Clinical Trial Protocol

Continuation of osimertinib in EGFR-mutant non-small-cell lung cancer patients bearing CNS metastasis (EPONA study)

https://orcid.org/0000-0001-5743-0149

Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan

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Shogo Nomura

Department of Biostatistics & Bioinformatics, The University of Tokyo, Tokyo, Japan

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Kiichiro Ninomiya

Department of Hematology, Oncology & Respiratory Medicine, Okayama University, Okayama, Japan

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Hiroshi Gyotoku

https://orcid.org/0000-0002-5026-8078

Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

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Shuji Murakami

https://orcid.org/0000-0001-5104-5493

Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama, Japan

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Yoshihito Kogure

https://orcid.org/0000-0001-7935-7202

Department of Respiratory Medicine, National Hospital Organization Nagoya Medical Center, Nagoya, Japan

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Daijiro Harada

https://orcid.org/0000-0002-5314-2489

Department of Thoracic Oncology & Medicine, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan

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Kyoichi Okishio

Department of Internal Medicine, National Hospital Organization Kinki-chuo Chest Medical Center, Sakai, Japan

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Hiroaki Okamoto

https://orcid.org/0000-0003-3110-5545

Department of Respiratory Medicine & Medical Oncology, Yokohama Municipal Citizen's Hospital, Yokohama, Japan

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Yasushi Goto

*Author for correspondence: Tel.: +81 354 225 11;

E-mail Address: ygoto@ncc.go.jp

https://orcid.org/0000-0002-7437-5054

Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan

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Published Online:14 Aug 2023https://doi.org/10.2217/fon-2022-1128

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Abstract

The patients harboring EGFR-mutated non-small-cell lung cancer, treated with EGFR tyrosine kinase inhibitor will lead to longer survival than those having non-small-cell lung cancer (NSCLC) patient who do not harbor EGFR mutations. This ongoing clinical trial is to investigate the secondary chemoprevention effect of osimertinib from CNS with platinum doublets chemotherapy in patients who had progressive disease outside of CNS lesions. The aim of this randomized, phase II trial is to evaluate platinum and pemetrexed chemotherapy followed by pemetrexed maintenance with or without continuation of osimertinib for secondary CNS prevention in patients with brain metastatic NSCLC with EGFR mutation, with other than CNS lesions, but no progressive disease in the CNS lesion after osimertinib. The primary end point is to assess progression-free survival by investigator assessment. The key secondary end points are overall survival, response rate, time to CNS controlling, time to whole-brain irradiation and safety.

Clinical trial registration: Japan Registry of Clinical Trials (jRCT), Japan (jRCTs071200029)

Plain language summary

The authors are conducting a clinical trial aimed at improving treatment for individuals diagnosed with non-small-cell lung cancer, a specific type of lung cancer. In some cases, this cancer can spread to the brain. This study focuses on patients whose cancer is stable in the brain but progressing in other parts of the body. The study is comparing two different treatment approaches. One involves a combination of two drugs, platinum and pemetrexed, while the other combines these drugs with a third one called osimertinib. The main objective is to determine if continuing osimertinib treatment benefits these patients. The authors are evaluating the time it takes for the cancer to start growing again, known as progression-free survival, to identify the most effective treatment. Progression-free survival represents the duration that patients live without their disease worsening. This study, the EPONA study, will provide valuable insights into optimizing the treatment of this type of cancer.

Tweetable abstract

This randomized, phase II study is evaluating chemotherapy +/- the continuation of osimertinib for EGFR-mutant non-small-cell lung cancer patients bearing CNS metastasis and having systemic progressive disease outside of brain metastasis.

Keywords:

