Annual Report 2021

Department of Gastrointestinal Oncology

Takayuki Yoshino, Toshihiko Doi, Takashi Kojima, Kouhei Shitara, Nozomu Fuse, Yasutoshi Kuboki, Akihito Kawazoe, Daisuke Kotani, Yoshiaki Nakamura, Saori Mishima, Ayumu Yoshikawa

Introduction

 In 2020, approximately 800 gastrointestinal (GI) cancer patients were treated by staff oncologists and skilled residents in the Department of GI Oncology, which focuses on the optimal chemotherapy W/ or W/O radiation for the treatment of GI cancers.

The Team and What We Do

 Inter-divisional tumor board conferences with the Surgical/Radiation Oncology Divisions are held regularly to review the current treatment for each patient and to discuss the further treatment strategies. Our activities for each type of GI cancer in 2020 are shown in Table 1. There are ongoing clinical trials which consist of 70 phase I trials including globally first-in-class (FIC), first-in-human (FIH), and investigational new drugs (INDs), 70 phase II/III clinical trials in order to approve the INDs, and 20 investigator-initiated clinical trials (IITs). In addition, young skilled residents in their early 30s have become principal investigators for several IITs.

Table 1. Number of new patients

Activities

Esophageal Cancer (EC)

 Enrollment for a phase I trial to evaluate the safety and efficacy of an oncolytic virus with pembrolizumab and a phase Ib/II study to investigate the safety, efficacy, and proof-of-concept (POC) of Anti PD-L1 antibody monotherapy following radical chemoradiotherapy were completed. In addition, an observational study to clarify the clinical utility of detecting MRD and monitoring using ctDNA analysis in patients with gastrointestinal cancer who plan to undergo curative treatment is ongoing.

Gastric Cancer (GC)

 We reported several research projects to clarify the immune profiles in gastric cancer or investigate biomarkers to predict treatment outcomes or resistance mechanisms after PD-1 blockade as collaborations with the division of cancer immunology. Two global phase 3 studies (LEAP-015 and INTEGRATE2b) are ongoing based on our investigator-initiated trials of lenvatinib plus pembrolizumab or regorafenib plus nivolumab for gastric cancer. Also, we have conducted a phase 2 study of first-line chemotherapy and regorafenib plus nivolumab. Enrollment for a phase 1 trial of photoimmunotherapy plus nivolumab for patients with EGFR expressing gastric cancer was completed. Furthermore, a phase 2 trial of neoadjuvant treatment with lenvatinib plus pembrolizumab and a phase 2 study of neoadjuvant trastuzumab deruxtecan are ongoing. Our department contributed to several international global studies such as a phase 3 trial of nivolumab plus chemotherapy (Checkmate649) for gastric cancer and published the results in major journals such as Nature as the first/lead author.

Colorectal Cancer (CRC)

 We have been conducting our initiative SCRUM-Japan platform, which is a nationwide cancer genome screening system using tissue/plasma-based next-generation sequencing (MONSTAR-SCREEN-1, GOZILA) and whole exome/whole transcriptome sequencing for metastatic solid tumors. Utilizing these screening systems, the umbrella type of IITs for metastatic CRC or solid tumor patients with HER2 amplification, BRAF non-V600E mutation, MET amplification, tumor mutational burden-high, ROS1 fusion, BRCA mutation, and NFE2L2 mutation are on-going. We have also launched IITs in resectable colorectal cancer (CIRCULATE-Japan project) to stratify them according to recurrence risk based on Signatera assay for detecting minimal residual disease.

Education

 Our residents learn the latest evidence-based medicine and apply this knowledge pragmatically to enhance care for patients with GI cancers, and eventually have qualifications as comprehensive GI oncologists through daily practice and direct training from our staff. Accordingly, our staff actively provide numerous valuable opportunities to polish their chemotherapy skills, especially in collaboration with the Department of Experimental Therapeutics, as well as diagnostic & therapeutic endoscopy skills in collaboration with the Department of Digestive Endoscopy. We regularly hold tumor board meetings and frequently hold numerous face-to-face meetings with experts in different fields. We instruct them on how to conduct valuable clinical trials, help them to attend international academic conferences, and explain the best way to present at academic meetings and work on many high-impact articles in scholarly journals. To date, our department has helped many residents to become ‘true’ skilled GI oncologists who play major roles at leading cancer centers across the country.

Future Prospects

 We continue to provide the best treatment for cancer patients and the best education for residents, and aim to perform the following activities:

1) To provide more the latest, cutting-edge medicine to cancer patients and to foster the next generation of skilled GI oncologists.

2) To achieve medical innovation in Japan, we aim to play a leading role in the clinical development of INDs by contributing to various types of clinical trials including FIC, FIH early trials, IITs with proof-of-concept, and international clinical trials.

3) To enhance our research activity, we will establish global research networks with cutting-edge researchers.

