666P - Updated efficacy and safety data of entrectinib in patients (pts) with locally advanced/metastatic NTRK fusion-positive (fp) solid tumours

Background

NTRK gene fusions are oncogenic drivers of various solid tumour types. Entrectinib, a potent CNS-active TRK inhibitor, yielded systemic and intracranial responses in pts with NTRK-fp solid tumours in previous integrated analyses of three phase I/II trials (ALKA-372-001 [EudraCT 2012-000148-88]; STARTRK-1 [NCT02097810]; STARTRK-2 [NCT02568267]). We present updated data with ∼30% more pts and longer follow-up (data cut-off: 2 Aug 2022).

Methods

Adults with measurable, locally advanced/metastatic NTRK-fp solid tumours and ≥12 months’ follow-up from first on-study scan, who received ≥1 dose of entrectinib, were efficacy evaluable. The safety population comprised all pts who received ≥1 dose of entrectinib. Eligible pts from TAPISTRY (NCT04589845) were also included. Tumour responses were assessed by blinded independent central review per RECIST v1.1 at Week 4 and then every 8 weeks. Primary endpoints: objective response rate (ORR); duration of response (DoR). Key secondary endpoints: progression-free survival (PFS); overall survival (OS); safety.

Results

The efficacy-evaluable population comprised 194 pts with 17 types of solid tumours. Median age: 58 years (range 19–92); 63 (32.5%) pts received ≥2 prior lines of therapy. Median survival follow-up was 38.7 months. ORR was 62.4% (95% CI 55.2–69.2); the table shows responses in histologies with n>10. Median DoR was 29.4 months (95% CI 17.2–36.8). Median PFS and OS were 15.7 months (95% CI 13.7–22.9) and 38.2 months (95% CI 28.6–56.5), respectively. In the safety cohort (N=296), median treatment duration was 8.3 months (range 0.0–72.0). Of all pts with treatment-related adverse events (TRAEs; n=265), 57% had grade 1–2 TRAEs; dose reduction, interruption and discontinuation occurred in 24%, 34% and 6% of all pts, respectively. Table: 666P

*Other tumour types in the efficacy-evaluable cohort: neuroendocrine (n=7); head and neck (n=5); pancreatic (n=4); cancer of unknown primary (n=3); gynaecological (n=2); adrenal (n=1); cholangiocarcinoma (n=1); gastrointestinal (n=1); neuroblastoma (n=1); penile (n=1); prostate (n=1).

Conclusions

In this updated analysis, entrectinib was well tolerated and continued to induce clinically meaningful responses in pts with NTRK-fp solid tumours.

Clinical trial identification

EudraCT 2012-000148-88; NCT02097810; NCT02568267; NCT04589845.

Editorial acknowledgement

Medical writing support for the development of this abstract, under the direction of the authors, was provided by Emily Hollebon, MSc, of Ashfield MedComms, an Inizio company, and 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

