www.thelancet.com/oncology Vol 21 June 2020 843 Articles Lancet Oncol 2020; 21: 843–50 See Comment page 745 Department of Experimental Therapeutics (J Sato MD, N Yamamoto MD), Clinical Research Support Office (K Nakamura MD, Y Nagasaka BS, M Kawasaki MS, T Yamada MPH), Department of Thoracic Oncology (Y Ohe MD), and Biostatistics Division, Center for Research Administration and Support (R Machida ME, A Kuchiba PhD), National Cancer Center Hospital, Tokyo, Japan; Department of Thoracic Oncology, Hyogo Cancer Center, Hyogo, Japan (M Satouchi MD, S Itoh MD); Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan (Y Okuma MD); Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan (S Niho MD); First Department of Medicine, Hokkaido University Hospital, Hokkaido, Japan (H Mizugaki MD); Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan (H Murakami MD); Department of Respiratory Medicine and Thoracic Oncology/Clinical Research Center, Osaka Medical College Hospital, Osaka, Japan (Y Fujisaka MD); and Department of Thoracic Oncology and Medicine, National Hospital Organization Shikoku Cancer Center, Ehime, Japan (T Kozuki MD) Correspondence to: Dr Noboru Yamamoto, Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo 104–0045, Japan nbryamam@ncc.go.jp Lenvatinib in patients with advanced or metastatic thymic carcinoma (REMORA): a multicentre, phase 2 trial Jun Sato, Miyako Satouchi, Shoichi Itoh, Yusuke Okuma, Seiji Niho, Hidenori Mizugaki, Haruyasu Murakami, Yasuhito Fujisaka, Toshiyuki Kozuki, Kenichi Nakamura, Yukari Nagasaka, Mamiko Kawasaki, Tomoaki Yamada, Ryunosuke Machida, Aya Kuchiba, Yuichiro Ohe, Noboru Yamamoto Summary Background Thymic carcinoma is a rare malignant disease and standard treatment for advanced or metastatic thymic carcinoma previously treated with platinum-based chemotherapy has not been established. Lenvatinib is a novel multi-targeted inhibitor of VEGFR, FGFR, RET, c-Kit, and other kinases. The aim of this trial was to assess the activity and safety of lenvatinib as a second-line treatment in thymic carcinoma. Methods This single-arm, phase 2 trial done in eight institutions in Japan (fve cancer centres, two medical university hospitals, and one public hospital) enrolled patients with pathologically confrmed unresectable advanced or metastatic thymic carcinoma that progressed following at least one platinum-based chemotherapy. Key inclusion criteria were age 20 years or older, at least one measurable lesion as defned by the Response Evaluation Criteria in Solid Tumors version 1.1, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received 24 mg of lenvatinib orally once daily in 4-week cycles until disease progression or occurrence of unacceptable adverse events. The primary endpoint was objective response rate evaluated at the data cutof date (Feb 22, 2019), by independent central review in the intention-to-treat population. This trial is registered on JMACCT, JMA-IIA00285, and on UMIN-CTR, UMIN000026777. Findings Between April 21, 2017, and Feb 22, 2018, 42 patients were enrolled and all patients were included in the activity and safety analysis. The median follow-up period was 15·5 months (IQR 13·1–17·5). The objective response rate was 38% (90% CI 25·6–52·0, p<0·0001). 16 (38%) of 42 patients had a partial response and 24 (57%) had stable disease. The most frequent grade 3 treatment-related adverse events were hypertension (27 [64%]) and palmar-plantar erythrodysaesthesia syndrome (three [7%]). No patient died from adverse events. Interpretation The activity and safety of lenvatinib in patients with advanced or metastatic thymic carcinoma was confrmed. These results suggest that lenvatinib could become a standard treatment option for patients with previously treated advanced or metastatic thymic carcinoma. Funding Center for Clinical Trials, Japan Medical Association. Copyright © 2020 Elsevier Ltd. All rights reserved. Introduction Thymic carcinoma is a rare malignant disease with an incidence of about 0·02 per 100 000 person-years, 1,2 and about 30% of patients have advanced disease at the time of diagnosis. Patients with advanced or thymic carcinoma have poor prognosis, and cytotoxic chemotherapies have been used to achieve prolonged disease control in such cases. 3 Several retrospective studies and phase 2 trials have been done to investigate the efcacy of cytotoxic agents, immune checkpoint inhibitors, and molecular targeted drugs. 4–8 On the basis of the results of these studies, platinum-based chemotherapy has been recommended as a frst-line chemotherapy by some practice guidelines. 9,10 However, standard second-line treatment for advanced or metastatic thymic carcinoma patients previously treated with platinum-based chemo- therapy has not yet been established. VEGF plays a key role in tumour angiogenesis, with a negative efect on prognosis in various types of cancer. VEGF receptors (VEGFR) are mainly classifed into VEGFR1, VEGFR2, and VEGFR3. VEGFR2 expression is an important mediator of VEGF-induced angiogenesis, and VEGFR2 and PDGFR-α are known to be activated in thymic carcinoma. 11–13 In our retrospective analysis, 14 we analysed the antitumor activity of multi- targeted kinase inhibitors in phase 1 trials. Several phase 2 trials have reported the activity and safety of multi-targeted kinase inhibitors, mainly targeting VEGR, as second-line treatment for thymic carci- noma. 5,8,11,15–17 The activity of sunitinib malate, a multi- targeted kinase inhibitor targeting VEGFR, was tested in 23 patients with thymic carcinoma and 16 patients with thymoma in a phase 2 trial, in which six (26%) of 23 patients with thymic carcinoma achieved a partial response. 5 Lenvatinib is a novel orally administered multi-targeted kinase inhibitor for VEGFR, FGFR, c-Kit, and other kinases, and has shown antitumour activity in several cancer types. 18,19 Lenvatinib has been approved for the treatment of thyroid cancer and hepatocellular cancer in