In vivo efficacy of triplet therapy with osimertinib, cetuximab and bevacizumab for lung cancer cells harboring EGFR T790M

• Project/Area Number: 16K19454
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Respiratory organ internal medicine
• Research Institution: Okayama University
• Principal Investigator: Ohashi Kadoaki 岡山大学, 大学病院, 講師 (60729193)
• Research Collaborator: Makimoto Go ; Nishii Kazuya
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 非小細胞肺癌 / EGFR変異 / オシメルチニブ / セツキシマブ / ベバシズマブ / 非小細胞癌 / 呼吸器の腫瘍 / 肺癌 / EGFR / AZD9291 / 臨床呼吸器学

Outline of Final Research Achievements

Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is the standard treatment for patients with lung cancer harboring EGFR T790M. However, acquired resistance to osimertinib is inevitable, and alternative strategies are needed. We hypothesized that the combination of osimertinib with cetuximab and/or bevacizumab is a more effective treatment than osimertinib monotherapy for lung tumors harboring EGFR T790M. In the xenograft model, the triplet therapy showed no superior effect than doublet therapies (osimertinib plus bevacizumab or osimertinib plus cetuximab) in xenograft model with small tumors. However, the triplet therapy had stronger antitumor effects than osimertinib monotherapy or doublet therapies in xenograft model with larger tumors. The triplet therapy may have an advantage in advanced lung cancer with high tumor volume.

Academic Significance and Societal Importance of the Research Achievements

EGFR遺伝子に変異が起こることで肺癌が発症する。EGFRチロシンキナーゼ阻害薬（TKI）が標準治療であるが、いずれ耐性化して根治は期待できない。本研究では第3世代EGFR-TKIであるオシメルチニブと抗EGFR抗体であるセツキシマブにてがんの原因であるEGFRをより強力に阻害し、さらに血管新生阻害薬ベバシズマブを上乗せする3剤併用療法の効果を基礎的に検討した。この新規3剤併用療法により、単剤治療と比べて強い腫瘍抑制効果が確認できたため、臨床試験で有効性をさらに検討するべき有望な治療法と考える。

