A phase 1b/2 study of QLS1304, a novel, highly potent, and selective dual inhibitor of KAT6A/6B, plus endocrine therapy (ET) in patients (pts) with estrogen receptor–positive (ER+), human epidermal growth factor receptor 2–negative (HER2−) breast cancer (BC).

Abstract

TPS1144 Background: QLS1304 is a novel, highly-potent, and selective dual inhibitor of KAT6A/6B. KAT6A acetylates histone H3 at the 23rd lysine residue, thereby modulating gene transcription, and implicated in ER+/HER2- BC. QLS1304 showed potent efficacy in standard of care resistant, KAT6A-high and ESR1 -mutant ER+/HER2- BC patient-derived xenograft model, whether administered as a monotherapy or combination therapy ( Cancer Res (2025) 85 (8_Supplement_1): 457 ). In the ongoing phase 1 trial, QLS1304 monotherapy showed an acceptable safety profile and potential anti-tumor activity in pts with BC. This study aimed to evaluate the safety and preliminary efficacy of QLS1304 + ET combination (fulvestrant or QLC1401, a novel oral selective ER degrader) ± CDK4/6 inhibitor (CDK4/6i) in pts with ER+/HER2- locally advanced or metastatic (LA/M) BC. Methods: This multicenter, open-label, phase 1b/2 trial consists of phase 1b combination dose-escalation and phase 2 dose-expansion. The phase Ib study will enroll pts with LA/M ER+/HER2- BC, who have received prior ET plus CDK4/6i, utilizing the Rolling-Six design. There are 2 cohorts: Cohort 1A QLS1304 + fulvestrant and Cohort 1B QLS1304 + QLC1401. Three dose levels of QLS1304 are planned, which are 4 mg/d, 8 mg/d, and 12 mg/d. The dose of QLC1401 is 150 mg, which is the recommended phase 2 dose (RP2D) of monotherapy. Both QLS1304 and QLC1401 are orally administered in a 28-day cycle. A total of 12~18 pts per cohort are planned to be enrolled, which might be adjusted based on the occurrence of dose-limiting toxicities (DLTs) during the first cycle. The primary endpoints are safety, tolerability, and RP2D of QLS1304 combined with fulvestrant/QLC1401. In phase 2, 1~2 dose levels of QLS1304 will be explored in 5 cohorts. In Cohort 2A (QLS1304 + fulvestrant) and Cohort 2B (QLS1304 + QLC1401), pts with LA/M ER+/HER2- BC who received prior ET plus CDK4/6i will be enrolled. In Cohort 2C (QLS1304 + CDK4/6i + letrozole), pts with LA/M ER+/HER2- BC with no prior therapy will be enrolled. In Cohort 2D (QLS1304 + CDK4/6i + fulvestrant), adjuvant ET-resistant or ET+CDK4/6i pretreated LA/M ER+/HER2- BC pts will be enrolled in 2 subgroups. In Cohort 2E (QLS1304 + CDK4/6i + QLC1401), adjuvant ET-resistant, treatment naïve, or ET+CDK4/6i pretreated LA/M ER+/HER2- BC pts will be enrolled in 3 subgroups. Doublet combination will be firstly explored, which will support the dose selection of triplet combination. In triplet cohorts 2C–2E, 6 pts will be enrolled in a safety run-in to assess the preliminary safety profile in each cohort. Expansion will be started after safety confirmation. A total of 316~366 pts will be enrolled. The primary endpoint of phase 2 is ORR per RECIST v1.1. Patient enrollment is currently ongoing. Clinical trial information: NCT07235176 .