Papers of special note have been highlighted as: •• of considerable interest

References

1. Sequist LV, Soria JC, Goldman JW et al. Rociletinib in EGFR-mutated non-small-cell lung cancer. N. Engl. J. Med. 372(18), 1700–1709 (2015).
MedlineGoogle Scholar
2. Janne PA, Yang JC, Kim DW et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N. Engl. J. Med. 372(18), 1689–1699 (2015).
MedlineGoogle Scholar
3. Engelman JA, Janne PA. Mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Clin. Cancer Res. 14(10), 2895–2899 (2008).
MedlineGoogle Scholar
4. Soria JC, Ohe Y, Vansteenkiste J et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N. Engl. J. Med. 378(2), 113–125 (2018). •• Double-blind, randomized, multicenter, international, phase III trial (FLAURA) reporting the efficacy and safety of osimertinib versus standard-of-care EGFR tyrosine kinase inhibitors as the first-line therapy in previously untreated patients with EGFR+ non-small-cell lung cancer.
Medline CASGoogle Scholar
5. Scagliotti GV, Parikh P, von Pawel J et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J. Clin. Oncol. 26(21), 3543–3551 (2008).
Medline CASGoogle Scholar
6. Okamoto I, Aoe K, Kato T et al. Pemetrexed and carboplatin followed by pemetrexed maintenance therapy in chemo-naive patients with advanced nonsquamous non-small-cell lung cancer. Invest. New Drugs 31(5), 1275–1282 (2013).
Medline CASGoogle Scholar
7. Yoneshima Y, Morita S, Ando M et al. Phase 3 trial comparing nanoparticle albumin-bound paclitaxel with docetaxel for previously treated advanced NSCLC. J. Thorac. Oncol. 16(9), 1523–1532 (2021).
Medline CASGoogle Scholar
8. Nokihara H, Lu S, Mok TSK et al. Randomized controlled trial of S-1 versus docetaxel in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy (East Asia S-1 Trial in Lung Cancer). Ann. Oncol. 28(11), 2698–2706 (2017).
Medline CASGoogle Scholar
9. Garon EB, Ciuleanu TE, Arrieta O et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet 384(9944), 665–673 (2014).
Medline CASGoogle Scholar
10. Soria JC, Wu YL, Nakagawa K et al. Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial. Lancet Oncol. 16(8), 990–998 (2015). •• International phase III trial (IMPRESS) reporting the efficacy and safety of continuing gefitinib combined with chemotherapy versus. chemotherapy alone in patients with EGFR+ non-small-cell lung cancer after progression to first-line gefitinib.
Medline CASGoogle Scholar
11. Ballard P, Yates JW, Yang Z et al. Preclinical comparison of osimertinib with other EGFR-TKIs in EGFR-mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity. Clin. Cancer Res. 22(20), 5130–5140 (2016). •• Preclinical assessment of brain penetration and activity of osimertinib for animal models of EGFR-mutant non-small-cell lung cancer brain metastasis.
Medline CASGoogle Scholar
12. Rangachari D, Yamaguchi N, VanderLaan PA et al. Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers. Lung Cancer 88(1), 108–111 (2015).
MedlineGoogle Scholar
13. Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer 45(2), 228–247 (2009).
Medline CASGoogle Scholar
14. Camidge DR, Lee EQ, Lin NU et al. Clinical trial design for systemic agents in patients with brain metastases from solid tumours: a guideline by the Response Assessment in Neuro-Oncology Brain Metastases working group. Lancet Oncol. 19(1), e20–e32 (2018).
MedlineGoogle Scholar
15. Lin NU, Lee EQ, Aoyama H et al. Response assessment criteria for brain metastases: proposal from the RANO group. Lancet Oncol. 16(6), e270–e278 (2015).
MedlineGoogle Scholar
16. Mok TS, Wu YL, Ahn MJ et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N. Engl. J. Med. 376(7), 629–640 (2017).
Medline CASGoogle Scholar
17. Mok TSK, Kim SW, Wu YL et al. Gefitinib plus chemotherapy versus chemotherapy in epidermal growth factor receptor mutation-positive non-small-cell lung cancer resistant to first-line gefitinib (IMPRESS): overall survival and biomarker analyses. J. Clin. Oncol. 35(36), 4027–4034 (2017). •• Updated analysis of the IMPRESS study reporting the efficacy and safety of continuing gefitinib combined with chemotherapy versus chemotherapy alone in patients with EGFR+ non-small-cell lung cancer after progression to first-line gefitinib.
Medline CASGoogle Scholar
18. Hosomi Y, Morita S, Sugawara S et al. Gefitinib alone versus gefitinib plus chemotherapy for non-small-cell lung cancer with mutated epidermal growth factor receptor: NEJ009 study. J. Clin. Oncol. 38(2), 115–123 (2020). •• Open-label Japanese phase III trial (NEJ009) evaluating the efficacy and safety of continuing gefitinib combined with chemotherapy versus chemotherapy alone in previously untreated patients with EGFR+ non-small-cell lung cancer.
Medline CASGoogle Scholar
19. Wu YL, Tsuboi M, He J et al. Osimertinib in resected EGFR-mutated non-small-cell lung cancer. N. Engl. J. Med. 383(18), 1711–1723 (2020).
Medline CASGoogle Scholar
20. Planchard D, Feng PH, Karaseva N et al. Osimertinib plus platinum-pemetrexed in newly diagnosed epidermal growth factor receptor mutation-positive advanced/metastatic non-small-cell lung cancer: safety run-in results from the FLAURA2 study. ESMO Open 6(5), 100271 (2021).
Medline CASGoogle Scholar
21. Okada M, Tanaka K, Asahina H et al. Safety analysis of an open label, randomized phase 2 study of osimertinib alone versus osimertinib plus carboplatin-pemetrexed for patients with non–small cell lung cancer (NSCLC) that progressed during prior epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy and which harbors a T790M mutation of EGFR. J. Clin. Oncol. 36(Suppl. 15), e21073 (2018). •• A phase II trial (LOGIJ1604/NEJ032A) evaluating the efficacy and safety of continuing osimertinib combined with chemotherapy versus chemotherapy alone in previously treated patients with T790M+ EGFR+ non-small-cell lung cancer.
Google Scholar
22. Saito R, Sugawara S, Ko R et al. Phase 2 study of osimertinib in combination with platinum and pemetrexed in patients with previously untreated EGFR-mutated advanced non-squamous non-small cell lung cancer: the OPAL study. Eur. J. Cancer 185, 83–93 (2023).
Medline CASGoogle Scholar