Research Products

• [Journal Article] Beneficial Effect of Osimertinib Readministration in Non-small-cell Lung Cancer Harboring an Epidermal Growth Factor Receptor (<i>EGFR</i>) Mutation with a History of Acquired Resistance to Osimertinib (2019)
  • Author(s): Makimoto G, Ohashi K, Senoo S, Hotta K, Maeda Y, Kiura K
  • Journal Title: Internal Medicine Volume: 58 Issue: 11 Pages: 1625-1627
  • DOI: 10.2169/internalmedicine.2152-18
  • NAID: 130007658147
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2019-06-01
  • Peer Reviewed / Open Access
• [Journal Article] Combined effect of cabozantinib and gefitinib in crizotinib-resistant lung tumors harboring ROS1 fusions (2018)
  • Author(s): Kato Yuka、Ninomiya Kiichiro、Ohashi Kadoaki、Tomida Shuta、Makimoto Go、Watanabe Hiromi、Kudo Kenichiro、Matsumoto Shingo、Umemura Shigeki、Goto Koichi、Ichihara Eiki、Ninomiya Takashi、Kubo Toshio、Sato Akiko、Hotta Katsuyuki、Tabata Masahiro、Toyooka Shinichi、Maeda Yoshinobu、Kiura Katsuyuki
  • Journal Title: Cancer Science Volume: 109 Issue: 10 Pages: 3149-3158
  • DOI: 10.1111/cas.13752
  • Peer Reviewed / Open Access
• [Journal Article] Osimertinib Depletes EGFR T790M in the Spinal Fluid of Patients with Carcinomatous Meningitis of Lung Adenocarcinoma Harboring De Novo EGFR T790M. (2018)
  • Author(s): Senoo S, Ohashi K, Nishii K, Hara N, Kano H, Ninomiya K, Maeda Y, Kiura K.
  • Journal Title: J Thorac Oncol. Volume: 13 Issue: 8 Pages: e140-e142
  • DOI: 10.1016/j.jtho.2018.03.016
  • Peer Reviewed
• [Journal Article] Potential influence of interleukin-6 on the therapeutic effect of gefitinib in patients with advanced non-small cell lung cancer harbouring EGFR mutations. (2018)
  • Author(s): Tamura T, Kato Y, Ohashi K, Ninomiya K, Makimoto G, Gotoda H, Kubo T, Ichihara E, Tanaka T, Ichimura K, Maeda Y, Hotta K, Kiura K.
  • Journal Title: Biochem Biophys Res Commun. Volume: 495 Issue: 1 Pages: 360-367
  • DOI: 10.1016/j.bbrc.2017.10.175
  • Peer Reviewed
• [Journal Article] A phase I trial of afatinib and bevacizumab in chemo-naive patients with advanced non-small-cell lung cancer harboring EGFR mutations: Okayama Lung Cancer Study Group Trial 1404. (2018)
  • Author(s): Ninomiya T, Nogami N, Kozuki T, Harada D, Kubo T, Ohashi K, Kuyama S, Kudo K, Bessho A, Fukamatsu N, Fujimoto N, Aoe K, Shibayama T, Sugimoto K, Takigawa N, Hotta K, Kiura K.
  • Journal Title: Lung Cancer. Volume: 115 Pages: 103-108
  • DOI: 10.1016/j.lungcan.2017.11.025
  • Peer Reviewed
• [Journal Article] MET or NRAS amplification is an acquired resistance mechanism to the third-generation EGFR inhibitor naquotinib (2018)
  • Author(s): Ninomiya Kiichiro、Ohashi Kadoaki、Makimoto Go、Tomida Shuta、Higo Hisao、Kayatani Hiroe、Ninomiya Takashi、Kubo Toshio、Ichihara Eiki、Hotta Katsuyuki、Tabata Masahiro、Maeda Yoshinobu、Kiura Katsuyuki
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 1955-1955
  • DOI: 10.1038/s41598-018-20326-z
  • Peer Reviewed / Open Access
• [Journal Article] Triplet therapy with afatinib, cetuximab, and bevacizumab induces deep remission in lung cancer cells harboring EGFR T790M in vivo. (2017)
  • Author(s): Kudo K, Ohashi K, Makimoto G, Higo H, Kato Y, Kayatani H, Kurata Y, Takami Y, Minami D, Ninomiya T, Kubo T, Ichihara E, Sato A, Hotta K, Yoshino T, Tanimoto M, Kiura K.
  • Journal Title: Mol Oncol Volume: Epub Issue: 6 Pages: 670-681
  • DOI: 10.1002/1878-0261.12063
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Discomfort during bronchoscopy performed after endobronchial intubation with fentanyl and midazolam: a prospective study. (2017)
  • Author(s): Minami D, Takigawa N, Kano H, Ninomiya T, Kubo T, Ichihara E, Ohashi K, Sato A, Hotta K, Tabata M, Tanimoto M, Kiura K.
  • Journal Title: Jpn J Clin Oncol. Volume: Epub Issue: 5 Pages: 434-437
  • DOI: 10.1093/jjco/hyx022
  • Peer Reviewed
• [Journal Article] Potential influence of being overweight on the development of hepatic dysfunction in Japanese patients with EGFR-mutated non-small cell lung cancer undergoing gefitinib monotherapy: the Okayama Lung Cancer Study Group experience. (2016)
  • Author(s): Oda N, Hotta K, Yoshioka H, Kudo K, Ichihara E, Kato Y, Ninomiya K, Minami D, Ninomiya T, Kubo T, Ohashi K, Sato A, Takigawa N, Tabata M, Tanimoto M, Kiura K.
  • Journal Title: Cancer Chemother Pharmacol. Volume: ７８ Pages: 941-947
  • Peer Reviewed
• [Journal Article] Effect of Vandetanib on Lung Tumorigenesis in Transgenic Mice Carrying an Activating Egfr Gene Mutation. (2016)
