Evaluation of RAD1901, a novel investigational, selective estrogen receptor degrader (SERD), for the treatment of ER-positive (ER+) advanced breast cancer.

Abstract

1014 Background: The treatment of advanced ER+ breast cancer remains a clinical challenge with the majority of patients eventually progressing due to resistance to endocrine therapy. RAD1901 is a novel, nonsteroidal, oral SERD that has demonstrated dose dependent degradation of ER, and ER regulated genes in preclinical studies. In multiple in vivo patient derived xenograft models of breast cancer, including those harboring ESR1 mutations, RAD1901 demonstrated significant antitumor activity. Methods: In a phase-1 Study RAD1901-005 (ClinicalTrials.gov ID: NCT02338349), patients with advanced ER+ breast cancer were enrolled in dose escalation cohorts, followed by a safety expansion cohort. Key inclusion criteria include postmenopausal women aged 18 years or older, with advanced ER+, HER2- breast cancer, who have received ≤ 2 prior chemotherapy regimens in the metastatic setting and > 6 months of prior endocrine therapy. ESR1 mutation status was determined from circulating tumor DNA (ctDNA) samples. Clinical outcomes were evaluated based on RECIST v1.1 criteria. Results: As of January 25, 2017, total of 39 patients were enrolled at the 400 mg qd dose. Patients were heavily pre-treated (median lines of prior therapy = 3), with 38% and 41% having previously received fulvestrant and palbociclib/CDK4/6 inhibitor, respectively. RAD1901 was generally well-tolerated, with the most common adverse events being low grade nausea (Grade 3/4 = 0%) and dyspepsia (Grade 3/4 = 0%). ESR1 mutations, including D538G, Y537S/N/C, L536H/P/R, S436P and E380Q, were detected at baseline in 44% of patients and dynamic changes in the allele frequency of ESR1 mutations were observed in response to treatment. Confirmed partial responses were observed in patients with ESR1 mutations, and those who had previously received fulvestrant and palbociclib. Conclusions: RAD1901 has demonstrated evidence of single agent activity, with confirmed partial responses in heavily pre-treated patients with advanced ER+ breast cancer, including those with ESR1 mutations, warranting additional clinical development. Clinical trial information: NCT02338349.