Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Patients With NTRK Fusion-Positive Solid Tumors

George D. Demetri, Filippo De Braud, Alexander Drilon, Salvatore Siena, Manish R. Patel, Byoung Chul Cho, Stephen V. Liu, Myung Ju Ahn, Chao Hua Chiu, Jessica J. Lin, Koichi Goto, Jeeyun Lee, Lyudmila Bazhenova, Thomas John, Marwan Fakih, Sant P. Chawla, Rafal Dziadziuszko, Takashi Seto, Sebastian Heinzmann, Bethany PitcherDavid Chen, Timothy R. Wilson, Christian Rolfo

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Purpose: Entrectinib potently inhibits tropomyosin receptor kinases (TRKAs)/B/C and ROS1, and previously induced deep [objective response rate (ORR) 57.4%] and durable [median duration of response (DoR) 10.4 months] responses in adults with NTRK fusion-positive solid tumors from three phase I/II trials. This article expands prior reports with additional patients and longer follow-up. Patients and Methods: Patients with locally advanced/metastatic NTRK fusion-positive solid tumors and ≥12 months' follow-up were included. Primary endpoints were ORR and DoR by blinded independent central review (BICR); secondary endpoints included progression-free survival (PFS), intracranial efficacy, and safety. The safety-evaluable populations included all patients who had received ≥1 entrectinib dose. Results: At clinical cut-off (August 31, 2020), the efficacyevaluable population comprised 121 adults with 14 tumor types and ≥30 histologies. Median follow-up was 25.8 months; 61.2% of patients had a complete (n = 19) or partial response (n = 55). Median DoR was 20.0 months [95% confidence interval (CI), 13.0- 38.2]; median PFS was 13.8 months (95% CI, 10.1-19.9). In 11 patients with BICR-assessed measurable central nervous system (CNS) disease, intracranial ORR was 63.6% (95% CI, 30.8-89.1) and median intracranial DoR was 22.1 (95% CI, 7.4-not estimable) months. The safety profile of entrectinib in adults and pediatric patients was aligned with previous reports. Most treatment-related adverse events (TRAEs) were grade 1/2 and manageable/reversible with dose modifications. TRAE-related discontinuations occurred in 8.3% of patients. Conclusions: With additional clinical experience, entrectinib continues to demonstrate durable systemic and intracranial responses and can address the unmet need of a CNS-active treatment in patients with NTRK fusion-positive solid tumors.

Original languageEnglish (US)
Pages (from-to)1302-1312
Number of pages11
JournalClinical Cancer Research
Volume28
Issue number7
DOIs
StatePublished - Apr 1 2022

