Abstract 543P
Background
Neurotrophic receptor tropomyosin kinase (NTRK) gene fusions are therapeutically actionable oncogenic drivers. In an integrated analysis of global multicentre trials, entrectinib (a CNS active, potent inhibitor of TRKA/B/C) achieved clinically meaningful responses in pts with NTRK fusion-positive (NTRK-fp) solid tumours. We present updated data focusing on NTRK-fp NSCLC pts.
Methods
Pts with locally advanced/metastatic NTRK-fp tumours (with/without baseline CNS metastases) confirmed by nucleic acid-based methods, enrolled in global phase I/II clinical trials (ALKA-372-001, STARTRK-1, STARTRK-2; EudraCT 2012-000148-88, NCT02097810, NCT02568267) were included. Response was assessed by blinded independent central review (BICR), RECIST v1.1 after 4 wks then every 8 wks. Primary endpoints were objective response rate (ORR) and duration of response (DoR). Progression-free survival (PFS), overall survival (OS), and safety were also assessed (data cut-off: 31 October 2018).
Results
The efficacy-evaluable population included 74 pts with 12 tumour types (>25 histopathologies); ORR was 64% (95% CI 51.5–74.4). Thirteen pts had NTRK-fp NSCLC (NTRK1, n=8; NTRK2, n=1; NTRK3, n=4). Median age 60y (range 46–77); 9 pts (69%) had adenocarcinoma; 8 pts (62%) were current/former smokers; 9 pts (69%) had CNS metastases at baseline; 5 pts (38%) received ≥2 prior systemic therapies. Entrectinib was active in NSCLC pts with and without baseline CNS metastases (Table). In the safety population (n=504 pts who received ≥1 entrectinib dose), 65% of treatment-related AEs (TRAEs) were grade 1–2; 29% were grade 3; 3% were grade 4; there were two grade 5 TRAEs (one sudden death, one cardiac arrest). TRAEs led to dose interruption in 27% of pts, dose reduction in 25% and discontinuations in 5%.
Conclusions
In this updated analysis with longer follow-up, entrectinib was highly active, achieving durable responses in pts with NTRK-fp NSCLC, including pts with baseline CNS metastases. Table: 543P
| Endpoint | All pts with NTRK-fp NSCLC (N=13) | Pts with NTRK-fp NSCLC with baseline CNS metastases* (n=9) | Pts with NTRK-fp NSCLC without baseline CNS metastases* (n=4) |
| ORR, % (95% CI) | 69 (38.6–90.9) | 67 (29.9–92.5) | 75 (19.4–99.4) |
| Complete response, n (%) | 1 (8) | 0 | 1 (25) |
| Partial response, n (%) | 8 (62) | 6 (67) | 2 (50) |
| Stable disease, n (%) | 2 (15) | 2 (22) | 0 |
| Progressive disease, n (%) | 0 | 0 | 0 |
| Missing/unevaluable, n (%) | 2 (15) | 1 (13) | 1 (25) |
| Median DoR, months (95% CI) | NE (5.6–NE)† | NE (3.6–NE)‡ | NE (10.4–NE)§ |
| Median OS, months (95% CI) | 14.9 (5.9–NE) | 8.9 (5.6–NE) | NE (14.9–NE) |
| Median PFS, months (95% CI) | 14.9 (4.7–NE) | 6.5 (4.5–NE) | NE (14.9–NE) |
∗Baseline CNS metastases assessed by investigator; †n=9; ‡n=6; §n=3.
Clinical trial identification
ALKA-372-001 (EudraCT 2012-000148-88); STARTRK-1 (NCT02097810); STARTRK-2 (NCT02568267).
Editorial acknowledgement
Third-party medical writing assistance, under the direction of the authors, was provided by Lewis Cawkwell, PhD, of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd.
