Department of Experimental Therapeutics

Noboru Yamamoto, Takafumi Koyama, Kan Yonemori, Shunsuke Kondo, Satoru Iwasa, Hirokazu Shoji, Kazuki Sudo, Jun Sato, Yuki Katsuya, Takaaki Mizuno, Ryoko Yamazaki

Introduction

 In April 2015, the affiliation of the Department of Experimental Therapeutics was updated from the NCC-EPOC (cf. the Exploratory Oncology Research & Clinical Trial Center) to the NCC-Hospital. The goal of this department is to perform initial clinical evaluations of promising new anti-cancer compounds emerging from the laboratory in phase I trials. The staff consists of specialists from various oncology fields (i.e., thoracic oncology, breast and medical oncology, gastro-intestinal oncology, hepato-biliary and pancreatic oncology, and immuno-oncology).

The Team and What We Do

 This department plays a key role in new anti-cancer drug development in Japan and other countries in Asia. Our top priority is to conduct FIH trials, but we also perform phase I trials for solid tumors (i.e., all comers). We recently joined the global phase I trials to accelerate the new drug development in Japan. We hold web conferences or teleconferences with EU and US sites, and discuss patient enrollment and further developmental strategies. Routine web conferences are also held between the NCC-Hospital (Tokyo) and the NCC-East hospital (Chiba) every Friday morning, and we share information on adverse events and patient enrollment and refer the candidates to each other to accelerate enrollment. Currently, most of the phase I trials in Japan (i.e., first in Japan phase I trials, first in human trials) are conducted at the NCC-Hospital and NCC-East hospital with close collaboration.

Research Activities

 Elucidating the proof of concept (POC) is essential in new anti-cancer drug development especially in early phases. We therefore conduct several translational research (TR) projects in collaboration with research institutes. We are also conducting TR with the pharmaceutical industry to discover new targets for anti-immune therapy using human tissue (tumor and normal tissue) samples. To facilitate the POC analyses in phase I trials, a phase I biobank study has been launched in 2018.

Clinical Trials

 In fiscal year 2022, 119 phase I trials including 64 FIH trials were conducted.

Education

 In 2022, the 4th NCCH & RI Tsukiji TR Board activity Web was held on December 7th at the NCC-Tsukiji campus.

List of papers published in 2022

Journal

1. Iwasa S, Koyama T, Nishino M, Kondo S, Sudo K, Yonemori K, Yoshida T, Tamura K, Shimizu T, Fujiwara Y, Kitano S, Shimomura A, Sato J, Yokoyama F, Iida H, Kondo M, Yamamoto N. First-in-human study of ONO-4578, an antagonist of prostaglandin E(2) receptor 4, alone and with nivolumab in solid tumors. Cancer science, 114:211-220, 2023

2. Tanaka T, Yoshida T, Masuda K, Takeyasu Y, Shinno Y, Matsumoto Y, Okuma Y, Goto Y, Horinouchi H, Yamamoto N, Ohe Y. Prognostic role of modified Glasgow Prognostic score in elderly non-small cell lung cancer patients treated with anti-PD-1 antibodies. Respiratory investigation, 61:74-81, 2023

3. Takamizawa S, Katsuya Y, Chen YN, Mizuno T, Koyama T, Sudo K, Yoshida T, Kondo S, Iwasa S, Yonemori K, Shimizu T, Yamamoto N, Suzuki S. Ocular toxicity of investigational anti-cancer drugs in early phase clinical trials. Investigational new drugs, 41:173-181, 2023

4. Fukuda A, Yoshida T, Yagishita S, Shiotsuka M, Kobayashi O, Iwata S, Umeguchi H, Yanagida M, Irino Y, Masuda K, Shinno Y, Okuma Y, Goto Y, Horinouchi H, Hamada A, Yamamoto N, Ohe Y. Real-world Data on the Incidence of Coronavirus Disease (COVID-19) in Patients With Advanced Thoracic Cancer During the Early Phase of the Pandemic in Japan. Anticancer research, 43:919-926, 2023

5. Fujiwara Y, Makihara R, Hase T, Hashimoto N, Naito T, Tsubata Y, Okuno T, Takahashi T, Kobayashi H, Shinno Y, Zenke Y, Ikeda T, Hosomi Y, Watanabe K, Kitazono S, Sakiyama N, Makino Y, Yamamoto N. Pharmacokinetic and dose-finding study of osimertinib in patients with impaired renal function and low body weight. Cancer science, 114:2087-2097, 2023

