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Annual Report 2018

Division of Experimental Therapeutics

[Kashiwa Campus] Toshihiko Doi, Kiyotaka Yo, Yoichi Naito, Takahiro Kogawa, Kohei Shitara, Hideaki Takahashi, Yasutoshi Kuboki

[Tsukiji Campus] Noboru Yamamoto, Toshio Shimizu, Yutaka Fujiwara, Kan Yonemori, Kiyoshi Yoshimura, Shigehisa Kitano, Shunsuke Kondo, Satoru Iwasa, Akihiko Shimomura, Takafumi Koyama, Jun Sato

Introduction

The Department of Experimental Therapeutics supports efforts toward the creation of new drugs and other products from breakthroughs originating from academic institutions by achieving results at the level of basic research. We evaluate and discover excellent research and development proposals, and provide integrated management of the program so that basic research outcomes are linked through to clinical research and clinical trial for approval. We have conducted several IITs as applications for approval and also have promoted research and development in the field of medicine.

The Team and What We Do

This department plays a key role in new anti-cancer drug development in Japan as well as in Asia. The top priority is to conduct FIH trials, and we also perform phase I trials for solid tumors (i.e., all-comers). Recently, we have been joining global phase I trials to accelerate new drug development in Japan. Web- or teleconferences are held with EU and US sites, and we discuss patient enrollment as well as further developmental strategies. Routine webconferences are also held between the NCChospital (Tokyo) and the NCC-East hospital (Chiba) every Friday morning, and we are sharing information about adverse events, patient enrollment and are referring candidates to each other to accelerate enrollment.

Research activities

We promote the following activities to conduct appropriate research and trials.

To plan clinical trials as IITs to achieve POC of new academic seeds
Explanation meetings for researchers and office employees on compliance with laws, ordinances and guidelines.
To consider development design to create a new with the goal of creating innovative drugs, medical devices, as well as ensuring that research projects on promising results proceed more rapidly and in greater depth.

List of papers published in 2018

Journal

1. Shimokawa M, Hayashi T, Kogawa T, Matsui R, Mizuno M, Kikkawa F, Saeki T, Aiba K, Tamura K. Evaluation of Combination Antiemetic Therapy on CINV in Patients With Gynecologic Cancer Receiving TC Chemotherapy. Anticancer Res, 39:225-230, 2019

2. Yoh K, Takamochi K, Shukuya T, Hishida T, Tsuboi M, Sakurai H, Goto Y, Yoshida K, Ohde Y, Okumura S, Ohashi Y, Kunitoh H. Pattern of care in adjuvant therapy for resected Stage I non-small cell lung cancer: real-world data from Japan. Jpn J Clin Oncol, 49:63-68, 2019

3. Takashima A, Shitara K, Fujitani K, Koeda K, Hara H, Nakayama N, Hironaka S, Nishikawa K, Kimura Y, Amagai K, Fujii H, Muro K, Esaki T, Choda Y, Takano T, Chin K, Sato A, Goto M, Fukushima N, Hara T, Machida N, Ohta M, Boku N, Shimura M, Morita S, Koizumi W. Peritoneal metastasis as a predictive factor for nab-paclitaxel in patients with pretreated advanced gastric cancer: an exploratory analysis of the phase III ABSOLUTE trial. Gastric Cancer, 22:155-163, 2019

4. Nakamura M, Kageyama SI, Niho S, Okumura M, Hojo H, Motegi A, Nakamura N, Zenda S, Yoh K, Goto K, Akimoto T. Impact of EGFR Mutation and ALK Translocation on Recurrence Pattern After Definitive Chemoradiotherapy for Inoperable Stage III Non-squamous Non-small-cell Lung Cancer. Clin Lung Cancer, 20:e256-e264, 2019

5. Naito T, Umemura S, Nakamura H, Zenke Y, Udagawa H, Kirita K, Matsumoto S, Yoh K, Niho S, Motoi N, Aokage K, Tsuboi M, Ishii G, Goto K. Successful treatment with nivolumab for SMARCA4- deficient non-small cell lung carcinoma with a high tumor mutation burden: A case report. Thoracic cancer, 10:1285-1288, 2019

6. Mehnert JM, Varga A, Brose MS, Aggarwal RR, Lin CC, Prawira A, de Braud F, Tamura K, Doi T, Piha-Paul SA, Gilbert J, Saraf S, Thanigaimani P, Cheng JD, Keam B. Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with advanced, PD-L1-positive papillary or follicular thyroid cancer. BMC Cancer, 19:196, 2019

