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A phase Ib study of the highly selective MET-TKI savolitinib plus gefitinib in patients with EGFR-mutated, MET-amplified advanced non-small-cell lung cancer

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Summary

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are recommended first-line treatments in EGFR-mutated (EGFRm) non-small-cell lung cancer (NSCLC). However, acquired resistance (e.g. MET amplification) is frequently observed. Savolitinib (volitinib, HMPL-504, AZD6094) is an oral, potent, and highly selective MET-TKI. In this phase Ib, open-label, multicenter study, we enrolled Chinese patients with EGFRm advanced NSCLC, whose disease progressed following prior EGFR-TKI treatment. 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 endpoint was safety/tolerability. Secondary endpoints included antitumor activity. Thirteen patients were enrolled in the safety phase (median age 52 years, 46% female) and 51 enrolled in the expansion phase (median age 61 years, 67% female). No dose-limiting toxicities were reported in either dose group during the safety run-in. Adverse events of grade ≥ 3 in the safety run-in and expansion phases (n = 57) were reported in 21 (37%) patients. The most frequently reported adverse events (all grades) were: vomiting (n = 26, 46%), nausea (n = 23, 40%), increased aspartate aminotransferase (n = 22, 39%). Of four deaths, none were treatment-related. The objective response rates in EGFR T790M-negative, −positive, and -unknown patients were 52% (12/23), 9% (2/23), and 40% (2/5), respectively. Savolitinib 600 mg plus gefitinib 250 mg once daily had an acceptable safety profile and demonstrated promising antitumor activity in EGFRm, MET-amplified advanced NSCLC patients who had disease progression on EGFR-TKIs. NCT02374645, Date of registration: March 2nd 2015.

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Acknowledgments

We thank all the patients who participated in this study and their families, as well as the staff and investigators at all of the study sites. We would also like to thank Julia DeCesare for her contribution in management of the study, Xinying Su for her help in overseeing the central testing of MET, Harry Yang for expert advice on the Human Genetics Resources Administration of China, Song Ren for her help with managing and reporting pharmacokinetic data and Paul Frewer for assistance with statistical analysis. Medical writing support funded by AstraZeneca in accordance with Good Publications Practice (GPP3) guidelines (http://www.ismpp.org/gpp3) was provided by Bernadette Tynan, MSc, on behalf of Ashfield Healthcare communications, Macclesfield, UK, part of UDG Healthcare plc.

Role of the funder/sponsor

AstraZeneca were involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication and as such are included in the author list and acknowledgments.

Data sharing statement

Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca’s data sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Funding

The study (NCT02374645) was funded by AstraZeneca, Cambridge, UK, the manufacturer of savolitinib and gefitinib. Hutchison MediPharma authorized AstraZeneca to conduct this study.

Author information

Authors and Affiliations

  1. Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital and Guangdong Academy of Medical Sciences, 106 Zhongshan Er Rd, Guangzhou, 510080, China

    Jin-Ji Yang & Yi-Long Wu

  2. Beijing Cancer Hospital, Beijing, China

    Jian Fang

  3. Department of Oncology, First Affiliated Hospital, Nanjing Medical University, Nanjing, China

    Yong-Qian Shu

  4. Fudan University Cancer Hospital, Shanghai, China

    Jian-Hua Chang

  5. Harbin Medical University Cancer Hospital, Harbin, China

    Gong-Yan Chen

  6. The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China

    Jian Xing He

  7. The First Hospital of Jilin University, Changchun, China

    Wei Li

  8. 307th Hospital of Chinese People’s Liberation Army, Beijing, China

    Xiao-Qing Liu

  9. Hunan Cancer Hospital, Changsha, China

    Nong Yang

  10. Shanghai Pulmonary Hospital, Shanghai, China

    Caicun Zhou

  11. The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China

    Jian An Huang

  12. Translational Medicine, Oncology R&D, AstraZeneca, Boston, MA, USA

    Melanie M. Frigault & Ryan Hartmaier

  13. Formerly: Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK

    Ghada F. Ahmed

  14. Precision Medicine, R&D Oncology, AstraZeneca, Cambridge, UK

    Coumaran Egile

  15. Late Phase Oncology R&D, AstraZeneca, Cambridge, UK

    Shethah Morgan & Anders Mellemgaard

  16. Formerly: Late Phase Oncology R&D, AstraZeneca, Cambridge, UK

    Remy B. Verheijen

  17. Global Medicines Development, Oncology, AstraZeneca, Shanghai, China

    Liu Yang

Authors
  1. Jin-Ji Yang
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  2. Jian Fang
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  19. Liu Yang
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Contributions

Yi-Long Wu (International co-ordinating investigator) had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Dr. Jin-Ji Yang, Dr. Yong-Qian Shu, Dr. Caicun Zhou, Dr. Melanie M. Frigault, Dr. Coumaran Egile, Dr. Shethah Morgan and Dr. Yi-Long Wu designed the study.

Dr. Jin-Ji Yang, Mr. Jian Fang, Dr. Yong-Qian Shu, Dr. Jian-Hua Chang, Dr. Gong-Yan Chen, Dr. Jian Xing He, Dr. Wei Li, Ms. Xiao-Qing Liu, Dr. Nong Yang, Dr. Caicun Zhou, Dr. Jian An Huang, Dr. Melanie M. Frigault, Dr. Ryan Hartmaier, Dr. Shethah Morgan and Dr. Remy B. Verheijen collected the data.

Dr. Jin-Ji Yang, Dr. Yong-Qian Shu, Dr. Melanie M. Frigault, Dr. Ghada F. Ahmed, Dr. Coumaran Egile, Dr. Shethah Morgan, Dr. Remy B. Verheijen, Dr. Anders Mellemgaard, Ms. Liu Yang and Dr. Yi-Long Wu analyzed and interpreted the study data.

All authors critically reviewed the manuscript and approved the final version for submission.

Corresponding author

Correspondence to Yi-Long Wu.

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Conflict of interest

Melanie M. Frigault, Ryan Hartmaier, Ghada F. Ahmed, Coumaran Egile, Shethah Morgan, Remy B. Verheijen and Anders Mellemgaard are AstraZeneca employees and shareholders. Ryan Hartmaier also owns shares in Foundation Medicine, and has a patent pending for Foundation Medicine. Melanie M. Frigault is also a patent holder for AstraZeneca. Yi-Long Wu has received personal fees from AstraZeneca, Roche, Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, Merck Sharp & Dohme, and Sanofi; and grants from AstraZeneca, Roche, and Boehringer Ingelheim. Jin-Ji Yang declares no conflict of interest. Jian Fang declares no conflict of interest. Yong-Qian Shu declares no conflict of interest. Jian-Hua Chang declares no conflict of interest. Jian Xing He declares no conflict of interest. Wei Li declares no conflict of interest. Xiao-Qing Liu declares no conflict of interest. Nong Yang declares no conflict of interest. Caicun Zhou declares no conflict of interest. Jian An Huang declares no conflict of interest. Liu Yang declares no conflict of interest. No other disclosures were reported.

Ethical approval

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Yang, JJ., Fang, J., Shu, YQ. et al. A phase Ib study of the highly selective MET-TKI savolitinib plus gefitinib in patients with EGFR-mutated, MET-amplified advanced non-small-cell lung cancer. Invest New Drugs 39, 477–487 (2021). https://doi.org/10.1007/s10637-020-01010-4

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