Abstract PD7-07: Final analysis of phase 1 study of elacestrant (RAD1901), a novel selective estrogen receptor degrader (SERD), in estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer
Authors: Kaklamani Virginia , Bardia Aditya , Wilks Sharon , Weise Amy , Richards Donald , Harb Wael , Osborne Cynthia , Wesolowski Robert , Karuturi Meghan , Conkling Paul , Bagley Rebecca , Jung JungAh , Bihani Teeru , Conlan Maureen , Kabos Peter 
Published: March 2020

Abstract
Background: The majority of patients (pts) with advanced ER+ breast cancer (BC) will experience progression of disease after endocrine therapy (ET) due to acquired resistance, including development of ESR1 mutations (mut). Response to conventional ET agents, including aromatase inhibitors and fulvestrant, in late lines of therapy is poor with overall response rates (ORR) less than 10% and median progression free survival (mPFS) of 2-3 months. Elacestrant is a novel, nonsteroidal, oral SERD with marked antitumor activity documented in multiple in vivo pt derived xenograft models of BC, including those derived from heavily pretreated pts and those with ESR1 mut.
Methods: RAD1901-005 is a multi-part phase 1 study of elacestrant with the primary objective to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). Secondary objectives are safety, tolerability, pharmacokinetics, and preliminary antitumor activity. Part A was dose escalation with 3+3 design (capsule; doses 200, 400 and 600 mg QD); Part B was safety expansion (capsule); Part C was expansion (tablet); Part D expansion (tablet) was added by amendment to study later line pts including prior CDK4/6 inhibitor (i) use (NCT02338349). Key eligibility criteria: advanced or metastatic (m) ER+, HER2- BC; postmenopausal status. For Parts A-C: ≤2 prior chemotherapy regimens (CT) for mBC and &gt;6 mo ET with progression (PD). For Part D: ≤1 prior CT for mBC, ≥2 prior lines of ET including PD on fulvestrant, and CDK4/6i. We present updated and final results from the trial (all parts).
Results: From April 2015 to March 2018, 57 pts were enrolled: Part A: 13, B: 20, C: 14, D: 10 (of 36 planned; enrollment was terminated due to change in regulatory strategy). MTD/RP2D was 400 mg QD. For all pts treated at 400 mg (n=50): stage IV 100%; visceral disease 70%; median prior lines of tx 3 (Part D: 4), including median of 1 prior line of CT and 3 prior lines of ET; prior CDK4/6i 52% (Part D: 100%); prior fulvestrant 50% (Part D: 100%); prior mTORi 26%. At baseline, 51% of pts had detectable ESR1 mut, including D538G, Y537S/N/C, L536H/P/R, S436P and E380Q. Among pts treated with 400 mg tablet (n=24), treatment-emergent adverse events in ≥20% were nausea, hypertriglyceridemia, hypophosphatemia, vomiting, dyspepsia, constipation, hypokalemia, fatigue, back pain, myalgia, headache, and urinary tract infection; the majority were grade 1 and 2. There were no treatment-related deaths. 13% of pts discontinued due to AEs. Antitumor activity is summarized in Table 1. There were 6 confirmed partial responses; median duration of response was 24.9 wk; median time to response was 8.2 wk. One pt with ESR1 mut with best response of SD remains on treatment at 3 yr.
Conclusion: Elacestrant at the RP2D of 400 mg QD has an acceptable safety profile and demonstrated significant single-agent anti-tumor activity in heavily pretreated (mostly 4th line or greater) ER+, HER2- mBC pts. Activity was seen following prior fulvestrant, prior CDK4/6i, and in pts with ESR1 mut. The ORR of 19.4% and mPFS of 4.5 mo compare favorably with those reported for fulvestrant and AIs given in earlier treatment settings. Elacestrant monotherapy vs. standard of care ET monotherapy is currently being studied in ER+, HER2- mBC with 1 or 2 lines of prior tx including prior CDK4/6i, in the phase 3 “EMERALD” study (NCT03778931).
Table 1. Efficacy OutcomesParts A-CPart DOverallORR, % (RECIST-evaluable pts) (n/N)27.3% (6/22)0% (0/9)19.4% (6/31)Clinical Benefit Rate, % (PR+SD ≥24 wk) (n/N)47.4% (18/38)22.2% (2/9)42.6% (20/47)mPFS (95% CI), mo, N=50 (ITT population)5.4 (3.7, 11.2)1.9 (1.8, 8.6)4.5 (1.9, 7.4)
Citation Format: Virginia Kaklamani, Aditya Bardia, Sharon Wilks, Amy Weise, Donald Richards, Wael Harb, Cynthia Osborne, Robert Wesolowski, Meghan Karuturi, Paul Conkling, Rebecca Bagley, JungAh Jung, Teeru Bihani, Maureen Conlan, Peter Kabos. Final analysis of phase 1 study of elacestrant (RAD1901), a novel selective estrogen receptor degrader (SERD), in estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD7-07.