7. Kawazoe A, Shitara K, Kuboki Y, Bando H, Kojima T, Yoshino T, Ohtsu A, Ochiai A, Togashi Y, Nishikawa H, Doi T, Kuwata T. Clinicopathological features of 22C3 PD-L1 expression with mismatch repair, Epstein-Barr virus status, and cancer genome alterations in metastatic gastric cancer. Gastric Cancer, 22:69- 76, 2019

8. Yonemori K, Shimomura A, Yasojima H, Masuda N, Aogi K, Takahashi M, Naito Y, Shimizu S, Nakamura R, Hashimoto J, Yamamoto H, Hirakawa A, Michimae H, Hamada A, Yoshida T, Sukigara T, Tamura K, Fujiwara Y. A phase I/II trial of olaparib tablet in combination with eribulin in Japanese patients with advanced or metastatic triple-negative breast cancer previously treated with anthracyclines and taxanes. Eur J Cancer, 109:84-91, 2019

9. Mishima S, Kawazoe A, Nakamura Y, Sasaki A, Kotani D, Kuboki Y, Bando H, Kojima T, Doi T, Ohtsu A, Yoshino T, Kuwata T, Tsuji A, Shitara K. Clinicopathological and molecular features of responders to nivolumab for patients with advanced gastric cancer. J Immunother Cancer, 7:24, 2019

10. Nakamura Y, Yamanaka T, Chin K, Cho H, Katai H, Terashima M, Misawa K, Hirao M, Yoshida K, Oki E, Sasako M, Emi Y, Bando H, Kawashima Y, Fukunaga T, Gotoh M, Ishibashi T, Shitara K. SurSurvival Outcomes of Two Phase 2 Studies of Adjuvant Chemotherapy with S-1 Plus Oxaliplatin or Capecitabine Plus Oxaliplatin for Patients with Gastric Cancer After D2 Gastrectomy. Ann Surg Oncol, 26:465-472, 2019

11. Doi T, Yang JC, Shitara K, Naito Y, Cheng AL, Sarashina A, Pronk LC, Takeuchi Y, Lin CC. Phase I Study of the Focal Adhesion Kinase Inhibitor BI 853520 in Japanese and Taiwanese Patients with Advanced or Metastatic Solid Tumors. Target Oncol, 14:57- 65, 2019

12. Nakamura Y, Yamanaka T, Shitara K. Reply to: "Multimodal Treatment of Locally Advanced Gastric Cancer: Will the West Meet the East?", by Marino, Elisabetta et al. Ann Surg Oncol, 26:919- 920, 2019

13. Shitara K, Yamanaka T, Denda T, Tsuji Y, Shinozaki K, Komatsu Y, Kobayashi Y, Furuse J, Okuda H, Asayama M, Akiyoshi K, Kagawa Y, Kato T, Oki E, Ando T, Hagiwara Y, Ohashi Y, Yoshino T. REVERCE: a randomized phase II study of regorafenib followed by cetuximab versus the reverse sequence for previously treated metastatic colorectal cancer patients. Ann Oncol, 30:259-265, 2019

14. Shitara K, Chen X. The KEYNOTE-061 trial - Authors' reply. Lancet, 393:1099, 2019

15. Ott PA, Bang YJ, Piha-Paul SA, Razak ARA, Bennouna J, Soria JC, Rugo HS, Cohen RB, O'Neil BH, Mehnert JM, Lopez J, Doi T, van Brummelen EMJ, Cristescu R, Yang P, Emancipator K, Stein K, Ayers M, Joe AK, Lunceford JK. T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated With Pembrolizumab Across 20 Cancers: KEYNOTE-028. J Clin Oncol, 37:318-327, 2019

16. Fuchs CS, Shitara K, Di Bartolomeo M, Lonardi S, Al-Batran SE, Van Cutsem E, Ilson DH, Alsina M, Chau I, Lacy J, Ducreux M, Mendez GA, Alavez AM, Takahari D, Mansoor W, Enzinger PC, Gorbounova V, Wainberg ZA, Hegewisch-Becker S, Ferry D, Lin J, Carlesi R, Das M, Shah MA. Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol, 20:420-435, 2019

17. Shimomura A, Yamamoto N, Kondo S, Fujiwara Y, Suzuki S, Yanagitani N, Horiike A, Kitazono S, Ohyanagi F, Doi T, Kuboki Y, Kawazoe A, Shitara K, Ohno I, Banerji U, Sundar R, Ohkubo S, Calleja EM, Nishio M. First-in-Human Phase I Study of an Oral HSP90 Inhibitor, TAS-116, in Patients with Advanced Solid Tumors. Mol Cancer Ther, 18:531-540, 2019