S. Lu: Financial Interests, Personal, Invited Speaker, Received speaker fees: AstraZeneca, Roche, Hansoh; Financial Interests, Personal, Advisory Board, Advisor and consultant fees: AstraZeneca, Pfizer, Hutchison MediPharma, ZaiLab, GenomiCare ， Novarti, Yuhan Corporation, Menarini., Mirati Therapeutics Inc., Daiichi Sankyo, Inc., D3 Bio Limited, Simcere, Takeda, Roche; Financial Interests, Personal, Research Grant: AstraZeneca, Hutchison, BMS, Heng Rui BeiGene and Roche, Hansoh. F.G.M. De Braud: Financial Interests, Personal, Speaker’s Bureau: BMS, Roche, Merck & Co., Kenilworth, NJ, Bayer, Ignyta, Dephaforum, Biotechespert, Prime Oncology, Pfizer, Nadirex, Ambrosetti, Incyte, Motore Sanità, Events, Fare Comunicazione, Itanet, Nadirex, ESO; Financial Interests, Personal, Advisory Board: Tiziana Life Sciences, BMS, Celgene, Novartis, Servier, Pharm Research Associated, Daiichi Sankyo, Ignyta, Amgen, Pfizer, Octimet Oncology, Incyte, Pierre Fabre, Eli Lilly, Roche, AstraZeneca, Gentili, Dephaforum, Merck & Co., Kenilworth, NJ, Bayer, Fondazione Menarini, Sanofi, Incyte, Taiho; Financial Interests, Personal, Research Grant: Novartis, Roche, BMS, Celgene, Incyte, NMS, the healthcare business of Merck KGaA, Darmstadt, Germany, Kymab, Pfizer, Tesaro, and Merck & Co., Kenilworth, NJ; Financial Interests, Personal, Principal Investigator: Novartis, Roche, BMS, Ignyta Operating Inc., Merck Sharp & Dohme Spa, Kymab, Pfizer, Tesaro, MSD, MedImmune LCC, Exelixis Inc., Loxo Oncology Incorporated, Daiichi Sankyo Dev. Limited, Basilea Pharmaceutica International AG, Janssen-Cilag International NV, Merck KGAA; Financial Interests, Personal, Other, Consulting: BMS, Pierre Fabre, Mattioli 1885 , MCCann Health, MSD, IQVIA; Financial Interests, Personal, Other, Travel expenses: Bristol Myers Squibb, Roche, Celgene, Amgen. Y. Ohe: Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai, Eli Lilly, ONO, BMS, Boehringer Ingelheim, Bayer, Pfizer, MSD, Taiho, Nippon Kayaku, Kyowa Hakko Kirin, Eisai; Financial Interests, Personal, Advisory Board: AstraZeneca, Chugai, ONO, AnHeart Therapeutics Inc. Celltrion; Non-Financial Interests, Personal, Member of Board of Directors: JSMO, JLCS; Financial Interests, Personal, Research Grant: AstraZeneca, Chugai, Lilly, ONO, BMS, Kyorin, Dainippon- Sumitomo, Pfizer, Taiho, Novartis, Takeda, Kissei, Daiichi Sankyo, Janssen; Financial Interests, Personal, Principal Investigator: AstraZeneca, Chugai, Lilly, ONO, Pfizer, Taiho, Takeda, Janssen; Non-Financial Interests, Personal, Leadership Role: JCOG. M. Ahn: Financial Interests, Personal, Invited Speaker: AstraZeneca, Merck, Amgen, MSD, Daiichi Sankyo, Yuhan, Takeda, Roche; Financial Interests, Personal, Advisory Board: AstraZeneca, Merck, Amgen, MSD, Daiichi Sankyo, Yuhan, Takeda, Alpha-pharmaceuticals, Eutilex, Pfizer, Roche. P. Cassier: Financial Interests, Personal, Other, Honoraria: Amgen; Financial Interests, Personal, Advisory Role: OSE Immunotherapeutics, Bristol Myers Squibb/Celgene, Janssen Ocology, Boehringer Ingelheim; Financial Interests, Personal, Research Grant, Research funding: Boehringer Ingelheim; Financial Interests, Institutional, Research Grant, Research funding: Novartis, Roche/Genentech, Lilly, Blueprint Medicines, Bayer, AstraZeneca, Celgene, Plexxikon, AbbVie, Bristol Myers Squibb, Merck Sharp & Dohme, Taiho Pharmaceutical, Toray Industries, Transgene, Loxo, GSK, Innate Pharma, Janssen; Financial Interests, Personal, Other, Travel, Accommodation, Expenses: Roche, OSE Immunotherapeutics. J.J. Lin: Financial Interests, Personal, Advisory Board, Consulting/Ad Board: Pfizer, Nuvalent, C4 Therapeutics, Turning Point Therapeutics, Elevation Oncology, Genentech, Blueprint Medicines, Bayer, Mirati Therapeutics, Novartis, Regeneron, CLaiM Therapeutics; Financial Interests, Personal, Funding, Institutional Research Funding: Hengrui Therapeutics, Turning Point Therapeutics, Novartis, Neon Therapeutics, Bayer, Roche/Genentech, Pfizer, Elevation Oncology, Relay Therapeutics, Linnaeus Therapeutics, Nuvalent; Financial Interests, Personal, Other, Travel: Pfizer; Financial Interests, Personal, Other, CME: OncLive, Northwell Health, Medstar Health, DKBMed, MLI PeerView. L. Paz-Ares: Financial Interests, Personal, Invited Speaker: MSD, Lilly, Janssen, Mirati, BMS, AstraZeneca, PharmaMar, GSK, Sanofi; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Janssen, Merck, Mirati; Financial Interests, Personal, Advisory Board: Lilly, MSD, Roche, PharmaMar, Merck, AstraZeneca, Novartis, Servier, Amgen, Pfizer, Sanofi, Bayer, BMS, Mirati, GSK, Janssen, Takeda, Daiichi Sankyo; Financial Interests, Personal, Member of Board of Directors: STAb Therapeutics Altum Sequencing; Financial Interests, Personal, Member: Scientific Societies, Associations and Foundations: IASLC, ESMO, SEOM, ASEICA, CNIO, ONCOSUR, AECC, CRIS; Financial Interests, Personal, Advisory Role: Lilly, MSD, Roche, PharmaMar, Merck, AstraZeneca, Novartis, Servier, Amgen, Pfizer, Sanofi, Bayer, BMS, Mirati, GSK, Janssen, Takeda, Daiichi Sankyo. C. Xue, H. Zeuner: Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche Ltd. W. Bordogna: Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche. S. Patel: Financial Interests, Personal, Full or part-time Employment: Genentech, Inc. All other authors have declared no conflicts of interest.