First results from the RETgistry: A global consortium for the study of resistance to RET inhibition in RET-altered solid tumors.
Year: 2023
Type: conference-abstract
Abstract: 9065 Background: Rearranged during transfection ( RET) gene alterations are the oncogenic driver in diverse tumor types, including RET fusions identified in 1-2% of non-small cell lung cancers (NSCLC). While RET-selective tyrosine kinase inhibitors (TKIs) selpercatinib and pralsetinib are effective, acquired drug resistance remains a challenge. Here, we report the initial results from the RETgistry, an international consortium aimed at elucidating mechanisms of resistance to RET TKIs across RET-altered solid tumors. Methods: This was a retrospective analysis performed across 16 institutions. Patients (pts) were eligible if they had advanced solid tumor harboring an oncogenic RET alteration, received ≥1 RET TKI with disease progression, and underwent resistant tumor or liquid biopsy for next-generation sequencing (NGS). Results: A total of 103 time-distinct biopsies (62 tissue, 30 plasma, 11 paired tissue/plasma) were included in analysis, obtained from 88 pts with progression on a RET-selective TKI [selpercatinib (n = 70), pralsetinib (n = 14), selpercatinib and pralsetinib sequentially (n = 4)]. Pts had the following tumor types: 72 NSCLC (69% KIF5B-RET, 21% CCDC6-RET, 10% other RET fusion), 13 medullary thyroid cancer (TC) (54% RET M918T, 46% other RET mutation), and 2 papillary and 1 anaplastic TC (all, RET fusion). Median age was 58 (range, 21-86); 48% were male with 89% never/light smokers. Median duration of RET TKI preceding biopsies [first-line, n = 32 (31%); second-line, n = 42 (41%); third-/greater-line, n = 29 (28%)] was 16.5 months (mos) (95% CI, 14.0-19.6); median PFS was 14.1 mos (95% CI, 9.3-17.0). Resistant biopsies were obtained at median 15.0 mos from TKI initiation (range, 1.8-58.8). Acquired RET mutations were detected in 14 (14%), most common being G810 substitutions in 12 (12%). Potential off-target resistance gene alterations identified in 43 cases (42%) included MET amplification (14%), BRAF V600E or fusion (2%), KRAS gain or mutation (5%), ERBB2 amplification (2%), EGFR amplification (3%), ROS1 fusion (1%), and activating PIK3CA mutation or PTEN loss (4%). No resistant lung cancer biopsy demonstrated small cell transformation. The duration of TKI therapy (HR 0.64, p = 0.11) or PFS (HR 0.75, p = 0.33) did not differ according to the presence of on-target vs off-target resistance. NGS analyses of pre-RET-selective TKI tumors (n = 92) revealed frequent co-occurring alterations in TP53 (29%) and CDKN2A/B (12%). Conclusions: On-target resistance to RET inhibition due to acquired RET mutations was less common than off-target resistance, identified in 14%. The majority of RET TKI resistance is mediated by off-target mechanisms such as bypass receptor tyrosine kinase activation. Further studies are warranted to enable the development of therapeutic strategies to address resistance in pts with RET-altered tumors. The RETgistry accrual and data analyses continue.
Source: Journal of Clinical Oncology
Authors: Alissa Jamie Cooper, Alexander E. Drilon, Julia K. Rotow, Stephen V. Liu, Oliver Gautschi, Katherine Emilie Rhoades Smith, Dae Ho Lee, Misako Nagasaka, Herbert H. F. Loong, Nathan A. Pennell, Jyoti D. Patel, Martin Früh, Benjamin J. Solomon, Georg Pall, Natalie F. Uy, Jonathan W. Riess, Lori J. Wirth, Beow Y. Yeap, Justin F. Gainor, Jessica Jiyeong Lin
Institutions: Massachusetts General Hospital, Memorial Sloan Kettering Cancer Center, Dana-Farber Cancer Institute, Georgetown University, Georgetown University Medical Center, Georgetown Lombardi Comprehensive Cancer Center, University of Bern, Luzerner Kantonsspital, Mayo Clinic, Asan Medical Center, University of California, Irvine, Chinese University of Hong Kong, Cleveland Clinic, Northwestern University, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Kantonsspital St. Gallen, Peter MacCallum Cancer Centre, University Hospital Innsbruck, University of Washington, UC Davis Comprehensive Cancer Center, Harvard University
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4379280852