centers. Median age was 61.8 (range: 26.3-78.7). Median follow-up was: 7.2 months. Median number of previous treatment lines was: 3 (range: 1-7). 41 (87.2%) pts experienced at least 1 dose modification or treatment interruption. The most common grade 3/4 adverse events were palmar-plantar erythro-dysesthesia syndrome (29.8%), hypertension (23.4%) and diarrhea (12.8%). No death was related to the treatment. Among 40 pts who had at least one imaging tumor assessment, 12 (30%) had reduction in tumor burden. Best response was stable disease for 23 pts (57.5%) and progressive disease for 17 pts (42.5%). The median PFS and OS were 3.6 months (CI 95% : [1.8 – 5.4]) and 10.8 months (CI 95% : [5.9 – NA]) respectively. Baseline tumor samples and paired biopsies were available for 24 and 15 pts respectively. High infiltration by TAMs at baseline was significantly associated with adverse outcome (PFS: 1.9 vs 3.7 months, p=0.045; OS: 4.8 months vs NR, p=0.027). Increased tumor infiltration by CD8+ at C2D1 compared to baseline was significantly associated with better PFS (p=0.011). Combining low TAMs infiltration and low tumor cells to CD8+ T cells distance enabled the identification of a subgroup of pts (n= 6/24, 25%) more likely to benefit from R+A combination: median PFS: 5.3 vs 1.9 months (p=0.037); median OS: NR vs 5.3 months (p=0.02). Conclusions: The R+A combination achieved PFS and OS that compared favourably with historical data of R alone in this clinical setting. High-resolution analysis of tumor samples identified a composite score based on TAMs infiltration and tumor cell to CD8+ T cells distance which could be used as a biomarker in further studies investigating this approach in mCRC pts. Clinical trial information: NCT03475953 .