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Ref Type abstract
PMID
Authors G. Shapiro   J.E. Ang   E. Castanon Alvarez   A.I. Spira   P. Cassier   P. Lorusso   S. Gaillard   H.A. Chen   S. Kummar   M.G. Krebs   R. Plummer   E. Carcereny   E. Meshoulam Nikolaeva   J. Munck   D. Chan   M. Dijkstra   H.N. Keer   E.K. Lee
Title 791P Activity of ERK1/2 inhibitor ASTX029 in patients with gynecological malignancies harboring genomic alterations in the MAPK pathway
Journal Vol Issue Date Pages Journal Short Title
Annals of Oncology 35 Supplement 2 2024
URL https://www.annalsofoncology.org/article/S0923-7534(24)03670-6/fulltext
Abstract Text 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 AUC0-24 as 10321 ng*hr/mL (76%CV) and Cmax as 3457 ng/mL (160%CV), n=11. Four subjects had a PR including: NRASQ61K ovarian adenocarcinoma who progressed on prior MEKi treatment (14+ cycles), KRASG12V cervical (mesonephric) adenocarcinoma (17+ cycles), KRASG12D endometrioid ovarian (11 cycles), and KRASG12D 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
NRAS Q61K ovary adenocarcinoma predicted - sensitive ASTX029 Case Reports/Case Series Actionable In a Phase II trial, ASTX029 treatment was well tolerated in patients with relapsed/refractory gynecological tumors harboring MAPK pathway alterations, and resulted in an objective response rate of 12.5% (4/32, all partial responses), a median duration of response of 8.5 months, and a median overall survival of 11.2 months, with a partial response in a patient with ovarian adenocarcinoma harboring NRAS Q61K who progressed on prior MEKi therapy (Ann Oncol (2024) 35 (Suppl_2): S591; NCT03520075). detail...