Landscape of Genomic Mechanisms of Resistance to Selective RET Inhibitors in RET-Altered Solid Tumors: Analysis of the RETgistry Global Consortium.
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Waliany Sarah, Cooper Alissa J, Liu Stephen V, Gautschi Oliver, Rotow Julia K, Smith Katherine Emilie Rhoades, Weber Urs M, Lee Dae Ho, Loong Herbert H F, Patel Jyoti D, Pennell Nathan A, Nagasaka Misako, Patel Shetal A, Tan Daniel S W, Solomon Benjamin J, Kim Tae Min, Pall Georg, Riess Jonathan W, Sun Lova, Früh Martin, Uy Natalie F, Gadgeel Shirish, Feng Jamie, Do Andrew, Falcon Christina, Leighl Natasha B, Baik Christina S, Lai Gillianne G Y, Ou S Ignatius, Cheung Kingsley S Y, Patil Tejas, Mansfield Aaron S, Weiler Daniela, Yeap Beow Y, Wirth Lori J, Gainor Justin F, Drilon Alexander, Lin Jessica J
Аннотация
EXPERIMENTAL DESIGN: We established "RETgistry," a global consortium of patients with advanced RET-altered solid tumors who received SRI and underwent postprogression 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 the 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). The median PFS and TTD were 13.9 months [95% confidence interval (CI), 10.1-16.6] and 17.3 months (95% CI, 14-20.2), respectively. Secondary RET mutations were detected in 20 (14%) biopsies [lung cancer, 15 (12.4%) and thyroid carcinoma, 5 (22.7%)]. Common acquired off-target alterations involved MET (18.2%; amplification, 15%), 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: The prevalence of secondary RET mutations after SRI was low, underscoring a 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 the development of novel therapeutic strategies.