18. Oono Y, Kuwata T, Takashima K, Shinmura K, Hori K, Yoda Y, Ikematsu H, Shitara K, Kinoshita T, Yano T. Human epidermal growth factor receptor 2-, epidermal growth factor receptor-, and mesenchymal epithelial transition factor-positive sites of gastric cancer using surgical samples. Gastric Cancer, 22:335-343, 2019

19. Sawaki A, Yamada Y, Yamaguchi K, Nishina T, Doi T, Satoh T, Chin K, Boku N, Omuro Y, Komatsu Y, Hamamoto Y, Koizumi W, Saji S, Shah MA, Van Cutsem E, Kang YK, Iwasaki J, Kuriki H, Ohtsuka W, Ohtsu A. Regional differences in advanced gastric cancer: exploratory analyses of the AVAGAST placebo arm. Gas- List of papers published in 2018 Journal 442 tric Cancer, 21:429-438, 2018

20. Matsubara N, Naito Y, Nakano K, Fujiwara Y, Ikezawa H, Yusa W, Namiki M, Okude T, Takahashi S. Lenvatinib in combination with everolimus in patients with advanced or metastatic renal cell carcinoma: A phase 1 study. Int J Urol, 25:922-928, 2018

21. Kogawa T, Fujii T, Fouad TM, Liu DD, Harano K, Masuda H, Iwase T, Barnett C, Park YS, Lim B, Tripathy D, Litton JK, Ueno NT. Impact of change in body mass index during neoadjuvant chemotherapy and survival among breast cancer subtypes. Breast Cancer Res Treat, 171:501-511, 2018

22. Naito Y, Urasaki T. Precision medicine in breast cancer. Chin Clin Oncol, 7:29, 2018

23. Nakamura M, Onozawa M, Motegi A, Hojo H, Zenda S, Nakamura N, Udagawa H, Kirita K, Matsumoto S, Umemura S, Yoh K, Niho S, Goto K, Akimoto T. Impact of prophylactic cranial irradiation on pattern of brain metastases as a first recurrence site for limited-disease small-cell lung cancer. J Radiat Res, 59:767-773, 2018

24. Kiura K, Yoh K, Katakami N, Nogami N, Kasahara K, Takahashi T, Okamoto I, Cantarini M, Hodge R, Uchida H. Osimertinib in patients with epidermal growth factor receptor T790M advanced non-small cell lung cancer selected using cytology samples. Cancer Sci, 109:1177-1184, 2018

25. Hosomi Y, Tanai C, Yoh K, Goto Y, Sakai H, Kato T, Kaburagi T, Nishio M, Kim YH, Inoue A, Hasegawa Y, Isobe H, Tomizawa Y, Mori Y, Minato K, Yamada K, Ohashi Y, Kunitoh H. Characteristics and outcomes of patients with EGFR-mutation positive nonsmall- cell lung cancer receiving gefitinib beyond radiological progression. Expert Opin Pharmacother, 19:1049-1056, 2018

26. Shitara K, Nishikawa H. Regulatory T cells: a potential target in cancer immunotherapy. Ann N Y Acad Sci, 1417:104-115, 2018

27. Matsumoto H, Sasaki A, Nakamura Y, Kawazoe A, Kuboki Y, Okinaka K, Shitara K. Tuberculous Meningitis during Chemotherapy for Advanced Gastric Cancer. Case reports in oncology, 11:228-233, 2018

28. Kuboki Y, Schatz CA, Koechert K, Schubert S, Feng J, Wittemer- Rump S, Ziegelbauer K, Krahn T, Nagatsuma AK, Ochiai A. In situ analysis of FGFR2 mRNA and comparison with FGFR2 gene copy number by dual-color in situ hybridization in a large cohort of gastric cancer patients. Gastric Cancer, 21:401-412, 2018

29. Shitara K, Ozguroglu M, Bang YJ, Di Bartolomeo M, Mandala M, Ryu MH, Fornaro L, Olesinski T, Caglevic C, Chung HC, Muro K, Goekkurt E, Mansoor W, McDermott RS, Shacham-Shmueli E, Chen X, Mayo C, Kang SP, Ohtsu A, Fuchs CS. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet, 392:123- 133, 2018

30. Shitara K, Doi T, Dvorkin M, Mansoor W, Arkenau HT, Prokharau A, Alsina M, Ghidini M, Faustino C, Gorbunova V, Zhavrid E, Nishikawa K, Hosokawa A, Yalcin S, Fujitani K, Beretta GD, Van Cutsem E, Winkler RE, Makris L, Ilson DH, Tabernero J. Trifluridine/ tipiracil versus placebo in patients with heavily pretreated metastatic gastric cancer (TAGS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol, 19:1437-1448, 2018

