791P - Activity of ERK1/2 inhibitor ASTX029 in patients with gynecological malignancies harboring genomic alterations in the MAPK pathway

Background

ASTX029 is an extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor which both prevents phosphorylation of ERK and directly inhibits ERK kinase activity. MAPK pathway genomic alterations are common in gynecological (GYN) malignancies. Here we report on the GYN cohort of an open-label Phase 2 study of ASTX029 in subjects with relapsed/refractory solid tumors (NCT03520075).

Methods

The primary objective was objective response rate (ORR) by RECIST v1.1. Subjects with relapsed/refractory GYN solid tumors with MAPK pathway genomic alterations were eligible. ASTX029 was administered continuously in 21-day cycles (once daily oral dosing at 200 mg).

Results

Thirty-two subjects were treated (mean age 64 years; 15 ovarian, 13 endometrial, 1 cervical, and 3 other). As of 05Apr2024, the only grade ≥3 AE assessed as related to ASTX029 in ≥5% of subjects was anemia (n=3; 9.4%); no SAEs (of 12; 38%) or deaths were related to ASTX029. Related grade 2 AEs in ≥5% of subjects included anemia (n=6; 19%), blurred vision (n=2; 6%), diarrhoea (n=6; 19%), nausea (n=4; 13%), fatigue (n=4; 13%), ejection fraction decreased (n=2; 6%), decreased appetite (n=2; 6%), and rash maculo-papular (n=2; 6%). Six subjects (18.8%) interrupted treatment due to a related AE but none permanently discontinued treatment for this reason. The most frequent reason for treatment discontinuation was progressive disease (n=27; 84.4%). PK exposures were in the pharmacologically active range with mean cycle 1 AUC_0-24 as 10321 ng*hr/mL (76%CV) and C_max as 3457 ng/mL (160%CV), n=11. Four subjects had a PR including: NRAS^Q61K ovarian adenocarcinoma who progressed on prior MEKi treatment (14+ cycles), KRAS^G12V cervical (mesonephric) adenocarcinoma (17+ cycles), KRAS^G12D endometrioid ovarian (11 cycles), and KRAS^G12D endometrioid endometrial (8 cycles). ORR (CR+PR) was 12.5% (% 95% CI, 1.0-24.0). Median overall survival was 11.2 months (95% CI, 8.4-NE); median duration of response was 8.5 months (95% CI, 3.4-11.1). Median follow-up on study was 7.7 months (95% CI, 5.6-13.9).

Conclusions

ASTX029 was well-tolerated and induced PR in four subjects (ORR of 12.5%). The response following MEKi therapy suggests further study in this population is warranted.

Clinical trial identification

NCT03520075.

Editorial acknowledgement

Legal entity responsible for the study

Astex Pharmaceuticals.

Funding

Astex Pharmaceuticals (now Taiho Oncology).

Disclosure

All authors have declared no conflicts of interest.