1293P - Mechanisms of resistance to selpercatinib in RET activated NSCLC and MTC from the LIBRETTO-001 trial

Background

The phase 1/2 LIBRETTO-001 trial (NCT03157128) led to approval of selpercatinib treatment (tx) for RET altered solid tumors including non-small cell lung cancer (NSCLC) and medullary thyroid cancer (MTC). Acquired resistance to selpercatinib occurs via on-target and bypass mechanisms (mechanisms of resistance; MoR). Using a subset of 115 trial patients (pts) this study expands our understanding of MoR, guiding tx strategies against potent RET inhibition.

Methods

At data cutoff (13/01/23), the Resistance Analysis (RA) cohort comprised of 115 LIBRETTO-001 pts (NSCLC; 71/122 [1L; 24%, 2L; 62%], MTC; 44/59 [1L; 11%, 2L; 80%]) who had: experienced clinical benefit, later discontinued tx due to progressive disease (PD), available plasma for ctDNA analysis at baseline and PD (Guardant360, 74 genes), and a locally confirmed RET mutation (mut).

Results

The RA cohort had similar baseline characteristics to overall and PD pts, best overall responses of 1% Complete, 74% Partial, 25% Stable Disease, and median time to PD (range 4-40) of 11 mos (NSCLC) and 21 mos (MTC). Acquired MoR were identified in 45% (52/115) of RA pts (Table). On-target MoR were more frequent in MTC (43%) vs NSCLC (13%) pts; Solvent Front (SF) G810 (NSCLC; 89%, MTC; 84%) and gatekeeper V804 (NSCLC; 11%, MTC; 42%) mut were most common. Bypass MoR occurred in 28% of NSCLC and 32% of MTC pts; MET amplification (amp) (21%) and BRAF muts (26%) were most common. Table: 1293P

Conclusions

Acquired MoR was identified in 45% of liquid biopsies in the largest prospective dataset studying MoR to RET inhibition. On-target MoR including RET SF G810 muts were more common in MTC than NSCLC. Bypass MoR (30%) included RAS/RAF activating and potentially targetable MET amps. To optimally guide post-selpercatinib tx strategies, more comprehensive testing (including tissue NGS) may be warranted to further study the 55% of pts with unknown MoR.

Clinical trial identification

NCT03157128.

Editorial acknowledgement

Legal entity responsible for the study

Eli Lilly and Company.

Funding

Eli Lilly and Company.

Disclosure

B.J. Solomon: Financial Interests, Institutional, Advisory Board: AstraZeneca, Novartis, Merck, Bristol Myers Squibb; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Personal, Advisory Board: Amgen, Roche-Genentech, Eli Lilly, Takeda, Janssen; Financial Interests, Personal, Invited Speaker: AstraZeneca, Roche/Genentech; Financial Interests, Personal, Full or part-time Employment, Employed as a consultant Medical Oncologist at Peter MacCallum Cancer Centre: Peter MacCallum Cancer Centre; Financial Interests, Personal, Member of Board of Directors: Cancer Council of Victoria, Thoracic Oncology Group of Australasia; Financial Interests, Personal, Royalties: UpToDate; Financial Interests, Institutional, Steering Committee Member, Principal Investigator and Steering committee Chair: Roche/Genentech, Pfizer; Financial Interests, Institutional, Steering Committee Member: Novartis. A.E. Drilon: Financial Interests, Personal, Advisory Board: 14ner/Elevation Oncology, AbbVie, Amgen, ArcherDX, AstraZeneca, BeiGene, BerGenBio, Blueprint Medicines, EcoR1, Exelixis, Helsinn, Hengrui Therapeutics, Ignyta/Genentech/Roche, Janssen, Liberum, Loxo/Bayer/Lilly, Melendi, Monopteros, Monte Rosa, Novartis, Pfizer, Remedica Ltd., TP Therapeutics, Takeda/Ariad/Millennium, Tyra Biosciences, Verastem Oncology; Financial Interests, Personal, Other, CME: AiCME, Clinical Care Options, MJH Life Sciences, Med Learning, Medscape, Medscape, Onclive, Paradigm Medical Communications, PeerView Institute, PeerVoice, Physicians Education Resources, Targeted Oncology, WebMD; Financial Interests, Personal, Other, Consulting: Applied Pharmaceutical Science, Inc., EPG Health, Entos, Harborside Nexus, Merus, Nuvalent, Ology, Prelude, TouchIME, Treeline Bio, mBrace; Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical, RV More, Remedica Ltd.; Financial Interests, Personal, Stocks/Shares: Treeline Biosciences; Financial Interests, Personal, Royalties: Wolters Kluwer; Financial Interests, Personal, Other, stocks: mBrace; Financial Interests, Institutional, Funding, Research funding: Pfizer, Exelixis, PharmaMar, GSK, Teva, Taiho; Financial Interests, Personal, Funding, Research: Foundation Medicine; Non-Financial Interests, Member: ASCO, AACR, IASLC; Other, Food/Beverage: Merck, PUMA, Merus; Other: Boehringer Ingelheim. L.J. Wirth: Financial Interests, Personal, Advisory Board: Bayer, Coherus, Eli Lilly, Eisai, Exelixis; Financial Interests, Personal, Other, Consultant: Curie Therapeutics, Morphic Therapeutics, Tome Biosciences; Financial Interests, Personal, Other, DMSC: PDS Biotherapeutics; Financial Interests, Institutional, Steering Committee Member: Novartis, Eli Lilly. A. Szpurka, J. Wright: Financial Interests, Personal, Full or part-time Employment: Eli Lilly and Company; Other, Institutional, Stocks/Shares: Eli Lilly and Company. X. Rao, A.C. Massey, S. Barker: Financial Interests, Personal, Full or part-time Employment: Eli Lilly and Company. H. Won: Other, Institutional, Stocks/Shares: Eli Lilly and Company. M.E. Cabanillas: Financial Interests, Personal, Advisory Board, clinical trial planning: Thryv; Financial Interests, Personal, Advisory Board, advising on patient education materials: Novartis; Financial Interests, Personal, Advisory Board: Exelixis, Bayer; Financial Interests, Personal, Invited Speaker: Endocrine Society; Financial Interests, Institutional, Local PI, Grant funding for clinical trial: Genentech; Financial Interests, Institutional, Local PI, Grant funding for clinical trials: Merck; Non-Financial Interests, Member of Board of Directors: American Thyroid Association.