Annual Report 2021

Department of Experimental Therapeutics

Toshihiko Doi, Yasutoshi Kuboki, Kiyotaka Yoh, Yoichi Naito, Kohei Shitara, Kenichi Harano, Junichiro Yuda, Nobuhiko Yamauchi, Shigehiro Koganemaru, Takehiro Nakao, Hiromichi Nakajima

Introduction

 The NCC-EPOC Phase I Group was organized to promote early drug development, especially first in human (FIH) trials, and in 2012 the Phase I Group comprised two sub-units (NCCE-Kashiwa & NCC-Tsukiji) organized by each hospital. The goal of each of the units was to perform initial clinical evaluation of promising new anti-cancer compounds emerging from the laboratory. Our Phase 1 unit is the largest program in Japan - indeed in Asia - and we help develop new cancer drugs through early-phase trials.

 In April 2013, the Department of Experimental Therapeutics was launched to strongly promote the EPOC missions as previously described. The members of the Department of Experimental Therapeutics comprised specialists in oncology fields. We also contributed to IITs using unapproved drugs and new academic seeds.

The Team and What We Do

 Our team has conducted and managed early drug development, especially first in human (FIH) trials.

Research activities

 This department is key to developing new anti-cancer drugs in our center as well as nationally, and while conducting FIH trials is the top priority, we also perform phase I trials. Recently, we joined the global phase I trial to accelerate new drug development in Japan. Video or teleconferences have been held with the EU and US sites, and we are discussing details of patient enrollment as well as further developmental strategy. Routine web-conferences are also held between Kashiwa and Tsukiji campuses every Friday morning, and we share information about adverse events and patient enrollment as well as referring candidates to each other to accelerate enrollment. Several IIT-FIH trials using new class seeds and also unapproved company agents are conducted by each unit.

Clinical trials

 In 2021, 151 patients were enrolled in the phase I trial.

List of papers published in 2021

Journal

1. Ohe Y, Yamazaki N, Yamamoto N, Murakami H, Yoh K, Kitano S, Hashimoto H, Murayama A, Nakane S, Gemma A. The real-world safety of atezolizumab as second-line or later treatment in Japanese patients with non-small-cell lung cancer: a post-marketing surveillance study. Japanese journal of clinical oncology, 52:623-632, 2022

2. Kumagai S, Koyama S, Itahashi K, Tanegashima T, Lin YT, Togashi Y, Kamada T, Irie T, Okumura G, Kono H, Ito D, Fujii R, Watanabe S, Sai A, Fukuoka S, Sugiyama E, Watanabe G, Owari T, Nishinakamura H, Sugiyama D, Maeda Y, Kawazoe A, Yukami H, Chida K, Ohara Y, Yoshida T, Shinno Y, Takeyasu Y, Shirasawa M, Nakama K, Aokage K, Suzuki J, Ishii G, Kuwata T, Sakamoto N, Kawazu M, Ueno T, Mori T, Yamazaki N, Tsuboi M, Yatabe Y, Kinoshita T, Doi T, Shitara K, Mano H, Nishikawa H. Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments. Cancer cell, 40:201-218.e9, 2022

3. Muro K, Kojima T, Moriwaki T, Kato K, Nagashima F, Kawakami H, Ishihara R, Ogata T, Satoh T, Iwakami K, Han S, Yatsuzuka N, Takami T, Bhagia P, Doi T. Second-line pembrolizumab versus chemotherapy in Japanese patients with advanced esophageal cancer: subgroup analysis from KEYNOTE-181. Esophagus: official journal of the Japan Esophageal Society, 19:137-145, 2022

4. Kang YK, Chen LT, Ryu MH, Oh DY, Oh SC, Chung HC, Lee KW, Omori T, Shitara K, Sakuramoto S, Chung IJ, Yamaguchi K, Kato K, Sym SJ, Kadowaki S, Tsuji K, Chen JS, Bai LY, Oh SY, Choda Y, Yasui H, Takeuchi K, Hirashima Y, Hagihara S, Boku N. Nivolumab plus chemotherapy versus placebo plus chemotherapy in patients with HER2-negative, untreated, unresectable advanced or recurrent gastric or gastro-oesophageal junction cancer (ATTRACTION-4): a randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. The Lancet. Oncology, 23:234-247, 2022

5. Doi T, Kuboki Y, Naito Y, Ishida M, Tanaka T, Takeuchi Y. A phase 1 trial of xentuzumab, an IGF-neutralizing antibody, in Japanese patients with advanced solid tumors. Cancer science, 113:1010-1017, 2022

6. Masuda H, Harano K, Miura S, Wang Y, Hirota Y, Harada O, Jolly MK, Matsunaga Y, Lim B, Wood AL, Parinyanitikul N, Jin Lee H, Gong G, George JT, Levine H, Lee J, Wang X, Lucci A, Rao A, Schweitzer BL, Lawrence OR, Seitz RS, Morris SW, Hout DR, Nakamura S, Krishnamurthy S, Ueno NT. Changes in Triple-Negative Breast Cancer Molecular Subtypes in Patients Without Pathologic Complete Response After Neoadjuvant Systemic Chemotherapy. JCO precision oncology, 6:e2000368, 2022

7. Nakamura Y, Okamoto W, Denda T, Nishina T, Komatsu Y, Yuki S, Yasui H, Esaki T, Sunakawa Y, Ueno M, Shinozaki E, Matsuhashi N, Ohta T, Kato K, Ohtsubo K, Bando H, Hara H, Satoh T, Yamazaki K, Yamamoto Y, Okano N, Terazawa T, Kato T, Oki E, Tsuji A, Horita Y, Hamamoto Y, Kawazoe A, Nakajima H, Nomura S, Mitani R, Yuasa M, Akagi K, Yoshino T. Clinical Validity of Plasma-Based Genotyping for Microsatellite Instability Assessment in Advanced GI Cancers: SCRUM-Japan GOZILA Substudy. JCO precision oncology, 6:e2100383, 2022

