TY - JOUR
T1 - Phase I study of everolimus, letrozole, and trastuzumab in patients with hormone receptor-positive metastatic breast cancer or other solid tumors
AU - Ballhausen, Alexej
AU - Wheler, Jennifer J.
AU - Karp, Daniel D.
AU - Piha-Paul, Sarina A.
AU - Fu, Siqing
AU - Pant, Shubham
AU - Tsimberidou, Apostolia M.
AU - Hong, David S.
AU - Subbiah, Vivek
AU - Holley, Veronica R.
AU - Huang, Helen J.
AU - Brewster, Abenaa M.
AU - Koenig, Kimberly B.
AU - Ibrahim, Nuhad K.
AU - Meric-Bernstam, Funda
AU - Janku, Filip
N1 - Funding Information:
J.J. Wheler reports leaving MD Anderson in 2015, joining Novartis, and has worked at Novartis from July 2015 until August 2018. D.D. Karp reports grants from Novartis and Genentech during the conduct of the study, and grants from National Center for Accelerating Translational Science (NCATS), Clinical Translational Sciences Award, NIH; The Jazz Connection Foundation, and National Academy of Recording Arts & Sciences. S.A. Piha-Paul reports other from AbbVie, Inc., ABM Therapeutics, Inc., Acepodia, Inc., Alkermes, Aminex Therapeutics, Amphivena Therapeutics Inc., BioMarin Pharmaceutical, Inc., Boehringer Ingelheim, Bristol Myers Squib, Cerulean Pharma, Inc., Chugai Pharmaceutical Co., Ltd., Curis, Inc., Daiichi Sanko, Eli Lilly, ENB Therapeutics, Five Prime Therapeutics, Gene Quantum, Genmab A/S, GlaxoSmithKline, Helix BioPharma Corp., Incyte Corp., Jacobio Pharmaceuticals Co., Ltd., Medimmune, LLC, Medivation, Inc., Merk Sharp and Dohme Corp., Novartis Pharmaceuticals, Pieris Pharmaceuticals, Inc., Pfizer, Principia Biopharma, Inc., Puma Biotechnology, Inc., Rapt Therapeutics, Inc., Seattle Genetics, Silverback Therapeutics, Taiho Oncology, Tesaro, Inc., TransThera Bio, and NCI/NIH P30CA016672, core grant (CCG Shared Resources) outside the submitted work. A.M. Tsimberidou reports grants from IMMATICS, OBI Pharmaceuticals, Parker Institute for Cancer Immunotherapy, EMD Serono, T-vardi, Karus, and Boston Biomedical, grants and other from Tempus, and other from Covance, Roche, and Genentech outside the submitted work. D.S. Hong reports research/grant funding from AbbVie, Adaptimmune, Aldi-Norte, Amgen, Astra-Zeneca, Bayer, BMS, Daiichi Sankyo, Eisai, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa, Lilly, LOXO, Merck, MedImmune, Mirati, miRNA, Molecular Templates, Mologen, NCI-CTEP, Novartis, Numab, Pfizer, Seattle Genetics, Takeda, Turning Point Therapeutics, and Verstatem, travel, accommodations, expenses from Bayer, LOXO, miRNA, Genmab, AACR, ASCO, and SITC, consulting or advisory role with Alpha Insights, Acuta, Amgen, Axiom, Adaptimmune, Baxter, Bayer, Boxer Capital, COG, ECOR1, Expert Connect, Genentech, GLG, Group H, Guidepoint, H.C. Wainwright, Infinity, Janssen, Merrimack, Medscape, NTRK Connect, Numab, Pfizer, Prime Oncology, Seattle Genetics, SlingShot, Takeda, Trieza Therapeutics, and WebMD, and other ownership interests with Molecular Match (advisor), OncoResponse (founder), and Presagia Inc (advisor). V. Subbiah reports grants from Novartis during the conduct of the study, research funding/grant support for clinical trials (to institution) from Novartis, Bayer, Berghealth, Incyte, Fujifilm, PharmaMar, D3, Pfizer, Multivir, Amgen, AbbVie, Alfa-Sigma, Agensys, Boston Biomedical, Idera Pharma, InhibRx, Exelixis, Blueprint medicines, Loxo oncology, Medimmune, Altum, Dragonfly therapeutics, Takeda, National Comprehensive Cancer Network, NCI-CTEP and UT MD Anderson Cancer Center, Turning point therapeutics, and Boston Pharmaceuticals, travel funding from Novartis, PharmaMar, ASCO, ESMO, Helsinn, and Incyte, and ad hoc advisory board relation with Helsinn, LOXO Oncology/Eli Lilly, R-Pharma US, INCYTE, QED pharma, Medimmune, Novartis, and Signant Health. F. Meric-Bernstam reports personal fees from DebioPharm, Pfizer Inc, Samsung Bioepis, Seattle Genetics Inc, Tyra Biosciences, Xencor, Zyme-works, Immunomedics, Inflection Biosciences, Mersana Therapeutics, Seattle Genetics, Silverback Therapeutics, Spectrum Pharmaceuticals, Zentalis, Chugai Biophar-maceuticals, Mayo Clinic, and Rutgers Cancer Institute of New Jersey, grants from Aileron Therapeutics, Inc, Bayer Healthcare Pharmaceutical, Calithera Biosciences, Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo, Debiopharm International, Guardant Health Inc., Millennium Pharmaceuticals, Novartis, and Taiho Pharmaceutical Co, grants and personal fees from Puma Biotechnology Inc, and other from Beth Israel Deaconess Medical Center outside the submitted work. F. Janku reports other from Novartis during the conduct of the study, and other from Genentech, BioMed Valley Discoveries, Astellas, Agios, Plexxikon, Piqur, Symphogen, Bristol-Myers Squibb, Asana, Synthorx, FujiFilm Pharmaceuticals, and Proximagen, personal fees and other from Deciphera, Ideaya Biosciences, Sotio, and Cardiff Oncology, and personal fees from Guardant Health, Illumina, IFM Therapeutics, Synlogic, PureTech Health, and ImmunoMet outside the submitted work. No disclosures were reported by the other authors.
