Background: Rintodestrant (G1T48) is a potent oral selective estrogen receptor degrader (SERD) that competitively binds to the estrogen receptor (ER) and blocks ER signaling in tumors resistant to other endocrine therapies. Preliminary results from Part 1 dose escalation showed robust target engagement on 18F-fluoroestradiol positron emission tomography (FES-PET), a favorable safety profile, and encouraging antitumor activity in patients with heavily pretreated ER+/HER2- advanced breast cancer (ABC), including those with ESR1 mutations (Dees et al., ESMO 2019 [abstract #3587]). Here, we present updated results from dose escalation and expansion (Parts 1 and 2). Methods: This Phase 1, first-in-human, open-label study evaluated rintodestrant monotherapy in women with ER+/HER2- ABC after progression on endocrine therapy. Part 1 was a 3+3 dose escalation (200-1000 mg once daily [QD]); Part 2 expanded 600 and 1000 mg QD; and Part 3 was added to assess rintodestrant with palbociclib in patients in earlier lines in the advanced setting. Primary objectives included dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), safety, and recommended Phase 2 dose. Secondary objectives included pharmacokinetics and antitumor activity (RECIST v1.1). Exploratory objectives included pharmacodynamic inhibition of ER target engagement (FES-PET), mutation profiling (cell-free DNA [cfDNA]), and change in ER expression from baseline to on-treatment tumor biopsies. Results: As of May 13, 2020, 67 patients (Part 1: n = 26; Part 2: n = 41) were treated, with a median age of 61 years (range 34-83) and ECOG PS of 0 (49%) or 1 (51%). Median number of prior lines in the advanced setting was 2 (range 0-9), including prior fulvestrant (64%), CDK4/6 inhibitor (69%), mTOR inhibitor (22%), and/or chemotherapy (46%). Median number of prior lines of endocrine therapy in the advanced setting was 2 (range 0-5), with 61% of patients having received ≥2 lines. Treatment-related adverse events (TRAEs) were reported in 70% of patients. The most common TRAEs in ≥10% of patients included hot flush (24%), fatigue (21%), nausea (19%), diarrhea (18%), and vomiting (10%), mostly grade 1 or 2. No DLTs were reported and MTD was not reached. Dose reduction due to TRAEs occurred in 1 patient (1%), with elevated transaminases (grade 3 ALT and grade 2 AST) at 600 mg. Serious TRAEs occurred in 2 patients at 1000 mg (grade 5 cerebral hemorrhage in the setting of low molecular weight heparin and grade 2 upper abdominal pain). Two patients (3%) discontinued treatment due to TRAEs. Overall, the frequency of patients with TRAEs at 800 mg was comparable with that at 600 mg (57% vs 63%) and less than that at 1000 mg (81%). Of 67 patients, 16 were on study treatment for ≥24 weeks and 3 (n = 1 at 600 mg; n = 2 at 1000 mg, including 1 with ESR1 mutation) had a confirmed partial response (clinical benefit rate [CBR]: 28%). FES-PET standard uptake values decreased at week 4 with a mean reduction of 87% (±8%) at doses ≥ 600 mg. Of 59 patients tested for baseline cfDNA, 41% harbored ≥1 ESR1 mutation, with a similar CBR in both groups (33% in ESR1 mutant and 29% in ESR1 wild-type). Seven of 9 patients had a decrease in ER immunohistochemistry H-score at both 600 and 1000 mg (median [range]: -27.8% [-33.8%, -3.4%]), irrespective of ESR1 mutation status. Based on safety, efficacy, and ER degradation, 800 mg was selected as the optimal dose for further study. Conclusions: Rintodestrant continues to demonstrate an excellent safety/tolerability profile across all doses, with promising antitumor activity in patients with heavily pretreated ER+/HER2- ABC, including those with tumors harboring ESR1 mutations. Part 3 of this study, evaluating rintodestrant 800 mg QD with palbociclib in a more endocrine-sensitive population, is ongoing (NCT03455270).
Citation Format: Philippe Aftimos, Patrick Neven, Mark Pegram, Catharina Willemien Menke-van der Houven van Oordt, E. Claire Dees, Carolien Schröder, Agnes Jager, Iurie Bulat, Linnea Chap, Marina Maglakelidze, Erika Hamilton, Massimo Cristofanilli, Susanna Ulahannan, Jorianne Boers, Ramsha Iqbal, Adrian Crijanovschi, Curt D Wolfgang, Wenli Tao, Christina Sipes, Rajesh Malik, Sarika Jain. Rintodestrant (G1T48), an oral selective estrogen receptor degrader in ER+/HER2- locally advanced or metastatic breast cancer: Updated phase 1 results and dose selection [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 PS12-04.
