Abstract B145: Clinical features of progression and outcomes with subsequent therapies in patients treated with RET-inhibitors
Authors: Marinello Arianna , Zrafi Wael Salem , Massa Giacomo , Tabbò Fabrizio , Citarella Fabrizio , Dall'Olio Filippo Gustavo , Colin Lindsay , Bria Emilio , Metro Giulio , Minatta Josè Nicolas , Calles Antonio , Monnet Isabelle , Tagliamento Marco , Basile Hortense Gaultier De Saint , Girard Nicolas , Pagliaro Arianna , Cortinovis Diego Luigi , Raimbourg Judith , Zanchetta Carol , Mountzios Giannis , Nana Frank Aboubakar , Terrisse Safae , Russo Alessandro , Iranzo Patricia , Audigier-Valette Clarisse , Rochigneux Philippe , Fallet Vincent , Duruisseaux Michael , Cousin Sophie , Guisier Florian , Mezquita Laura , Remon Jordi , Gazzah Anas , Planchard David , Besse Benjamin , Aldea Mihaela 
Published: December 2023

Abstract
Background: RET fusions can be found in 1-2% of patients (pts) with advanced non-small cell lung cancer (aNSCLC). While targeted treatment with RET inhibitors (RETi) has significantly improved prognosis, resistance eventually develops. Current knowledge regarding the pattern of disease progression and the optimal therapeutic sequence for patients treated with RETi is limited.
Methods: We conducted a retrospective multicentric collection of clinical and biological data on pts with RET-rearranged (RET+) aNSCLC treated with first-generation RETi. Patients with a progression-free survival (PFS) period of less than 8 months on RETi were classified as poor responders. We investigated the clinical patterns of disease progression (PD) and outcomes with subsequent therapies, evaluated by the overall response rate (ORR by investigator assessment) and PFS. PFS2 was calculated from RETi start to PD after subsequent line.
Results: 173 pts from 32 centres were identified. Median age was 65, 61% were female, 41% were smokers, 81% had an ECOG performance status &lt;2, 95% had adenocarcinoma, 18% had brain metastasis, 76% had RETi in first or second line. The administered RETi were selpercatinib in 55%, pralsertinib in 42%, other first generation RETi in 3% of pts. After a median follow up of 30.4 months (mo) (95%CI 26-32.1), 84 pts (48.6%) had PD after RETi, with a median PFS (mPFS) of 15.6 mo (95%CI 12.2-23.3) and an ORR of 72.2%. Radiological PD patterns included multisite PD in 46 (71%), oligoPD in 15 (23%), mixed response in 4 (6%). 7/15(47%) received local treatment while continuing RETi. Subsequent treatment line after RETi was administered in 37 pts (21%). Considering chemotherapy-based treatments, ORR and mPFS were 46% and 5.52 mo (4.07-11.3) overall, 57% and 4.53 mo (95%CI 1.4-NA) in 9 pts with chemo-immunotherapy, 27% and 5.88 mo (95%CI 2.1-NA) in 11 pts with platinum-doublet, 83% and 10.4 mo (8.28-NR) in 6 pts with bevacizumab plus chemotherapy (p=0.77 vs chemotherapy alone). Targeted therapy was administered in 8 patients: 6 received RETi after RETi (first generation) with 33% ORR and 3.83 mo (1.77-NR) mPFS, one patient had crizotinib plus RETi to target MET amplification found at resistance, with a PFS of 5.95 mo, one had alectinib alone, targeting SQSTM1-ALK fusion found at resistance, with PD after 1.58 mo. Cabozantinib was chosen for one pt, with a PFS of 5.52 mo and obtaining PR; one pt was treated with single-agent immunotherapy, with rapid PD after 1 month; one pt had an investigational antibody-drug conjugate, experiencing SD and a 4 mo PFS. PFS to subsequent treatment was not different between long and poor responders to RETi (13 and 15 pts,5.88 vs 4.53 m, respectively, p=0.75); PFS2 was longer in good responders to RETi (25 vs 16 mo,p=0.012).
Conclusions: Disease progression to RETi most frequently involved multiple sites. Chemotherapy plus bevacizumab seemed to perform better than chemotherapy alone or chemo-immunotherapy. The benefit of tailored treatment basing on the molecular profile at PD needs to be further explored.
Citation Format: Arianna Marinello, Wael Salem Zrafi, Giacomo Massa, Fabrizio Tabbò, Fabrizio Citarella, Filippo Gustavo Dall'Olio, Lindsay Colin, Emilio Bria, Giulio Metro, Josè Nicolas Minatta, Antonio Calles, Isabelle Monnet, Marco Tagliamento, Hortense Gaultier De Saint Basile, Nicolas Girard, Arianna Pagliaro, Diego Luigi Cortinovis, Judith Raimbourg, Carol Zanchetta, Giannis Mountzios, Frank Aboubakar Nana, Safae Terrisse, Alessandro Russo, Patricia Iranzo, Clarisse Audigier-Valette, Philippe Rochigneux, Vincent Fallet, Michael Duruisseaux, Sophie Cousin, Florian Guisier, Laura Mezquita, Jordi Remon, Anas Gazzah, David Planchard, Benjamin Besse, Mihaela Aldea. Clinical features of progression and outcomes with subsequent therapies in patients treated with RET-inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B145.