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Phase 1b study of ramucirumab in combination with erlotinib or osimertinib for untreated EGFR-mutated non–small cell lung cancer patients with asymptomatic brain metastases

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Summary

Objectives: The study was designed to investigate the safety of ramucirumab administered in combination with erlotinib or osimertinib for patients with untreated EGFR-mutated non–small cell lung cancer (NSCLC) and asymptomatic brain metastases, a patient subgroup in which these regimens have remained untested. Materials and methods: This phase 1b study (RELAY-Brain) consisted of two cohorts with three patients each. Patients with asymptomatic brain metastases received ramucirumab every 2 weeks plus either daily oral erlotinib or osimertinib until disease progression or intolerable toxicity. The primary objective was to assess dose-limiting toxicity (DLT), defined as central nervous system (CNS) hemorrhage of grade ≥ 2. Results: Six patients were enrolled. Neither DLT nor serious or unexpected adverse events were observed. One treatment-related adverse event of grade ≥ 3 (hypertension of grade 3) was apparent. Common adverse events were generally manageable. The median number of ramucirumab administrations was 18.5 (range, 13 to 31), and there were no detected episodes of CNS hemorrhage. Five of the six patients showed an objective systemic response. Although only one patient had a measurable CNS lesion at baseline, a confirmed intracranial partial response was observed. Conclusion: Ramucirumab in combination with erlotinib or osimertinib showed safety for EGFR-mutated NSCLC with brain metastases.

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Acknowledgements

This study was conducted with support from both the Translational Research Center for Medical Innovation, Foundation for Biomedical Research and Innovation at Kobe, Japan, and the Center for Clinical Research and Innovation, Osaka City University hospital, Osaka, Japan. We thank Chikako Minami and Mieko Nishiu as members of the study support staff.

Funding

This work was supported by Eli Lilly and Company.

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Authors and Affiliations

  1. Department of Clinical Oncology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan

    Hiroyasu Kaneda, Yoko Tani, Shigeki Mitsuoka & Tomoya Kawaguchi

  2. Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan

    Kenji Sawa, Yoshiya Matsumoto, Koichi Ogawa, Kenji Nakahama, Motohiro Izumi & Tomoya Kawaguchi

  3. Department of Medical Oncology, Osaka City General Hospital, Osaka, Japan

    Haruko Daga, Asuka Okada & Yuki Nakatani

  4. Department of Thoracic Oncology, National Hospital Organization Kinki-Chuo Chest Medical Center, Sakai, Japan

    Shinji Atagi & Kyoichi Okishio

Authors
  1. Hiroyasu Kaneda
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  2. Kenji Sawa
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  3. Haruko Daga
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  4. Asuka Okada
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  5. Yuki Nakatani
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  6. Shinji Atagi
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  7. Kyoichi Okishio
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  8. Yoko Tani
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  9. Yoshiya Matsumoto
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  10. Koichi Ogawa
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  11. Kenji Nakahama
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  12. Motohiro Izumi
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  13. Shigeki Mitsuoka
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  14. Tomoya Kawaguchi
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Contributions

H.K. and K.S. participated in the conception and design of this study. H.K had a funding acquisition. H.K drafted the article. All authors critically reviewed and contributed to all drafts, approved the final version, and made the decision to submit the report for publication.

Corresponding author

Correspondence to Hiroyasu Kaneda.

Ethics declarations

Ethics approval

The study was approved by the institutional review board of each participating institution and was conducted in compliance with the ethical principles of the Declaration of Helsinki, the International Council for Harmonisation Good Clinical Practice Guideline, and applicable local regulations.

Informed consent

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

Conflict of interest

Dr. Kaneda reports grants from Eli Lilly, during the conduct of the study; personal fees from Chugai, Astrazeneca, Novartis Pharma, Bristol-Myers Squibb, Ono, Boehringer Ingelheim, MSD, Taiho, Pfizer, Nippon KAYAKU, and Merck, outside the submitted work. Dr. Sawa reports personal fees from Chugai Pharmaceutical, Daiichi Sankyo, and Nippon Boehringer Ingelheim, all outside the submitted work. Dr. Daga reports personal fees from Chugai, and Ono; grants from Astrazeneca, all outside the submitted work. Dr. Atagi reports grants and personal fees from AstraZeneca, Ono, Taiho Pharmaceutical, Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, MSD, Eli Lilly, Chugai, and Merck; grants and non-financial support from F. Hoffmann-La Roche; personal fees from Hisamitsu, Kyowa Hakko Kirin, Novartis Pharma, and Thermo Fisher Scientific, all outside the submitted work. Dr. Mitsuoka reports personal fees from Ono, Bristol-Myers Squibb, and Kyowa Hakko Kirin; grants from Taiho Pharmaceutical, all outside the submitted work. Dr. Kawaguchi reports grants and personal fees from Chugai Pharma, Taiho Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, and Bristol-Myers Squibb Japan; grants, personal fees and non-financial support from Eli Lilly; personal fees from Astra Zeneca, MSD Oncology, Pfizer, Novartis, and Astellas Pharma; grants from Daiichi Sankyo,all outside the submitted work. All remaining authors have declared no conflicts of interest.

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Kaneda, H., Sawa, K., Daga, H. et al. Phase 1b study of ramucirumab in combination with erlotinib or osimertinib for untreated EGFR-mutated non–small cell lung cancer patients with asymptomatic brain metastases. Invest New Drugs 39, 1598–1603 (2021). https://doi.org/10.1007/s10637-021-01147-w

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  • DOI: https://doi.org/10.1007/s10637-021-01147-w

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