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Clinical Trial
. 2025 Jan;30(1):72-82.
doi: 10.1007/s10147-024-02648-3. Epub 2024 Nov 20.

Safety and pharmacokinetics of vepdegestrant in Japanese patients with ER+ advanced breast cancer: a phase 1 study

Hiroji Iwata  1   2 , Yoichi Naito  3 , Masaya Hattori  4 , Akiyo Yoshimura  4 , Kan Yonemori  5 , Mana Aizawa  6 , Yuko Mori  7 , Junichiro Yoshimitsu  7 , Yoshiko Umeyama  7 , Toru Mukohara  3
Affiliations
Clinical Trial

Safety and pharmacokinetics of vepdegestrant in Japanese patients with ER+ advanced breast cancer: a phase 1 study

Hiroji Iwata et al. Int J Clin Oncol. 2025 Jan.

Abstract

Background: Vepdegestrant (ARV-471) is an oral PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader.

Methods: This phase 1 study (NCT05463952) investigated safety, pharmacokinetics, and antitumor activity of vepdegestrant in Japanese patients with ER-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer at the 200-mg once daily (QD) recommended phase 3 dose. Eligible patients had ER+/HER2- advanced breast cancer resistant to standard therapy, with no standard therapy available, or had received two or more prior endocrine therapies in any setting. The primary endpoint was dose-limiting toxicities (DLTs) in cycle 1; secondary endpoints included safety, pharmacokinetics, and antitumor activity.

Results: Six female patients (median age, 58 [range: 47-62] years) were treated. For advanced disease, three (50.0%) patients received three or more prior regimens and five (83.3%) patients received prior cyclin-dependent kinase 4/6 inhibitors. At data cutoff, median treatment duration was 9.8 (range: 6-28) weeks; two patients remained on treatment. No DLTs were observed. Four (66.7%) patients experienced adverse events; none led to dose reduction or discontinuation. Four (66.7%) patients had treatment-related adverse events; all were grade 1 except anemia (grade 2). Geometric mean maximum plasma concentration and 24-h area under the plasma concentration-time curve of vepdegestrant were 630.9 ng/mL and 10,400 ng∙hr/mL after a single dose and 1056 ng/mL and 18,310 ng∙hr/mL after multiple doses. Two (33.3%) patients demonstrated stable disease at week 24.

Conclusion: Vepdegestrant 200 mg QD was well tolerated in Japanese patients with ER+/HER2- advanced breast cancer with no notable differences in pharmacokinetics from Western patients.

Clinical trial registration: ClinicalTrials.gov: NCT05463952 (date of registration: July 19, 2022).

Keywords: Advanced breast cancer; Estrogen receptor–positive; Human epidermal growth factor receptor 2–negative; Japanese patients; Safety; Vepdegestrant.

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Conflict of interest statement

Declarations. Conflict of interest: H Iwata has received honoraria and research funding from Pfizer. Y Naito has received honoraria and/or other fees for conference attendance from Chugai, Daiichi Sankyo, and Eli Lilly; received research funds from AbbVie, AstraZeneca, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Eisai, Pfizer, Taiho, and Takeda. M Hattori has received honoraria from Daiichi Sankyo, MSD, and Eli Lilly; received research funding from Konica Minolta. A Yoshimura has nothing to disclose. K Yonemori has received honoraria from Pfizer, Eisai, AstraZeneca, Eli Lilly, Takeda, Chugai, Fuji Film Pharma, PDR pharma, MSD, Boehringer Ingelheim, Ono, Daiichi Sankyo, Bayer, Jansen, Asteras, Bristol Myers Squibb, Novartis, Sanofi, and Merk Biopharma; received research support (to institution) from MSD, Daiichi Sankyo, Merk Biopharma, AstraZeneca, Taiho, Pfizer, Novartis, Takeda, Chugai, Ono, Sanofi, Seattle Genetics, Eisai, Eli Lilly, Genmab, Boehringer Ingelheim, Kyowa Hakko Kirin, Nihon Kayaku, and Haihe. M Aizawa is an employee of Pfizer R&D Japan. Y Mori is an employee of Pfizer R&D Japan and holds stock in Pfizer Inc. J Yoshimitsu is an employee of Pfizer R&D Japan. Y Umeyama is an employee of Pfizer R&D Japan and holds stock in Pfizer Inc. T Mukohara has received honoraria from Daiichi Sankyo, Eli Lilly, Eisai, Pfizer, Novartis, Chugai, AstraZeneca, Kyowa Kirin, and Taiho; received research funds from AstraZeneca, Chugai, Daiichi Sankyo, Eisai, Gilead Sciences, MSD, Novartis, Ono, Pfizer, Sanofi, and Sysmex. Role of the sponsor: The funders had a role in the design and conduct of the study; data collection, management, and analysis of the data. The drafting of the manuscript, review, and decision to submit for publication were made by all the authors. Ethical approval: Approval of the study protocol by an Institutional Reviewer Board: The protocol, ICF, Investigator Brochure, and other relevant documents were submitted to an IRB/EC by the investigator and reviewed and approved by the IRB/EC before the study was initiated. These IRBs include the following: IRB at Aichi Cancer Center Hospital, IRB at National Cancer Center Hospital East, and IRB at National Cancer Center Hospital. This study was conducted in accordance with the protocol and consensus ethical principles derived from international guidelines, including the Declaration of Helsinki Council and CIOMS International Ethical Guidelines, applicable ICH GCP Guidelines, applicable ISO 14155 guidelines, medical device guidelines, and other applicable laws and regulations, including privacy laws. Informed consent: All patients provided written informed consent prior to the study. Registry and the Registration no. of the study/trial: This study is registered on ClinicalTrials.gov (NCT05463952). Research involving human and animal rights: Not applicable.