Vol. 19, No. 22

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History

Received 13 November 2022

Accepted 4 July 2023

Published online 14 August 2023

Published in print July 2023

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Keywords

Author contributions

All the authors listed in the manuscript have sufficiently contributed to the project to be included as authors, and all those who are qualified as authors are listed in the author byline. The first draft of the manuscript was written by Y Okuma. All the co-authors have read the final version of the manuscript and have agreed to its submission.

Acknowledgments

The authors appreciate data management and other support staff of the Clinical Research Support Center (CReS) Kyushu. The authors also thank Shuji Nakamura, Yutaka Fujiwara and Yoshitaka Zenke as members of the Data and Safety Monitoring Committee. It is supported by the National and Cancer Research Development Fund (26-A-22) and is chaired by Haruhiko Fukuda and Nobuyuki Yamamoto. The authors would like to thank Editage (www.editage.com) for English language editing.

Financial & competing interests disclosure

The study was provided monetary support by AstraZeneca as a collaborative intergroup trial, of which the leading group is TORG. The cooperative groups include National Health Organization, Central Japan Lung Study Group (CJLCG), Okayama Lung Cancer Study Group (OLCSG) and Lung Oncology Group in Kyushu (LoGiK). Also, the trial framework is supported by Yamamoto-Fukuda. Y Okuma has received consulting or advisory fee from AstraZenec; grants from AstraZeneca, AbbVie, Merck Sharp & Dohme, Chugai and Ono Pharmaceutical; and honoraria from AstraZeneca, Ono Pharmaceutical, Nippon Boehringer-Ingelheim, Chugai, Eli Lilly, Eisai, Taiho Pharmaceutical and Takeda. S Nomura has received grants from AstraZeneca and Amgen and honoraria from AstraZeneca, Chugai and Kyowa Hakko. K Ninomiya has received honoraria from AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Chugai, Kyowa Kirin, Lilly Japan, MSD, Nippon Kayaku, Novartis Pharma, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical and Takeda Pharmaceutical. H Gyotoku has no conflict of interest. S Murakami has received honoraria from AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Chugai, Eli Lilly, Merck BioPharma, MSD, Novartis, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, Takeda Pharmaceutical and grants from Chugai, Daiichi Sankyo, Janssen Pharmaceutical, MSD, Ono Pharmaceutical and Sanofi. Y Kogure has received honoraria from AstraZeneca, Lilly Japan, Chugai, MSD, Boehringer-Ingelheim and Ono Pharmaceutical and grants from MSD. D Harada has received honoraria from Takeda Pharmaceutical, Boehringer-Ingelheim, Taiho Pharmaceutical, AstraZeneca, Chugai, Eli Lilly, Ono Pharmaceutical, Bristol Myers Squibb, Towa Pharmaceutical, Kyowa Hakko Kirin and MSD. K Okishio has received honoraria from AstraZeneca, Bristol Myers Squibb and Chugai. K Okishio has received speaker's bureau fee from Bristol-Myers Squibb K.K., AstraZeneca K.K., Chugai Pharmaceutical, Nippon Kayaku and Takeda Pharmaceutical. H Okamoto has received grants from Bristol Myers Squibb, Chugai, Taiho Pharmaceutical, Astellas, Eli Lilly, Merck BioPharma, AstraZeneca, MSD, Boehringer-Ingelheim, Novartis and Chugai. Y Goto has received consulting or advisory fee from Eli Lilly, Chugai, Taiho Pharmaceutical, Boehringer-Ingelheim, Pfizer, Novartis, AstraZeneca, Glaxo Smith Kline, MSD, Guardant Health, Daiichi Sankyo, Kyorin, Chugai, Illumina, Thermo Fisher Scientific and Johnson & Johnson and speaker's bureau fee from AstraZeneca, Eli Lilly, Chugai, Taiho Pharmaceutical, Boehringer-Ingelheim, Ono Pharmaceutical, Bristol Myers Squibb, Pfizer, MSD, Shionogi Pharma, Novartis, Merck and Johnson & Johnson. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

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