Abstract P1-17-02: ZN-c5, an oral selective estrogen receptor degrader (SERD), in women with advanced estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer
Authors: Kalinksy Kevin , Abramson Vandana , Chalasani Pavani , Linden Hannah M. , Alidzanovic Jasmina , Layman Rachel M. , Vranješ Živko , Nangia Julie R. , Crew Katherine D. , Andric Zoran , Milovic-Kovacevic Marijana , Trifunovic Jasna , Suarez Jose , Suster Matt , Ptaszynski Mieke , Mortimer Joanne 
Published: March 2022

Abstract
Background: Hormone receptor+/HER2- breast cancer is the most common subtype of breast cancer. Resistance to endocrine therapy is a major clinical challenge. Although fulvestrant binds and degrades the ER and shows anti-tumor activity in patients with advanced breast cancer, intramuscular injection is inconvenient and precludes achievement of higher and potentially more efficacious exposure. ZN-c5 is a novel, orally bioavailable SERD with high potency and has demonstrated activity in estrogen-dependent tumor models. Methods: This Phase 1/2, open-label, multicenter study is evaluating the safety, pharmacokinetics and preliminary anti-tumor activity of ZN-c5 as monotherapy or in combination with palbociclib. In the Phase 1 portion evaluating ZN-c5 as monotherapy, participants were adult, post-menopausal (or receiving a gonadotropin-releasing hormone agonist) women with advanced adenocarcinoma of the breast, ER+/HER2- disease, and sensitive to endocrine therapy for metastatic disease (partial response [PR], complete response or stable disease [SD] lasting &gt; 6 months or disease recurrence after at least 24 months of adjuvant endocrine treatment). ZN-c5 was administered orally and continuously in 28-day cycles until disease progression or unacceptable toxicity. Dose escalation cohorts of subjects were enrolled at several dose levels of ZN-c5, based on a modified 3+3 design. Enrollment in the Phase 1 ZN-c5 monotherapy dose escalation and expansion has been completed and results are presented. Phase 1 testing of ZN-c5 in combination with palbociclib and Phase 2 testing in monotherapy are ongoing and will be presented at a future meeting. Results: In Phase 1 monotherapy, a total of 56 female subjects were enrolled to receive ZN-c5 at dose levels of 50 mg once daily (QD, n=16), 75 mg QD (n=3), 100 mg QD (n=3), 75 mg twice daily (BID, n=6), 150 mg QD (n=15), 150 mg BID (n=3), or 300 mg QD (n=10). Median age was 58.5 years (range, 38 - 89) and ECOG performance status was 0 (55%) or 1 (45%). Subjects had a median of 2 prior therapies for advanced/metastatic disease (range, 0 - 9), with a median of 2 prior hormonal-based therapies (range, 0 - 6) and a median of 0 prior chemotherapies (range, 0 - 3). Twenty-six subjects (46%) received prior fulvestrant and 38 (68%) received a prior CDK4/6 inhibitor. Twenty subjects (38%) had a baseline ESR1 mutation. The cut-off date for this analysis was 11 May 2021. There was no increase in severity of treatment-emergent adverse events (TEAEs) with increase in dose level. No dose-limiting toxicities were reported. The most common TEAEs were nausea (30%), fatigue (25%), and arthralgia (20%). Grade 3 TEAEs reported in &gt; 1 subject were gamma-glutamyltransferase (GGT) increased and hyponatremia (2 subjects each); no Grade 4 TEAEs were reported. Among treatment-related events, the most common were hot flushes and nausea (14% each); the only Grade 3 events were GGT increased and hypersensitivity in 1 subject each. ZN-c5 was rapidly absorbed, with a median Tmax of 2 to 4 hours. AUC and Cmax on Days 1 and 15 were less than dose proportional. No ZN-c5 accumulation after 15 days of dosing was observed. Confirmed PRs have been observed in 2 subjects (at 150 and 300 mg QD, respectively), and 14/45 (31%) evaluable subjects have experienced clinical benefit (PR or SD ≥ 24 weeks). Five of the 14 subjects with long SD received prior fulvestrant. Median progression-free survival (PFS) was 3.8 months (95% CI: 3.2, 5.3). Conclusions: In this first-in-human study, ZN-c5 monotherapy was well tolerated and showed clinical benefit, including confirmed PRs, in subjects with advanced ER+/HER2- breast cancer. These data warrant further evaluation of ZN-c5 as monotherapy and in combination with palbociclib.
Citation Format: Kevin Kalinksy, Vandana Abramson, Pavani Chalasani, Hannah M. Linden, Jasmina Alidzanovic, Rachel M. Layman, Živko Vranješ, Julie R. Nangia, Katherine D. Crew, Zoran Andric, Marijana Milovic-Kovacevic, Jasna Trifunovic, Jose Suarez, Matt Suster, Mieke Ptaszynski, Joanne Mortimer. ZN-c5, an oral selective estrogen receptor degrader (SERD), in women with advanced estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-17-02.