6. Akagi K, Yagishita S, Ohuchi M, Hayashi Y, Takeyasu Y, Masuda K, Shinno Y, Okuma Y, Yoshida T, Goto Y, Horinouchi H, Yamamoto N, Mukae H, Ohe Y, Hamada A. Impact of ramucirumab pharmacokinetics in combination with docetaxel on the efficacy and survival in patients with advanced non-small cell lung cancer. Lung cancer (Amsterdam, Netherlands), 178:247-253, 2023

7. Shimizu T, Nakagawa K, Hayashi H, Iwasa T, Kawakami H, Watanabe S, Yamamoto N, Yonemori K, Koyama T, Sato J, Tamura K, Kikuchi K, Akaike K, Takeda S, Takeda M. Oral formulation of bendamustine hydrochloride for patients with advanced solid tumors; a phase 1 study. Investigational new drugs, 41:1-12, 2023

8. Mizuno S, Ikegami M, Koyama T, Sunami K, Ogata D, Kage H, Yanagaki M, Ikeuchi H, Ueno T, Tanikawa M, Oda K, Osuga Y, Mano H, Kohsaka S. High-Throughput Functional Evaluation of MAP2K1 Variants in Cancer. Molecular cancer therapeutics, 22:227-239, 2023

9. Heymach J, Opdam F, Barve M, Gibson N, Sadrolhefazi B, Serra J, Yamamoto N. A Phase I, Open-Label, Dose Confirmation, Escalation, and Expansion Trial of BI 1810631 as Monotherapy in Patients With Advanced or Metastatic Solid Tumors With HER2 Aberrations. Clinical lung cancer, 24:e65-e68, 2023

10. Asami Y, Kobayashi Kato M, Hiranuma K, Matsuda M, Shimada Y, Ishikawa M, Koyama T, Komatsu M, Hamamoto R, Nagashima M, Terao Y, Itakura A, Kohno T, Sekizawa A, Matsumoto K, Kato T, Shiraishi K, Yoshida H. Utility of molecular subtypes and genetic alterations for evaluating clinical outcomes in 1029 patients with endometrial cancer. British journal of cancer, 128:1582-1591, 2023

11. Shimada K, Nakamura K, Yamamoto N. Mission of the National Cancer Center Hospital in Japan to promote clinical trials for precision medicine. Cancer biology & medicine, j.issn.2095-3941.2022.0643, 2023

12. Higashiyama RI, Horinouchi H, Kuchiba A, Matsumoto Y, Murakami S, Goto Y, Kanda S, Fujiwara Y, Yamamoto N, Ohe Y. Non-specific symptoms as a prodrome of immune-related adverse events in patients with non-small cell lung cancer receiving nivolumab: a consecutive analysis of 200 patients. Journal of cancer research and clinical oncology, 2022

13. So C, Yoshida T, Mizuno T, Yatabe Y, Ohe Y. Rapidly progressing metastatic malignant melanoma mimicking primary pleural tumor: A case report. Thoracic cancer, 13:1423-1426, 2022

14. Torasawa M, Yoshida T, Yagishita S, Shimoda Y, Shirasawa M, Matsumoto Y, Masuda K, Shinno Y, Okuma Y, Goto Y, Horinouchi H, Yamamoto N, Takahashi K, Ohe Y. Nivolumab versus pembrolizumab in previously-treated advanced non-small cell lung cancer patients: A propensity-matched real-world analysis. Lung cancer (Amsterdam, Netherlands), 167:49-57, 2022

15. Koyama T, Shimizu T, Sato J, Katsuya Y, Iwasa S, Kondo S, Yoshida T, Sudo K, Nishino M, Takiguchi Y, Yonemori K, Yamamoto N. Practical consideration for successful sequential tumor biopsies in first-in-human trials. Investigational new drugs, 40:841-849, 2022

16. Takeyasu Y, Yoshida T, Masuda K, Matsumoto Y, Shinno Y, Okuma Y, Goto Y, Horinouchi H, Yamamoto N, Ohe Y. Lorlatinib Versus Pemetrexed-Based Chemotherapy in Patients With ALK-rearranged NSCLC Previously Treated With Alectinib. JTO clinical and research reports, 3:100311, 2022

17. Shinno Y, Yoshida A, Masuda K, Matsumoto Y, Okuma Y, Yoshida T, Goto Y, Horinouchi H, Yamamoto N, Yatabe Y, Ohe Y. Efficacy of Immune Checkpoint Inhibitors in SMARCA4-Deficient Thoracic Tumor. Clinical lung cancer, 23:386-392, 2022

18. Shimoda Y, Shibaki R, Yoshida T, Murakami S, Shirasawa M, Torasawa M, Matsumoto Y, Masuda K, Shinno Y, Okuma Y, Goto Y, Horinouchi H, Yamamoto N, Ohe Y, Motoi N. Concurrent High PD-L1 Expression and CD8(+) Immune Cell Infiltration Predict PD-1 Blockade Efficacy in Advanced EGFR-Mutant NSCLC Patients. Clinical lung cancer, 23:477-486, 2022