Bibliographical note

Funding Information:
G.D. Demetri reports grants, personal fees, and nonfinancial support to institution from Roche/Genentech and Bayer during the conduct of the study; personal fees and other support from Blueprint Medicines, Caris Life Sciences, G1 Therapeutics, Relay Therapeutics, CellCarta, Ikena Oncology, Kojin Therapeutics, Acrivon Therapeutics, EMD-Serono, WCG/Arsenal Capital and McCann Health; other support from Erasca Pharmaceuticals; personal fees, nonfinancial support, and other support from Pfizer and Epizyme; personal fees and nonfinancial support from Novartis; grants, personal fees, nonfinancial support, and other support from GlaxoSmithKline, PharmaMar, and Daiichi-Sankyo; grants from Janssen and Adaptimmune; and personal fees from Mirati, C4 Therapeutics, Synlogic, and RAIN Therapeutics outside the submitted work; in addition, G.D. Demetri has a patent for Imatinib for GIST issued, licensed, and with royalties paid from Novartis. F. De Braud reports personal fees from Roche, EMD Serono, NMS Nerviano Medical Science, Sanofi, Merck, Sharp & Dohme, Novartis, Incyte, Bristol Myers Squibb, Menarini, Merck Group, Pfizer, Servier, Amgen, Merck, Sharp & Dohme Serono, and Pharmadoc outside the submitted work. A. Drilon reports personal fees from Ignyta/Genentech/Roche during the conduct of the study; personal fees from Loxo/Bayer HealthCare/Eli Lilly and Company, Takeda/Ariad/Millenium, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Helsinn, BeiGene, BergenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem, MORE Health, AbbVie, 14ner/Elevation Oncology, ArcherDX, Monopteros, Novartis, EMD Serono, Medendi, Repare RX, Nuvalent, Merus, Chugai Pharmaceutical Co., Ltd., Remedica Ltd., mBrace, AXIS, EPG Health, Harborside, Liberum Nexus, RV More Ology, Amgen, TouchIME, Janssen, Entos Pharmaceuticals, Treeline Biosciences, Prelude Therapeutics, and Applied Pharmaceutical Science, Inc. outside the submitted work; in addition, A. Drilon has a patent for Osimertinib-Selpercatinib pending and associated research paid to institution from Pfizer, Exelixis, GlaxoSmithKlein, Teva, Taiho Pharmaceutical Co., Ltd., PharmaMar; research from Foundation Medicine; royalties from Wolters Kluwer; other (food/beverage) from Boehringer Ingelheim, Merck, Puma, Merus; CME honoraria from Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, Research to Practice, Axis, Peerview Institute, Paradigm Medical Communications, WebMD, MJH Life Sciences, Med Learning, Imedex, Answers in CME, Clinical Care Options, EPG Health, JNCC/Harborside, Liberum, and Remedica Ltd. M.R. Patel reports other support (advisory board) from Sanofi outside the submitted work. B.C. Cho reports grants from Novartis, Bayer HealthCare, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono Pharmaceutical Co., Ltd., Dizal Pharma, Merck, Sharp & Dohme, AbbVie, Medpacto, GIInnovation, Eli Lilly and Company, Blueprint Medicines, and Interpark Bio Convergence Corp.; personal fees from Novartis, AstraZeneca, Boehringer-Ingelheim, Roche, Bristol Myers Squibb, Ono Pharmaceutical Co., Ltd., Yuhan, Pfizer, Eli Lilly and Company, Janssen, Takeda, Merck, Sharp & Dohme, Medpacto, Blueprint Medicines, TheraCanVac Inc, Gencurix Inc, Bridgebio Therapeutics, KANAPH Therapeutic Inc., Cyrus Therapeutics, Interpark Bio Convergence Corp., Guardant Health, Joseah BIO, and Champions Oncology; and was the founder of DAAN Biotherapeutics outside the submitted work. S.V. Liu reports grants from Alkermes, Merus, Nuvalent, Pfizer, Rain Therapeutics, and RAPT; personal fees from Amgen, AstraZeneca, BeiGene, Daiichi Sankyo, Eisai, Gilead, Guardant Health, Janssen, Jazz Pharmaceuticals, Eli Lilly and Company, Novartis, Regeneron, Sanofi, and Takeda; grants and personal fees from Bayer HealthCare, Blueprint Medicines, Bristol Myers Squibb, Elevation Oncology, Genentech, and Merck; and grants and Turning Point Therapeutics outside the submitted work. M.-J. Ahn reports personal fees from AstraZeneca, Alpha Pharmaceuticals, Merck, Takeda, Eli Lilly and Company, Yuhan, Merck, Sharp & Dohme, and Ono Pharmaceutical Co., Ltd. outside the submitted work. C.-H. Chiu reports personal fees from AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical Co., Ltd., Eli Lilly and Company, Janssen, Merck KGaA, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical Co., Ltd., Pfizer, Roche, and Takeda outside the submitted work. J.J. Lin reports personal fees and other support from Roche/Genentech, Nuvalent, Turning Point Therapeutics, Novartis, Elevation Oncology, and Bayer HealthCare; personal fees from C4 Therapeutics, Blueprint Medicines, Pfizer, and Mirati Therapeutics; and other support from Hengrui Therapeutics, Neon Therapeutics, Linnaeus Therapeutics, Relay Therapeutics, OncLive, MedStar Health, and Northwell Health outside the submitted work. K. Goto reports grants and personal fees from Chugai Pharmaceutical Co., Ltd. and grants from Ignyta during the conduct of the study; grants and personal fees from Amgen K.K., AstraZeneca K.K., Boehringer Ingelheim Japan, Inc., Bristol Myers Squibb K.K., Daiichi Sankyo, Eisai, Eli Lilly and Company Japan K.K., Janssen Pharmaceutical K.K., Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda; grants from Kissei Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Loxo Oncology, Inc., Medical & Biological Laboratories Co., Ltd., Merck Biopharma Co., Ltd., Merus N.V., Merck, Sharp & Dohme K.K., NEC Corporation., Pfizer Japan Inc., Sumitomo Dainippon Pharma Co., Ltd., Spectrum Pharmaceuticals,

Funding Information:
This work was funded by F. Hoffmann-La Roche Ltd.

