PMID- 33569315
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220420
IS  - 2218-6751 (Print)
IS  - 2226-4477 (Electronic)
IS  - 2218-6751 (Linking)
VI  - 10
IP  - 1
DP  - 2021 Jan
TI  - Phase 1/2 study of alectinib in RET-rearranged previously-treated non-small cell 
      lung cancer (ALL-RET).
PG  - 314-325
LID - 10.21037/tlcr-20-549 [doi]
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-naive 
      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 AUC(0-10) 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-naive 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.
CI  - 2021 Translational Lung Cancer Research. All rights reserved.
FAU - Takeuchi, Shinji
AU  - Takeuchi S
AD  - Division of Medical Oncology, Cancer Research Institute, Kanazawa University, 
      Kanazawa, Ishikawa, Japan.
AD  - Cancer Center, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan.
FAU - Yanagitani, Noriko
AU  - Yanagitani N
AD  - Department of Thoracic Medical Oncology, The Cancer Institute Hospital of 
      Japanese Foundation for Cancer Research, Koto-ku, Tokyo, Japan.
FAU - Seto, Takashi
AU  - Seto T
AD  - Department of Thoracic Oncology, National Kyusyu Cancer Center, Minami-Ku, 
      Fukuoka, Japan.
FAU - Hattori, Yoshihiro
AU  - Hattori Y
AD  - Department of Thoracic Oncology, Hyogo Cancer Center, Akashi, Hyogo, Japan.
FAU - Ohashi, Kadoaki
AU  - Ohashi K
AD  - Department of Respiratory Medicine and Allergy, Kita-ku, Okayama University 
      Hospital, Okayama, Japan.
FAU - Morise, Masahiro
AU  - Morise M
AD  - Department of Respiratory Medicine, Nagoya University Graduate School of 
      Medicine, Nagoya, Aichi, Japan.
FAU - Matsumoto, Shingo
AU  - Matsumoto S
AD  - Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, 
      Chiba, Japan.
FAU - Yoh, Kiyotaka
AU  - Yoh K
AD  - Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, 
      Chiba, Japan.
FAU - Goto, Koichi
AU  - Goto K
AD  - Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, 
      Chiba, Japan.
FAU - Nishio, Makoto
AU  - Nishio M
AD  - Department of Thoracic Medical Oncology, The Cancer Institute Hospital of 
      Japanese Foundation for Cancer Research, Koto-ku, Tokyo, Japan.
FAU - Takahara, Shizuko
AU  - Takahara S
AD  - Innovative Clinical Research Center (iCREK), Kanazawa University Hospital, 
      Kanazawa, Ishikawa, Japan.
FAU - Kawakami, Takahiro
AU  - Kawakami T
AD  - Innovative Clinical Research Center (iCREK), Kanazawa University Hospital, 
      Kanazawa, Ishikawa, Japan.
FAU - Imai, Yasuhito
AU  - Imai Y
AD  - Innovative Clinical Research Center (iCREK), Kanazawa University Hospital, 
      Kanazawa, Ishikawa, Japan.
FAU - Yoshimura, Kenichi
AU  - Yoshimura K
AD  - Innovative Clinical Research Center (iCREK), Kanazawa University Hospital, 
      Kanazawa, Ishikawa, Japan.
AD  - Medical Center for Translational and Clinical Research, Hiroshima University 
      Hospital, Hiroshima University, Minami, Hiroshima, Japan.
FAU - Tanimoto, Azusa
AU  - Tanimoto A
AD  - Division of Medical Oncology, Cancer Research Institute, Kanazawa University, 
      Kanazawa, Ishikawa, Japan.
AD  - Cancer Center, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan.
FAU - Nishiyama, Akihiro
AU  - Nishiyama A
AD  - Division of Medical Oncology, Cancer Research Institute, Kanazawa University, 
      Kanazawa, Ishikawa, Japan.
AD  - Cancer Center, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan.
FAU - Murayama, Toshinori
AU  - Murayama T
AD  - Innovative Clinical Research Center (iCREK), Kanazawa University Hospital, 
      Kanazawa, Ishikawa, Japan.
FAU - Yano, Seiji
AU  - Yano S
AD  - Division of Medical Oncology, Cancer Research Institute, Kanazawa University, 
      Kanazawa, Ishikawa, Japan.
AD  - Cancer Center, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan.
LA  - eng
PT  - Journal Article
PL  - China
TA  - Transl Lung Cancer Res
JT  - Translational lung cancer research
JID - 101646875
PMC - PMC7867784
OTO - NOTNLM
OT  - RET rearrangement
OT  - Rearranged during transfection (RET)
OT  - alectinib
OT  - clinical trial
OT  - lung cancer
OT  - precision medicine
COIS- 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.
EDAT- 2021/02/12 06:00
MHDA- 2021/02/12 06:01
PMCR- 2021/01/01
CRDT- 2021/02/11 05:54
PHST- 2021/02/11 05:54 [entrez]
PHST- 2021/02/12 06:00 [pubmed]
PHST- 2021/02/12 06:01 [medline]
PHST- 2021/01/01 00:00 [pmc-release]
AID - tlcr-10-01-314 [pii]
AID - 10.21037/tlcr-20-549 [doi]
PST - ppublish
SO  - Transl Lung Cancer Res. 2021 Jan;10(1):314-325. doi: 10.21037/tlcr-20-549.