19. Seki Y, Yoshida T, Kohno T, Masuda K, Okuma Y, Goto Y, Horinouchi H, Yamamoto N, Kuwano K, Ohe Y. Liquid biopsy for the detection of resistance mutations to ROS1 and RET inhibitors in non-small lung cancers: A case series study. Respiratory investigation, 60:852-856, 2022

20. Ida H, Koyama T, Mizuno T, Sunami K, Kubo T, Sudo K, Tao K, Hirata M, Yonemori K, Kato K, Okusaka T, Ohe Y, Matsui Y, Yamazaki N, Ogawa C, Kawai A, Narita Y, Esaki M, Yamamoto N. Clinical utility of comprehensive genomic profiling tests for advanced or metastatic solid tumor in clinical practice. Cancer science, 113:4300-4310, 2022

21. Ohuchi M, Yagishita S, Jo H, Akagi K, Inaba Higashiyama R, Masuda K, Shinno Y, Okuma Y, Yoshida T, Goto Y, Horinouchi H, Makino Y, Yamamoto N, Ohe Y, Hamada A. Early change in the clearance of pembrolizumab reflects the survival and therapeutic response: A population pharmacokinetic analysis in real-world non-small cell lung cancer patients. Lung cancer (Amsterdam, Netherlands), 173:35-42, 2022

22. Katsuya Y, Kitano S, Yamashita M, Ouchi M, Yagishita S, Hamada A, Nakamura H, Hosoda F, Shibata T, Motoi N, Nakayama T, Seto T, Umemura S, Hosomi Y, Satouchi M, Nishio M, Kozuki T, Hida T, Ohe Y, Horinouchi H. Comprehensive biomarker analysis from phase II study of nivolumab in patients with thymic carcinoma. Frontiers in oncology, 12:966527, 2022

23. Nishimura R, Ishiki H, Sato J, Satomi E. Dexamethasone for cancer-related dyspnoea. The Lancet. Oncology, 23:e525, 2022

24. Sato J, Shimizu T, Koyama T, Iwasa S, Shimomura A, Kondo S, Kitano S, Yonemori K, Fujiwara Y, Tamura K, Suzuki T, Takase T, Nagai R, Yamaguchi K, Semba T, Zhao ZM, Ren M, Yamamoto N. Dose Escalation Data from the Phase 1 Study of the Liposomal Formulation of Eribulin (E7389-LF) in Japanese Patients with Advanced Solid Tumors. Clinical cancer research, 28:1783-1791, 2022

25. Doki Y, Ueno M, Hsu CH, Oh DY, Park K, Yamamoto N, Ioka T, Hara H, Hayama M, Nii M, Komuro K, Sugimoto M, Tahara M. Tolerability and efficacy of durvalumab, either as monotherapy or in combination with tremelimumab, in patients from Asia with advanced biliary tract, esophageal, or head-and-neck cancer. Cancer medicine, 11:2550-2560, 2022

26. Yonemori K, Kuboki Y, Hasegawa K, Iwata T, Kato H, Takehara K, Hirashima Y, Kato H, Passey C, Buchbjerg JK, Harris JR, Andreassen CM, Nicacio L, Soumaoro I, Fujiwara K. Tisotumab vedotin in Japanese patients with recurrent/metastatic cervical cancer: Results from the innovaTV 206 study. Cancer science, 113:2788-2797, 2022

27. Ishihara M, Kitano S, Kageyama S, Miyahara Y, Yamamoto N, Kato H, Mishima H, Hattori H, Funakoshi T, Kojima T, Sasada T, Sato E, Okamoto S, Tomura D, Nukaya I, Chono H, Mineno J, Kairi MF, Diem Hoang Nguyen P, Simoni Y, Nardin A, Newell E, Fehlings M, Ikeda H, Watanabe T, Shiku H. NY-ESO-1-specific redirected T cells with endogenous TCR knockdown mediate tumor response and cytokine release syndrome. Journal for immunotherapy of cancer, 10:e003811, 2022

28. Hosomi Y, Seto T, Nishio M, Goto K, Yamamoto N, Okamoto I, Tajima K, Kajihara Y, Yamamoto N. Erlotinib with or without bevacizumab as a first-line therapy for patients with advanced nonsquamous epidermal growth factor receptor-positive non-small cell lung cancer: Exploratory subgroup analyses from the phase II JO25567 study. Thoracic cancer, 13:2192-2200, 2022