List of papers published in 2021

Journal

1. 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

2. 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

3. 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

4. Kotani D, Nakamura Y, Fujisawa T, Bando H, Sakamoto N, Johns AL, Park K, Casolino R, Yoshino T, Biankin AV. ICGC-ARGO precision medicine: targeted therapy according to longitudinal assessment of tumour heterogeneity in colorectal cancer. The Lancet. Oncology, 23:463-464, 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. 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

7. Okunaka M, Kotani D, Demachi K, Fujiwara H, Sakashita S, Yoshino T, Fujita T, Kojima T. Significance of chemotherapy-free interval and tumor regression grade in patients with recurrent esophageal squamous cell carcinoma receiving chemotherapy with fluorouracil and platinum after esophagectomy following preoperative chemotherapy. Esophagus: official journal of the Japan Esophageal Society, 19:240-249, 2022

8. 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

9. Bando H, Tsukada Y, Ito M, Yoshino T. Novel Immunological Approaches in the Treatment of Locally Advanced Rectal Cancer. Clinical colorectal cancer, 21:3-9, 2022

10. Oki E, Ando K, Taniguchi H, Yoshino T, Mori M. Sustainable Clinical Development of Adjuvant Chemotherapy for Colon Cancer. Annals of gastroenterological surgery, 6:37-45, 2022

11. 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

12. Yin J, Salem ME, Dixon JG, Jin Z, Cohen R, DeGramont A, Van Cutsem E, Taieb J, Alberts SR, Wolmark N, Schmoll HJ, Saltz LB, George TJ, Goldberg RRM, Kerr R, Lonardi S, Yoshino T, Yothers G, Grothey A, Andre T, Shi Q. Reevaluating Disease-Free Survival as an Endpoint vs Overall Survival in Stage III Adjuvant Colon Cancer Trials. Journal of the National Cancer Institute, 114:60-67, 2022

13. 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

14. Milella M, Luchini C, Lawlor RT, Johns AL, Casolino R, Yoshino T, Biankin AV. ICGC-ARGO precision medicine: familial matters in pancreatic cancer. The Lancet. Oncology, 23:25-26, 2022

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

16. Yothers G, Venook AP, Oki E, Niedzwiecki D, Lin Y, Crager MR, Chao C, Baehner FL, Wolmark N, Yoshino T. Patient-specific meta-analysis of 12-gene colon cancer recurrence score validation studies for recurrence risk assessment after surgery with or without 5FU and oxaliplatin. Journal of gastrointestinal oncology, 13:126-136, 2022

17. 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

18. Bando H, Tsukada Y, Inamori K, Togashi Y, Koyama S, Kotani D, Fukuoka S, Yuki S, Komatsu Y, Homma S, Taketomi A, Uemura M, Kato T, Fukui M, Wakabayashi M, Nakamura N, Kojima M, Kawachi H, Kirsch R, Yoshida T, Suzuki Y, Sato A, Nishikawa H, Ito M, Yoshino T. Preoperative Chemoradiotherapy plus Nivolumab before Surgery in Patients with Microsatellite Stable and Microsatellite Instability-High Locally Advanced Rectal Cancer. Clinical cancer research: an official journal of the American Association for Cancer Research, 28:1136-1146, 2022

19. 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

20. Papamichael D, Lopes GS, Olswold CL, Douillard JY, Adams RA, Maughan TS, Van Cutsem E, Venook AP, Lenz HJ, Heinemann V, Kaplan R, Bokemeyer C, Chibaudel B, Grothey A, Yoshino T, Zalcberg J, De Gramont A, Shi Q. Efficacy of anti-epidermal growth factor receptor agents in patients with RAS wild-type metastatic colorectal cancer ≥ 70 years. European journal of cancer (Oxford, England: 1990), 163:1-15, 2022

21. 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

22. Kasi PM, Fehringer G, Taniguchi H, Starling N, Nakamura Y, Kotani D, Powles T, Li BT, Pusztai L, Aushev VN, Kalashnikova E, Sharma S, Malhotra M, Demko ZP, Aleshin A, Rodriguez A, Billings PR, Grothey A, Taieb J, Cunningham D, Yoshino T, Kopetz S. Impact of Circulating Tumor DNA-Based Detection of Molecular Residual Disease on the Conduct and Design of Clinical Trials for Solid Tumors. JCO precision oncology, 6:e2100181, 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. Miyo M, Kato T, Nakamura Y, Taniguchi H, Takahashi Y, Ishii M, Okita K, Ando K, Yukami H, Mishima S, Yamazaki K, Kotaka M, Watanabe J, Oba K, Aleshin A, Billings PR, Rabinowitz M, Kotani D, Oki E, Takemasa I, Mori M, Yoshino T. DENEB: Development of new criteria for curability after local excision of pathological T1 colorectal cancer using liquid biopsy. Cancer science, 113:1531-1534, 2022

