Phase I Study of Elacestrant (RAD1901), a Novel Selective Estrogen Receptor Degrader, in ER-Positive, HER2-Negative Advanced Breast Cancer

Abstract

Purpose: This phase I study (RAD1901-005; NCT02338349) evaluated elacestrant, an investigational oral selective estrogen receptor degrader (SERD), in heavily pretreated women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer, including those with estrogen receptor gene alpha (ESR1) mutation. The primary objective was to determine the maximum tolerated dose and/or recommended phase II dose (RP2D).

Methods: The study consisted of a 3 + 3 design (elacestrant capsules) followed by expansion at RP2D (400-mg capsules, then 400-mg tablets) for the evaluation of safety and antitumor activity. Elacestrant was taken once daily until progression or intolerability.

Results: Of 57 postmenopausal women enrolled, 50 received RP2D (400 mg once daily): median age, 63 years; median three prior anticancer therapies, including cyclin-dependent kinase 4,6 inhibitors (CDK4/6i; 52%), SERD (52%), and ESR1 mutation (circulating tumor DNA; 50%). No dose-limiting toxicities occurred; the most common adverse events at RP2D (400-mg tablet; n = 24) were nausea (33.3%) and increased blood triglycerides and decreased blood phosphorus (25.0% each). Most adverse events were grade 1-2 in severity. The objective response rate was 19.4% (n = 31 evaluable patients receiving RP2D), 15.0% in patients with prior SERD, 16.7% in patients with prior CDK4/6i, and 33.3% in patients with ESR1 mutation (n = 5/15). The clinical benefit rate (24-week) was 42.6% overall (n = 47 patients receiving RP2D), 56.5% (n = 23, ESR1 mutation), and 30.4% (n = 23, prior CDK4/6i). Elacestrant clinical benefit was associated with decline in ESR1 mutant allele fraction.

Conclusion: Elacestrant 400 mg orally once daily has an acceptable safety profile and demonstrated single-agent activity with confirmed partial responses in heavily pretreated patients with estrogen receptor-positive metastatic breast cancer. Notably, responses were observed in patients with ESR1 mutation as well as those with prior CDK4/6i and prior SERD. A phase III trial investigating elacestrant versus standard endocrine therapy is ongoing.

FIG 1.

ESR1 mutation distribution and correlation with therapy in the intent-to-treat population receiving elacestrant 400 mg (n = 50). (A) Distribution and prevalence of baseline ESR1 mutations/indels. (B) Alteration frequency of ESR1 at baseline versus prior treatment history in correlation with the number of lines of prior ET in the mBC setting or type of prior ET (AI, SERM, or SERD) in any setting. Baseline ESR1 mutation status is based on Guardant360 assay; when Guardant results were unavailable, ESR1 status was based on Sysmex OncoBEAM assay. AI, aromatase inhibitor; ESR1, estrogen receptor gene alpha; ET, endocrine therapy; mBC, metastatic breast cancer; SERD, selective estrogen receptor degrader; SERM, selective estrogen receptor modulator.

FIG 2.

Duration of treatment in patients treated with 400 mg of elacestrant in parts A-D (A) and maximum percent change in sum of diameters of all target lesions (B) in response-evaluable patients treated with 400 mg of elacestrant in parts A-D. Baseline ESR1 mutation status is based on Guardant360 assay. When Guardant results were unavailable, ESR1 status was based on Sysmex OncoBEAM assay. ^aOther includes Y537C, E542D, L536_Y537del, S463P, and V534L. CBE, clinical benefit–evaluable; CDK4/6i, cyclin-dependent kinase 4,6 inhibitors; ESR1, estrogen receptor gene alpha; PD, progressive disease; PR, partial response; RE, response-evaluable; SD, stable disease; SERD, selective estrogen receptor degrader.

FIG 3.

Change in ESR1 MAF for patients who received elacestrant 400 mg. Change in ESR1 MAF for all mutations in all patients with any baseline (screen) ESR1 mutation and at least one baseline and postbaseline sample tested with the same assay (A). Change in ESR1 D538G MAF for all patients with baseline D538G mutation and at least one baseline and postbaseline sample tested with the same assay (B). Change in ESR1 MAF for all ESR1 mutations in four patients with PR who had paired ESR1 data (C). C, cycle; CB, clinical benefit; EOT, end of treatment; ESR1, estrogen receptor gene alpha; MAF, mutant allele fraction; ND, mutation not detected; PR, partial response.

FIG 3.

Change in ESR1 MAF for patients who received elacestrant 400 mg. Change in ESR1 MAF for all mutations in all patients with any baseline (screen) ESR1 mutation and at least one baseline and postbaseline sample tested with the same assay (A). Change in ESR1 D538G MAF for all patients with baseline D538G mutation and at least one baseline and postbaseline sample tested with the same assay (B). Change in ESR1 MAF for all ESR1 mutations in four patients with PR who had paired ESR1 data (C). C, cycle; CB, clinical benefit; EOT, end of treatment; ESR1, estrogen receptor gene alpha; MAF, mutant allele fraction; ND, mutation not detected; PR, partial response.