TY - JOUR
T1 - A phase I study of LY3164530, a bispecific antibody targeting MET and EGFR, in patients with advanced or metastatic cancer
AU - Patnaik, Amita
AU - Gordon, Michael
AU - Tsai, Frank
AU - Papadopoulous, Kyri
AU - Rasco, Drew
AU - Beeram, S. Muralidhar
AU - Fu, Siqing
AU - Janku, Filip
AU - Hynes, Scott M.
AU - Gundala, Sushma R.
AU - Willard, Melinda D.
AU - Zhang, Wei
AU - Lin, Aimee Bence
AU - Hong, David
N1 - Funding Information:
This study was supported by Eli Lilly and Company. The authors would like to thank all of the patients and their families for participation in the study; the study coordinators, nurses, nurse practitioners, clinical research assistants, and doctors who assisted with the research; Tonya Quinlan and John R. Baldwin of Eli Lilly and Company for for the PK/PD data analysis; Erin Wagner of BioStat Solutions for assistance with the biomarker data; Meghan Greenwood of Syneos Health for writing assistance; Antonia Baldo and Teri Tucker of Syneos Health for editorial assistance; and the preclinical colleagues who provided supporting data including Ling Liu, Wei Zeng, Marcio Chedid, Yi Zheng, Sheng-Hung Tschang, Yu Tian, Ying Tang and Jirong Lu. AP has received institutional research funding from Eli Lilly. MG reports a pending patent on clinical trial decision-making. DR has served on a scientific advisory board for Eli Lilly. SF has received clinical study support from Aneropharma Science, Inc, Aprea AB, AstraZeneca, Eli Lilly, Endocyte, Ignyta, Millennium, NCCI, Novartis, OncoMed Pharmaceuticals, Inc, Vertex Pharmaceuticals, Inc, and Hengrui. FJ has received grant funding from Symphogen and Deciphera. SH, SRG, MDW, WZ, and ABL are employees and stockholders of Eli Lilly. ABL’s spouse is also an employee and stockholder of Eli Lilly. DH has received grant funding from Bayer, Eli Lilly, Genentech, LOXO, Pfizer, Amgen, Mirati, Ignyta, Merck, Daichii-Sanko, Eisai, and Mirno; travel fees from Mirna and LOXO; served as a consultant/advisor for Bayer, Baxter, and Guidepoint Global; and is the owner and founder of Oncoresponse. All other authors have no conflict of interest.
Funding Information:
Acknowledgements This study was supported by Eli Lilly and Company. The authors would like to thank all of the patients and their
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/9/1
Y1 - 2018/9/1
N2 - Purpose: The phase I study characterized the safety, pharmacokinetics, anti-tumor activity, and recommended phase II dose/schedule of LY3164530 in patients with advanced or metastatic cancer. Methods: Patients received LY3164530 on days 1 and 15 (Schedule 1: 300, 600, 1000, and 1250 mg) or Days 1, 8, 15, and 22 (Schedule 2: 500 and 600 mg) of each 28 days cycle. Dose escalation used a modified toxicity probability interval model. Results: Dose escalation defined a maximum tolerated dose (MTD) of 1000 mg on Schedule 1 and 500 mg on Schedule 2. Treatment-emergent adverse events related to study treatment were consistent with epidermal growth factor receptor (EGFR) inhibition and included maculopapular rash/dermatitis acneiform (83%, Grade 3/4 17%), hypomagnesemia (55%, Grade 3/4 7%), paronychia (35%), fatigue (28%, Grade 3/4 3%), skin fissures (24%), and hypokalemia (21%, Grade 3/4 7%). Partial response was achieved in three patients on Schedule 2 with colorectal cancer (n = 2) or squamous cell cancer. Overall response rate (ORR) was 10.3%, disease control rate (ORR + stable disease [SD]) was 51.7 and 17.2% of patients had SD ≥ 4 months. The in vivo stability of the bispecific antibody was confirmed. Schedule 2 provided greater and more consistent inhibition of mesenchymal-epithelial transition (MET)/EGFR throughout the dosing interval than Schedule 1. Conclusions: Although this study defined the LY3164530 MTD and pharmacokinetics on both schedules, significant toxicities associated with EGFR inhibition and lack of a potential predictive biomarker limit future development. Nonetheless, the results provide insight into the development of bispecific antibody therapy.
AB - Purpose: The phase I study characterized the safety, pharmacokinetics, anti-tumor activity, and recommended phase II dose/schedule of LY3164530 in patients with advanced or metastatic cancer. Methods: Patients received LY3164530 on days 1 and 15 (Schedule 1: 300, 600, 1000, and 1250 mg) or Days 1, 8, 15, and 22 (Schedule 2: 500 and 600 mg) of each 28 days cycle. Dose escalation used a modified toxicity probability interval model. Results: Dose escalation defined a maximum tolerated dose (MTD) of 1000 mg on Schedule 1 and 500 mg on Schedule 2. Treatment-emergent adverse events related to study treatment were consistent with epidermal growth factor receptor (EGFR) inhibition and included maculopapular rash/dermatitis acneiform (83%, Grade 3/4 17%), hypomagnesemia (55%, Grade 3/4 7%), paronychia (35%), fatigue (28%, Grade 3/4 3%), skin fissures (24%), and hypokalemia (21%, Grade 3/4 7%). Partial response was achieved in three patients on Schedule 2 with colorectal cancer (n = 2) or squamous cell cancer. Overall response rate (ORR) was 10.3%, disease control rate (ORR + stable disease [SD]) was 51.7 and 17.2% of patients had SD ≥ 4 months. The in vivo stability of the bispecific antibody was confirmed. Schedule 2 provided greater and more consistent inhibition of mesenchymal-epithelial transition (MET)/EGFR throughout the dosing interval than Schedule 1. Conclusions: Although this study defined the LY3164530 MTD and pharmacokinetics on both schedules, significant toxicities associated with EGFR inhibition and lack of a potential predictive biomarker limit future development. Nonetheless, the results provide insight into the development of bispecific antibody therapy.
KW - Bispecific
KW - EGFR
KW - MET
KW - Phase I
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U2 - 10.1007/s00280-018-3623-7
DO - 10.1007/s00280-018-3623-7
M3 - Article
C2 - 29926131
AN - SCOPUS:85048744520
SN - 0344-5704
VL - 82
SP - 407
EP - 418
JO - Cancer chemotherapy and pharmacology
JF - Cancer chemotherapy and pharmacology
IS - 3
ER -