31. Mishima S, Kawazoe A, Matsumoto H, Kuboki Y, Bando H, Kojima T, Doi T, Ohtsu A, Yoshino T, Nonte EM, Chintharlapalli S, Nasir A, Kuwata T, Shitara K. Efficacy and safety of ramucirumab- containing chemotherapy in patients with pretreated metastatic gastric neuroendocrine carcinoma. ESMO open, 3:e000443, 2018

32. Segal NH, He AR, Doi T, Levy R, Bhatia S, Pishvaian MJ, Cesari R, Chen Y, Davis CB, Huang B, Thall AD, Gopal AK. Phase I Study of Single-Agent Utomilumab (PF-05082566), a 4-1BB/ CD137 Agonist, in Patients with Advanced Cancer. Clin Cancer Res, 24:1816-1823, 2018

33. Bang YJ, Takano T, Lin CC, Fasanmade A, Yang H, Danaee H, Asato T, Kalebic T, Wang H, Doi T. TAK-264 (MLN0264) in Previously Treated Asian Patients with Advanced Gastrointestinal Carcinoma Expressing Guanylyl Cyclase C: Results from an Open-Label, Non-randomized Phase 1 Study. Cancer Res Treat, 50:398-404, 2018

34. Fuchs CS, Doi T, Jang RW, Muro K, Satoh T, Machado M, Sun W, Jalal SI, Shah MA, Metges JP, Garrido M, Golan T, Mandala M, Wainberg ZA, Catenacci DV, Ohtsu A, Shitara K, Geva R, Bleeker J, Ko AH, Ku G, Philip P, Enzinger PC, Bang YJ, Levitan D, Wang J, Rosales M, Dalal RP, Yoon HH. Safety and Efficacy of Pembrolizumab Monotherapy in Patients With Previously Treated Advanced Gastric and Gastroesophageal Junction Cancer: Phase 2 Clinical KEYNOTE-059 Trial. JAMA oncology, 4:e180013, 2018

35. Nishina T, Takahashi S, Iwasawa R, Noguchi H, Aoki M, Doi T. Safety, pharmacokinetic, and pharmacodynamics of erdafitinib, a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, in patients with advanced or refractory solid tumors. Invest New Drugs, 36:424-434, 2018

36. Naito Y, Takahashi H, Shitara K, Okamoto W, Bando H, Kuwata T, Kuboki Y, Matsumoto S, Miki I, Yamanaka T, Watanabe A, Kojima M. Feasibility study of cancer genome alterations identified by next generation sequencing: ABC study. Jpn J Clin Oncol, 48:559-564, 2018

37. Sunami K, Takahashi H, Tsuchihara K, Takeda M, Suzuki T, Naito Y, Sakai K, Dosaka-Akita H, Ishioka C, Kodera Y, Muto M, Wakai T, Yamazaki K, Yasui W, Bando H, Fujimoto Y, Fukuoka S, Harano K, Kawazoe A, Kimura G, Koganemaru S, Kogawa T, Kotani D, Kuboki Y, Matsumoto H, Matsumoto S, Mishima S, Nakamura Y, Sawada K, Shingaki S, Shitara K, Umemoto K, Umemura S, Yasuda K, Yoshino T, Yamamoto N, Nishio K. Clinical practice guidance for next-generation sequencing in cancer diagnosis and treatment (Edition 10). Cancer Sci, 109:2980-2985, 2018

38. Tada Y, Togashi Y, Kotani D, Kuwata T, Sato E, Kawazoe A, Doi T, Wada H, Nishikawa H, Shitara K. Targeting VEGFR2 with Ramucirumab strongly impacts effector/ activated regulatory T cells and CD8+ T cells in the tumor microenvironment. J Immunother Cancer, 6:106, 2018

39. Udagawa H, Umemura S, Murakami I, Mimaki S, Makinoshima H, Ishii G, Miyoshi T, Kirita K, Matsumoto S, Yoh K, Niho S, Tsuchihara K, Goto K. Genetic profiling-based prognostic prediction of patients with advanced small-cell lung cancer in large scale analysis. Lung Cancer, 126:182-188, 2018

40. Oono Y, Kuwata T, Takashima K, Yoda Y, Ikematsu H, Shitara K, Kinoshita T, Yano T. Clinicopathological features and endoscopic findings of HER2-positive gastric cancer. Surg Endosc, 32:3964- 3971, 2018