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A Phase 1b Study of Savolitinib Plus Gefitinib for Patients with EGFR-Mutated MET-Amplified Advanced Non-Small-Cell Lung Cancer

40 Pages Posted: 20 Jan 2020

See all articles by Jin-Ji Yang

Jin-Ji Yang

Guangdong Academy of Medical Sciences - Guangdong Lung Cancer Institute

Jian Fang

Beijing Cancer Hospital

Yong-Qian Shu

Nanjing Medical University - Department of Oncology

Jian-Hua Chang

Fudan University

Gong-Yan Chen

Harbin Medical University - Cancer Hospital

Jian Xing He

Guangzhou Medical University - First Affiliated Hospital

Wei Li

Jilin University (JLU) - First Affiliated Hospital

Xiao-Qing Liu

Government of the People's Republic of China - 307th Hospital

Nong Yang

Central South University - Hunan Cancer Hospital

Caicun Zhou

Tongji University - Shanghai Pulmonary Hospital

Jian An Huang

Soochow University - First Affiliated Hospital

Melanie M. Frigault

AstraZeneca Pharmaceuticals - United States

Ryan Hartmaier

AstraZeneca Pharmaceuticals - United States

Ghada F. Ahmed

AstraZeneca Pharmaceuticals - United Kingdom

Coumaran Egile

AstraZeneca Pharmaceuticals - United Kingdom

Shethah Morgan

AstraZeneca Pharmaceuticals - United Kingdom

Remy B. Verheijen

AstraZeneca Pharmaceuticals - United Kingdom

Anders Mellemgaard

AstraZeneca Pharmaceuticals - United Kingdom

Liu Yang

AstraZeneca Pharmaceuticals - China

Yi-Long Wu

Guangdong Academy of Medical Sciences - Guangdong Lung Cancer Institute; Guangdong Academy of Medical Sciences, Guangdong General Hospital, Guangdong Lung Cancer Institute, Department of Pulmonary Oncology

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Abstract

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are recommended first-line treatments in EGFR- mutated non-small-cell lung cancer (NSCLC). However, acquired resistance (e.g. MET amplification) is common. Savolitinib (volitinib, HMPL-504, AZD6094) is an oral, potent, and highly selective MET-TKI.

Methods: In this phase 1b, open-label, multicentre study, we enrolled Chinese patients with EGFR-mutated, advanced NSCLC, whose disease progressed during or after treatment with prior EGFR-TKIs. In the safety run-in, patients received savolitinib 600 or 800 mg plus gefitinib 250 mg orally, once-daily and dose-limiting toxicities were recorded. In the expansion phase, patients with MET amplification received savolitinib plus gefitinib. The primary endpoints were safety and tolerability. Secondary endpoints included antitumour activity and pharmacokinetics.

Findings: No dose-limiting toxicities were reported in either dose group during the safety run-in (n=13). Savolitinib 600 mg plus gefitinib 250 mg once daily was selected as the recommended phase 2 dose and evaluated in the expansion phase (n=51). The objective response rates in EGFR T790M-negative, -positive and -unknown patients were 52% (12/23), 9% (2/23), and 40% (2/5), respectively. Thirty-five patients (69%) were evaluable for longitudinal circulating tumour DNA analysis. Pharmacokinetic parameters for savolitinib plus gefitinib were consistent with previous monotherapy studies, showing no evidence of drug-drug interactions. Adverse events of grade 3 or more in the safety run-in and expansion phases (n=57) were reported in 21 (37%) patients. The most common adverse events (all grades) were: vomiting (n=26, 46%), nausea (n=23, 40%), increased aspartate aminotransferase (n=22, 39%). There were four deaths, none treatment-related.

Interpretation: Savolitinib 600 mg plus gefitinib 250 mg once daily had an acceptable safety profile and demonstrated promising antitumour activity in EGFR-mutated, MET- amplified advanced NSCLC patients who had progressed on EGFR-TKIs.

Trial Registration: NCT02374645.

Funding Statement: The study was funded by AstraZeneca, Cambridge, UK, the manufacturer of savolitinib and gefitinib. Hutchison MediPharma authorised AstraZeneca to conduct this study.

