Entrectinib is a small molecule inhibitor of ROS1 and TRKA,B,C, with deep and durable responses observed in ROS1 fusion-positive NSCLC (ROS1+) and NTRK1,2,3 fusion-positive solid tumours (NTRK+). Despite clinically meaningful activity, progression on entrectinib eventually occurs. Understanding the mechanisms of resistance could inform subsequent new personalised therapeutic options in these patients.
Blood samples were collected at baseline and at the time of progression from most patients in the NTRK+ and ROS1+ patient populations enrolled on STARTRK-2 (NCT02568267). These were tested using the Foundation Medicine FoundationOne Liquid NGS-based test that assesses base substitutions, indels and rearrangements from 324 genes (including ROS1 and NTRK1,2,3), as well as copy number alterations from select genes using circulating tumour DNA (ctDNA) extracted from the plasma of patients from pre-treatment and following progression on entrectinib.
Of the 54 patients with NTRK+ tumours, 29 had paired samples at baseline and at progression at the time of data cut-off. Ten patients (34%) had a detectable NTRK solvent front mutation at disease progression (NTRK1: n = 5; NTRK3: n = 5), which were not detected in the pre-treatment sample. BRAF V600E and KRAS G12D mutations were detected at progression from a pancreatic cancer patient who had a partial response. Of the 53 patients with ROS1+ NSCLC, 18 had paired samples at baseline and at progression at the time of data cut-off. Four CD74-ROS1 and one SLC34A2-ROS1 patients showed the emergence of an acquired ROS1 resistance mutation (G2032R and F2004C/I) at disease progression (28%), which were not present before treatment. One NRAS Q61K mutation was detected at the end of treatment collection sample from a patient who had a partial response.
From blood analysis, acquired resistance mutations were detected in 34% of NTRK+ solid tumour and 28% of the ROS1+ NSCLC cohorts, all of which were mutations in the kinase domain of the oncogenic driver. One additional patient from each cohort showed the emergence of a mutation in an oncogene within the MAPK pathway. Resistance to entrectinib can occur by multiple mechanisms, which should be studied in larger cohorts.
Clinical trial identification
Legal entity responsible for the study
F. Hoffman-La Roche.
F. Hoffman-La Roche.
R.C. Doebele: Shareholder / Stockholder / Stock options: Rain Therapeutics; Advisory / Consultancy: Chair of Scientific Advisory Board for Rain Therapeutics; Honoraria (self): Guardant; Advisory / Consultancy: Pfizer, Trovagene, Ariad, Takeda, AstraZeneca, Genentech/Roche, Ignyta, Loxo, Rain.; Research grant / Funding (self), Research grant / Funding (institution): Ignyta, Loxo, Mirati.; Licensing / Royalties: Abbott Molecular, Rain Therapeutics, GVKbio, Chugai, Loxo, Ignyta, Genentech, Ariad, Foundation Medicine, Black Diamond.. R. Dziadziuszko: Advisory / Consultancy: Roche, Bristol-Myers Squibb, Merck, AstraZeneca, Pfizer, Novartis; Research grant / Funding (institution): Roche, Bristol-Myers Squibb, Merck, AstraZeneca, Pfizer, Novartis, Boehringer Ingelheim, Clovis; Travel / Accommodation / Expenses: Travels: Roche, AstraZeneca. A. Drilon: Honoraria (self), Advisory / Consultancy: Ignyta/Genentech/Roche, Loxo/Bayer/Lilly, Takeda/Ariad/Millenium, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Helsinn, Beigene, BergenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem, MORE Health; Research grant / Funding (institution): Pfizer, Exelixis, GlaxoSmithKlein, Teva, Taiho, PharmaMar; Research grant / Funding (self): Foundation Medicine; Travel / Accommodation / Expenses: Merck - Food/Beverage, Puma - Food/Beverage; Honoraria (self): Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, Research to Practice. A. Shaw : Honoraria (self), Advisory / Consultancy: ARIAD, Bayer, Blueprint Medicines, Chugai, Daiichi Sankyo, EMD Serono, Foundation Medicine, Genentech/Roche, Guardant, Ignyta, KSQ Therapeutics, Natera, Novartis, Pfizer, Taiho Pharmaceutical, Takeda, and TP Therapeutics; Research grant / Funding (institution): Daiichi Sankyo, Ignyta, Novartis, Pfizer, Roche/Genentech, and TP Therapeutics. J. Wolf: Advisory / Consultancy, Officer / Board of Directors: AbbVie, AstraZeneca, Blueprint, BMS, Boehringer Ingelheim, Chugai, Ignyta, Janssen, Lilly, Loxo, MSD, Novartis, Pfizer, Roche, Takeda; Research grant / Funding (institution): BMS, Jannsen, MSD, Novartis, Pfizer. A.F. Farago: Research grant / Funding (institution): AstraZeneca, AbbVie, Genentech, BMS, Merck, PharmaMar, Amgen, Bayer, Loxo, Ignyta; Advisory / Consultancy: Genentech, Bayer, AbbVie, AstraZeneca, Boehringer Ingelheim, Loxo, PharmaMar. L. Dennis: Research grant / Funding (institution), Full / Part-time employment: Foundation Medicine. T. Riehl: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche. B. Simmons: Full / Part-time employment: Roche. C. Wu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche. C. Chang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genentech. V. Choeurng: Full / Part-time employment: Genentech, Inc. T.R. Wilson: Shareholder / Stockholder / Stock options: Roche; Full / Part-time employment: Genentech.