8. Nakajima H, Harano K, Nakai T, Kusuhara S, Nakao T, Funasaka C, Kondoh C, Matsubara N, Naito Y, Hosono A, Mitsunaga S, Ishii G, Mukohara T. Impacts of clinicopathological factors on efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer. Breast (Edinburgh, Scotland), 61:136-144, 2022

9. Taira N, Kashiwabara K, Tsurutani J, Kitada M, Takahashi M, Kato H, Kikawa Y, Sakata E, Naito Y, Hasegawa Y, Saito T, Iwasa T, Takashima T, Aihara T, Mukai H, Hara F. Quality of life in a randomized phase II study to determine the optimal dose of 3-week cycle nab-paclitaxel in patients with metastatic breast cancer. Breast cancer (Tokyo, Japan), 29:131-143, 2022

10. Taira N, Kashiwabara K, Tsurutani J, Kitada M, Takahashi M, Kato H, Kikawa Y, Sakata E, Naito Y, Hasegawa Y, Saito T, Iwasa T, Takashima T, Aihara T, Mukai H, Hara F. Correction to: Quality of life in a randomized phase II study to determine the optimal dose of 3-week cycle nab-paclitaxel in patients with metastatic breast cancer. Breast cancer (Tokyo, Japan), 29:186-188, 2022

11. Tan RSYC, Ong WS, Lee KH, Lim AH, Park S, Park YH, Lin CH, Lu YS, Ono M, Ueno T, Naito Y, Onishi T, Lim GH, Tan SM, Lee HB, Ryu HS, Han W, Tan VKM, Wong FY, Im SA, Tan PH, Chan JY, Yap YS. HER2 expression, copy number variation and survival outcomes in HER2-low non-metastatic breast cancer: an international multicentre cohort study and TCGA-METABRIC analysis. BMC medicine, 20:105, 2022

12. Remon J, Lacas B, Herbst R, Reck M, Garon EB, Scagliotti GV, Ramlau R, Hanna N, Vansteenkiste J, Yoh K, Groen HJM, Heymach JV, Mandrekar SJ, Okamoto I, Neal JW, Heist RS, Planchard D, Pignon JP, Besse B. ANtiangiogenic Second-line Lung cancer Meta-Analysis on individual patient data in non-small cell lung cancer: ANSELMA. European journal of cancer (Oxford, England: 1990), 166:112-125, 2022

13. Ota T, Kirita K, Matsuzawa R, Udagawa H, Matsumoto S, Yoh K, Niho S, Ishii G, Goto K. Correction to: Validity of using immunohistochemistry to predict treatment outcome in patients with non-small cell lung cancer not otherwise specified. Journal of cancer research and clinical oncology, 148:281-282, 2022

14. Takahashi T, Sakai K, Kenmotsu H, Yoh K, Daga H, Ohira T, Ueno T, Aoki T, Hayashi H, Yamazaki K, Hosomi Y, Chen-Yoshikawa TF, Okumura N, Takiguchi Y, Sekine A, Haruki T, Yamamoto H, Sato Y, Akamatsu H, Seto T, Saeki S, Sugio K, Nishio M, Inokawa H, Yamamoto N, Nishio K, Tsuboi M. Predictive value of EGFR mutation in non-small-cell lung cancer patients treated with platinum doublet postoperative chemotherapy. Cancer science, 113:287-296, 2022

15. Watanabe K, Yoh K, Hosomi Y, Usui K, Naka G, Kishi K, Uemura K, Ohashi Y, Kunitoh H. Efficacy and safety of first-line osimertinib treatment and postprogression patterns of care in patients with epidermal growth factor receptor activating mutation-positive advanced non-small cell lung cancer (Reiwa study): study protocol of a multicentre, real-world observational study. BMJ open, 12:e046451, 2022

16. Hasegawa H, Shitara K, Takiguchi S, Takiguchi N, Ito S, Kochi M, Horinouchi H, Kinoshita T, Yoshikawa T, Muro K, Nishikawa H, Suna H, Kodera Y. A multicenter, open-label, single-arm phase I trial of neoadjuvant nivolumab monotherapy for resectable gastric cancer. Gastric cancer: official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association, 25:619-628, 2022

17. Fuchs CS, Özgüroğlu M, Bang YJ, Di Bartolomeo M, Mandala M, Ryu MH, Fornaro L, Olesinski T, Caglevic C, Chung HC, Muro K, Van Cutsem E, Elme A, Thuss-Patience P, Chau I, Ohtsu A, Bhagia P, Wang A, Shih CS, Shitara K . Pembrolizumab versus paclitaxel for previously treated PD-L1-positive advanced gastric or gastroesophageal junction cancer: 2-year update of the randomized phase 3 KEYNOTE-061 trial. Gastric cancer: official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association, 25:197-206, 2022

18. Diab A, Hamid O, Thompson JA, Ros W, Eskens FALM, Doi T, Hu-Lieskovan S, Klempner SJ, Ganguly B, Fleener C, Wang X, Joh T, Liao K, Salek-Ardakani S, Taylor CT, Chou J, El-Khoueiry AB. A Phase I, Open-Label, Dose-Escalation Study of the OX40 Agonist Ivuxolimab in Patients with Locally Advanced or Metastatic Cancers. Clinical cancer research: an official journal of the American Association for Cancer Research, 28:71-83, 2022

19. Takei S, Kawazoe A, Shitara K. The New Era of Immunotherapy in Gastric Cancer. Cancers, 14:2022

20. Fucà G, Cohen R, Lonardi S, Shitara K, Elez ME, Fakih M, Chao J, Klempner SJ, Emmett M, Jayachandran P, Bergamo F,García MD, Mazzoli G, Provenzano L, Colle R, Svrcek M, Ambrosini M, Randon G, Shah AT, Salati M, Fenocchio E, Salvatore L, Chida K, Kawazoe A, Conca V, Curigliano G, Corti F, Cremolini C, Overman M, Andre T, Pietrantonio F. Ascites and resistance to immune checkpoint inhibition in dMMR/MSI-H metastatic colorectal and gastric cancers. Journal for immunotherapy of cancer, 10:2022

