1288P - Efficacy of entrectinib in patients with <italic>NTRK</italic> or <italic>ROS1</italic> fusion-positive NSCLC with CNS metastases at baseline

Background

CNS metastases are particularly common in NSCLC; effective targeted therapy requires potent intracranial activity. Entrectinib crosses the blood-brain barrier and has shown robust systemic and intracranial efficacy in pts with NTRK and ROS1 fusion-positive (NTRK-fp and ROS1-fp, respectively) solid tumours based on an integrated analysis of three phase 1/2 clinical trials (ALKA-372-001 [EudraCT 2012-000148-88]; STARTRK-1 [NCT02097810]; STARTRK-2 [NCT02568267]). We report an updated analysis of these studies with longer follow-up, focusing on pts with CNS metastases at baseline.

Methods

Pts with NTRK-fp or ROS1-fp (data cut-off: 31 October 2018 and 1 May 2019, respectively) locally advanced/metastatic NSCLC with CNS metastases at baseline (asymptomatic or pretreated and controlled) as judged by blinded independent central review (BICR) were included. Responses were evaluated by BICR (RECIST v1.1) after wk 4, then every 8 wks. Intracranial objective response rate (ORR), intracranial duration of response (DoR) and intracranial progression-free survival (PFS) were assessed.

Results

Among 13 evaluable pts with NTRK-fp NSCLC, median age was 60 years, 53.8% were female, and 69.2% had adenocarcinoma; eight pts (61.5%) had CNS lesions at baseline. Five pts (38.5%) had received prior radiotherapy (RT) of the brain, with three completing RT ≥2 months prior to entrectinib. Among 161 evaluable pts with ROS1-fp NSCLC, median age was 54 years, 64.6% were female and 96.9% had adenocarcinoma; 46 pts (28.6%) had baseline CNS lesions. Twenty-seven pts (16.8%) had received prior RT of the brain, with 10 completing RT ≥2 months prior to entrectinib. Intracranial ORR, median intracranial DoR and median intracranial PFS for these two cohorts are shown in the table. The safety profile was consistent with that reported previously. Table: 1288P

Confidence intervals (CI) calculated using the Clopper-Pearson method*CNS metastases at baseline judged by BICR^†Proportion of pts achieving a complete or partial intracranial responseNE, not estimable

Conclusions

Entrectinib induced clinically meaningful intracranial responses in pts with NTRK-fp or ROS1-fp NSCLC with CNS metastases at baseline.

