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

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 21^st 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.

Editorial acknowledgement

Legal entity responsible for the study

Scorpion Therapeutics.

Funding

Scorpion Therapeutics.

Disclosure

A.J. Montero: Financial Interests, Personal, Advisory Board: Gilead, AstraZeneca, Welwaze Medical; Financial Interests, Personal, Full or part-time Employment, Medical Director: Paragon health care. A. Giordano: Financial Interests, Personal, Advisory Board: Pfizer. J. Rodon: Financial Interests, Personal, Advisory Board: Ellipses Pharma, Ionctura SA, Aadi Bioscience, Envision Pharma, Molecular Partners, Mekanistic, Amgen; Financial Interests, Personal, Other, Consultancy: Clarion Healthcare, Debiopharm, Cullgen, Pfizer, Macrogenics, Oncology One, Columbus Venture Partners, Sardona Therapeutics, Avoro Capital Advisors, Vall d'Hebron Institute of Oncology/Ministero De Empleo Y Seguridad, Chinese University of Hong Kong, Boxer Capital, LLC, Tang Advisors, LLC, Alnylam Pharmaceuticals, Bridgebio Pharma; Financial Interests, Personal, Other, Consultancy/Advisory Board: Monte Rosa Therapeutics, Merus N.V., Incyte; Financial Interests, Institutional, Other, Clinical Research: Novartis, Spectrum Pharmaceuticals, Symphogen, BioAtla, Pfizer, GenMab, CytomX, Kelun-Biotech, Takeda-Millenium, GSK; Financial Interests, Institutional, Other, Research Funding: Blueprint Medicines, Black Diamond, Merck Sharp & Dohme; Financial Interests, Institutional, Research Grant, Research Funding/Clinical Research: Hummingbird, Yingli; Financial Interests, Institutional, Research Grant, Research Funding: Vall d'Hebron Institute of Oncology/Cancer Core Europe; Financial Interests, Institutional, Research Grant, Clinical Research: Bicycle Therapeutics, Taiho, Roche Pharmaceuticals, Merus, Curis, AadiBioscience, Nuvation, ForeBio, BioMed Valley Discoveries, Loxo Oncology, Cellestia, Deciphera, Ideaya, Amgen, Tango Therapeutics, Mirati, Linnaeus Therapeutics, Bayer, Hutchinson MediPharma; Other, Other: VHIO/Ministero De Empleo Y Seguridad Social; Other, Travel: European Society for Medical Oncology, Loxo Oncology. A. Italiano: Financial Interests, Personal, Advisory Board: Bayer, Roche, Philips, Chugai, GSK; Financial Interests, Institutional, Coordinating PI: Bayer, AstraZeneca, Roche, MSD, Ipsen, Merck. M. De Miguel: Financial Interests, Institutional, Invited Speaker: Janssen, MSD; Non-Financial Interests, Principal Investigator: Janssen, MSD, Roche, PharmaMar, Replimune, Novartis, AbbVie, Achilles, Amunix, Arcus, Furmo, Biontech, Catalym, Dizal, Genentech, Loxo, Numab, Seagen. G. Daniele: Financial Interests, Personal, Invited Speaker: GSK, Gilead, Bayer; Financial Interests, Institutional, Research Grant: Gilead. J. O'Shaughnessy: Financial Interests, Personal, Advisory Board: AbbVie, Agendia, Amgen, Aptitude Health, AstraZeneca, Eisai, G1 Therapeutics, Lilly, Merck, Novartis, Pfizer, Puma, Roche, Carrick Therapeutics, Daiichi Sankyo, Gilead Sciences, Ontada, Pierre Fabre Pharmaceuticals, Samsung Bioepis, Sanofi, BioNtech, Byondis, Dava Oncology, Fishawack Health, Genzyme, GSK, Genentech, Loxo Oncology, Seagen, Stemline Therapeutics, Taiho Oncology, Veru; Financial Interests, Personal, Other, Advisory Board: BioNTech, Duality. M. Chao: Financial Interests, Institutional, Full or part-time Employment: scorpion therapeutics. All other authors have declared no conflicts of interest.