21. Shitara K, Ajani JA, Moehler M, Garrido M, Gallardo C, Shen L, Yamaguchi K, Wyrwicz L, Skoczylas T, Bragagnoli AC, Liu T, Tehfe M, Elimova E, Bruges R, Zander T, de Azevedo S, Kowalyszyn R, Pazo-Cid R, Schenker M, Cleary JM, Yanez P, Feeney K, Karamouzis MV, Poulart V, Lei M, Xiao H, Kondo K, Li M, Janjigian YY. Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer. Nature, 603:942-948, 2022

22. Kawazu M, Ueno T, Saeki K, Sax N, Togashi Y, Kanaseki T, Chida K, Kishigami F, Sato K, Kojima S, Otsuka M, Kawazoe A, Nishinakamura H, Yuka M, Yamamoto Y, Yamashita K, Inoue S, Tanegashima T, Matsubara D, Tane K, Tanaka Y, Iinuma H, Hashiguchi Y, Hazama S, Khor SS, Tokunaga K, Tsuboi M, Niki T, Eto M, Shitara K, Torigoe T, Ishihara S, Aburatani H, Haeno H, Nishikawa H, Mano H. HLA Class I Analysis Provides Insight Into the Genetic and Epigenetic Background of Immune Evasion in Colorectal Cancer With High Microsatellite Instability. Gastroenterology, 162:799-812, 2022

23. Chida K, Kawazoe A, Suzuki T, Kawazu M, Ueno T, Takenouchi K, Nakamura Y, Kuboki Y, Kotani D, Kojima T, Bando H, Mishima S, Kuwata T, Sakamoto N, Watanabe J, Mano H, Ikeda M, Shitara K, Endo I, Nakatsura T, Yoshino T. Transcriptomic Profiling of MSI-H/dMMR Gastrointestinal Tumors to Identify Determinants of Responsiveness to Anti-PD-1 Therapy. Clinical cancer research: an official journal of the American Association for Cancer Research, 28:2110-2117, 2022

24. Shitara K, Doi T, Hosaka H, Thuss-Patience P, Santoro A, Longo F, Ozyilkan O, Cicin I, Park D, Zaanan A, Pericay C, Özgüroğlu M, Alsina M, Makris L, Benhadji KA, Ilson DH . Efficacy and safety of trifluridine/tipiracil in older and younger patients with metastatic gastric or gastroesophageal junction cancer: subgroup analysis of a randomized phase 3 study (TAGS). Gastric cancer: official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association, 25:586-597, 2022

25. Maron SB, Moya S, Morano F, Emmett MJ, Chou JF, Sabwa S, Walch H, Peterson B, Schrock AB, Zhang L, Janjigian YY, Chalasani S, Ku GY, Disel U, Enzinger P, Uboha N, Kato S, Yoshino T, Shitara K, Nakamura Y, Saeed A, Kasi PM, Chao J, Lee J, Capanu M, Wainberg Z, Petty R, Pietrantonio F, Klempner SJ, Catenacci DVT. Epidermal Growth Factor Receptor Inhibition in Epidermal Growth Factor Receptor-Amplified Gastroesophageal Cancer: Retrospective Global Experience. Journal of clinical oncology: official journal of the American Society of Clinical Oncology, JCO2102453, 2022

26. Jinnouchi F, Mori Y, Yoshimoto G, Yamauchi T, Nunomura T, Yurino A, Hayashi M, Yuda J, Shima T, Odawara J, Takashima S, Kamezaki K, Kato K, Miyamoto T, Akashi K, Takenaka K. Incidence of refractory cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation. International journal of hematology, 115:96-106, 2022

27. Tabata R, Sato N, Yamauchi N, Guo YM, Nakamura H, Nagata A, Song-Gi C, Minami Y, Yuda J. Cytomegalovirus reactivation in patients with multiple myeloma administered daratumumab-combination regimens. Annals of hematology, 101:465-467, 2022

28. Mizuno T, Yoshida T, Sunami K, Koyama T, Okita N, Kubo T, Sudo K, Shimoi T, Ueno H, Saito E, Katanoda K, Shibata T, Yonemori K, Okusaka T, Boku N, Ohe Y, Hiroshima Y, Ueno M, Kuboki Y, Doi T, Nakamura K, Kohno T, Yatabe Y, Yamamoto N. Study protocol for NCCH1908 (UPFRONT-trial): a prospective clinical trial to evaluate the feasibility and utility of comprehensive genomic profiling prior to the initial systemic treatment in advanced solid tumour patients. Japanese journal of clinical oncology, 51:1757-1760, 2021

29. Yazaki S, Yoshida T, Kojima Y, Yagishita S, Nakahama H, Okinaka K, Matsushita H, Shiotsuka M, Kobayashi O, Iwata S, Narita Y, Ohba A, Takahashi M, Iwasa S, Kobayashi K, Ohe Y, Yoshida T, Hamada A, Doi T, Yamamoto N. Difference in SARS-CoV-2 Antibody Status Between Patients With Cancer and Health Care Workers During the COVID-19 Pandemic in Japan. JAMA oncology, 7:1141-1148, 2021

30. Yoh K, Hirashima T, Saka H, Kurata T, Ohe Y, Hida T, Mellemgaard A, Verheijen RB, Ou X, Ahmed GF, Hayama M, Sugibayashi K, Oxnard GR. Savolitinib ± Osimertinib in Japanese Patients with Advanced Solid Malignancies or EGFRm NSCLC: Ph1b TATTON Part C. Targeted oncology, 16:339-355, 2021

31. Shah MA, Bennouna J, Doi T, Shen L, Kato K, Adenis A, Mamon HJ, Moehler M, Fu X, Cho BC, Bordia S, Bhagia P, Shih CS, Desai A, Enzinger P. KEYNOTE-975 study design: a Phase III study of definitive chemoradiotherapy plus pembrolizumab in patients with esophageal carcinoma. Future oncology (London, England), 17:1143-1153, 2021

