625P - Initial results from the phase I, first-in-human study of the covalent, PI3Kα inhibitor TOS-358 in patients with solid tumors, expressing PI3Kα mutations or amplifications

Background

TOS-358 is an oral, highly selective covalent inhibitor of PI3Kα capable of achieving deep, durable inhibition of PI3K-AKT signaling, with virtually no off-target effects. Preclinically, TOS-358 showed anti-cancer activity superior to non-covalent compounds targeting PI3Kα in patient (pt)-derived xenograft models, including breast (BC), colorectal (CRC), head and neck (SCCHN), bladder, and esophageal cancers.

Methods

TOS-358-001 is a dose escalation (phase 1a), dose expansion (phase 1b) study evaluating safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of TOS-358. Eligible pts with specific tumors expressing PIK3CA mutation or amplification, adequate organ function without indication/history of diabetes, ECOG PS 0-1, and no prior treatment with PI3K, AKT or mTOR inhibitors (except pts with BC). The phase 1a was a 3+3 escalation to identify a minimum effective dose (MED) and a maximum tolerated dose (MTD) of TOS-358 when taken once daily (QD) or twice daily (BID). Tumor response was evaluated every 8 weeks by RECIST 1.1. PK was analyzed by non-compartmental analysis. PD was assessed by a TOS-358-specific target engagement assay.

Results

As of April 2024, 28 pts (19 CRC, 1 ovarian, 2 non-small cell lung cancer, 1 endometrial, 1 ovarian, 1 SCCHN, 3 BC) received TOS-358 in 6 cohorts (10 to 30 mg QD, 5 to 15 mg BID). The QD MTD was 20 mg. No MTD has been reached with BID dosing. PK was dose-proportional, and concentrations were within target range. Target engagement >90% was observed at all dose levels, and no MED has been identified thus far. Adverse events were mostly low-grade, dose-dependent, and manageable without dose reduction. Initial monotherapy clinical activity has been observed at multiple dose levels across several PIK3CA-mutant cancer subtypes.

Conclusions

Phase 1a data support covalent inhibition of PI3Kα using TOS-358 as a promising therapeutic that can achieve anti-tumor effects at low doses with minimal toxicity. A phase 1b study evaluating the combination of TOS-358 and fulvestrant in HER2- breast cancer pts and TOS-358 monotherapy in bladder cancer pts is planned to initiate in 2H of 2024.

Clinical trial identification

NCT05683418; Release date: January 13, 2023.

Editorial acknowledgement

Legal entity responsible for the study

Totus Medicines Inc.

Funding

Totus Medicines Inc.

Disclosure

M. Fakih: Financial Interests, Personal, Advisory Board, Consultant: AbbVie, Inc., AstraZeneca, Bayer Corporation; Financial Interests, Personal, Advisory Board, Consultant/One Meeting: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board, One meeting: Eisai Oncology; Financial Interests, Personal, Advisory Board, One meeting: Entos, Seattle Genetics, Xenthera; Financial Interests, Personal, Advisory Board, One Meeting: Janssen; Financial Interests, Personal, Advisory Board: Merck, Nouscom, Roche / Genentech; Financial Interests, Personal, Advisory Board, Also Editorial Boards & Consulting: Mirati Therapeutics; Financial Interests, Personal, Advisory Board, Consulting/One Meeting: Pfizer; Financial Interests, Personal, Advisory Board, Consulting: Taiho Oncology; Financial Interests, Institutional, Research Grant: AgenusBio, Genentech / imCORE, Verastem. D. Sohal: Financial Interests, Personal, Invited Speaker: InCyte, SeaGen, AstraZeneca; Financial Interests, Personal, Advisory Board: Totus, Regeneron, Elevar; Financial Interests, Institutional, Trial Chair: Ability Pharma, AstraZeneca; Financial Interests, Institutional, Local PI: Amgen, Apexigen, Astellas, Bexion, BMS, FibroGen, Genentech, Hengrui, Merck, Mirati, NextCure, PanCAN, Regeneron, Roche. A.B. El-Khoueiry: Financial Interests, Personal, Advisory Board: Exelixis, AstraZeneca, Genentech, Agenus, Tallac, ABL Bio, Senti Biosciences, Qurient; Financial Interests, Institutional, Funding: Fulgent, Astex, AstraZeneca; Financial Interests, Personal, Steering Committee Member: Merck, Genentech; Financial Interests, Personal, Coordinating PI: Genentech; Financial Interests, Institutional, Coordinating PI, trial; funding: Auransa; Non-Financial Interests, Principal Investigator: Agenus, Affimed, Bayer. A.I. Spira: Financial Interests, Personal, Other, Consulting or Advisory Role: Incyte, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Janssen Research & Development, Mersana, Gritstone Bio, Daiichi Sankyo/AstraZeneca, Array Biopharma, Blueprint Medicines, Regeneron, Lilly, Black Diamond Therapeutics, Sanofi; Financial Interests, Personal, Other, Consulting or Advisory Role / Honoraria: Amgen, Novartis, Takeda, AstraZeneca/MedImmune, Merck, Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria: CytomX Therapeutics, Janssen Oncology, Bayer; Financial Interests, Institutional, Officer, CEO: NEXT Oncology Virginia; Financial Interests, Personal, Stocks/Shares: Eli Lilly; Financial Interests, Institutional, Local PI: LAM Therapeutics, Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, AbbVie, Ignyta, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol Myers Squibb, Loxo, Arch Therapeutics, Gritstone, Plexxikon, Amgen, Daiichi Sankyo, ADCT, Janssen Oncology, Mirati Therapeutics, Rubius, Synthekine, Mersana, Blueprint Medicines, Kezar, Revolution Med, Regeneron, Loxo, Alkermes, Medikine, Black Diamond Therapeutics, Nalo Therapeutics, Scorpion Therapeutics, Arrivent Biopharma, GV20 Therapeutics. H. Merrit, K. Hari: Financial Interests, Institutional, Full or part-time Employment: Totus Medicines. O.C. Trifan: Financial Interests, Personal, Stocks or ownership: Totus Medicines. N. Dhawan: Financial Interests, Personal and Institutional, Full or part-time Employment: Totus Medicines. All other authors have declared no conflicts of interest.