NTRK gene fusions are clinically actionable oncogenic drivers in solid tumours. CNS metastases are diagnosed in 10–30% of solid tumours and associated with poor outcome. Entrectinib is a CNS-active TRK inhibitor that crosses the blood-brain barrier and has demonstrated systemic and intracranial (IC) efficacy in patients (pts) with NTRK fusion-positive (fp) solid tumours in three phase 1/2 clinical trials (ALKA-372-001 [EudraCT 2012-000148-88]; STARTRK-1 [NCT02097810]; STARTRK-2 [NCT02568267]). We report an updated integrated analysis of these entrectinib studies, focussing on IC activity (data cut-off: 31 Oct 2018).
Pts with NTRK-fp solid tumours and baseline CNS metastases (asymptomatic or pretreated and controlled; measurable or non-measurable) were included. IC tumour assessments, performed at the end of week 4 and every 8 weeks thereafter, were evaluated by blinded independent central review (BICR) using RECIST v1.1. Study endpoints were IC objective response rate (IC ORR), IC duration of response (IC DoR) and IC progression-free survival (IC PFS). Safety was evaluated in the integrated safety population, all pts who received ≥1 dose entrectinib (N=504).
Full analysis set (FAS) comprised 16 pts with baseline CNS metastases per BICR (measurable or non-measurable), with 5 tumour types (8 NSCLC; 4 thyroid; 2 sarcoma; 1 salivary; 1 breast). Of these 16 pts, 8 had measurable CNS metastases (measurable set) and were evaluable for response. IC outcomes for FAS and measurable set are summarised (Table). IC ORRs were high in the FAS (50.0%) and measurable set (62.5%). IC efficacy was evident regardless of prior brain radiotherapy. In the safety population, neurotoxicity profile was similar in pts with (n=176) and without (n=328) baseline CNS metastases (per investigator), including cognitive disorders (6.3% and 6.4% respectively).
Entrectinib shows durable IC activity in pts with NTRK-fp solid tumours and baseline CNS metastases. Table: 364O
|Intracranial outcomes||Pts with NTRK-fp solid tumours and baseline CNS metastases per BICR|
|Measurable set (n=8)||Full analysis set* (n=16)|
|IC ORR, n (%)||5 (62.5)||8 (50.0)|
|CR||1 (12.5)||4 (25.0)|
|PR||4 (50.0)||4 (25.0)|
|SD, n (%)||1 (12.5)||1 (6.3)|
|PD, n (%)||1 (12.5)||1 (6.3)|
|Non-CR/non-PD, n (%)||0||5 (31.3)|
|Missing/unevaluable, n (%)||1 (12.5)||1 (6.3)|
|Median IC DoR in responders (95% CI)||NE (5.0–NE)||8.0 (6.7–NE)|
|Median IC PFS (95% CI)||10.1 (2.8–NE)†||8.9 (5.9–14.3)‡|
IC, intracranial; NE, not estimable.*As per RECIST v1.1 non-measurable CNS disease could only be categorised as CR, non-CR/non-PD, or PD.†IC PFS events occurred in 4 pts (2 PD, 2 deaths).‡IC PFS events occurred in 10 pts (3 PD, 7 deaths).
Clinical trial identification
ALKA-372-001 (EudraCT 2012-000148-88); STARTRK-1 (NCT02097810); STARTRK-2 (NCT02568267).
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.
F. Hoffmann-La Roche Ltd.
T. John: Honoraria (self): AZ, Roche, Merck, MSD; Advisory/Consultancy: BMS, AstraZeneca, Boehringer Ingelheim, Takeda, Pfizer, Novartis, Merck, Ignyta, and Roche. C-H. Chiu: Honoraria (self): Pfizer, AstraZeneca/MedImmune, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly, MSD, Novartis, Ono Pharmaceutical, and Roche; Advisory/Consultancy: AstraZeneca/MedImmune, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, MSD, Novartis, Ono Pharmaceutical, and Roche. B.C. Cho: Advisory/Consultancy: Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, MSD, Janssen, 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 Therapeutics, Kanaph Therapeutic Inc; Licensing/Royalties: Champions Oncology; Officer/Board of Directors: Daan biotherapeutics. M. Fakih: Honoraria (self): Amgen; Advisory/Consultancy: Array, Amgen, Pfizer, and Bayer Pharmaceuticals; Speaker Bureau/Expert testimony: Amgen, Guardant360; Research grant/Funding (institution): Amgen, AstraZeneca, Novartis. 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. G.D. Demetri: Honoraria (self): M.J. 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K. Goto: Honoraria (self): Astellas Pharma Inc.; AstraZeneca; Boehringer Ingelheim; Bristol-Myers Squibb; Chugai Pharma; Daiichi Sankyo Co., Ltd.; Guardant Health Inc.; IQVIA Services Japan K.K.;Janssen Pharmaceutical K.K.; Kyowa Hakko Kirin Co., Ltd; Life Technologies; Lilly; MSD; Advisory/Consultancy: Amgen Inc; Otsuka Pharma; Research grant/Funding (institution): Amgen Inc; Astellas Pharma; AstraZeneca; Boehringer Ingelheim; Bristol-Myers Squibb; Chugai Pharma; Daiichi Sankyo; Eisai; Ignyta; Janssen; Kyowa Hakko Kirin; Life Technologies; Lilly; Loxo; Medical & Biological Laboratories Co., Ltd; Merck Serono; MSD; Honoraria (self): Nippon Kayaku; Novartis; Ono Pharmaceutical; Otsuka Pharmaceutica; Pfizer; Taiho Pharmaceutical; Takeda; Research grant/Funding (institution): Novartis; Ono Pharmaceutical; Pfizer; Riken Genesis; Sumitomo Dainippon; Sysmex Corporation; Taiho Pharmaceutical; Takeda; Xcoo. 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. S. Siena: Advisory/Consultancy: Amgen, Bayer, BMS, CheckMab, Celgene, Daiichi Sankyo, Incyte, Merck, Novartis, Roche, and Seattle Genetics. A. Drilon: Honoraria (institution): Ignyta/Roche/Genentech, Loxo, Bayer, lilly, 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. M.R. Patel: Advisory/Consultancy: Nektar Therapeutics; Research grant/Funding (self): Merck, Vyriad and Fate Therapeutics. 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. M-J. Ahn: Honoraria (self): AstraZeneca, Lilly, Takeda, Roche, MSD; Advisory/Consultancy: AstraZeneca, Lilly, Takeda, Roche, MSD, Merck, Boehringer Ingelheim, Ono Pharmaceutical, Bristol-Myers Squibb, Alpha Pharmaceutical, and Progeneer. L. Bazhenova: Advisory/Consultancy: Genentech, BeyondSpring Pharma, AstraZeneca, BI, Takeda, Blueprint, Novartis; Research grant/Funding (self): BeyondSpring Pharma; Shareholder/Stockholder/Stock options: Epic Sciences. T.R. 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