Funding Information:
This study was funded by a research grant from Novartis (to F. Janku). The correlative studies were funded by the Sabin Family Foundation (to F. Janku). The study was also supported by MD Anderson Cancer Center Support grant (NIH/ NCI P30 CA016672), Clinical Translational Science Award (NIH/HHS 1UL1 TR003167) and Cancer Prevention Research Institute of Texas (CPRIT) Precision Oncology Decision Support Core (RP150535), and Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy. Authors would like to acknowledge Joe Munch in MD Anderson’s Research Medical Library for editing the article.
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2021/3/1
Y1 - 2021/3/1
N2 - PURPOSE: Doublets of everolimus with letrozole or trastuzumab have demonstrated activity against HER2-positive breast cancer, suggesting that the triple combination can have synergistic anticancer activity.EXPERIMENTAL DESIGN: This first-in-human dose escalation study (NCT02152943) enrolled patients with hormone receptor-positive, HER2-positive (defined by amplification, overexpression or mutation)treatment-refractory advanced cancers to receive escalating doses (3+3 design) of daily oral letrozole (days 1-21), daily oral everolimus (days 1-21) and intravenous trastuzmab (day 1) every 21 days todetermine dose-limiting toxicities (DLTs) and maximum tolerated dose or recommended phase 2 dose (RP2D).RESULTS: Total of 32 patients with hormone receptor-positive, HER2-positive (amplification, n=27; overexpression, n=1; mutation, n=4) advanced breast cancer (n=26) or other cancers (n=6) were enrolled. The most frequent grade greater than or equal to 3 adverse events included hyperglycemia (n=4), anemia (n=3), thrombocytopenia (n= 2) and mucositis (n=2).DLTs included grade 3 mucositis and grade 4 neutropenia, and trastuzumab given as an 8-mg/kg loading dose on day 1 of cycle 1 followed by a 6-mg/kg maintenance dose on day 1 of subsequent cycles plus 10 mg everolimus daily and 2.5 mg letrozole daily every 21 days was declared as RP2D. Five breast cancer patients (4 with HER2amplification and 1 with HER2mutation) had partial responses. HER2amplification in circulating cell-free DNA at baseline was associated with shorter progression-free and overall survival durations (P<0.05).CONCLUSIONS: Everolimus, letrozole, and trastuzumab has a favorable safety profile and elicits encouraging signals of anticancer activity in patients with heavily pretreated hormone receptor-and HER2-positive advanced cancers.
AB - PURPOSE: Doublets of everolimus with letrozole or trastuzumab have demonstrated activity against HER2-positive breast cancer, suggesting that the triple combination can have synergistic anticancer activity.EXPERIMENTAL DESIGN: This first-in-human dose escalation study (NCT02152943) enrolled patients with hormone receptor-positive, HER2-positive (defined by amplification, overexpression or mutation)treatment-refractory advanced cancers to receive escalating doses (3+3 design) of daily oral letrozole (days 1-21), daily oral everolimus (days 1-21) and intravenous trastuzmab (day 1) every 21 days todetermine dose-limiting toxicities (DLTs) and maximum tolerated dose or recommended phase 2 dose (RP2D).RESULTS: Total of 32 patients with hormone receptor-positive, HER2-positive (amplification, n=27; overexpression, n=1; mutation, n=4) advanced breast cancer (n=26) or other cancers (n=6) were enrolled. The most frequent grade greater than or equal to 3 adverse events included hyperglycemia (n=4), anemia (n=3), thrombocytopenia (n= 2) and mucositis (n=2).DLTs included grade 3 mucositis and grade 4 neutropenia, and trastuzumab given as an 8-mg/kg loading dose on day 1 of cycle 1 followed by a 6-mg/kg maintenance dose on day 1 of subsequent cycles plus 10 mg everolimus daily and 2.5 mg letrozole daily every 21 days was declared as RP2D. Five breast cancer patients (4 with HER2amplification and 1 with HER2mutation) had partial responses. HER2amplification in circulating cell-free DNA at baseline was associated with shorter progression-free and overall survival durations (P<0.05).CONCLUSIONS: Everolimus, letrozole, and trastuzumab has a favorable safety profile and elicits encouraging signals of anticancer activity in patients with heavily pretreated hormone receptor-and HER2-positive advanced cancers.
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U2 - 10.1158/1078-0432.CCR-20-2878
DO - 10.1158/1078-0432.CCR-20-2878
M3 - Article
C2 - 33115815
SN - 1078-0432
VL - 27
SP - 1247
EP - 1255
JO - Clinical cancer research : an official journal of the American Association for Cancer Research
JF - Clinical cancer research : an official journal of the American Association for Cancer Research
IS - 5
ER -