32. Sun JM, Shen L, Shah MA, Enzinger P, Adenis A, Doi T, Kojima T, Metges JP, Li Z, Kim SB, Cho BC, Mansoor W, Li SH, Sunpaweravong P, Maqueda MA, Goekkurt E, Hara H, Antunes L, Fountzilas C, Tsuji A, Oliden VC, Liu Q, Shah S, Bhagia P, Kato K. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet (London, England), 398:759-771, 2021

33. Kawai A, Naka N, Shimomura A, Takahashi S, Kitano S, Imura Y, Yonemori K, Nakatani F, Iwata S, Kobayashi E, Outani H, Tamiya H, Naito Y, Yamamoto N, Doi T. Efficacy and safety of TAS-115, a novel oral multi-kinase inhibitor, in osteosarcoma: an expansion cohort of a phase I study. Investigational new drugs, 39:1559-1567, 2021

34. Lin CC, Doi T, Muro K, Hou MM, Esaki T, Hara H, Chung HC, Helwig C, Dussault I, Osada M, Kondo S. Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGFβ and PD-L1, in Patients with Esophageal Squamous Cell Carcinoma: Results from a Phase 1 Cohort in Asia. Targeted oncology, 16:447-459, 2021

35. Sunami K, Bando H, Yatabe Y, Naito Y, Takahashi H, Tsuchihara K, Toyooka S, Mimori K, Kohsaka S, Uetake H, Kinoshita I, Komine K, Takeda M, Hayashida T, Tamura K, Nishio K, Yamamoto N. Appropriate use of cancer comprehensive genome profiling assay using circulating tumor DNA. Cancer science, 112:3911-3917, 2021

36. Doi T, Yamamoto N, Naito Y, Kuboki Y, Koyama T, Piao Y, Tsujimoto N, Asou H, Inoue K, Kondo S. Merestinib monotherapy or in combination for japanese patients with advanced and/or metastatic cancer: A phase 1 study. Cancer medicine, 10:6579-6589, 2021

37. Calvo E, Spira A, Miguel M, Kondo S, Gazzah A, Millward M, Prenen H, Rottey S, Warburton L, Alanko T, Cassier PA, Yoh K, Italiano A, Moreno V, Peltola K, Seto T, Toyozawa R, Afar DE, Englert S, Komarnitsky P, Lambert S, Parikh A, Vosganian G, Gao B . Safety, pharmacokinetics, and efficacy of budigalimab with rovalpituzumab tesirine in patients with small cell lung cancer. Cancer treatment and research communications, 28:100405, 2021

38. Shimoi T, Nagai SE, Yoshinami T, Takahashi M, Arioka H, Ishihara M, Kikawa Y, Koizumi K, Kondo N, Sagara Y, Takada M, Takano T, Tsurutani J, Naito Y, Nakamura R, Hattori M, Hara F, Hayashi N, Mizuno T, Miyashita M, Yamashita N, Yamanaka T, Saji S, Iwata H, Toyama T. Correction to: The Japanese Breast Cancer Society Clinical Practice Guidelines for systemic treatment of breast cancer, 2018 edition. Breast cancer (Tokyo, Japan), 28:985-986, 2021

39. Mamishin K, Naito Y, Nomura S, Ogawa G, Niguma K, Baba K, Sakaeda S, Nakajima H, Kusuhara S, Funasaka C, Nakao T, Fukasawa Y, Kondoh C, Harano K, Kogawa T, Matsubara N, Hosono A, Kawasaki T, Mukohara T. Comparison of Treatment Completion Rate Between Conventional and Dose-dense Doxorubicin and Cyclophosphamide (AC) Followed by a Taxane in Patients With Breast Cancer: A Propensity Score-matched Analysis. Anticancer research, 41:6217-6224, 2021

40. Sakaeda S, Naito Y. Circulating Tumor DNA in Oncology. Processes, 9:2198, 2021

41. Naito Y, Kuboki Y, Ikeda M, Harano K, Matsubara N, Toyoizumi S, Mori Y, Hori N, Nagasawa T, Kogawa T. Safety, pharmacokinetics, and preliminary efficacy of the PARP inhibitor talazoparib in Japanese patients with advanced solid tumors: phase 1 study. Investigational new drugs, 39:1568-1576, 2021

42. Kawazoe A, Itahashi K, Yamamoto N, Kotani D, Kuboki Y, Taniguchi H, Harano K, Naito Y, Suzuki M, Fukutani M, Higuchi T, Ikeno T, Wakabayashi M, Sato A, Koyama S, Nishikawa H, Shitara K. TAS-116 (Pimitespib), an Oral HSP90 Inhibitor, in Combination with Nivolumab in Patients with Colorectal Cancer and Other Solid Tumors: An Open-Label, Dose-Finding, and Expansion Phase Ib Trial (EPOC1704). Clinical cancer research: an official journal of the American Association for Cancer Research, 27:6709-6715, 2021

43. Colombo N, Dubot C, Lorusso D, Caceres MV, Hasegawa K, Shapira-Frommer R, Tewari KS, Salman P, Hoyos Usta E, Yañez E, Gümüş M, Olivera Hurtado de Mendoza M, Samouëlian V, Castonguay V, Arkhipov A, Toker S, Li K, Keefe SM, Monk BJ . Pembrolizumab for Persistent, Recurrent, or Metastatic Cervical Cancer. The New England journal of medicine, 385:1856-1867, 2021

44. Akimoto E, Tokunaga M, Sato R, Yoshida A, Naito Y, Yamashita R, Kinoshita T, Kuwata T. Gastric mesenchymal tumor with smooth muscle differentiation and echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion. Pathology international, 71:707-711, 2021

