Landscape of Genomic Mechanisms of Resistance to Selective RET Inhibitors in RET -Altered Solid Tumors: Analysis of the RETgistry Global Consortium

Abstract Purpose: Rearranged during transfection (RET) alterations are oncogenic drivers across solid tumors. Selective RET inhibitors (SRIs) selpercatinib and pralsetinib have transformed outcomes for patients with RET-altered malignancies. Limited knowledge exists on genomic mechanisms of resistance to SRIs. Experimental Design: We established 'RETgistry,' a global consortium of patients with advanced RET-altered solid tumors who received SRIs and underwent post-progression tissue or plasma biopsies assessed by next-generation sequencing. Frequencies of secondary RET resistance mutations and acquired non-RET gene alterations were determined. Progression-free survival (PFS) and time to treatment discontinuation (TTD) on first SRI were estimated with Kaplan-Meier method. Results: RETgistry included 109 patients with RET-altered advanced solid tumors (lung: n=94; thyroid: n=15) who underwent 143 post-SRI progression biopsies (tissue: 91; plasma: 52). Median PFS and TTD were 13.9 months (95% confidence interval CI 10.1-16.6) and 17.3 months (95% CI 14.0-20.2), respectively. Secondary RET mutations were detected in 20 (14.0%) biopsies (lung cancer: 15 12.4%, thyroid carcinoma: 5 22.7%). Common acquired off-target alterations involved MET (18.2%; amplification: 15.0%), TP53 (8.2%), APC (7.6%), KRAS (7.1%), KEAP1 (5.9%), and CDKN2A/B (5.3%). MET alterations were enriched in post-SRI versus pre-SRI specimens (full cohort: 17.6% vs 2.0%, p=0.022; lung cancer: 19.1% vs 2.1%, p=0.022). Conclusions: Prevalence of secondary RET mutations after SRIs was low, underscoring greater role for off-target resistance. Recurrent acquired alterations involving tumor suppressor genes or upstream regulators of MAPK and PI3K pathways were identified, most commonly MET amplification. Continued efforts to characterize SRI resistance biology are critical to guide development of novel therapeutic strategies.