TY - JOUR
T1 - A phase I trial of afatinib and bevacizumab in chemo-naïve patients with advanced non-small-cell lung cancer harboring EGFR mutations
T2 - Okayama Lung Cancer Study Group Trial 1404
AU - Ninomiya, Takashi
AU - Nogami, Naoyuki
AU - Kozuki, Toshiyuki
AU - Harada, Daijiro
AU - Kubo, Toshio
AU - Ohashi, Kadoaki
AU - Kuyama, Shoichi
AU - Kudo, Kenichiro
AU - Bessho, Akihiro
AU - Fukamatsu, Nobuaki
AU - Fujimoto, Nobukazu
AU - Aoe, Keisuke
AU - Shibayama, Takuo
AU - Sugimoto, Keisuke
AU - Takigawa, Nagio
AU - Hotta, Katsuyuki
AU - Kiura, Katsuyuki
N1 - Funding Information:
TN received honoraria outside the current work from MSD, Boehringer–Ingelheim, and Chugai Pharmaceutical. NN received honoraria outside the current work from AstraZeneca, Ono Pharmaceutical, Astellas, Taiho Pharmaceutical, Eli Lilly Japan, Pfizer Inc. Japan, Boehringer–Ingelheim, and Chugai Pharmaceutical. TK received honoraria outside the current work from AstraZeneca, Ono Pharmaceutical, BMS, Kyowa Hakko Kirin, Eli Lilly Japan, Pfizer Inc. Japan, Boehringer–Ingelheim, and Chugai Pharmaceutical. TK has also received research funding outside the current work from AstraZeneca , Ono Pharmaceutical , BMS , Eli Lilly Japan , MSD , and Chugai Pharmaceutical . DH received honoraria outside the current work from Ono Pharmaceutical, BMS, Kyowa Hakko Kirin and Yakult Honsha Co. Ltd. KO has received a research grant from Novartis Pharmaceuticals Japan . SK received honoraria outside the current work from Ono Pharmaceutical, BMS, Eli Lilly Japan, Boehringer–Ingelheim, Meiji Seika Pharma Co., and Chugai Pharmaceutical. AB received honoraria outside the current work from AstraZeneca, Novartis, Eli Lilly Japan, Taiho Pharmaceutical, Pfizer Inc. Japan and Chugai Pharmaceutical. AB has also received research funding outside the current work from AstraZeneca and Amgen. NF received honoraria outside the current work from KISSEI Co. Ltd. KA received honoraria outside the current work from AstraZeneca, Eli Lilly Japan, Ono Pharmaceutical, and BMS. NT has received honoraria outside the current work from Eli Lilly Japan, AstraZeneca, Daiichi–Sankyo Pharmaceutical, Chugai Pharmaceutical, Taiho Pharmaceutical, Pfizer Inc. Japan, Boehringer–Ingelheim, and Ono Pharmaceutical, and research funding from AstraZeneca, Pfizer Inc. Japan, Kyowa Hakko Kirin, Eli Lilly Japan, Chugai Pharmaceutical, Nippon Kayaku Co. Ltd, Taiho Pharmaceutical, Takeda Pharmaceutical Co. Ltd, Boehringer–Ingelheim, and Ono Pharmaceutical. KH received honoraria outside the current work from AstraZeneca, Ono Pharmaceutical, Astellas, Novartis, BMS, MSD, Eli Lilly Japan, Daiichi–Sankyo Pharmaceutical, Boehringer–Ingelheim, Nihon Kayaku, Taiho Pharmaceutical, and Chugai Pharmaceutical. KH has also received research funding outside the current work from AstraZeneca, Boehringer–Ingelheim, Ono Pharmaceutical, Astellas, Novartis, BMS, Eli Lilly Japan, MSD, and Chugai Pharmaceutical. KK has received honoraria from Eli Lilly Japan, Nihon Kayaku, AstraZeneca, Daiichi-Sankyo Pharmaceutical, Chugai Pharmaceutical, Taiho Pharmaceutical, and Sanofi-Aventis. All of the other authors declare no conflicts of interest regarding this study.
Funding Information:
The authors wish to acknowledge and thank the coordinators and all the other investigators who contributed to this study as independent data-monitoring committee members, including Drs. Yoshiko Ogata, Makoto Sakugawa (Japanese Red Cross Okayama Hospital), Tomoko Yamagishi, Sae Wada (Okayama Rosai Hospital), Daisuke Minami, Takamasa Nakasuka (Okayama Medical Center), Daisuke Nojima (Iwakuni Medical Center), Nobuaki Ochi (Kawasaki Medical School General Medical Center), Yusuke Hata, Hirohisa Kano (Okayama University Hospital), Yosuke Toyota (Fukuyama Medical Center), Mikio Kataoka, and Masafumi Fujii. This study has been conducted with support from the Center for Innovative Clinical Medicine, Okayama University Hospital.
Funding Information:
The authors wish to acknowledge and thank the coordinators and all the other investigators who contributed to this study as independent data-monitoring committee members, including Drs. Yoshiko Ogata, Makoto Sakugawa (Japanese Red Cross Okayama Hospital), Tomoko Yamagishi, Sae Wada (Okayama Rosai Hospital), Daisuke Minami, Takamasa Nakasuka (Okayama Medical Center), Daisuke Nojima (Iwakuni Medical Center), Nobuaki Ochi (Kawasaki Medical School General Medical Center), Yusuke Hata, Hirohisa Kano (Okayama University Hospital), Yosuke Toyota (Fukuyama Medical Center), Mikio Kataoka, and Masafumi Fujii. This study has been conducted with support from the Center for Innovative Clinical Medicine, Okayama University Hospital .
Publisher Copyright:
© 2017 Elsevier B.V.
PY - 2018/1
Y1 - 2018/1
N2 - 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, 40 mg/day (level 0) and 30 mg/day (level −1), were evaluated in combination with 15 mg/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.
AB - 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, 40 mg/day (level 0) and 30 mg/day (level −1), were evaluated in combination with 15 mg/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.
KW - Afatinib
KW - Bevacizumab
KW - EGFR
KW - EGFR-TKI
KW - Non-small-cell lung cancer
KW - Phase Ib
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U2 - 10.1016/j.lungcan.2017.11.025
DO - 10.1016/j.lungcan.2017.11.025
M3 - Article
C2 - 29290249
AN - SCOPUS:85035745240
VL - 115
SP - 103
EP - 108
JO - Lung Cancer
JF - Lung Cancer
SN - 0169-5002
ER -