Background: Rintodestrant is an orally bioavailable, potent and selective estrogen receptor degrader (SERD) that inhibits estrogen receptor (ER) gene transcription, degrades the ER, and delays tumor proliferation in preclinical models. Preliminary results from Part 1 dose escalation (200-1000 mg once daily) demonstrated that rintodestrant has a favorable safety profile and encouraging antitumor activity in patients (pts) with heavily pretreated ER+/HER2- advanced breast cancer (ABC) (Dees et al., ESMO 2019 [abstract #3587]). Here, we report the pharmacodynamic (PD) analysis in peripheral blood and tumor biopsies from pts who received rintodestrant in Part 1 and 2 (600 and 1000 mg dose expansion) to characterize the pt population and mechanisms of response. Methods: This Phase 1, first-in-human, open-label study evaluated rintodestrant in women with ER+/HER- ABC after progression on endocrine therapy. PD analysis included inhibition of ER target engagement with 18F-fluoroestradiol positron emission tomography (FES-PET), mutational profiling (cell-free DNA [cfDNA]), and circulating tumor cell (CTC) enumeration. Tumor biopsies sampled at baseline and 6 weeks on treatment were evaluated for ER degradation (immunohistochemistry [IHC]) and proliferation (Ki67, IHC) to understand the on-target effects of rintodestrant. Results: As of May 13, 2020, 67 pts had been treated. FES-PET data were obtained in 14 pts and showed a decrease in all pts, with maximum standard uptake values (SUVmax) ranging from 70% to 98% after 4 weeks of rintodestrant monotherapy across all doses. Fifty-nine pts were tested for cfDNA at baseline; 95% (n = 56) harbored ≥1 somatic variant (median = 3 mutations per pt). Among pts with somatic variants, 41% had ESR1 mutations, with D538G being the most common (58%). Additionally, 46% and 42% of pts harbored mutations in TP53 and PIK3CA, respectively, and 10% had mutations in both ESR1 and PIK3CA. Similar clinical benefit rates were observed in wild-type vs ESR1 and/or PIK3CA mutant tumors. An analysis of change of variant allele fraction (VAF) in 55 pts between baseline and 2 weeks of treatment revealed that 58% had a decrease in mean VAF, with a decrease in ESR1 VAF in 16/20 pts that had ESR1 mutations at baseline. Furthermore, of 24 pts who had samples collected at baseline and progression, 16 (67%) developed additional variants (median [range]: 2 [1, 15]), including EGFR, ERBB2, TP53, and ESR1. CTC analysis (n = 45) showed the mean value of Epi+CD45- CTCs decreased from 2.8 cells/mL to 1.8 cells/mL after 8 weeks of treatment. Tumor biopsies were collected in 9 pts (5 received 600 mg and 4 received 1000 mg) at baseline and 6 weeks on treatment. Of the 7/9 pts that had a decrease in the ER H-score (median [range]: -27.8% [-33.8%, -3.4%]), 4 had ≥1 variant in ESR1 at baseline. Overall, 4 pts had a decrease in Ki67, with reductions mostly observed in pts who received 600 mg rintodestrant. Additional analyses, including correlations with clinical response, are ongoing and will be presented. Conclusions: Rintodestrant demonstrated robust ER target engagement on FES-PET, as well as substantial decreases in ER H-score, cfDNA VAF, and Epi+CD45- CTCs. These data, along with promising clinical benefit in pts with heavily pretreated ER+/HER2- ABC, regardless of ESR1 or PIK3CA mutation status, warrant additional investigation of rintodestrant (NCT03455270).

Citation Format: Philippe Aftimos, Marina Maglakelidze, Andor WJM Glaudemans, Erika Hamilton, Linnea Chap, Elisabeth de Vries, Catharina Willemien Menke-van der Houven van Oordt, Agnes Jager, E. Claire Dees, Massimo Cristofanilli, Mark Pegram, Susanna Ulahannan, Patrick Neven, Iurie Bulat, Ruhi Rai, Wenli Tao, Sarika Jain, Andrew P Beelen, Jessica A Sorrentino. Pharmacodynamic analysis from a phase 1 study of rintodestrant (G1T48), an oral selective estrogen receptor degrader, in ER+/HER2- locally advanced or metastatic breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD8-07.