45. Funasaka C, Naito Y, Kusuhara S, Nakao T, Fukasawa Y, Mamishin K, Komuro A, Okunaka M, Kondoh C, Harano K, Kogawa T, Matsubara N, Hosono A, Kawasaki T, Mukohara T. The efficacy and safety of paclitaxel plus bevacizumab therapy in breast cancer patients with visceral crisis. Breast (Edinburgh, Scotland), 58:50-56, 2021

46. Aoki H, Ueha S, Nakamura Y, Shichino S, Nakajima H, Shimomura M, Sato A, Nakatsura T, Yoshino T, Matsushima K. Greater extent of blood-tumor TCR repertoire overlap is associated with favorable clinical responses to PD-1 blockade. Cancer science, 112:2993-3004, 2021

47. Nakajima H, Kotani D, Bando H, Kato T, Oki E, Shinozaki E, Sunakawa Y, Yamazaki K, Yuki S, Nakamura Y, Yamanaka T, Yoshino T, Ohta T, Taniguchi H, Kagawa Y. REMARRY and PURSUIT trials: liquid biopsy-guided rechallenge with anti-epidermal growth factor receptor (EGFR) therapy with panitumumab plus irinotecan for patients with plasma RAS wild-type metastatic colorectal cancer. BMC cancer, 21:674, 2021

48. Nishida T, Yoshinaga S, Takahashi T, Naito Y. Recent Progress and Challenges in the Diagnosis and Treatment of Gastrointestinal Stromal Tumors. Cancers, 13:2021

49. Zhu A, Yuan P, Hu N, Li M, Wang W, Wang X, Yue J, Wang J, Luo Y, Ma F, Zhang P, Li Q, Xu B, Cao S, Lippi G, Naito Y, Osman MA, Marta GN, Franceschini G, Orlandi A. Phase II study of apatinib in combination with oral vinorelbine in heavily pretreated HER2-negative metastatic breast cancer and clinical implications of monitoring ctDNA. Cancer biology & medicine, 18:875-887, 2021

50. Doi T, Tajimi M, Mori J, Asou H, Inoue K, Benhadji KA, Naito Y. A phase 1 study of crenigacestat (LY3039478), the Notch inhibitor, in Japanese patients with advanced solid tumors. Investigational new drugs, 39:469-476, 2021

51. Sagara Y, Mori M, Yamamoto S, Eguchi K, Iwatani T, Naito Y, Kogawa T, Tanaka K, Kotani H, Yasojima H, Ozaki Y, Noguchi E, Miyasita M, Kondo N, Niikura N, Toi M, Shien T, Iwata H. Current Status of Advance Care Planning and End-of-life Communication for Patients with Advanced and Metastatic Breast Cancer. The oncologist, 26:e686-e693, 2021

52. Izumi H, Matsumoto S, Liu J, Tanaka K, Mori S, Hayashi K, Kumagai S, Shibata Y, Hayashida T, Watanabe K, Fukuhara T, Ikeda T, Yoh K, Kato T, Nishino K, Nakamura A, Nakachi I, Kuyama S, Furuya N, Sakakibara-Konishi J, Okamoto I, Taima K, Ebi N, Daga H, Yamasaki A, Kodani M, Udagawa H, Kirita K, Zenke Y, Nosaki K, Sugiyama E, Sakai T, Nakai T, Ishii G, Niho S, Ohtsu A, Kobayashi SS, Goto K. The CLIP1-LTK fusion is an oncogenic driver in non-small-cell lung cancer. Nature, 600:319-323, 2021

53. Cho BC, Yoh K, Perets R, Nagrial A, Spigel DR, Gutierrez M, Kim DW, Kotasek D, Rasco D, Niu J, Satouchi M, Ahn MJ, Lee DH, Maurice-Dror C, Siddiqi S, Ren Y, Altura RA, Bar J. Anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody quavonlimab in combination with pembrolizumab: Safety and efficacy from a phase I study in previously treated extensive-stage small cell lung cancer. Lung cancer (Amsterdam, Netherlands), 159:162-170, 2021

54. Sakai T, Udagawa H, Kirita K, Nomura S, Itotani R, Tamiya Y, Sugimoto A, Ota T, Naito T, Izumi H, Nosaki K, Ikeda T, Zenke Y, Matsumoto S, Yoh K, Niho S, Nakai T, Ishii G, Goto K. Comparison of the efficiency of endobronchial ultrasound-guided transbronchial needle aspiration using a 22G needle versus 25G needle for the diagnosis of lymph node metastasis in patients with lung cancer: a prospective randomized, crossover study. Translational lung cancer research, 10:3745-3758, 2021

55. Yoh K, Matsumoto S, Furuya N, Nishino K, Miyamoto S, Oizumi S, Okamoto N, Itani H, Kuyama S, Nakamura A, Nishi K, Fukuda I, Tsuta K, Hayashi Y, Motoi N, Ishii G, Goto K. Comprehensive assessment of PD-L1 expression, tumor mutational burden and oncogenic driver alterations in non-small cell lung cancer patients treated with immune checkpoint inhibitors. Lung cancer (Amsterdam, Netherlands), 159:128-134, 2021

56. Miura K, Sano Y, Niho S, Kawasumi K, Mochizuki N, Yoh K, Matsumoto S, Zenke Y, Ikeda T, Nosaki K, Kirita K, Udagawa H, Goto K, Kawasaki T, Hanada K. Impact of concomitant medication on clinical outcomes in patients with advanced non-small cell lung cancer treated with immune checkpoint inhibitors: A retrospective study. Thoracic cancer, 12:1983-1994, 2021

57. Sugimoto A, Umemura S, Miyoshi T, Nakai T, Kuroe T, Nosaki K, Ikeda T, Udagawa H, Kirita K, Zenke Y, Matsumoto S, Yoh K, Niho S, Tsuboi M, Goto K, Ishii G. High proportion of tumor necrosis predicts poor survival in surgically resected high-grade neuroendocrine carcinoma of the lung. Lung cancer (Amsterdam, Netherlands), 157:1-8, 2021

