Reference Detail

Ref Type

Abstract

PMID

Authors

A.J. Montero, A. Giordano, K. Jhaveri, P. Munster, J. Rodon, P. Lorusso, D. Orr, J. Bartolome Arcilla, A. Italiano, A. Elias, A. Soyano, M. De Miguel, B. Doger de Speville, G. Daniele, J. O'Shaughnessy, T.C. Hernandez Guerrero, R. Wesolowski, C. Saura Manich, M. Chao, D. Juric

Title

LBA27 First-in-human results of STX-478, a mutant-selective PI3Ka inhibitor, in advanced solid tumor patients

Journal	Vol	Issue	Date	Pages	Journal Short Title
Annals of Oncology	35	Supplement 2	September 2024	S1220	Ann Oncol

URL

https://www.annalsofoncology.org/article/S0923-7534(24)03846-8/fulltext

Abstract Text

Background The PI3Kα pathway is commonly mutated in cancer. PI3Kα inhibitors have shown clinical benefit in hormone receptor positive (HR+), HER2- breast cancer (BC) in Phase 3 studies, but are limited by toxicities from wild type (WT) PI3Kα inhibition. STX-478 is an oral, allosteric, CNS-penetrant, mutant-selective PI3Kα inhibitor designed to improve efficacy while sparing WT toxicities. STX-478 led to robust efficacy without WT toxicities in PI3Kα mutant (PI3Kαm) tumors in vivo. Initial Phase 1 monotherapy trial results are reported. Methods This first-in-human, Phase 1/2 study evaluated STX-478 alone or in combination in advanced PI3Kαm solid tumor patients. Dose escalation occurred per 3+3 design followed by expansion. Pre-diabetics/diabetics and those intolerant to PI3K inhibitors were permitted. Results As of June 21st 2024, 61 patients (29 HR+/HER2- BC, 32 other solid tumors) were treated at STX-478 doses of 20 mg to 160 mg daily. 52% of patients were pre-diabetic/diabetic; 41% of BC patients had a prior PI3K pathway inhibitor. Median prior lines of therapy was 3 (range 1-7). STX-478 was well-tolerated with a MTD of 100 mg daily. Treatment-related adverse events (TRAEs) of 15% included: fatigue (30%), hyperglycemia (23%), nausea (20%), and diarrhea (15%). PI3Kα WT AEs (hyperglycemia, diarrhea and rash) were Grade 1/2. No patient discontinued due to an AE. STX-478 exposure was dose proportional up to the MTD, reaching steady state by day 15. At 40mg dose, STX-478 achieved target coverage several fold higher than other PI3Kα inhibitors. In 43 evaluable patients, the confirmed/unconfirmed ORR was 21%; 23% (5/22) in HR+/HER2- BC; and 44% (4/9) in gynecologic cancers. The disease control rate across tumors was 70%. Responses were seen in both kinase and helical domain mutant tumors; several deepened over time. PI3Kαm ctDNA levels markedly decreased on therapy in most patients. Conclusions In heavily pre-treated patients, STX-478 was well-tolerated with favorable PI3Kα WT toxicity, including in diabetic patients or those intolerant to PI3K inhibitors. STX-478 was active in breast and non-breast cancers, with an ORR exceeding historical comparisons to other PI3K inhibitors. Enrollment is ongoing. Clinical trial identification NCT05768139. Study start date: April 17, 2023.

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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
PIK3CA act mut	female reproductive organ cancer	predicted - sensitive	STX-478	Case Reports/Case Series	Actionable	In a Phase I/II trial, STX-478 treatment was well tolerated and resulted in a response rate of 21% in heavily pre-treated patients with advanced solid tumors harboring mutations in PIK3CA (n=43), with a response rate of 44% (4/9) in patients with gynecologic cancers (Ann Oncol (2024) 35 (suppl_2): S1220; NCT05768139).	detail...
PIK3CA act mut	Her2-receptor negative breast cancer	predicted - sensitive	STX-478	Phase Ib/II	Actionable	In a Phase I/II trial, STX-478 treatment was well tolerated and resulted in a response rate of 21% in heavily pre-treated patients with advanced solid tumors harboring mutations in PIK3CA (n=43), with a response rate of 23% (5/22) in patients with hormone receptor-positive, ERBB2 (HER2)-negative breast cancer (Ann Oncol (2024) 35 (suppl_2): S1220; NCT05768139).	detail...