1385P - Genomics of early progression on selpercatinib in patients with RET fusion-positive lung cancers

Background

Selective RET inhibitors transformed the treatment (tx) paradigm of RET fusion-positive (RET+) lung cancers. For selpercatinib, the median progression free survival (PFS) is 22.0 months (mos) for tx naive patients and 24.9 mos for platinum doublet pretreated patients. Genomic factors associated with early versus late progression are unknown.

Methods

We analyzed data from 80 patients with RET+ LC identified between January 2014 and March 2023 utilizing a DNA-based hybrid capture tumor next generation tumor sequencing assay (MSK-IMPACT) and plasma ctDNA assay (MSK-ACCESS). Patients with radiologic progression (PD) on selpercatinib ≤ 3 mos from initiation were classified as “rapid progressors”, >3- 24 mos as “intermediate progressors”, and ≥24 months as“late progressors.” Baseline and post-PD MSK-IMPACT and MSK-ACCESS specimens were evaluated. Patients with post-PD biopsies were evaluated for acquired resistance (AR) (classified as on-target (secondary RET mutations), off-target (non-RET OncoKB level 1-4), and unknown).

Results

Among 80 patients with RET+ LC, 63 had pre-tx tumor sequencing and 35 patients had post-tx tumor/ctDNA sequencing. 58% (n=46/80) progressed on selpercatinib. PD was classified as rapid, intermediate, and late in 9% (n=7), 35% (n=28), 14% (n=11), respectively. Acquired resistance (AR) was identified in 48% of cases. Six patients had on-target AR and 17 patients had off-target AR. Most common off-target AR included MET amp (9%), KRAS mutation (6%), PIK3CA mutation (6%), CDKN2A mutation (6%), and FGFR1 amp (6%). There were no differences in age, gender, ethnicity, prior tx, or PDL1 status between these groups. Pre-tx TP53, KEAP1, and ARID1A mutations were more common in rapid and intermediate versus late PD (p=0.03, p=0.02, p=0.06). Off-target mechanisms of resistance appeared to be enriched in rapid and early progressors vs late progressors (75% vs 51% vs 25%, p=0.3).

Conclusions

RET fusion+ NSCLCs that progressed on selpercatinib prior to two years, an approximation of the drug’s median PFS, were enriched for select co-occurring alterations (e.g., TP53, KEAP1, and ARID1A mutations) in pre-tx samples and off-target resistance in post-PD samples.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

R01 CA251591.

Disclosure

E. Rosen: Financial Interests, Personal, Research Funding: Bayer. S.R. Yang: Financial Interests, Personal, Other, Honoraria: Prime Education; Financial Interests, Personal, Advisory Role: InVitae. M.G. Kris: Financial Interests, Personal, Research Grant: Boehringer Ingelheim, National Lung Cancer Partnership, Pfizer, Puma, Stand up to cancer; Financial Interests, Personal, Speaker, Consultant, Advisor: Ariad, AstraZeneca, Bind Biosciences, Boehringer Ingelheim, Chugai Pharma, Clovis, Covidien, Daiichi Sankyo, Genentech, Novartis, Millenium, Pfizer, Roche. A. Drilon: Financial Interests, Personal, Advisory Board: Ignyta/Genentech/Roche, Loxo/Bayer/Lilly, Takeda/Ariad/Millennium, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Helsinn, BeiGene, BerGenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem Oncology, More Health, AbbVie, 14ner/Elevation Oncology, Remedica Ltd., ArcherDX, Monopteros, Novartis, EMD Serono, Melendi, Liberum, Repare RX, Amgen, Janssen, EcoR1, Monte Rosa; Financial Interests, Personal, Other, CME: Medscape, Onclive, PeerVoice, Physicians Education Resources, Targeted Oncology, Research to Practice, PeerView Institute, Paradigm Medical Communications, WebMD, MJH Life Sciences, Med Learning, Imedex, Answers in CME, Medscape, Clinical Care Options, AiCME; Financial Interests, Personal, Other, CME, Consulting: Axis; Financial Interests, Personal, Other, Consulting: Nuvalent, Merus, EPG Health, mBrace, Harborside Nexus, Ology, TouchIME, Entos, Treeline Bio, Prelude, Applied Pharmaceutical Science, Inc; Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical, Remedica Ltd, RV More; 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. All other authors have declared no conflicts of interest.