{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T15:16:33Z","timestamp":1759331793485},"reference-count":17,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2021,6,12]],"date-time":"2021-06-12T00:00:00Z","timestamp":1623456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>In a phase I study, afatinib (30\u00a0mg\/body daily) plus bevacizumab (15\u00a0mg\/kg every 3\u00a0weeks) was well tolerated and showed favourable outcomes in patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer. Herein, we report the 2-year progression-free survival, overall survival and safety profile of these patients.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Chemo-na\u00efve patients with EGFR-mutant advanced non-small-cell lung cancer were enrolled. One group of patients received 40\u00a0mg afatinib daily and 15\u00a0mg\/kg bevacizumab every 3\u00a0weeks (level 0) until disease progression or severe toxicity. Another group of patients received 30\u00a0mg afatinib daily and the same dose of bevacizumab (level 1). Dose-limiting toxicity was the primary endpoint, whereas long-term progression-free survival, overall survival and tolerability were secondary endpoints. Survival rates were estimated using the Kaplan\u2013Meier method.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The study included 19 patients (level 0: 5; level\u00a0\u2212\u00a01: 14). Until the data cut-off date, seven patients continued the treatment, whereas 12 discontinued due to disease progression (n\u00a0=\u00a05) or toxicity (n\u00a0=\u00a07). The median PFS was 24.2\u00a0months, while the median overall survival was not reached. All patients developed adverse effects. Diarrhoea and skin rash were frequently observed as severe adverse events (grade 3). A secondary EGFR mutation (T790M) was detected in two patients after progression.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Prolonged follow-up revealed that combination therapy with afatinib and bevacizumab might improve survival outcomes in EGFR-mutant advanced non-small-cell lung cancer patients and seems to be promising.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Trial registration<\/jats:title>\n                  <jats:p>UMIN000015944.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jjco\/hyab084","type":"journal-article","created":{"date-parts":[[2021,5,30]],"date-time":"2021-05-30T11:07:31Z","timestamp":1622372851000},"page":"1269-1276","source":"Crossref","is-referenced-by-count":5,"title":["Survival of chemo-na\u00efve patients with <i>EGFR<\/i> mutation-positive advanced non-small cell lung cancer after treatment with afatinib and bevacizumab: updates from the Okayama Lung Cancer Study Group Trial 1404"],"prefix":"10.1093","volume":"51","author":[{"given":"Takashi","family":"Ninomiya","sequence":"first","affiliation":[{"name":"Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan"},{"name":"Department of Thoracic Oncology and Medicine, National Hospital Organization, Shikoku Cancer Center, Matsuyama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naoyuki","family":"Nogami","sequence":"additional","affiliation":[{"name":"Department of Community Medicine, Pulmonology and Cardiology, Ehime University Graduate School of Medicine, Toon, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshiyuki","family":"Kozuki","sequence":"additional","affiliation":[{"name":"Department of Thoracic Oncology and Medicine, National Hospital Organization, Shikoku Cancer Center, Matsuyama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daijiro","family":"Harada","sequence":"additional","affiliation":[{"name":"Department of Thoracic Oncology and Medicine, National Hospital Organization, Shikoku Cancer Center, Matsuyama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshio","family":"Kubo","sequence":"additional","affiliation":[{"name":"Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan"},{"name":"Center for Clinical Oncology, Okayama University Hospital, Okayama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kadoaki","family":"Ohashi","sequence":"additional","affiliation":[{"name":"Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eiki","family":"Ichihara","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Okayama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shoichi","family":"Kuyama","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Iwakuni Clinical Center, Iwakuni, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenichiro","family":"Kudo","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Iwakuni Clinical Center, Iwakuni, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akihiro","family":"Bessho","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Japanese Red Cross Okayama Hospital, Okayama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Makoto","family":"Sakugawa","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Japanese Red Cross Okayama Hospital, Okayama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nobukazu","family":"Fujimoto","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Okayama Rosai Hospital, Okayama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keisuke","family":"Aoe","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, National Hospital Organization, Yamaguchi-Ube Medical Center, Ube, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daisuke","family":"Minami","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, National Hospital Organization, Okayama Medical Center, Okayama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keisuke","family":"Sugimoto","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Japanese Red Cross Kobe Hospital, Kobe, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nobuaki","family":"Ochi","sequence":"additional","affiliation":[{"name":"Department of General Internal Medicine 4, Kawasaki Medical School, Okayama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nagio","family":"Takigawa","sequence":"additional","affiliation":[{"name":"Department of General Internal Medicine 4, Kawasaki Medical School, Okayama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katsuyuki","family":"Hotta","sequence":"additional","affiliation":[{"name":"Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshinobu","family":"Maeda","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Okayama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katsuyuki","family":"Kiura","sequence":"additional","affiliation":[{"name":"Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2021,6,12]]},"reference":[{"key":"2021080204312133700_ref1","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1056\/NEJMoa1913662","article-title":"Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC","volume":"382","author":"Ramalingam","year":"2020","journal-title":"N Engl J Med"},{"key":"2021080204312133700_ref2","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1056\/NEJMoa1713137","article-title":"Osimertinib in Untreated EGFR-Mutated Advanced Non\u2013Small-Cell Lung Cancer","volume":"378","author":"Soria","year":"2018","journal-title":"N Engl J 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