26. Matsumura M, Hasegawa K, Oba M, Yamaguchi K, Uetake H, Yoshino T, Morita S, Takahashi K, Unno M, Shimada Y, Muro K, Matsuhashi N, Mori M, Baba H, Shimada M, Mise Y, Kawaguchi Y, Kagimura T, Ishigure K, Saiura A, Sugihara K, Kokudo N. A randomized controlled trial of surgery and postoperative modified FOLFOX6 versus surgery and perioperative modified FOLFOX6 plus cetuximab in patients with KRAS wild-type resectable colorectal liver metastases: EXPERT study. Langenbeck's archives of surgery, 2022

27. 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

28. Strickler JH, Yoshino T, Graham RP, Siena S, Bekaii-Saab T. Diagnosis and Treatment of ERBB2-Positive Metastatic Colorectal Cancer: A Review. JAMA oncology, 8:760-769, 2022

29. 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

30. 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

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. Nakamura Y, Okamoto W, Kato T, Esaki T, Kato K, Komatsu Y, Yuki S, Masuishi T, Nishina T, Ebi H, Sawada K, Taniguchi H, Fuse N, Nomura S, Fukui M, Matsuda S, Sakamoto Y, Uchigata H, Kitajima K, Kuramoto N, Asakawa T, Olsen S, Odegaard JI, Sato A, Fujii S, Ohtsu A, Yoshino T. Circulating tumor DNA-guided treatment with pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer: a phase 2 trial. Nature medicine, 27:1899-1903, 2021

34. 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

35. 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

36. 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

37. 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

38. Nakamura Y, Fujisawa T, Taniguchi H, Bando H, Okamoto W, Tsuchihara K, Yoshino T, Ohtsu A. SCRUM-Japan GI-SCREEN and MONSTAR-SCREEN: Path to the realization of biomarker-guided precision oncology in advanced solid tumors. Cancer science, 112:4425-4432, 2021

39. 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

40. 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

41. 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

42. 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

43. 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

44. 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

45. 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

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

47. Yoshino T, Uetake H, Funato Y, Yamaguchi Y, Koyama T, Ozawa D, Tajiri M, Muro K. Post-marketing surveillance study of trifluridine/tipiracil in patients with metastatic colorectal cancer. Japanese journal of clinical oncology, 51:700-706, 2021

48. 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

49. Sunami K, Naito Y, Aimono E, Amano T, Ennishi D, Kage H, Kanai M, Komine K, Koyama T, Maeda T, Morita S, Sakai D, Kohsaka S, Tsuchihara K, Yoshino T. Correction to: The initial assessment of expert panel performance in core hospitals for cancer genomic medicine in Japan. International journal of clinical oncology, 26:1007, 2021

50. Kagawa Y, Elez E, García-Foncillas J, Bando H, Taniguchi H, Vivancos A, Akagi K, García A, Denda T, Ros J, Nishina T, Baraibar I, Komatsu Y, Ciardiello D, Oki E, Kudo T, Kato T, Yamanaka T, Tabernero J, Yoshino T . Combined Analysis of Concordance between Liquid and Tumor Tissue Biopsies for RAS Mutations in Colorectal Cancer with a Single Metastasis Site: The METABEAM Study. Clinical cancer research: an official journal of the American Association for Cancer Research, 27:2515-2522, 2021

51. Andre T, Amonkar M, Norquist JM, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt CJA, Smith D, Garcia-Carbonero R, Sevilla I, De La Fouchardiere C, Rivera F, Elez E, Diaz LA Jr, Yoshino T, Van Cutsem E, Yang P, Farooqui M, Le DT. Health-related quality of life in patients with microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer treated with first-line pembrolizumab versus chemotherapy (KEYNOTE-177): an open-label, randomised, phase 3 trial. The Lancet. Oncology, 22:665-677, 2021

52. Yagisawa M, Sawada K, Nakamura Y, Fujii S, Yuki S, Komatsu Y, Yoshino T, Sakamoto N, Taniguchi H. Prognostic Value and Molecular Landscape of HER2 Low-Expressing Metastatic Colorectal Cancer. Clinical colorectal cancer, 20:113-120.e1, 2021

53. Siena S, Di Bartolomeo M, Raghav K, Masuishi T, Loupakis F, Kawakami H, Yamaguchi K, Nishina T, Fakih M, Elez E, Rodriguez J, Ciardiello F, Komatsu Y, Esaki T, Chung K, Wainberg Z, Sartore-Bianchi A, Saxena K, Yamamoto E, Bako E, Okuda Y, Shahidi J, Grothey A, Yoshino T. Trastuzumab deruxtecan (DS-8201) in patients with HER2-expressing metastatic colorectal cancer (DESTINY-CRC01): a multicentre, open-label, phase 2 trial. The Lancet. Oncology, 22:779-789, 2021

54. 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

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