399P - Results from a first-in-human phase Ia/b study of LX-039, an oral selective estrogen receptor (ER) degrader (SERD), in postmenopausal patients with ER+, HER2- advanced breast cancer (ABC)

Background

LX-039 is an oral SERD that blocks ER signaling pathway through receptor antagonism and degradation. LX-039 demonstrated robust antitumor efficacy and good PK profile in preclinical studies.

Methods

This was a multi-center, open-label, first in human, dose escalation and expansion phase I study to evaluate the safety, efficacy and PK/PD profiles of LX-039 monotherapy in postmenopausal patients(pts) with histologically confirmed ER+, HER2- ABC, who had failed ≥1 line endocrine therapy and ≤2 line chemotherapy. The initial dose was 50 mg, sequentially escalated from 100 mg to 1200 mg via traditional "3+3” design. LX-039 was administrated once daily in 28-day cycles until unacceptable toxicity, progression, or withdrawal of consent. ¹⁸FES PET/CT scan was undergone on baseline and day 28 after treatment. Primary endpoint was MTD, secondary endpoints included safety, efficacy, and PK/PD.

Results

44 pts (median age 56.5, ECOG = 1: 88.6%, visceral metastasis: 77.3%) were enrolled. All pts received prior endocrine therapy (range: 1-7 lines, 56.8% fulvestrant) and/or CDK4.6i(40.9%), chemotherapy(54.5%) in the advanced setting. Two pts experienced DLTs: G3 hepatic function abnormal in 1000 mg cohort (1/6) and G4 ALT increased in 1200 mg cohort (1/1), so MTD was not reached. TRAEs were mostly grade 1-2 and experienced by ≥20% of pts were diarrhea (81.8%, G3 15.9%), ALT increased (56.8%, ≥G3 15.9%); AST increased (47.7%, G3 4.5%), fatigue (38.6%), decreased appetite (29.5%), vomiting (29.5%), nausea (27.3%), weight decreased (22.7%). Dose-dependent plasma exposure was seen with an estimated half-life of approximately 7 h. In 29 pts with measurable lesions who received 600 mg or higher doses, 4 pts (13.8%) achieved partial response, with median DOR of 7.4 months. Median PFS in the ITT population was 5.5months (95% CI: 3.5, 5.9). CBR at 24 weeks was 40.0% and DCR was 70.3%. ¹⁸FES-PET scan (n = 13) showed that all patients experienced SUV_max decrease from baseline with a median reduction of > 70 %.

Conclusions

LX-039 was well tolerated with preliminary anti-tumor activity in ER+, HER2- ABC. RP2D was determined at 600 mg QD and a phase II trial is being planned.

Clinical trial identification

NCT04097756.

Editorial acknowledgement

Legal entity responsible for the study

Fudan University Shanghai Cancer Center.

Funding

Luoxin pharmaceutical.

Disclosure

All authors have declared no conflicts of interest.