Rintodestrant (G1T48), an oral selective estrogen receptor degrader, in combination with palbociclib for ER+/HER2– advanced breast cancer: Phase 1 results.

Abstract

1063 Background: Rintodestrant, a potent, oral selective estrogen receptor degrader, competitively binds and degrades the estrogen receptor (ER), thus blocking ER signaling in tumors resistant to other endocrine therapies (ET). Results from parts 1 and 2 dose-escalation/expansion indicate that once-daily (QD) rintodestrant has a favorable safety profile and antitumor activity in patients (pts) with heavily pretreated ER+/HER2– advanced breast cancer (ABC), including those with ESR1 variants (Aftimos et al. SABCS 2020 [PS12-04, PD8-07]). The optimal dose of rintodestrant was 800 mg. Here, we present part 3, combining rintodestrant with the CDK4/6 inhibitor palbociclib. Methods: This open-label study evaluated rintodestrant in pts with ER+/HER2– ABC after progression on ET (NCT03455270). Part 3 assessed rintodestrant 800 mg QD + palbociclib 125 mg QD for 21 days every 28 days. Key eligibility criteria included ≤1 line of chemotherapy and/or ≤1 line of ET in the advanced setting, with ≥6 months of ET in the advanced setting and/or ≥24 months in the adjuvant setting. Prior CDK4/6 inhibitor therapy was not allowed. Primary objectives included safety and efficacy. Secondary objectives included pharmacokinetics and antitumor activity (RECIST v1.1). Exploratory objectives included mutation profiling (cell-free DNA) at baseline and cycle 1 day 15. Results: Enrollment occurred Jul–Oct 2020. As of Dec 9, 2020, 40 pts were treated, with a median age of 58 years (35–76) and ECOG PS of 0 (70%) or 1 (30%); 20% had de novo stage 4 disease, 10% bone-only, and 68% visceral metastases. Median number of visceral sites was 1 (0–3): 30% of pts with lung and 40% with liver involvement. Median number of prior lines in the advanced setting was 1 (0–2), including chemotherapy (48%), fulvestrant (15%), and aromatase inhibitors (50%). Most recent ET was given in the adjuvant and metastatic settings in 28% and 73% of pts, respectively. Rintodestrant-related adverse events (AEs) were reported in 8% of pts—all nonserious and grade 2—and included nausea (3%), vomiting (3%), and neutropenia (3%). The most common (≥10%) treatment-related AEs (rintodestrant and/or palbociclib) were neutropenia (88%), leukopenia (45%), anemia (10%), and thrombocytopenia (10%); grade 3/4 neutropenia was 38%/15%, in line with the safety profile of palbociclib. No deaths or treatment discontinuations due to AEs were reported. At data cutoff (median treatment duration of 3 months [1.5–4.6]), 28 pts (70%) remained on study treatment, 2 (5%) had a confirmed partial response, and 27 (68%) had stable disease. Additional efficacy and pharmacodynamic data will be presented. Conclusions: Rintodestrant, as monotherapy or combined with palbociclib, continues to demonstrate an excellent safety/tolerability profile with promising antitumor activity in pts with ER+/HER2– ABC, including those with ESR1 variants. Clinical trial information: NCT03455270 .

Accelerating drug development in breast cancer: New frontiers for ER inhibition

“…However, among a larger group of 67 patients treated with monotherapy, 20 patients were on study >24 weeks but only 3 patients experienced partial response (PR), with a median PFS of 2 months. Similar response rates were observed when G1T48 was combined with palbociclib [54,55]. The toxicity profile appears to be favorable, with <10% of patients experiencing grade 1-2 nausea, vomiting, and neutropenia.…”

Evaluating Elacestrant in the Management of ER-Positive, HER2-Negative Advanced Breast Cancer: Evidence to Date

“… 32 Rintodestrant (G1T48) was tested in a phase I trial in pre-treated ER-positive, HER2-negative advanced breast cancer patients that had not received a CDK4/6i, and was found to be effective, including in patients with ESR1 mutations. 33 …”

Oral Selective Estrogen Receptor Degraders (SERDs) in Breast Cancer: Advances, Challenges, and Current Status

“…Pharmacokinetic studies found no interaction between palbociclib and camizestrant, 50 , 53 giredestrant 64 or rintodestrant. 63 An interaction between amcenestrant and palbociclib is possible, with amcenestrant having a moderate cytochrome P450 3A4 induction effect and reducing palbociclib exposure in a dose-dependent manner, hence the recommended dose for amcenestrant is 200 mg in combination with palbociclib, compared with 400 mg as monotherapy. 65 Several oral SERDs are undergoing evaluation in combination with abemaciclib, but no results are reported yet.…”

“…The objective response rates (ORRs) and clinical benefit rates (CBRs) reported for combination therapy have been higher than for oral SERD monotherapy, and even complete responses have been seen with the combination of high-dose giredestrant and palbociclib, 61 and with camizestrant plus palbociclib. 53 Anti-tumor activity has also been evident as reduction in the ESR1 mutation allele frequency or ctDNA levels with treatment, 50,[61][62][63][64] and as downregulation of ER, PR and Ki67 in paired pre-and on-treatment tumor biopsies in early stage breast cancer. 61,64 The combinations have been well tolerated and like AI plus CDK4/6 inhibitor therapy, the most frequent side effect of oral SERD and CDK4/6 inhibitor therapy has been neutropenia.…”