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. 2021 Jan;10(1):314-325.
doi: 10.21037/tlcr-20-549.

Phase 1/2 study of alectinib in RET-rearranged previously-treated non-small cell lung cancer (ALL-RET)

Shinji Takeuchi  1   2 , Noriko Yanagitani  3 , Takashi Seto  4 , Yoshihiro Hattori  5 , Kadoaki Ohashi  6 , Masahiro Morise  7 , Shingo Matsumoto  8 , Kiyotaka Yoh  8 , Koichi Goto  8 , Makoto Nishio  3 , Shizuko Takahara  9 , Takahiro Kawakami  9 , Yasuhito Imai  9 , Kenichi Yoshimura  9   10 , Azusa Tanimoto  1   2 , Akihiro Nishiyama  1   2 , Toshinori Murayama  9 , Seiji Yano  1   2
Affiliations
Free PMC article

Phase 1/2 study of alectinib in RET-rearranged previously-treated non-small cell lung cancer (ALL-RET)

Shinji Takeuchi et al. Transl Lung Cancer Res. 2021 Jan.
Free PMC article

Abstract

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.

Keywords: RET rearrangement; Rearranged during transfection (RET); alectinib; clinical trial; lung cancer; precision medicine.

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Conflict of interest statement

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.

Figures

Figure 1
Figure 1
PFS and OS of RET-TKI-naïve patients treated with 450 mg BID alectinib. The Kaplan-Meier curves estimating PFS (A) and OS (B) of 25 RET-TKI-naïve NSCLC patients (3 in phase 1 and 22 in phase 2) are shown. OS, overall survival; RET-TKI, rearranged during transfection-tyrosine kinase inhibitor; PFS, progression-free survival; NSCLC, non-small cell lung cancer.
Figure 2
Figure 2
Clinical outcome of RET rearranged NSCLC patients treated with alectinib. (A) Swimmer plot of all patients treated with alectinib. Bars indicate duration of alectinib treatment. The response [partial response (PD), stable disease (SD) and progressive disease (PD)] in 34 patients (9 in phase 1 and 25 in phase 2) was assessed by central review (RECIST v1.1). The fusion partner for RET in each patient is shown on the left side of the bars. Arrows indicate patients who were previously treated with other RET-TKIs. (B) Spider plot of all patients treated with alectinib. RET, rearranged during transfection; NSCLC, non-small cell lung cancer.
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References

    1. Kohno T, Nakaoku T, Tsuta K, et al. Beyond ALK-RET, ROS1 and other oncogene fusions in lung cancer. Transl Lung Cancer Res 2015;4:156-64. - PMC - PubMed
    1. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010;362:2380-8. 10.1056/NEJMoa0909530 - DOI - PubMed
    1. Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 2010;11:121-8. 10.1016/S1470-2045(09)70364-X - DOI - PubMed
    1. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 2018;378:113-25. 10.1056/NEJMoa1713137 - DOI - PubMed
    1. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013;368:2385-94. 10.1056/NEJMoa1214886 - DOI - PubMed

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