58. Udagawa H, Sugiyama E, Harada T, Atagi S, Koyama R, Watanabe S, Nakamura Y, Harada D, Hataji O, Tanaka F, Kida H, Satouchi M, Maeno K, Inoue A, Yoh K, Yamane Y, Urata Y, Yoshioka H, Yamanaka T, Goto K. Bevacizumab plus platinum-based chemotherapy in advanced non-squamous non-small-cell lung cancer: a randomized, open-label phase 2 study (CLEAR). Translational lung cancer research, 10:3059-3070, 2021

59. Ishii T, Suzuki A, Kuwata T, Hisamitsu S, Hashimoto H, Ohara Y, Yanagihara K, Mitsunaga S, Yoshino T, Kinoshita T, Ochiai A, Shitara K, Ishii G. Drug-exposed cancer-associated fibroblasts facilitate gastric cancer cell progression following chemotherapy. Gastric cancer: official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association, 24:810-822, 2021

60. Sasaki K, Kobayashi S, Kudo M, Sugimoto M, Takahashi S, Nakamura Y, Kawazoe A, Shitara K, Kinoshita T, Gotohda N. Hypothyroidism and hypopituitarism as immune-related adverse events due to lenvatinib plus pembrolizumab therapy in the immediate postoperative period after laparoscopic hepatectomy for liver metastases from gastric cancer: a case report. Surgical case reports, 7:267, 2021

61. Chida K, Kotani D, Nakamura Y, Kawazoe A, Kuboki Y, Shitara K, Kojima T, Taniguchi H, Watanabe J, Endo I, Yoshino T. Efficacy and safety of trifluridine/tipiracil plus bevacizumab and trifluridine/tipiracil or regorafenib monotherapy for chemorefractory metastatic colorectal cancer: a retrospective study. Therapeutic advances in medical oncology, 13:1.75884E+16, 2021

62. Shitara K, Tabernero J. Quantifying the Long-term Survival Benefit of Pembrolizumab for Patients With Advanced Gastric Cancer-Reply. JAMA oncology, 7:633, 2021

63. Wainberg ZA, Fuchs CS, Tabernero J, Shitara K, Muro K, Van Cutsem E, Bang YJ, Chung HC, Yamaguchi K, Varga E, Chen JS, Hochhauser D, Thuss-Patience P, Al-Batran SE, Garrido M, Kher U, Shih CS, Shah S, Bhagia P, Chao J. Efficacy of Pembrolizumab Monotherapy for Advanced Gastric/Gastroesophageal Junction Cancer with Programmed Death Ligand 1 Combined Positive Score ≥10. Clinical cancer research: an official journal of the American Association for Cancer Research, 27:1923-1931, 2021

64. Chao J, Fuchs CS, Shitara K, Tabernero J, Muro K, Van Cutsem E, Bang YJ, De Vita F, Landers G, Yen CJ, Chau I, Elme A, Lee J, Özgüroglu M, Catenacci D, Yoon HH, Chen E, Adelberg D, Shih CS, Shah S, Bhagia P, Wainberg ZA . Assessment of Pembrolizumab Therapy for the Treatment of Microsatellite Instability-High Gastric or Gastroesophageal Junction Cancer Among Patients in the KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 Clinical Trials. JAMA oncology, 7:895-902, 2021

65. Iida K, Abdelhamid Ahmed AH, Nagatsuma AK, Shibutani T, Yasuda S, Kitamura M, Hattori C, Abe M, Hasegawa J, Iguchi T, Karibe T, Nakada T, Inaki K, Kamei R, Abe Y, Nomura T, Andersen JL, Santagata S, Hemming ML, George S, Doi T, Ochiai A, Demetri GD, Agatsuma T. Identification and Therapeutic Targeting of GPR20, Selectively Expressed in Gastrointestinal Stromal Tumors, with DS-6157a, a First-in-Class Antibody-Drug Conjugate. Cancer discovery, 11:1508-1523, 2021

66. Oki E, Watanabe J, Sato T, Kagawa Y, Kuboki Y, Ikeda M, Ueno H, Kato T, Kusumoto T, Masuishi T, Yamaguchi K, Kanazawa A, Nishina T, Uetake H, Yamanaka T, Yoshino T. Impact of the 12-gene recurrence score assay on deciding adjuvant chemotherapy for stage II and IIIA/B colon cancer: the SUNRISE-DI study. ESMO open, 6:100146, 2021

67. Chida K, Kawazoe A, Kawazu M, Suzuki T, Nakamura Y, Nakatsura T, Kuwata T, Ueno T, Kuboki Y, Kotani D, Kojima T, Taniguchi H, Mano H, Ikeda M, Shitara K, Endo I, Yoshino T. A Low Tumor Mutational Burden and PTEN Mutations Are Predictors of a Negative Response to PD-1 Blockade in MSI-H/dMMR Gastrointestinal Tumors. Clinical cancer research: an official journal of the American Association for Cancer Research, 27:3714-3724, 2021

68. Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, Wyrwicz L, Yamaguchi K, Skoczylas T, Campos Bragagnoli A, Liu T, Schenker M, Yanez P, Tehfe M, Kowalyszyn R, Karamouzis MV, Bruges R, Zander T, Pazo-Cid R, Hitre E, Feeney K, Cleary JM, Poulart V, Cullen D, Lei M, Xiao H, Kondo K, Li M, Ajani JA. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet (London, England), 398:27-40, 2021

69. Shitara K, Baba E, Fujitani K, Oki E, Fujii S, Yamaguchi K. Discovery and development of trastuzumab deruxtecan and safety management for patients with HER2-positive gastric cancer. Gastric cancer: official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association, 24:780-789, 2021

70. Mishima S, Shitara K. Trastuzumab deruxtecan for the treatment of HER2-positive gastric cancer. Expert opinion on biological therapy, 21:825-830, 2021