  • Author(s): Osawa M, Ohashi K, Kubo T, Ichihara E, Takata S, Takigawa N, Takata M, Tanimoto M, Kiura K.
  • Journal Title: Acta Med Okayama. Volume: 70 Pages: 243-253
  • Peer Reviewed
• [Presentation] In vivo efficacy of triplet therapy with osimertinib, cetuximab and bevacizumab for lung cancer cells harboring EGFR T790M (2018)
  • Author(s): Kazuya Nishii, Kadoaki Ohashi, Go Makimoto, Hisao Higo, Kiichiro Ninomiya, Hiroe Kayatani, Takashi Ninomiya, Toshio Kubo, Kammei Rai, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Katsuyuki Kiura
  • Organizer: AACR Annual Meeting 2018
  • Int'l Joint Research
• [Presentation] The novel osimertinib resistant lung cancer mice model harboring EGFR mutations driven by the SP-C promoter (2018)
  • Author(s): Kadoaki Ohashi, Hisao Higo, Go Makimoto, Kenichiro Kudo, Kazuya Nishii, Kiichiro Ninomiya, Hiroe Kayatani, Takashi Ninomiya, Toshio Kubo, Kammei Rai, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Katsuyuki Kiura
  • Organizer: AACR Annual Meeting 2018
  • Int'l Joint Research
• [Presentation] Novel Syngenic Lung Cancer Mouse Model Harboring EGFR Mutations (2018)
  • Author(s): Kazuya Nishii, Kadoaki Ohashi, Hisao Higo, Kenichiro Kudo, Go Makimoto, Hiroe Kayatani, Hiromi Watanabe, Kiichiro Ninomiya, Takashi Ninomiya, Toshio Kubo, Kammei Rai, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Katsuyuki Kiura
  • Organizer: The 6th JCA-AACR Special Joint Conference
  • Int'l Joint Research
• [Presentation] Analysis of the Rapid Acquired Resistance of ALK-positive Lung Cancers to Alectinib: A Comprehensive Study Using Autopsied Specimens and Patient-derived Cell Lines (2018)
  • Author(s): Go Makimoto, Kadoaki Ohashi, Kazuya Nishii, (Shuta Tomida), Hiroe Kayatani, Hisao Higo, Kiichiro Ninomiya, Hiromi Watanabe, Takashi Ninomiya, Toshio Kubo, Eiki Ichihara, Akiko Sato, Katsuyuki Hotta, Masahiro Tabata, Sinichi Toyooka, Yoshinobu Maeda, Katsuyuki Kiura
  • Organizer: The 6th JCA-AACR Special Joint Conference
  • Int'l Joint Research
• [Presentation] Contribution of nationwide genome screening in Japan (LC-SCRUM-Japan) to the development of precision medicine for non-small cell lung cancer. (2018)
  • Author(s): Takashi Seto, Shingo Matsumoto, Kiyotaka Yoh, Yutaka Fujiwara, Takuma Yokoyama, Kazumi Nishino, Terufumi Kato, Shunichi Sugawara, Masato Shingoji, Masahiro Kodani, Kadoaki Ohashi, Katsuya Tsuchihara, Koichi Goto
  • Organizer: ASCO 2018
  • Int'l Joint Research
• [Presentation] Abstract 3152: Acquired resistance to the third-generation EGFR inhibitor ASP8273 is associated with MET or NRAS gene amplifications in preclinical models (2017)
  • Author(s): Kiichiro Ninomiya, Kadoaki Ohashi, Shuta Tomida, Hiroe Kayatani, Tomoki Tamura, Hisao Higo, Go Makimoto, Takashi Ninomiya, Toshio Kubo, Eiki Ichihara, Akiko Sato, Katsuyuki Hotta, Masahiro Tabata and Katsuyuki Kiura
  • Organizer: AACR 2017
  • Int'l Joint Research
• [Presentation] Abstract 3164: A comprehensive analysis of autopsied specimens and patient-derived cell lines in ALK-positive lung cancers with rapid acquired resistance to alectinib (2017)
  • Author(s): Go Makimoto, Kadoaki Ohashi, Kazuya Nishii, Shuta Tomida, Hiroe Kayatani, Tomoki Tamura, Hisao Higo, Kiichiro Ninomiya, Takashi Ninomiya, Toshio Kubo, Eiki Ichihara, Akiko Sato, Katsuyuki Hotta, Masahiro Tabata and Katsuyuki Kiura
  • Organizer: AACR 2017
  • Int'l Joint Research
• [Presentation] EGFR変異を有する肺癌細胞株における第三世代EGFR-TKI耐性機序の検討 (2016)
  • Author(s): 二宮 貴一朗、大橋 圭明 他
  • Organizer: JSMO 2016
  • Place of Presentation: 神戸国際展示場
  • Year and Date: 2016-07-28
• [Presentation] pCR induced by triplet therapy with low-dose afatinib, cetuximab and bevcizumab in lung cancer cells harboring EGFR T790M (2016)
  • Author(s): Kadoaki Ohashi, Kenichiro Kudo, Eiki Ichihara, Hiroe Kayatani, Hisao Higo, Yuka Kato, Yasuko Kurata, Daisuke Minami, Takashi Ninomiya, Toshio Kubo, Katsuyuki Hotta, Mitsune Tanimoto and Katsuyuki Kiura
  • Organizer: AACR 2016
  • Place of Presentation: Ernest N. Morial Convention Center New Orleans, Louisiana
  • Year and Date: 2016-04-16
  • Int'l Joint Research
• [Presentation] Combination effect of anti-VEGFR-2 antibody with erlotinib on EGFR mutant non-small cell lung cancer (2016)
  • Author(s): Hiroe Kayatani, Kadoaki Ohashi, Takeshi Imao, Kenichiro Kudo, Yuka Kato, Takashi Ninomiya, Toshio Kubo, Akiko Sato, Ktsuyuki Hotta, Mitsune Tanimoto and Katsuyuki Kiura
  • Organizer: AACR 2016
  • Place of Presentation: Ernest N. Morial Convention Center New Orleans, Louisiana
  • Year and Date: 2016-04-16
  • Int'l Joint Research