Figures

Fig. 1
Fig. 1
Study design. aPre- or perimenopausal women or men were eligible to be enrolled if treated with an LHRH agonist for ≥ 4 weeks prior to cycle 1 day 1. If a patient received an LHRH agonist, they were required to remain on it for the duration of the trial. bVepdegestrant 200 mg was given QD with food in 28-day cycles. DLT dose-limiting toxicity, ER + estrogen receptor–positive, ET endocrine therapy, HER2- human epidermal growth factor receptor 2–negative, LHRH luteinizing hormone–releasing hormone, QD once daily
Fig. 2
Fig. 2
Vepdegestrant and ARV-473 plasma concentration profiles following (a) a single dose and (b) multiple once-daily doses (N = 6). C cycle, D day, SD standard deviation
Fig. 3
Fig. 3
Investigator-assessed tumor response. For patient 4, insufficient amounts of DNA were available for ctDNA analysis. aNot a full list of all genetic alterations detected; genes shown are those associated with endocrine resistance when mutated and/or amplified [12]. CDK cyclin-dependent kinase, ctDNA circulating tumor DNA, ESR1 estrogen receptor 1 gene, FGFR1 fibroblast growth factor receptor 1 gene, NA not available, PIK3CA phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene, PTEN phosphatase and tensin homolog gene
Fig. 4
Fig. 4
Alterations in key non-ESR1 genes in individual patients. Key genes include ATRX, FANCG, FGFR1, IRS2, MSH3, MYC, PIK3CA, PTEN, RAD21, RET, WHSC1L1, and ZNF703. No alterations in these key genes were observed for patient 2. For patient 4, insufficient amounts of DNA were available for ctDNA analysis. Patient 1 was on treatment as of the cutoff date, thus no EOT sample was available. ATRX ATRX chromatin remodeler gene, C cycle, D day, ctDNA circulating tumor DNA, EOT end of treatment, ESR1 estrogen receptor 1 gene, FANCG FA complementation group G gene, FGFR1 fibroblast growth factor receptor 1 gene, IRS2 insulin receptor substrate 2 gene, MSH3 mutS homolog 3 gene, MYC MYC proto oncogene bHLH transcription factor gene, PIK3CA phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene, PTEN phosphatase and tensin homolog gene, RAD21 RAD21 cohesin complex component gene, RET ret proto oncogene, VAF variant allele fraction, WHSC1L1 nuclear receptor binding SET domain protein 3 gene, ZNF703 zinc finger protein 703 gene
Fig. 5
Fig. 5
Change in ESR1 variant allele fraction in individual patients. Plots show the change in ESR1 VAF in 2 patients. Patient 1 was on treatment as of the cutoff date, thus no EOT sample was available. C cycle, D day, EOT end of treatment, ESR1 estrogen receptor 1 gene, VAF variant allele fraction
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