Phase I study of H3B-6545 in patients with estrogen receptor-positive breast cancer.

BACKGROUND

This phase I study (NCT04568902) evaluated a novel selective estrogen receptor (ER)-α covalent antagonist (H3B-6545) at doses of 300-450 mg in Japanese women with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative, advanced/metastatic breast cancer (mBC).

PATIENTS AND

METHODS

This study consisted of three parts. In the dose-escalation (DE) part, two dose levels [300 and 450 mg once daily (QD)] were evaluated. The next two parts (antihistamine prophylactic administration and randomization) evaluated oral antihistamines for rash occurrence. Primary endpoints were dose-limiting toxicities (DLTs) and safety; secondary endpoints included objective response rate [ORR; i.e. complete response (CR) + partial response (PR)] and clinical benefit rate [CBR; i.e. CR + PR + stable disease (SD) for ≥23 weeks].

RESULTS

Thirty-three patients were enrolled to receive H3B-6545 (300 mg, n = 3; 450 mg with antihistamine, n = 15; 450 mg without antihistamine, n = 15). Median age was 57 years. The median number of prior therapies for mBC was three including fulvestrant (78.8%) and cyclin-dependent kinase 4/6 inhibitors (72.7%). In the DE part, no DLTs were observed with H3B-6545 300 mg. One DLT (grade 3 QT interval prolonged) occurred among six patients with H3B-6545 450 mg. Overall, the most common adverse event (AE) was sinus bradycardia (93.9%); the most common grade 3 AE was anemia (15.2%). No grade 4/5 AEs were reported. Rash maculopapular or rash occurred in 10 of 15 patients (66.7%) given H3B-6545 450 mg QD with prophylactic antihistamines and in 4 of 15 patients (26.7%) not given prophylactic antihistamines. Overall, 1 patient had a PR and 19 had SD; the ORR was 3.0% and the CBR was 33.3%. Of 12 patients with mutant ESR1, the CBR was 66.7% with 1 PR.

CONCLUSIONS

H3B-6545 at 450 mg QD was tolerated and showed preliminary antitumor effects in Japanese patients with ER-positive, HER2-negative mBC, particularly for those with ESR1 mutations.