71. Kato T, Kagawa Y, Kuboki Y, Gamoh M, Komatsu Y, Yasui H, Satake H, Oki E, Tanioka H, Kotaka M, Makiyama A, Denda T, Goto M, Yoshino T, Yamazaki K, Soeda J, Shibuya K, Iwata M, Oba K, Yamaguchi K. Safety and efficacy of panitumumab in combination with trifluridine/tipiracil for pre-treated patients with unresectable, metastatic colorectal cancer with wild-type RAS: The phase 1/2 APOLLON study. International journal of clinical oncology, 26:1238-1247, 2021

72. Mansoor W, Arkenau HT, Alsina M, Shitara K, Thuss-Patience P, Cuffe S, Dvorkin M, Park D, Ando T, Van Den Eynde M, Beretta GD, Zaniboni A, Doi T, Tabernero J, Ilson DH, Makris L, Benhadji KA, Van Cutsem E. Trifluridine/tipiracil in patients with metastatic gastroesophageal junction cancer: a subgroup analysis from the phase 3 TAGS study. Gastric cancer: official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association, 24:970-977, 2021

73. Curigliano G, Gelderblom H, Mach N, Doi T, Tai D, Forde PM, Sarantopoulos J, Bedard PL, Lin CC, Hodi FS, Wilgenhof S, Santoro A, Sabatos-Peyton CA, Longmire TA, Xyrafas A, Sun H, Gutzwiller S, Manenti L, Naing A. Phase I/Ib Clinical Trial of Sabatolimab, an Anti-TIM-3 Antibody, Alone and in Combination with Spartalizumab, an Anti-PD-1 Antibody, in Advanced Solid Tumors. Clinical cancer research: an official journal of the American Association for Cancer Research, 27:3620-3629, 2021

74. Nakamura Y, Kawazoe A, Lordick F, Janjigian YY, Shitara K. Biomarker-targeted therapies for advanced-stage gastric and gastro-oesophageal junction cancers: an emerging paradigm. Nature reviews. Clinical oncology, 18:473-487, 2021

75. Takushima Y, Igarashi A, Yoshihara H, Shitara K, Doi T. Cost-effectiveness of trifluridine/tipiracil against nivolumab for heavily pretreated metastatic gastric cancer in Japan. Japanese journal of clinical oncology, 51:1383-1390, 2021

76. Piha-Paul SA, Geva R, Tan TJ, Lim DW, Hierro C, Doi T, Rahma O, Lesokhin A, Luke JJ, Otero J, Nardi L, Singh A, Xyrafas A, Chen X, Mataraza J, Bedard PL. First-in-human phase I/Ib open-label dose-escalation study of GWN323 (anti-GITR) as a single agent and in combination with spartalizumab (anti-PD-1) in patients with advanced solid tumors and lymphomas. Journal for immunotherapy of cancer, 9:2021

77. Isoyama S, Mori S, Sugiyama D, Kojima Y, Tada Y, Shitara K, Hinohara K, Dan S, Nishikawa H. Cancer immunotherapy with PI3K and PD-1 dual-blockade via optimal modulation of T cell activation signal. Journal for immunotherapy of cancer, 9:2021

78. Shitara K, Özgüroğlu M, Bang YJ, Di Bartolomeo M, Mandalà M, Ryu MH, Caglevic C, Chung HC, Muro K, Van Cutsem E, Kobie J, Cristescu R, Aurora-Garg D, Lu J, Shih CS, Adelberg D, Cao ZA, Fuchs CS . Molecular determinants of clinical outcomes with pembrolizumab versus paclitaxel in a randomized, open-label, phase III trial in patients with gastroesophageal adenocarcinoma. Annals of oncology: official journal of the European Society for Medical Oncology, 32:1127-1136, 2021

79. Jogo T, Nakamura Y, Shitara K, Bando H, Yasui H, Esaki T, Terazawa T, Satoh T, Shinozaki E, Nishina T, Sunakawa Y, Komatsu Y, Hara H, Oki E, Matsuhashi N, Ohta T, Kato T, Ohtsubo K, Kawakami T, Okano N, Yamamoto Y, Yamada T, Tsuji A, Odegaard JI, Taniguchi H, Doi T, Fujii S, Yoshino T. Circulating Tumor DNA Analysis Detects FGFR2 Amplification and Concurrent Genomic Alterations Associated with FGFR Inhibitor Efficacy in Advanced Gastric Cancer. Clinical cancer research: an official journal of the American Association for Cancer Research, 27:5619-5627, 2021

80. Minashi K, Yamada T, Hosaka H, Amagai K, Shimizu Y, Kiyozaki H, Sato M, Soeda A, Endo S, Ishida H, Kamoshida T, Sakai Y, Shitara K. Cancer-related FGFR2 overexpression and gene amplification in Japanese patients with gastric cancer. Japanese journal of clinical oncology, 51:1523-1533, 2021

81. Ishii T, Shitara K. Trastuzumab deruxtecan and other HER2-targeting agents for the treatment of HER2-positive gastric cancer. Expert review of anticancer therapy, 21:1193-1201, 2021

82. Van Cutsem E, Amonkar M, Fuchs CS, Alsina M, Özgüroğlu M, Bang YJ, Chung HC, Muro K, Goekkurt E, Benson AB 3rd, Sun W, Wainberg ZA, Norquist JM, Chen X, Shih CS, Shitara K . Health-related quality of life in advanced gastric/gastroesophageal junction cancer with second-line pembrolizumab in KEYNOTE-061. Gastric cancer: official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association, 24:1330-1340, 2021

83. Van Cutsem E, Amonkar M, Fuchs CS, Alsina M, Özgüroğlu M, Bang YJ, Chung HC, Muro K, Goekkurt E, Benson AB 3rd, Sun W, Wainberg ZA, Norquist JM, Chen X, Shih CS, Shitara K . Correction to: Health-related quality of life in advanced gastric/gastroesophageal junction cancer with second-line pembrolizumab in KEYNOTE-061. Gastric cancer: official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association, 24:1341, 2021

