TY - JOUR
T1 - Phase 1/2 study of alectinib in RET-rearranged previously-treated non-small cell lung cancer (ALL-RET)
AU - Takeuchi, Shinji
AU - Yanagitani, Noriko
AU - Seto, Takashi
AU - Hattori, Yoshihiro
AU - Ohashi, Kadoaki
AU - Morise, Masahiro
AU - Matsumoto, Shingo
AU - Yoh, Kiyotaka
AU - Goto, Koichi
AU - Nishio, Makoto
AU - Takahara, Shizuko
AU - Kawakami, Takahiro
AU - Imai, Yasuhito
AU - Yoshimura, Kenichi
AU - Tanimoto, Azusa
AU - Nishiyama, Akihiro
AU - Murayama, Toshinori
AU - Yano, Seiji
N1 - Funding Information:
We thank the patients, their families, and all staff that participated in this study. We are grateful to Chugai Pharmaceutical for providing alectinib compassionately. Funding: This study was supported by grants from the Japan Agency for Medical Research and Development, AMED, Grant Number 15Ack0106147h0001 and 18ck0106423h0001 (to SY) and Kanazawa University Hospital.
Funding Information:
Peer Review File: Available at http://dx.doi.org/10.21037/ tlcr-20-549 Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi. org/10.21037/tlcr-20-549). Dr. NY, Dr. YH, and Dr. MM reports personal fees from Chugai Pharma, outside the submitted work. Dr. TS reports grants and personal fees from Chugai Pharma, grants and personal fees from AstraZeneca, grants and personal fees from Eisai, grants and personal fees from Eli Lilly Japan, grants and personal fees from Nippon Boehringer Ingelheim, grants and personal fees from Novartis Pharma, grants and personal fees from Pfizer Japan, grants and personal fees from Sanofi, grants and personal fees from Taiho Pharma, personal fees from Daiichi Sankyo, personal fees from Fuji Pharma, personal fees from Hisamitsu Pharma, personal fees from Kyowa Hakko Kirin, personal fees from Mochida Pharma, personal fees from Nippon Kayaku, personal fees from Ono Pharma, personal fees from Roche Diagnostics, personal fees from Showa Yakuhin Kako, personal fees from Sumitomo Dainippon Pharma, personal fees from Takeda Pharma, grants from Astellas Pharma, grants from Bayer Yakuhin, grants from Merck Serono, grants from MSD, grants from Verastem, grants from Yakult, outside the submitted work. Dr. SM reports grants and personal fees from Astellas Pharma, grants and personal fees from Novartis Pharma, grants and personal fees from Eli Lilly Japan, grants from Chugai Pharma, grants from AstraZeneca, grants from Amgen Astellas BioPharma, grants from Eisai, grants from Ono Pharma, grants from Kyowa Hakko Kirin, grants from MSD, grants from Daiichi Sankyo, grants from Taiho Pharma, grants from Takeda Pharma, grants from Pfizer, outside the submitted work. Dr. K Yoh reports grants and personal fees from AstraZeneca, grants and personal fees from Eli Lilly Japan, personal fees from Boehringer Ingelheim, personal fees from Pfizer, personal fees from Taiho Pharma, personal fees from Bristol-Myers Squibb, personal fees from Ono Pharma, grants from Bayer, grants from Novartis, grants from Takeda Pharma, outside the submitted work. Dr. KG reports grants and personal fees from Chugai, grants and personal fees from Taiho Pharma, grants and personal fees from AstraZeneca, grants and personal fees from Nippon Boehringer Ingelheim, grants and personal fees from Ono Pharma, grants and personal fees from Pfizer, grants and personal fees from Kyowa Hakko Kirin, grants and personal fees from Eli Lilly Japan, grants and personal fees from Daiichi Sankyo, grants from MSD, grants from Quintiles, grants from GlaxoSmithKline, grants from OxOnc, grants from Sumitomo Dainippon Pharma, grants from Takeda Pharma, grants from Astellas Pharma, grants from Eisai, grants from Amgen Astellas BioPharma, personal fees from Yakult Honsha, personal fees from Novartis Pharma, personal fees from Bristol-Myers Squibb, outside the submitted work. Dr. MN reports grants and personal fees from Chugai, grants and personal fees from Taiho Pharma, grants and personal fees from AstraZeneca, grants and personal fees from Bristol Myers Squibb, grants and personal fees from Ono Pharma, grants and personal fees from Pfizer, grants and personal fees from Novartis, grants and personal fees from Eli Lilly Japan, grants and personal fees from MSD, personal fees from Boehringer-Ingelheim, personal fees from Daiichi Sankyo Healthcare, personal fees from Merck Serono, personal fees from MSD, personal fees from Pfizer, grants from Astellas, outside the submitted work. Dr. K Yoshimura reports personal fees from Chugai Pharma, personal fees from Astra Zeneca, personal fees from Eli Lilly, outside the submitted work. Dr. SY reports grants from the Japan Agency for Medical Research and Development (AMED), during the conduct of the study; grants and personal fees from Chugai Pharma, grants and personal fees from Boehringer-Ingelheim Japan, grants and personal fees from Novartis, personal fees from AstraZeneca, personal fees from Pfizer, outside the submitted work. The other authors have no conflicts of interest to declare.
