RET-MAP: An international multi-center study on clinicobiologic features and treatment response in patients with lung cancer harboring a RET fusion

Introduction: Nearly 1-2% of non-small cell lung cancers (NSCLC) harbor RET fusions. Characterization of this rare population is still incomplete. Methods: This retrospective multi-center study included patients with any-stage RET+ NSCLC from 31 cancer centers. Molecular profiling included DNA/RNA sequencing and/or FISH analyses. Clinico-biological features and treatment outcomes (per investigator) with surgery, chemotherapy, immune-checkpoint blockers (ICB), chemotherapy-ICB, multi-tyrosine kinase inhibitors (MTKi) and RET inhibitors (RETi) were evaluated. Results: For 218 patients included between February 2012 and April 2022, median age was 63 years, 56% were females, 93% had adenocarcinoma, and 41% were smokers. The most frequent fusion partner was KIF5B (72%). Median tumor mutational burden (TMB) was 2.5 [range, 1-4] mut/Mb and median PD-L1 expression was 10% [range, 0-55]. The most common metastatic sites were lung (50%), bone (43%) and pleura (40%). Central nervous system metastases were found at diagnosis of advanced NSCLC in 21% of patients and at last follow-up or death in 31%. Overall response rate and median progression-free survival were 55% and 8.7 months with platinum doublet, 26% and 3.6 months with single-agent chemotherapy, 46% and 9.6 months with chemotherapy-ICB, 23% and 3.1 months with ICB, 37% and 3 months with MTKi, and 76% and 16.2 months with RETi, respectively. Median overall survival was longer in patients treated with RETi versus no RETi (50.6 months [37.7-72.1] versus 16.3 months [12.7-28.8], P<0.0001). Conclusions: Patients with RET+ NSCLC have mainly thoracic and bone disease, and low TMB and PD-L1 expression. RETi significantly improve survival, while ICB may be active in selected patients.