Initial results from a first-in-human study of AZD5335, a folate receptor α (FRα)-targeted antibody-drug conjugate, in patients (pts) with platinum-resistant recurrent ovarian cancer (PRROC)

BackgroundFRα is a highly expressed cell-surface target in many cancers including ovarian cancer, and internalises folate, a co-factor required for DNA and RNA synthesis. AZD5335 is an FRα-targeted antibody-drug conjugate that binds to FRα with high affinity and delivers a topoisomerase 1 inhibitor payload. FONTANA (NCT05797168) is a Phase 1/2a, first-in-human, modular open-label study of AZD5335 in pts with advanced solid tumours. We report results from module M1A, the ongoing dose escalation.MethodsPts aged ≥18 years with PRROC were recruited irrespective of tumour FRα expression and without a limit on the number of prior lines of therapy. AZD5335 was administered intravenously Q3W until disease progression, unacceptable toxicity, or other reason for discontinuation. The primary objective was to determine safety and tolerability. Key secondary objectives included assessing pharmacokinetics (PK) and preliminary efficacy per RECIST v1.1, assessed Q6W.ResultsAs of 30 March 2024, 28 pts (median age 62.0 [range 46–76] years; median 4 [range 1–15] lines of prior therapies) were treated across four dose levels. The most common (reported in ≥15% of pts) possibly treatment-related adverse events per investigator opinion (any Grade [G], G3–4) were nausea (61%, 0), anaemia (25%, 18%), neutrophil count decreased (21%, 7%), and pyrexia (21%, 0). No dose-limiting toxicities or deaths due to treatment were reported; maximum tolerated dose has not been reached. The PK of both AZD5335 and its payload were linear over the dose range. AZD5335 was stable in circulation with minimal accumulation prior to the second dose. Confirmed responses were observed at all doses. Among evaluable pts with high FRα expression (≥75% of tumour cells staining at ≥2+ intensity; n=8), 5 had an objective radiological response (1 pending confirmation); among those with high FRα expression receiving the top 3 dose levels (n=5), 4 had an objective radiological response (1 pending confirmation). Further updates will be provided at presentation.ConclusionsAZD5335 demonstrated a manageable safety profile and preliminary signs of efficacy. Dose optimisation is underway in module M1B. Ronnie Shapiro-Frommer and Kazuki Sudo have contributed equally to the study.Clinical trial identificationNCT05797168, 4/4/2023.Editorial acknowledgementMedical writing support for the development of this abstract, under the direction of the authors, was provided by Matthew Hallam of Ashfield MedComms (Macclesfield, UK), an Inizio company, and funded by AstraZeneca.Legal entity responsible for the studyAstraZeneca.FundingAstraZeneca.DisclosureR. Shapira-Frommer: Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Role: MSD, Novartis; Financial Interests, Institutional, Principal Investigator: MSD, Bristol Myers Squibb, AstraZeneca, Pfizer; Financial Interests, Institutional, Research Funding: MSD; Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Personal, Steering Committee Member: MSD. K. Sudo: Financial Interests, Institutional, Principal Investigator: Daiichi Sankyo, NanoCarrier, AstraZeneca, Takeda, Amgen, Merck, PRA Health Sciences, Gilead; Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, Pfizer, Eisai, Nihon Medi-Physics, Bayer Yakuhin, MSD. K. Harano: Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai, Kyowa Kirin, MSD, Sanofi, Takeda; Financial Interests, Institutional, Principal Investigator: AstraZeneca, Chugai, Daiichi Sankyo, MSD, Takeda; Financial Interests, Institutional, Research Funding: AstraZeneca, Chugai, Daiichi Sankyo, MSD, Takeda; Financial Interests, Personal, Advisory Role: AstraZeneca, Chugai, Eisai, Taiho, Takeda. L. Mileshkin: Financial Interests, Personal, Advisory Board, Participation in Dostarlimab advisory board: GSK; Financial Interests, Institutional, Coordinating PI, Institutional funding from Beigene for an investigator-initiated trial: BeiGene; Financial Interests, Personal, Coordinating PI, Support for flights to attend ESMO meetings in Madrid and Singapore to present results of the CUPISCO trial: Roche; Financial Interests, Personal, Other, Medical writing support for publications related to the CUPISCO trial: Roche; Non-Financial Interests, Other, Co-chair of the Steering Committee for the CUPISCO trial in CUP (non-remunerated): Roche; Non-Financial Interests, Member, Member of multiple other cancer organisations as above: ASCO, MOGA, COSA, IGCS, GCIG. R. Perets: Financial Interests, Personal, Other, Consultant: Galmed Therapeutics, Gilboa Therapeutics, 1E Therapuetics; Financial Interests, Institutional, Local PI: Jannsen, MSD, BMS, Genentech, Amgen, AbbVie, Ammune; Financial Interests, Institutional, Coordinating PI: Biomica; Non-Financial Interests, Institutional, Product Samples, Antibody for research: AbbVie. J. Cohen: Non-Financial Interests, Personal, Advisory Board: AstraZeneca, ImmunoGen. H. Ambrose, P.G. Fraenkel, C. Myers, A. Sykes, S. Turner: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. T. Brier: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks or ownership: AstraZeneca. A. Dosani, A. Kmieciak, P. Mitchell: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. F. Meric-Bernstam: Financial Interests, Personal, Other, Consultant: AstraZeneca, OnCusp Therapeutics, Zymeworks; Financial Interests, Personal, Other, Consulting: Calibr, Ecor1, Exelixis, GT Aperion, Infinity Pharmaceuticals, Loxo-Oncology, LegoChem Bio, Lengo Therapeutics, Tallac Therapeutics, Becton Dickinson, eFFECTOR Therapeutics, Jazz Pharmaceuticals; Financial Interests, Personal, Advisory Board: Daichii Sankyo, Incyte, Karyopharm, Protai, TheraTechnologies, Zentalis, FogPharma, Harbinger Health, Mersana Therapeutics, Sanofi Pharmaceuticals; Financial Interests, Personal, Other, Consutling: Menarini Group; Financial Interests, Personal, Advisory Board, Advisory Board/Consultant: Seagen; Financial Interests, Personal, Invited Speaker: Dava Oncology; Financial Interests, Institutional, Other, Local PI / Research Grant: Aileron Therapeutics, Bayer Healthcare, CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., eFFECTOR Therapeutics, Taiho Pharmaceutical Co.; Financial Interests, Institutional, Other, Local PI / Research Grant / Coordinating PI: AstraZeneca; Financial Interests, Institutional, Local PI: Calithera Biosciences, Curis Inc., Debiopharm International, Guardant Health Inc., Klus Pharma, Novartis, Jazz Pharmaceuticals, Zymeworks; Financial Interests, Institutional, Other, Local PI / Steering Committee Member: Genentech Inc.; Financial Interests, Institutional, Research Grant: Takeda Pharmaceutical Co., Puma Biotechnology Inc., Repare; Other, Travel support: European Organisation for Research and Treatment of Cancer (EORTC), European Society for Medical Oncology (ESMO); Other, Travel Support: Cholangiocarcinoma Foundation, Dava Oncology. All other authors have declared no conflicts of interest.