Funding Information:
Inc., Sysmex Corporation., Haihe Biopharma Co., Ltd., and Turning Point Therapeutics, Inc.; and personal fees from Amoy Diagnosties Co., Ltd., Bayer Yakuhin, Ltd., Guardant Health Inc., and Otsuka Pharmaceutical Co., Ltd. outside the submitted work. L. Bazhenova reports personal fees from ORIC, Turning Point Therapeutics, Inc., Neuvogen, Daichi Sankyo, Janssen, Merck, Beyond-Spring, Regeneron, Bayer HealthCare, Takeda, Boehringer-Ingelheim, Novartis, Genentech, and Sanofi outside the submitted work. T. John reports personal fees from Roche, Merck, Merck, Sharp & Dohme, Puma, AstraZeneca, Bristol Myers Squibb, Novartis, Amgen, Gilead, PharmaMar, and Specialised Thrapeutics outside the submitted work. M. Fakih reports grants and personal fees from Amgen; personal fees from Array, Bayer HealthCare, GlaxoSmithKline, Guardant360, HalioDx, Mirati, Nouscom, Pfizer, Seattle Genetics, Taiho Pharmaceutical Co., Ltd., and Zhuhai Yufan Biotech; grants from AstraZeneca, Novartis, Bristol Myers Squibb, and Verstem outside the submitted work. S.P. Chawla reports grants or contracts from Amgen, Roche, GlaxoSmithKline, Threshold Pharmaceuticals, CytRx Corporation, Ignyta, Immune Design, TRACON Pharma, Karyopharm Therapeutics, SARC: Sarcoma Alliance for Research though Collaboration, Janssen, Advenchen Laboratories, Bayer HealthCare, InhibRx, and NKMax; consulting fees from Amgen, Roche, GlaxoSmith-Kline, Threshold Pharmaceuticals, CytRx Corporation, Ignyta, Immune Design, TRACON Pharma, Karyopharm Therapeutics, SARC: Sarcoma Alliance for Research though Collaboration, Janssen, Advenchen Laboratories, Bayer HealthCare, NKMax, and InhibRx; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Amgen, Roche, GlaxoSmithKline, Threshold Pharmaceuticals, CytRx Corporation, Ignyta, Immune Design, TRACON Pharma, Karyopharm Therapeutics, SARC: Sarcoma Alliance for Research though Collaboration, Janssen, Advenchen Laboratories, Bayer HealthCare, InhibRx, NKMax, and Tyme; and stock or stock options of AADi, Cellestia Biotech, and Immix BioPharma. R. Dziad-ziuszko reports personal fees from Roche, AstraZeneca, FoundationMedicine, Merck, Sharp & Dohme, Takeda, Pfizer, Novartis, Karyopharm Therapeutics, and Boehringer-Ingelheim, and Bristol Myers Squibb during the conduct of the study. T. Seto reports personal fees from AstraZeneca, Bristol Myers Squibb, Kyowa Hakko Kirin, Mochida Pharmaceutical, Nippon Boehringer-Ingelheim, Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Towa Pharmaceutical, Covidien Japan; grants and personal fees from Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Eli Lilly and Company Japan, Merck, Sharp & Dohme, Novartis Pharma, Pfizer Japan, Takeda; grants from AbbVie and Kissei Pharmaceutical; and employment from Precision Medicine Asia outside the submitted work. S. Heinzmann reports employment and shares from F. Hoffmann-La Roche Ltd. B. Pitcher reports employment from F. Hoffmann-La Roche Ltd. during the conduct of the study; and employment from F. Hoffmann-La Roche Ltd. outside the submitted work. D. Chen reports employment from Genentech/ Roche during the conduct of the study and outside the submitted work. T.R. Wilson reports employment from Genentech during the conduct of the study and stocks from Roche outside the submitted work. C. Rolfo reports personal fees from ARCHER, Inivata, Bristol Myers Squibb, Novartis, Boston Pharmaceuticals, AstraZeneca, Roche, GuardantHealth, Merck, Sharp & Dohme, Mirati, Eisai, Daiichi Snakyo, and Sanofy Genzyme-Regeneron; personal fees and other support from EMD Serono; grants and personal fees from Pfizer; and personal fees from COR2RED outside the submitted work; in addition, C. Rolfo reports leadership

Publisher Copyright:
© 2022 TheAuthors.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

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