Takashi Ninomiya1, Naoyuki Nogami2, Toshiyuki Kozuki2, Daijiro Harada2, Toshio Kubo3, Kadoaki Ohashi4, Shoichi Kuyama5, Kenichiro Kudo5, Akihiro Bessho6, Nobuaki Fukamatsu6, Nobukazu Fujimoto7, Keisuke Aoe8, Takuo Shibayama9, Keisuke Sugimoto10, Nagio Takigawa11, Katsuyuki Hotta12, Katsuyuki Kiura13. 1. Department of Respiratory Medicine and Allergy, Okayama University Hospital, 2-5-1, Shikata-cho, Okayama, Japan. Electronic address: tninomiya5@okayama-u.ac.jp. 2. Department of Thoracic Oncology and Medicine, National Hospital Organization, Shikoku Cancer Center, 160, Minamiumemoto-ko, Matsuyama, Japan. 3. Department of Respiratory Medicine and Allergy, Okayama University Hospital, 2-5-1, Shikata-cho, Okayama, Japan; Center for Oncology, Okayama University Hospital, 2-5-1, Shikata-cho, Okayama, Japan. 4. Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Okayama, Japan. 5. Department of Respiratory Medicine, Iwakuni Clinical Center, 1-1-1, Atago-cho, Iwakuni, Japan. 6. Department of Respiratory Medicine, Japanese Red Cross Okayama Hospital, 2-1-1, Aoe, Okayama, Japan. 7. Department of Medical Oncology, Okayama Rosai Hospital, 1-10-25, Chikkomidorimachi, Okayama, Japan. 8. Department of Medical Oncology, National Hospital Organization, Yamaguchi-Ube Medical Center, 685, Higashikiwa, Ube, Japan. 9. Department of Respiratory Medicine, National Hospital Organization, Okayama Medical Center, 1711-1, Tamasu, Okayama, Japan. 10. Department of Respiratory Medicine, Japanese Red Cross Kobe Hospital, 1-3-1, Wakihamakaigann-dori, Chuo-ku, Kobe, Japan. 11. Department of General Internal Medicine 4, Kawasaki Medical School, 2-6-1, Nakasange, Okayama, Japan. 12. Center for Innovative Clinical Medicine, Okayama University Hospital, 2-5-1, Shikata-cho, Okayama, Japan. 13. Department of Respiratory Medicine and Allergy, Okayama University Hospital, 2-5-1, Shikata-cho, Okayama, Japan.
Abstract
OBJECTIVE: In advanced epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC), treatment with afatinib, a second-generation EGFR-tyrosine kinase inhibitor (TKI), confers a significant survival benefit over platinum-based chemotherapy. The first-generation EGFR-TKIs gefitinib and erlotinib in combination with bevacizumab have improved progression-free survival. We hypothesized that the combination of afatinib with bevacizumab would further improve efficacy, and conducted a phase I trial to test this hypothesis. MATERIALS AND METHODS: Untreated patients with advanced EGFR-mutant NSCLC were enrolled. The primary endpoint was safety. Two doses of afatinib, 40mg/day (level 0) and 30mg/day (level -1), were evaluated in combination with 15mg/kg bevacizumab every 3 weeks. Optimal dosing was determined by dose-limiting toxicity (DLT), with the concentration at which ≤4 of 12 patients experienced toxicity considered the recommended dose. RESULTS: Nineteen patients were enrolled (level 0:5, level -1:14). Three of the five patients at level 0 experienced a DLT, which indicated that this dose was unfeasible. Three patients at level -1 developed a DLT of grade 3 non-hematological toxicity, which was soon resolved. Grade 3 or worse adverse events were experienced by all five patients at dose level 0 (diarrhea in 2, skin rash in 1, hypoxia in 1, and paronychia in 1), and by three patients at level -1 (diarrhea in 2 and anorexia in 1). Among 16 evaluable patients, 1 had a complete response, 12 had partial responses, and 0 had progressive disease. CONCLUSION: Afatinib plus bevacizumab (level -1) was well tolerated and showed evidence of favorable disease control. This combination therapy may represent a potent therapeutic option for patients with EGFR-mutant NSCLC.
OBJECTIVE: In advanced epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC), treatment with afatinib, a second-generation EGFR-tyrosine kinase inhibitor (TKI), confers a significant survival benefit over platinum-based chemotherapy. The first-generation EGFR-TKIs gefitinib and erlotinib in combination with bevacizumab have improved progression-free survival. We hypothesized that the combination of afatinib with bevacizumab would further improve efficacy, and conducted a phase I trial to test this hypothesis. MATERIALS AND METHODS: Untreated patients with advanced EGFR-mutant NSCLC were enrolled. The primary endpoint was safety. Two doses of afatinib, 40mg/day (level 0) and 30mg/day (level -1), were evaluated in combination with 15mg/kg bevacizumab every 3 weeks. Optimal dosing was determined by dose-limiting toxicity (DLT), with the concentration at which ≤4 of 12 patients experienced toxicity considered the recommended dose. RESULTS: Nineteen patients were enrolled (level 0:5, level -1:14). Three of the five patients at level 0 experienced a DLT, which indicated that this dose was unfeasible. Three patients at level -1 developed a DLT of grade 3 non-hematological toxicity, which was soon resolved. Grade 3 or worse adverse events were experienced by all five patients at dose level 0 (diarrhea in 2, skin rash in 1, hypoxia in 1, and paronychia in 1), and by three patients at level -1 (diarrhea in 2 and anorexia in 1). Among 16 evaluable patients, 1 had a complete response, 12 had partial responses, and 0 had progressive disease. CONCLUSION:Afatinib plus bevacizumab (level -1) was well tolerated and showed evidence of favorable disease control. This combination therapy may represent a potent therapeutic option for patients with EGFR-mutant NSCLC.
Authors: Yang Liu; Zhi-Cheng Xiong; Xin Sun; Li Sun; Shu-Ling Zhang; Jie-Tao Ma; Cheng-Bo Han Journal: Transl Cancer Res Date: 2019-09 Impact factor: 1.241