84. Arai H, Inoue E, Yamaguchi K, Boku N, Hara H, Nishina T, Tsuda M, Shitara K, Shinozaki K, Nakamura S, Hyodo I, Muro K, Sasako M, Terashima M, Nakajima TE. Clinical implications of using both fluoropyrimidine and paclitaxel in patients with severe peritoneal metastasis of gastric cancer: A post hoc study of JCOG1108/WJOG7312G. Cancer medicine, 10:7673-7682, 2021

85. Maeda Y, Wada H, Sugiyama D, Saito T, Irie T, Itahashi K, Minoura K, Suzuki S, Kojima T, Kakimi K, Nakajima J, Funakoshi T, Iida S, Oka M, Shimamura T, Doi T, Doki Y, Nakayama E, Ueda R, Nishikawa H. Depletion of central memory CD8+ T cells might impede the antitumor therapeutic effect of Mogamulizumab. Nature communications, 12:7280, 2021

86. Yuda J, Yamauchi N, Kuzume A, Guo YM, Sato N, Minami Y. Molecular remission after combination therapy with blinatumomab and ponatinib with relapsed/refractory Philadelphia chromosome-positive acute lymphocytic leukemia: two case reports. Journal of medical case reports, 15:164, 2021

87. H Nakamura, Y Minami, SG Chi, A Nagata, S Uchiyama, N Yamauchi. Emerging Mitochondria-Associated Molecular Target Therapies for Acute Myeloid Leukemia. Arch Clin Biomed Res, 5:419-424, 2021

88. Nakamura Y, Shitara K, Lee J. The Right Treatment of the Right Patient: Integrating Genetic Profiling Into Clinical Decision Making in Advanced Gastric Cancer in Asia. American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting, 41:1-8, 2021

89. Kanemitsu Y, Shitara K, Mizusawa J, Hamaguchi T, Shida D, Komori K, Ikeda S, Ojima H, Ike H, Shiomi A, Watanabe J, Takii Y, Yamaguchi T, Katsumata K, Ito M, Okuda J, Hyakudomi R, Shimada Y, Katayama H, Fukuda H. Primary Tumor Resection Plus Chemotherapy Versus Chemotherapy Alone for Colorectal Cancer Patients With Asymptomatic, Synchronous Unresectable Metastases (JCOG1007; iPACS): A Randomized Clinical Trial. Journal of clinical oncology: official journal of the American Society of Clinical Oncology, 39:1098-1107, 2021

90. Noguchi M, Shitara K, Kawazoe A, Yamamoto D, Takii Y, Saito Y, Sato T, Horimatsu T, Ishikawa H, Ito Y, Ito M, Ikematsu H. Short-term safety of adjuvant chemoradiotherapy after local resection for patients with high-risk submucosal invasive rectal cancer: a single-arm, multicenter phase II trial. Japanese journal of clinical oncology, 51:707-712, 2021

91. Harding JJ, Moreno V, Bang YJ, Hong MH, Patnaik A, Trigo J, Szpurka AM, Yamamoto N, Doi T, Fu S, Calderon B, Velez de Mendizabal N, Calvo E, Yu D, Gandhi L, Liu ZT, Galvao VR, Leow CC, de Miguel MJ. Blocking TIM-3 in Treatment-refractory Advanced Solid Tumors: A Phase Ia/b Study of LY3321367 with or without an Anti-PD-L1 Antibody. Clinical cancer research: an official journal of the American Association for Cancer Research, 27:2168-2178, 2021

92. Yoh K, Seto T, Satouchi M, Nishio M, Yamamoto N, Murakami H, Nogami N, Nosaki K, Kohno T, Tsuta K, Nomura S, Ikeno T, Wakabayashi M, Sato A, Matsumoto S, Goto K. Final survival results for the LURET phase II study of vandetanib in previously treated patients with RET-rearranged advanced non-small cell lung cancer. Lung cancer (Amsterdam, Netherlands), 155:40-45, 2021

93. Koganemaru S, Shitara K. Antibody-drug conjugates to treat gastric cancer. Expert opinion on biological therapy, 21:923-930, 2021

94. Hellmann MD, Bivi N, Calderon B, Shimizu T, Delafontaine B, Liu ZT, Szpurka AM, Copeland V, Hodi FS, Rottey S, Aftimos P, Piao Y, Gandhi L, Galvao VR, Leow CC, Doi T. Safety and Immunogenicity of LY3415244, a Bispecific Antibody Against TIM-3 and PD-L1, in Patients With Advanced Solid Tumors. Clinical cancer research: an official journal of the American Association for Cancer Research, 27:2773-2781, 2021

95. Aoki H, Ueha S, Shichino S, Ogiwara H, Shitara K, Shimomura M, Suzuki T, Nakatsura T, Yamashita M, Kitano S, Kuroda S, Wakabayashi M, Kurachi M, Ito S, Doi T, Matsushima K. Transient Depletion of CD4(+) Cells Induces Remodeling of the TCR Repertoire in Gastrointestinal Cancer. Cancer immunology research, 9:624-636, 2021

96. Sakai T, Udagawa H, Matsumoto S, Yoh K, Nosaki K, Ikeda T, Zenke Y, Kirita K, Niho S, Akimoto T, Goto K, Ishii G. Morphological, immune and genetic features in biopsy sample associated with the efficacy of pembrolizumab in patients with non-squamous non-small cell lung cancer. Journal of cancer research and clinical oncology, 147:1227-1237, 2021

97. Mukohara T, Hosono A, Mimaki S, Nakayama A, Kusuhara S, Funasaka C, Nakao T, Fukasawa Y, Kondoh C, Harano K, Naito Y, Matsubara N, Tsuchihara K, Kuwata T. Effects of Ado-Trastuzumab Emtansine and Fam-Trastuzumab Deruxtecan on Metastatic Breast Cancer Harboring HER2 Amplification and the L755S Mutation. The oncologist, 26:635-639, 2021

98. Terao T, Yuda J, Yamauchi N, Guo YM, Shimada K, Sugano M, Ishii G, Minami Y. Brentuximab vedotin maintenance after autologous stem cell transplantation for refractory gray zone lymphoma with long-term remission. Molecular and clinical oncology, 14:125, 2021