TY - JOUR
T1 - Phase I Study of AMG 337, a Highly Selective Small-molecule MET Inhibitor, in Patients with Advanced Solid Tumors
AU - Hong, David S.
AU - LoRusso, Patricia
AU - Hamid, Omid
AU - Janku, Filip
AU - Kittaneh, Muaiad
AU - Catenacci, Daniel V.T.
AU - Chan, Emily
AU - Bekaii-Saab, Tanios
AU - Gadgeel, Shirish M.
AU - Loberg, Robert D.
AU - Amore, Benny M.
AU - Hwang, Yuying C.
AU - Tang, Rui
AU - Ngarmchamnanrith, Gataree
AU - Kwak, Eunice L.
N1 - Funding Information:
The authors would like to acknowledge Min Yi and Hui Yang (Biostatistical Sciences, Amgen Inc.) for providing biostatistical support. The authors would also like to acknowledge Meghan E. Johnson, PhD, and James Balwit, MS, CMPP (both Complete Healthcare Communications, LLC, an ICON plc company, North Wales, PA), whose work was funded by Amgen Inc., and Jenilyn J. Virrey, PhD, and Micah Robinson, PhD (both Amgen Inc.), for assistance in writing this manuscript, as well as Isabelle Dussault, PhD, and Darrin Beaupre, MD, PhD (both Amgen Inc.), for their contributions to the preclinical and early development of AMG 337. This study was sponsored by Amgen Inc.
Funding Information:
ownership interest (including patents) in Molecular Match, OncoResponse, and Presagia Inc.; is a consultant/advisory board member for Bayer, Alpha Insights, Axiom, Adaptimmune, Baxter, Genentech, GLG, Group H, Guide-point Global, Infinity, Janssen, Merrimack, Medscape, Numab, Pfizer, Seattle Genetics, Takeda, Trieza Therapeutics; and reports other remuneration in the form of travel accommodations and expenses from LOXO and MiRNA. P.M. LoRusso is a consultant/advisory board member for AbbVie, Roche/ Genentech, Agenus, Ipsen, Pfizer, Genmab, Bayer, Agios, Menarini, SOTIO, IMAB, CytomX, Five Prime, and Takeda. O. Hamid is a consultant/advisory board member for and reports receiving speakers bureau honoraria from Amgen. F. Janku reports receiving commercial research grants from Agios, BioMed Valley Discoveries, Novartis, Symphogen, Astellas, FujiFilm Pharma, and Piqur, and is a consultant/advisory board member for Deciphera. D.V.T. Catenacci reports receiving speakers bureau honoraria from Amgen, Lilly, Merck, Bristol-Myers Squibb, Taiho, Astellas, Roche, Gritstone, Guardant Health, and Five Prime, and is a consultant/advisory board member for Astellas, Merck, and Amgen. E. Chan is an employee of and holds ownership interest (including patents) in Amgen. T. Bekaii-Saab is a consultant/ advisory board member for Amgen, Bayer, Genentech, Roche, Seattle Genetics, Imugene, Immuneering, and Merck, and reports receiving other remuneration from Armo DSMB and Silajen DSMB. S. Gadgeel reports receiving other commercial research support from Merck and is a consultant/advisory board member for Bristol-Myers Squibb, Genentech/Roche, Takeda/Ariad, AbbVie, and AstraZeneca. R.D. Loberg is an employee of and holds ownership interest (including patents) in Amgen. B.M. Amore holds ownership interest (including patents) in Amgen. Y.C. Hwang is an employee of and holds ownership interest (including patents) in Amgen. G. Ngarmchamnanrith is an employee of and holds ownership interest (including patents) in Amgen. E.L. Kwak is an employee of Novartis Institutes for Biomedical research and reports receiving other commercial research support from Amgen. No potential conflicts of interest were disclosed by the other authors.
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2019/4/15
Y1 - 2019/4/15
N2 - Purpose: This first-in-human, open-label phase I study evaluated AMG 337, an oral, highly selective small-molecule inhibitor of MET in advanced solid tumors. Patients and Methods: Patients enrolled into dose-escalation cohorts received AMG 337 up to 400 mg once daily or up to 250 mg twice daily, following a modified 3þ3þ3 design. Dose expansion was conducted in MET-amplified patients at the maximum tolerated dose (MTD). Primary endpoints included assessment of adverse events (AEs), establishment of the MTD, and pharmacokinetics; clinical response was a secondary endpoint. Results: The safety analysis set included 111 patients who received 1 dose of AMG 337. Thirteen patients had 1 AE qualifying as dose-limiting toxicity. The MTD was determined to be 300 mg once daily; the MTD for twice-daily dosing was not reached. Most frequent treatment-related AEs were headache (63%) and nausea (31%). Grade 3 treatment-related AEs occurred in 23 patients (21%), most commonly headache (n ¼ 6) and fatigue (n ¼ 5). Maximum plasma concentration occurred at 3.0 hours following 300-mg once-daily dosing, indicating AMG 337 absorption soon after treatment. Objective response rate was 9.9% (11/111; 95% CI, 5.1%–17.0%) in all patients and 29.6% (8/27; 95% CI, 13.8%–50.2%) in MET-amplified patients; median (range) duration of response was 202 (51–1,430þ) days in all patients and 197 (64–1,430þ) days in MET-amplified patients. Conclusions: Oral AMG 337 was tolerated with manageable toxicities, with an MTD and recommended phase II dose of 300 mg once daily. The promising response rate observed in patients with heavily pretreated MET-amplified tumors warrants further investigation.
AB - Purpose: This first-in-human, open-label phase I study evaluated AMG 337, an oral, highly selective small-molecule inhibitor of MET in advanced solid tumors. Patients and Methods: Patients enrolled into dose-escalation cohorts received AMG 337 up to 400 mg once daily or up to 250 mg twice daily, following a modified 3þ3þ3 design. Dose expansion was conducted in MET-amplified patients at the maximum tolerated dose (MTD). Primary endpoints included assessment of adverse events (AEs), establishment of the MTD, and pharmacokinetics; clinical response was a secondary endpoint. Results: The safety analysis set included 111 patients who received 1 dose of AMG 337. Thirteen patients had 1 AE qualifying as dose-limiting toxicity. The MTD was determined to be 300 mg once daily; the MTD for twice-daily dosing was not reached. Most frequent treatment-related AEs were headache (63%) and nausea (31%). Grade 3 treatment-related AEs occurred in 23 patients (21%), most commonly headache (n ¼ 6) and fatigue (n ¼ 5). Maximum plasma concentration occurred at 3.0 hours following 300-mg once-daily dosing, indicating AMG 337 absorption soon after treatment. Objective response rate was 9.9% (11/111; 95% CI, 5.1%–17.0%) in all patients and 29.6% (8/27; 95% CI, 13.8%–50.2%) in MET-amplified patients; median (range) duration of response was 202 (51–1,430þ) days in all patients and 197 (64–1,430þ) days in MET-amplified patients. Conclusions: Oral AMG 337 was tolerated with manageable toxicities, with an MTD and recommended phase II dose of 300 mg once daily. The promising response rate observed in patients with heavily pretreated MET-amplified tumors warrants further investigation.
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U2 - 10.1158/1078-0432.CCR-18-1341
DO - 10.1158/1078-0432.CCR-18-1341
M3 - Article
C2 - 30425090
AN - SCOPUS:85064768094
SN - 1078-0432
VL - 25
SP - 2403
EP - 2413
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 8
ER -