Declaration of Interests: MF, RH, GFA, CE, SM, RBV and AM are AstraZeneca employees and shareholders. RH also owns shares in Foundation medicine, and has a patent pending for Foundation Medicine. MF is also a patent holder for AstraZeneca. Y-LW has received personal fees from AstraZeneca, Roche, Boehringer Ingeiheim, Pfizer, Bristol-Myers Squibb, Merck Sharp & Dohme, and Sanofi; and grants from AstraZeneca, Roche, and Boehringer Ingelheim. J-JY, JF, Y-QS, J-HC, G-YC, J-XH, WL, X-QL, NY, CZ, J-AH and LY declare no conflicts of interest.

Ethics Approval Statement: The study was approved by Institutional Review Boards/Independent Ethics Committees at each study centre, and by the Human Genetics Resources Administration of China. The trial was conducted in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines, the provisions of the Declaration of Helsinki, applicable regulatory requirements, and the AstraZeneca policy on Bioethics and Human Biological Samples. All patients provided written informed consent before study procedures.

Keywords: Savolitinib; Gefitinib; EGFR-TKI; NSCLC; China; MET

Suggested Citation

Yang, Jin-Ji and Fang, Jian and Shu, Yong-Qian and Chang, Jian-Hua and Chen, Gong-Yan and He, Jian Xing and Li, Wei and Liu, Xiao-Qing and Yang, Nong and Zhou, Caicun and Huang, Jian An and Frigault, Melanie M. and Hartmaier, Ryan and Ahmed, Ghada F. and Egile, Coumaran and Morgan, Shethah and Verheijen, Remy B. and Mellemgaard, Anders and Yang, Liu and Wu, Yi-Long, A Phase 1b Study of Savolitinib Plus Gefitinib for Patients with EGFR-Mutated MET-Amplified Advanced Non-Small-Cell Lung Cancer (January 6, 2020). Available at SSRN: https://ssrn.com/abstract=3514754 or http://dx.doi.org/10.2139/ssrn.3514754

Jin-Ji Yang

Guangdong Academy of Medical Sciences - Guangdong Lung Cancer Institute

China

Jian Fang

Beijing Cancer Hospital

Beijing
China

Yong-Qian Shu

Nanjing Medical University - Department of Oncology

China

Jian-Hua Chang

Fudan University

Beijing West District Baiyun Load 10th
Shanghai, 100045
China

Gong-Yan Chen

Harbin Medical University - Cancer Hospital

China

Jian Xing He

Guangzhou Medical University - First Affiliated Hospital

1 Kangda Rd
BinJiang Lu, Haizhu Qu
Guangzhou Shi, Guangdong Sheng 510230
China

Wei Li

Jilin University (JLU) - First Affiliated Hospital

71 Xinmin Street
Changchun, Jilin 130021
China

Xiao-Qing Liu

Government of the People's Republic of China - 307th Hospital

China

Nong Yang

Central South University - Hunan Cancer Hospital

Changsha, 410013
China

Caicun Zhou

Tongji University - Shanghai Pulmonary Hospital

507 Zhengmin Rd
Shanghai, Shanghai Shi
China

Jian An Huang

Soochow University - First Affiliated Hospital

Suzhou
China

Melanie M. Frigault

AstraZeneca Pharmaceuticals - United States

United States

Ryan Hartmaier

AstraZeneca Pharmaceuticals - United States

United States

Ghada F. Ahmed

AstraZeneca Pharmaceuticals - United Kingdom

Cambridge
United Kingdom

Coumaran Egile

AstraZeneca Pharmaceuticals - United Kingdom

Cambridge
United Kingdom

Shethah Morgan

AstraZeneca Pharmaceuticals - United Kingdom

Cambridge
United Kingdom

Remy B. Verheijen

AstraZeneca Pharmaceuticals - United Kingdom

Cambridge
United Kingdom

Anders Mellemgaard

AstraZeneca Pharmaceuticals - United Kingdom

Cambridge
United Kingdom

Liu Yang

AstraZeneca Pharmaceuticals - China

China

Yi-Long Wu (Contact Author)

Guangdong Academy of Medical Sciences - Guangdong Lung Cancer Institute ( email )

China

Guangdong Academy of Medical Sciences, Guangdong General Hospital, Guangdong Lung Cancer Institute, Department of Pulmonary Oncology ( email )

China

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