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

R. Dziadziuszko: Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy: Foundation Medicine; Advisory/Consultancy: Pfizer; Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy: Celon Pharma; Advisory/Consultancy: Merck; Advisory/Consultancy: MSD; Advisory/Consultancy: Takeda; Advisory/Consultancy: Seattle Genetics; Advisory/Consultancy: Novartis. S. Siena: Advisory/Consultancy: Amgen; Advisory/Consultancy: Bayer; Advisory/Consultancy: BMS; Advisory/Consultancy: CheckMab; Advisory/Consultancy: Celgene; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: Incyte; Advisory/Consultancy: Merck; Advisory/Consultancy: Novartis; Advisory/Consultancy: Roche; Advisory/Consultancy: Seattle Genetics. D.S.W. Tan: Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Honoraria (self), Research grant/Funding (institution): Bayer; Honoraria (self), Travel/Accommodation/Expenses: Boehringer Ingelheim; Honoraria (self), Travel/Accommodation/Expenses: Celgene; Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self): Eli Lilly; Honoraria (self): Loxo; Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Research grant/Funding (institution): GlaxoSmithKline; Travel/Accommodation/Expenses: Merck; Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Takeda. B.C. Cho: Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Roche; Advisory/Consultancy: BMS; Advisory/Consultancy, Research grant/Funding (institution): Ono; Advisory/Consultancy, Research grant/Funding (institution): Yuhan; Advisory/Consultancy: Pfizer; Advisory/Consultancy, Research grant/Funding (institution): Eli Lilly; Advisory/Consultancy, Research grant/Funding (institution): Janssen; Advisory/Consultancy: Medpacto; Advisory/Consultancy, Research grant/Funding (institution): Blueprint Medicines; Advisory/Consultancy, Shareholder/Stockholder/Stock options: KANAPH Therapeutic; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): MOGAM Institute; Research grant/Funding (institution): Dong-A ST; Research grant/Funding (institution), Licensing/Royalties: Champions Oncology; Research grant/Funding (institution): Dizal Pharma; Research grant/Funding (institution): MSD; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Medpacto; Research grant/Funding (institution): GI-Innovation; Research grant/Funding (institution): Eli Lilly; Shareholder/Stockholder/Stock options: TheraCanVac Inc.; Shareholder/Stockholder/Stock options: Gencurix Inc.; Shareholder/Stockholder/Stock options: Bridgebio Therapeutics; Officer/Board of Directors: Daan Biotherapeutics. M-J. Ahn: Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy: Lilly; Honoraria (self), Advisory/Consultancy: Takeda; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: MSD; Advisory/Consultancy: Merck; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Ono Pharmaceutical; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Alpha Pharmaceutical; Advisory/Consultancy: Progeneer. K. Goto: Honoraria (self), Research grant/Funding (institution): Astellas Pharma; Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self), Research grant/Funding (institution): Boehringer Ingelheim; Honoraria (self), Research grant/Funding (institution): Bristol-Myers Squibb; Honoraria (self), Research grant/Funding (institution): Chugai Pharma; Honoraria (self), Research grant/Funding (institution): Daiichi Sankyo; Honoraria (self), Research grant/Funding (institution): Guardant Health; Honoraria (self): IQVIA Services Japan; Honoraria (self), Research grant/Funding (institution): Janssen; Honoraria (self), Research grant/Funding (institution): Kyowa Hakko Kirin; Honoraria (self), Research grant/Funding (institution): Life Technologies; Honoraria (self), Research grant/Funding (institution): Lilly; Honoraria (self), Research grant/Funding (institution): MSD; Honoraria (self): Nippon Kayaku; Honoraria (self), Research grant/Funding (institution): Novartis; Honoraria (self), Research grant/Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant/Funding (institution): Pfizer; Honoraria (self), Research grant/Funding (institution): Taiho Pharmaceutical; Honoraria (self), Research grant/Funding (institution): Takeda; Research grant/Funding (institution): Eisai; Research grant/Funding (institution): Ignyta; Research grant/Funding (institution): Loxo; Research grant/Funding (institution): Medical & Biological Laboratories ; Research grant/Funding (institution): Merck Serono; Research grant/Funding (institution): Riken Genesis; Research grant/Funding (institution): Sumitomo Dainippon; Research grant/Funding (institution): Sysmex Corporation; Research grant/Funding (institution): Xcoo; Advisory/Consultancy, Research grant/Funding (institution): Amgen Inc; Honoraria (self), Advisory/Consultancy: Otsuka Pharma. P. Garrido-Lopez: Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Roche; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): MSD; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): BMS; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Novartis; Honoraria (self), Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: AbbVie; Advisory/Consultancy, Research grant/Funding (self): Lilly; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Janssen; Advisory/Consultancy, Research grant/Funding (self): Takeda; Research grant/Funding (self): PharmaMar; Research grant/Funding (self): Celgene; Research grant/Funding (self): Sanofi; Research grant/Funding (self): GSK; Research grant/Funding (self): Theradex Oncology; Advisory/Consultancy, Research grant/Funding (self): Blueprint; Research grant/Funding (self): Guardant Health; Research grant/Funding (self): Sysmex. A.F. Farago: Honoraria (self): DAVA Oncology; Honoraria (self): Clinical Care Options; Honoraria (self): Medical Learning Institute; Honoraria (self): Medscape; Honoraria (self): PeerView; Honoraria (self): Research to Practice; Advisory/Consultancy, Research grant/Funding (self): Bayer; Advisory/Consultancy, Research grant/Funding (self): Loxo Oncology; Advisory/Consultancy, Research grant/Funding (self): Genentech; Advisory/Consultancy, Research grant/Funding (self): Roche; Advisory/Consultancy, Research grant/Funding (self): Bristol-Myers Squibb; Advisory/Consultancy, Research grant/Funding (self): AstraZeneca; Advisory/Consultancy, Research grant/Funding (self): AbbVie; Advisory/Consultancy, Research grant/Funding (self): PharmaMar; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy, Research grant/Funding (self): Merck; Advisory/Consultancy: H3 Biomedicine; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Syros; Research grant/Funding (self): Ignyta; Research grant/Funding (self): Amgen; Research grant/Funding (self): Novartis. H.H.F.H.F. Loong: Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Celgene; Advisory/Consultancy, Speaker Bureau/Expert testimony: Eli Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy: Merck Serono; Advisory/Consultancy: Roche; Advisory/Consultancy: Takeda; Speaker Bureau/Expert testimony: AbbVie; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Bayer; Speaker Bureau/Expert testimony: Eisai; Speaker Bureau/Expert testimony: Guardant Health; Research grant/Funding (institution), Travel/Accommodation/Expenses: MSD; Research grant/Funding (institution): Mundipharma; Travel/Accommodation/Expenses: Pfizer. D. Tosi: Research grant/Funding (self): Ipsen; Research grant/Funding (self), Travel/Accommodation/Expenses: Janssen; Research grant/Funding (self), Travel/Accommodation/Expenses: Astellas; Travel/Accommodation/Expenses: Sanofi; Travel/Accommodation/Expenses: Pfizer; Licensing/Royalties, I have a pending patent on a new drug combination for prostate cancer treatment: GENERAL; Spouse/Financial dependant, Spouse: Remunerated advisor and travel/accommodation expenses: Biomarin; Spouse/Financial dependant, Spouse: Remunerated advisor: Actelion; Spouse/Financial dependant, Spouse: Travel/accommodation expenses: Nutricia; Spouse/Financial dependant, Spouse: Spouse: Travel/accommodation expenses: Amicus. T. John: Honoraria (self), Advisory/Consultancy: AstraZenca; Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: Merck; Honoraria (self): MSD; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Takeda; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Novartis; Advisory/Consultancy: Ignyta; Advisory/Consultancy: BMS. J. Wolf: Advisory/Consultancy: Amgen; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Bayer; Advisory/Consultancy: Blueprint; Advisory/Consultancy, Research grant/Funding (institution): BMS; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Chugai; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: Ignyta; Advisory/Consultancy, Research grant/Funding (institution): Janssen; Advisory/Consultancy: Lilly; Advisory/Consultancy: Loxo; Advisory/Consultancy: MSD; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy: Roche; Advisory/Consultancy: Seattle Genetics; Advisory/Consultancy: Takeda. C-H. Chiu: Honoraria (self): Pfizer; Honoraria (self), Advisory/Consultancy: AstraZeneca/MedImmune; Honoraria (self), Advisory/Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory/Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy: Chugai Pharmaceutical; Honoraria (self): Eli Lilly; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Ono Pharmaceutical; Honoraria (self), Advisory/Consultancy: Roche. S.V. Liu: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Advisory/Consultancy: Catalyst; Advisory/Consultancy: Celgene; Advisory/Consultancy: G1 Therapeutics; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Genentech/Roche; Advisory/Consultancy: Guardant Health; Advisory/Consultancy: Inivata; Advisory/Consultancy: Janssen; Advisory/Consultancy, Research grant/Funding (institution): Lilly; Advisory/Consultancy: Loxo; Advisory/Consultancy, Travel/Accommodation/Expenses: MSD; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy: PharmaMar; Advisory/Consultancy: Regeneron; Advisory/Consultancy: Takeda; Research grant/Funding (institution): Alkermes; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Blueprint; Research grant/Funding (institution): Corvus; Research grant/Funding (institution): Lycera; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Merus; Research grant/Funding (institution): Molecular Partners; Research grant/Funding (institution): Rain; Research grant/Funding (institution): RAPT; Research grant/Funding (institution): Spectrum; Research grant/Funding (institution): Turning Point Therapeutics. M.R. Patel: Advisory/Consultancy: Nektar Therapeutics; Research grant/Funding (self): Merck; Research grant/Funding (self): Vyriad; Research grant/Funding (self): Fate Therapeutics. A. Drilon: Honoraria (institution): Ignyta/Roche/Genentech; Honoraria (institution): Loxo, Bayer, Lilly; Honoraria (institution): TP Therapeutics; Honoraria (institution): AstraZeneca; Honoraria (institution), Research grant/Funding (institution): Pfizer; Honoraria (institution): Blueprint; Honoraria (institution): Takeda/Ariad/Millennium; Honoraria (institution): Helsinn; Honoraria (institution): BeiGene; Honoraria (institution): BerGenBio; Honoraria (institution): Hengrui; Honoraria (institution), Research grant/Funding (institution): Exelixis; Honoraria (institution): Tyra; Honoraria (institution): Verastem; Honoraria (institution): MORE Health; Honoraria (institution): AbbVie; Honoraria (institution): 14ner/Elevation Oncology; Honoraria (institution): Axis; Honoraria (institution): Peerview Institute; Honoraria (institution): OncLive; Honoraria (institution): Paradigm Medical Communications; Honoraria (institution): Remedica Ltd; Honoraria (institution): ArcherDX; Honoraria (institution), Research grant/Funding (self): Foundation Medicine; Honoraria (institution): PeerVoice; Honoraria (institution): Research to Practice; Research grant/Funding (institution): GlaxoSmithKline; Research grant/Funding (institution): PharmaMar; Research grant/Funding (institution): Taiho; Research grant/Funding (institution): Teva; Honoraria (institution): Medscape; Honoraria (institution): WebMD; Licensing/Royalties: Wolters Kluwer. B. Pitcher: Full/Part-time employment: F. Hoffmann-La Roche . B. Simmons: Shareholder/Stockholder/Stock options, Full/Part-time employment: Genentech/Roche. R.C. Doebele: Advisory/Consultancy, Research grant/Funding (institution), Licensing/Royalties, Includes patent and biologic material licensing fees: Ignyta; Advisory/Consultancy, Travel/Accommodation/Expenses, Licensing/Royalties, Includes patent and biologic material licensing fees: Genentech/Roche; Advisory/Consultancy, Research grant/Funding (institution), Includes patent and biologic material licensing fees: Loxo Oncology; Advisory/Consultancy: Bayer; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Eli Lilly; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Travel/Accommodation/Expenses: Blueprint Medicines; Advisory/Consultancy: Anchiano; Advisory/Consultancy, Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Includes patent and biologic material licensing fees: Rain Therapeutics; Research grant/Funding (institution): Mirati; Research grant/Funding (institution): Strategia; Licensing/Royalties, Patent and biologic material licensing fees: Abbott Molecular; Licensing/Royalties, Patent and biologic material licensing fees: Chugai; Licensing/Royalties, Patent and biologic material licensing fees: Foundation Medicine; Licensing/Royalties, Patent and biologic material licensing fees: Black Diamond; Licensing/Royalties, Patent and biologic material licensing fees: Voronoi; Licensing/Royalties, Patent and biologic material licensing fees: Pearl River; Licensing/Royalties, Patent and biologic material licensing fees: Ariad.