Publisher Copyright:
© 2021 Translational Lung Cancer Research.
PY - 2021/1
Y1 - 2021/1
N2 - Background: Rearranged during transfection (RET) rearrangements occur in 1-2% of non-small cell lung cancers (NSCLCs). Alectinib administered at doses of 300 mg and 600 mg twice daily (BID) is approved for ALK-rearranged NSCLC in Japan and other countries, respectively. Since alectinib has activity against RET, we conducted a phase (P) 1/2 study of alectinib to determine its activity in Japanese patients with RET-rearranged NSCLC. Methods: This study was a single-arm, open-label, multi-institutional P1/2 trial. Previously treated patients with RET-rearranged NSCLC, screened by nation-wide network (LC-SCRUM-Japan), were recruited. In P1, alectinib (600 or 450 mg BID) was administered following a 3+3 design and its safety was assessed. During P2, alectinib was administered at the recommended dose (RD) determined in P1. The primary endpoint was the objective response rate (ORR) in RET inhibitor-naïve patients treated with the RD of alectinib. Results: Thirty-four patients were administered alectinib. In cohort 1 (600 mg BID) of P1, we observed 5 dose-limiting toxicities (DLTs), including grade 3 rash and thromboembolic event, in 3 of 6 patients. In cohort 2 (450 mg BID), we observed no DLTs in 3 patients. Pharmacokinetic analysis revealed that AUC0-10 to 600 mg BID was higher than that previously reported in global trials. We determined 450 mg BID as the RD for P2. In 25 RET inhibitor-naïve patients, one achieved an objective response (4%) and 13 achieved disease control at 8 weeks (52%). The median progression-free survival (PFS) was 3.4 months (95% CI, 2.0-5.4), while the median overall survival was 19.0 months (5.4-NE). We observed grade 3 adverse events (AEs) (4%) including pneumonitis in P2. Conclusions: Alectinib exerts limited activity against RET-rearranged NSCLC. Further investigation to elucidate the mechanisms underlying sensitivity and resistance of RET inhibitors is required to improve outcomes for these patients.
AB - Background: Rearranged during transfection (RET) rearrangements occur in 1-2% of non-small cell lung cancers (NSCLCs). Alectinib administered at doses of 300 mg and 600 mg twice daily (BID) is approved for ALK-rearranged NSCLC in Japan and other countries, respectively. Since alectinib has activity against RET, we conducted a phase (P) 1/2 study of alectinib to determine its activity in Japanese patients with RET-rearranged NSCLC. Methods: This study was a single-arm, open-label, multi-institutional P1/2 trial. Previously treated patients with RET-rearranged NSCLC, screened by nation-wide network (LC-SCRUM-Japan), were recruited. In P1, alectinib (600 or 450 mg BID) was administered following a 3+3 design and its safety was assessed. During P2, alectinib was administered at the recommended dose (RD) determined in P1. The primary endpoint was the objective response rate (ORR) in RET inhibitor-naïve patients treated with the RD of alectinib. Results: Thirty-four patients were administered alectinib. In cohort 1 (600 mg BID) of P1, we observed 5 dose-limiting toxicities (DLTs), including grade 3 rash and thromboembolic event, in 3 of 6 patients. In cohort 2 (450 mg BID), we observed no DLTs in 3 patients. Pharmacokinetic analysis revealed that AUC0-10 to 600 mg BID was higher than that previously reported in global trials. We determined 450 mg BID as the RD for P2. In 25 RET inhibitor-naïve patients, one achieved an objective response (4%) and 13 achieved disease control at 8 weeks (52%). The median progression-free survival (PFS) was 3.4 months (95% CI, 2.0-5.4), while the median overall survival was 19.0 months (5.4-NE). We observed grade 3 adverse events (AEs) (4%) including pneumonitis in P2. Conclusions: Alectinib exerts limited activity against RET-rearranged NSCLC. Further investigation to elucidate the mechanisms underlying sensitivity and resistance of RET inhibitors is required to improve outcomes for these patients.
KW - Alectinib
KW - Clinical trial
KW - Lung cancer
KW - Precision medicine
KW - RET rearrangement
KW - Rearranged during transfection (RET)
UR - http://www.scopus.com/inward/record.url?scp=85100725158&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85100725158&partnerID=8YFLogxK
U2 - 10.21037/tlcr-20-549
DO - 10.21037/tlcr-20-549
M3 - Article
AN - SCOPUS:85100725158
SN - 2218-6751
VL - 10
SP - 314
EP - 325
JO - Translational Lung Cancer Research
JF - Translational Lung Cancer Research
IS - 1
ER -