29. Higashiyama RI, Yoshida T, Yagishita S, Ohuchi M, Sakiyama N, Torasawa M, Shirasawa M, Masuda K, Shinno Y, Matsumoto Y, Okuma Y, Goto Y, Horinouchi H, Yamamoto N, Hamada A, Ohe Y. Safety Implications of Switching Pembrolizumab Dosage From 200 mg Every 3 Weeks to 400 mg Every 6 Weeks in Patients With Advanced NSCLC. Journal of thoracic oncology, 17:1227-1232, 2022

30. Imai M, Nakamura Y, Sunami K, Kage H, Komine K, Koyama T, Amano T, Ennishi D, Kanai M, Kenmotsu H, Maeda T, Morita S, Sakai D, Bando H, Makiyama A, Suzuki T, Hirata M, Kohsaka S, Tsuchihara K, Naito Y, Yoshino T. Expert panel consensus recommendations on the use of circulating tumor DNA assays for patients with advanced solid tumors. Cancer science, 113:3646-3656, 2022

31. Shimizu T, Nakajima TE, Yamamoto N, Yonemori K, Koyama T, Kondo S, Sunakawa Y, Izawa N, Horie Y, Xiang S, Xu S, Qin L, Gong J, Liu D. Phase I study of envafolimab (KN035), a novel subcutaneous single-domain anti-PD-L1 monoclonal antibody, in Japanese patients with advanced solid tumors. Investigational new drugs, 40:1021-1031, 2022

32. Sunami K, Naito Y, Komine K, Amano T, Ennishi D, Imai M, Kage H, Kanai M, Kenmotsu H, Koyama T, Maeda T, Morita S, Sakai D, Kohsaka S, Tsuchihara K, Saigusa Y, Yoshino T. Chronological improvement in precision oncology implementation in Japan. Cancer science, 113:3995-4000, 2022

33. Mizuno T, Katsuya Y, Sato J, Koyama T, Shimizu T, Yamamoto N. Emerging PD-1/PD-L1 targeting immunotherapy in non-small cell lung cancer: Current status and future perspective in Japan, US, EU, and China. Frontiers in oncology, 12:925938, 2022

34. Wu YL, Lu S, Yang JC, Zhou J, Seto T, Ahn MJ, Su WC, Yamamoto N, Kim DW, Paolini J, Usari T, Iadeluca L, Wilner KD, Goto K. Final Overall Survival, Safety, and Quality of Life Results From a Phase 2 Study of Crizotinib in East Asian Patients With ROS1-Positive Advanced NSCLC. JTO clinical and research reports, 3:100406, 2022

35. Kitano S, Fujiwara Y, Shimizu T, Iwasa S, Yonemori K, Kondo S, Shimomura A, Koyama T, Ebata T, Ikezawa H, Hayata N, Minoshima Y, Miura T, Kubota T, Yamamoto N. A feasibility study of lenvatinib plus pembrolizumab in Japanese patients with advanced solid tumors. Cancer chemotherapy and pharmacology, 90:523-529, 2022

36. Hamamoto R, Koyama T, Kouno N, Yasuda T, Yui S, Sudo K, Hirata M, Sunami K, Kubo T, Takasawa K, Takahashi S, Machino H, Kobayashi K, Asada K, Komatsu M, Kaneko S, Yatabe Y, Yamamoto N. Introducing AI to the molecular tumor board: one direction toward the establishment of precision medicine using large-scale cancer clinical and biological information. Experimental hematology & oncology, 11:82, 2022

37. Kondo S, Iwasa S, Koyama T, Fujita T, Sugibayashi K, Murayama K, Yamamoto N. Safety, tolerability, pharmacokinetics, and antitumour activity of oleclumab in Japanese patients with advanced solid malignancies: a phase I, open-label study. International journal of clinical oncology, 27:1795-1804, 2022

38. Naito Y, Sunami K, Kage H, Komine K, Amano T, Imai M, Koyama T, Ennishi D, Kanai M, Kenmotsu H, Maeda T, Morita S, Sakai D, Watanabe K, Shirota H, Kinoshita I, Yoshioka M, Mamesaya N, Ito M, Kohsaka S, Saigusa Y, Yamamoto K, Hirata M, Tsuchihara K, Yoshino T. Concordance Between Recommendations From Multidisciplinary Molecular Tumor Boards and Central Consensus for Cancer Treatment in Japan. JAMA network open, 5:e2245081, 2022

39. Yoshimura K, Yamanoi K, Kanai M, Okunomiya A, Sagae Y, Sunada M, Taki M, Ukita M, Chigusa Y, Horie A, Yamaguchi K, Hamanishi J, Minamiguchi S, Yamamoto N, Muto M, Mandai M. Nivolumab for malignant transformation of ovarian mature cystic teratoma. Gynecologic oncology reports, 44:101115, 2022