Legal entity responsible for the study
F. Hoffmann-La Roche Ltd.
Funding
F. Hoffmann-La Roche Ltd.
Disclosure
A. Drilon: Honoraria (institution): Ignyta/Roche/Genentech, Loxo/Bayer/Lily, TP Therapeutics, AstraZeneca, Pfizer, Blueprint, Takeda/Ariad/Millennium, Helsinn, BeiGene, BerGenBio, Hengrui, Exelixis, Tyra, Verastem, MORE Health, AbbVie, 14ner/Elevation Oncology, Axis, Peerview Institute; Research grant/Funding (self): Foundation Medicine; Research grant/Funding (institution): Pfizer, Exelixis, Taiho, Teva, GlaxoSmithKline and Pharmamar; Licensing/Royalties: Wolters Kluwer; Honoraria (institution): OncLive, Paradigm Medical Communications, Remedica Ltd, ArcherDX, Foundation Medicine, PeerVoice, Research to Practice, Medscapem, WebMD. L. Paz-Ares: Advisory/Consultancy: Genentech/Roche, Loxo Oncology, Bayer, Eli Lilly, AstraZeneca, Pfizer, Bayer, Merck Sharp & Dohme, Novartis, Amgen, Pharmamar, Boehringer Ingelheim, Celgene, Servier, Sysmex, Incyte, Ipsen, Adacap, Sanofi, and Blueprint Medicines; Research grant/Funding (institution): BMS, AstraZeneca, and Merck Sharp & Dohme; Shareholder/Stockholder/Stock options: Altum sequencing; Officer/Board of Directors: Genómica, Altum sequencing. R.C. Doebele: Advisory/Consultancy: Ignyta, Genentech/Roche, Loxo Oncology, Bayer, Eli Lilly, AstraZeneca, Pfizer, Blueprint Medicines, Anchiano, and Rain Therapeutics; Research grant/Funding (institution): Ignyta, Loxo, Mirati, Pfizer, Eli Lilly, and Strategia; Travel/Accommodation/Expenses: Ignyta, Genentech/Roche, Eli Lilly, Pfizer, Blueprint Medicines, and Rain Therapeutics; Shareholder/Stockholder/Stock options: Rain Therapeutics; Licensing/Royalties, Patent and biologic material licensing fees: Ignyta, Loxo, Abbott Molecular, Genentech/Roche, Chugai, Foundation Medicine, Black Diamond, and Rain Therapeutics, Voronoi, Pearl River, Ariad. A.F. Farago: Honoraria (self): DAVA Oncology, Clinical Care Options, Medical Learning Institute, Medscape, PeerView, Research to Practice; Advisory/Consultancy: Bayer, Loxo Oncology, Inc., Genentech, Roche, Bristol-Myers Squibb, AstraZeneca, AbbVie, PharmaMar, Boehringer Ingelheim, Merck, H3 Biomedicine, Pfizer, Syros; Research grant/Funding (self): Bayer, Loxo Oncology, Inc., Genentech, Roche, Bristol-Myers Squibb, AstraZeneca, AbbVie, PharmaMar, Merck, Ignyta, Amgen, Novartis. S.V. Liu: Advisory/Consultancy: AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Catalyst, Celgene, G1 Therapeutics, Genentech/Roche, Guardant Health, Inivata, Janssen, Lilly, LOXO, MSD, Pfizer, PharmaMar, Regeneron, Takeda; Research grant/Funding (institution): Alkermes, AstraZeneca, Bayer, Blueprint, Bristol-Myers Squibb, Corvus, Genentech, Lilly, Lycera, Merck, Merus, Molecular Partners, Pfizer, Rain, RAPT, Spectrum, Turning Point Therapeutics; Travel/Accommodation/Expenses: AstraZeneca, Genentech/Roche, MSD. S.P. Chawla: Research grant/Funding (self): Advenchen Laboratories, Amgen, Bayer, Bristol-Myers-Squibb, Elevar Therapeutics, Five Prime Therapeutics, GlaxoSmithKline, Janssen Pharmaceutica, Karyopharm Therapeutics, NK Max America, Philogen, Roche, SpringWorks Therapeutics, Tyme Inc., US Biotest; Shareholder/Stockholder/Stock options: AADi Bioscience, Cellestia, Immix Biopharma. D. Tosi: Research grant/Funding (self): Ipsen, Janssen and Astellas; Travel/Accommodation/Expenses: Sanofi, Pfizer, Janssen, and Astellas; Licensing/Royalties, I have a pending patent on a new drug: Not specified; Spouse/Financial dependant, remunerated advisor: Biomarin, Actelion, travel/accommodation/expenses: Nutricia, Biomarin, Amicus: Biomarin, Actelion and Nutricia, Biomarin and Amicus. C.M. Blakely: Honoraria (self): Revolution Medicines, Amgen, Foundation Medicine; Research grant/Funding (self): Ignyta/Roche, Novartis, AstraZeneca, Mirati, Spectrum, and MedImmune, Takeda. J.C. Krauss: Research grant/Funding (institution): Boston Biomedical, AbbVie, Amgen, Isofol, AstraZeneca. L. Bazhenova: Advisory/Consultancy: Genentech, BeyondSpring pharma, AstraZenca, BI, Takeda, Blueprint, Novartis; Research grant/Funding (self): BeyondSpring pharma; Shareholder/Stockholder/Stock options: Epic Sciences. T. John: Honoraria (self): AZ, Roche, Merck, MSD; Advisory/Consultancy, Serves on advisory boards: BMS, AstraZeneca, Boehringer Ingelheim, Takeda, Pfizer, Novartis, Merck, Ignyta, and Roche. B. Besse: Research grant/Funding (institution): AbbVie, Amgen, AstraZeneca, BeiGene, Blueprint Medicines, BMS, Boehringer Ingelheim, Celgene, Cristal Therapeutics, Daiichi-Sankyo, Eli Lilly, GSK, Ignyta, Ipsen, Inivata, Janssen, Merck KGaA, MSD, Nektar, Onxeo, OSEimmunotherapeutics, Pfizer; Research grant/Funding (institution): Pharma Mar, Roche-Genentech, Sanofi, Servier, Spectrum Pharmaceuticals, Takeda, Tiziana Pharma, Tolero Pharmaceuticals. J. Wolf: Advisory/Consultancy, Advisory / consultancy and lecture fees : Amgen, AstraZeneca, Bayer, Blueprint, BMS, Boehringer-Ingelheim, Chugai, Daiichi Sankyo, Ignyta, Janssen, Lilly, Loxo, MSD, Novartis, Pfizer, Roche, Seattle Genetics, Takeda; Research grant/Funding (institution): BMS, Janssen Pharmaceutica, Novartis, Pfizer. T. Seto: Honoraria (self): Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, Kyowa Hakko Kirin, MSD, Nippon Boehringer Ingelheim, Novartis Pharma, Ono Pharmaceutical, Pfizer Japan, Taiho Pharmaceutical, Takeda Pharmaceutical; Research grant/Funding (institution): AbbVie, AstraZeneca, Bayer Yakuhin, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, Kissei Pharmaceutical, LOXO Oncology, Merck Serono, MSD, Nippon Boehringer Ingelheim, Novartis Pharma, Pfizer Japan, Takeda Pharmaceutical; Full/Part-time employment: Precision Medicine Asia; Honoraria (self): Thermo Fisher Scientific. B.C. Cho: Advisory/Consultancy: Novartis, AstraZeneca, Boehringer-Ingelheim, Roche, BMS, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, MSD, Medpacto, Blueprint med-icines, KANAPH Therapeutic Inc; Research grant/Funding (institution): Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD, AbbVie, Medpacto, GI-Innovation, Eli Lilly, Blueprint medicines; Shareholder/Stockholder/Stock options: TheraCanVac Inc, Gencurix Inc, Bridgebio thera-peutics, KANAPH Therapeutic Inc; Licensing/Royalties: Champions Oncology; Officer/Board of Directors: Daan biotherapeutics. C. Rolfo: Advisory/Consultancy: Mylan, Oncompass, Archer, Inivata and MD Serono; Speaker Bureau/Expert testimony: Merck Sharp and Dohme, AstraZeneca; Leadership role: IASLC Educational Committee Member and LATAM (IASLC) co-chair, ESO Scientific Committee Board, ISLB VIcepresident and Educational Chair, Educational Chair OLA; Research grant/Funding (self): Biomarkers and Guardant Health (Research collaboration) Lung Cancer Research Foundation-Pfizer Grant; Research grant/Funding (institution): American Cancer Society grant, PY30 NIH grant. S. Osborne: Full/Part-time employment: Roche. A. Aziez: Full/Part-time employment: Roche. G.D. Demetri: Advisory/Consultancy: Roche, Ignyta, Genentech, Bayer, EMD-Serono, Loxo Oncology, Daiichi-Sankyo, WCG/Arsenal Capital, Blueprint Medicines, Merrimack Pharmaceuticals, PharmaMar, Pfizer, Novartis, Epizyme, AbbVie, GlaxoSmithKline, Janssen, Mirati, Sanofi, ICON PLC, Ziopharm,; Research grant/Funding (institution): Roche, Ignyta, Bayer, Loxo Oncology, Daiichi-Sankyo, Janssen, Pfizer, Novartis, Epizyme, AbbVie; Travel/Accommodation/Expenses: Epizyme, Roche; Shareholder/Stockholder/Stock options: Blueprint Medicines, G1 Therapeutics, CARIS Life Sciences, Bessor Pharmaceuticals, ERASCA Pharmaceuticals, CHAMPIONS Oncology, Translate BIO, RELAY Therapeutics, Caprion HistoGeneX; Licensing/Royalties: Novartisto Dana-Farber Cancer Institute; Officer/Board of Directors, Board of Directors Member: Blueprint Medicines, Translate BIO; Non-remunerated activity/ies: Alexandria Real Estate Equities; Advisory/Consultancy: Polaris Pharmaceuticals, Medscape, Relay Therapeutics, Caprion/HistoGeneX, McCann Health.