606O - Initial results from a first-in-human study of the B7-H4-directed antibody-drug conjugate (ADC) AZD8205 (puxitatug samrotecan) in patients with advanced/metastatic solid tumors

Background

B7-H4 is a promising ADC target with high expression in several solid tumors and limited normal tissue expression. B7-H4 negatively regulates T cell function and high expression of B7-H4 is associated with disease progression. AZD8205 is a novel B7-H4–directed topoisomerase I inhibitor (Top1i) ADC with favorable preclinical antitumor activity in patient-derived xenograft models with an acceptable toxicity profile. This report presents initial results from the dose escalation part of a Phase 1/2a, open-label, multicenter study (NCT05123482; BLUESTAR) of AZD8205 monotherapy in patients (pts) with advanced/metastatic select solid tumors.

Methods

Eligible pts were ≥18 years old with advanced/metastatic ovarian, breast, endometrial cancer, or cholangiocarcinoma expressing B7-H4 (detected by immunohistochemistry in baseline tumor samples) with progression after available standard of care therapy, had measurable disease by RECIST v1.1 and ECOG PS 0–1. AZD8205 was administered at 0.8–3.2 mg/kg IV every 3 weeks. Safety was a primary objective. Preliminary efficacy was a secondary objective.

Results

As of February 23, 2024, 46 pts received AZD8205, 21 during dose escalation and 25 in backfill cohorts. Median age was 56 years (range, 24–88) and pts had received a median number of 4 previous treatment regimens at baseline (range, 2–9). Any grade treatment-emergent adverse events (TEAEs) occurred in 97.8% of pts, most commonly nausea (58.7%), neutropenia (56.5%), and anemia (50.0%). Grade ≥3 TEAEs occurred in 82.6% of pts, most commonly neutropenia (37.0%) and anemia (30.4%). Two pts (4.3%) discontinued treatment due to TEAEs. Two pts had dose-limiting toxicities at 3.2 mg/kg (neutrophil count decreased [n=1] and platelet count decreased [n=1]). Of the 43 pts treated at doses ≥1.6 mg/kg, 9 pts with ovarian, breast or endometrial cancer had a confirmed partial response (20.9%).

Conclusions

AZD8205 had a manageable safety profile consistent with other Top1i ADCs and showed preliminary efficacy in heavily pre-treated pts with prior progression on standard treatment. Phase 2 expansion cohorts are ongoing in ovarian, breast, endometrial and biliary tract cancer.

Clinical trial identification

NCT05123482; 17/11/2021.

Editorial acknowledgement

Medical writing support was provided by Ana Lopez, PhD, of Ashfield MedComms (London, UK).

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

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: Daiichi Sankyo, Incyte, Karyopharm, Protai, TheraTechnologies, Zentalis, FogPharma, Harbinger Health, Mersana Therapeutics, Sanofi Pharmaceuticals; Financial Interests, Personal, Other, Consulting: Menarini Group; Financial Interests, Personal, 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. Y. Naito: Financial Interests, Personal, Invited Speaker, Speakers Bureau: Chugai, Pfizer, Eli Lilly, Eisai, AstraZeneca, PDR Pharma, Novartis, Guardant, Ono, Takeda, Taiho, Bayer, Nihon Kayaku, Daiichi Sankyo, Bristol, MSD; Financial Interests, Personal, Funding: Roche; Financial Interests, Personal, Local PI: AbbVie, Boehringer Ingelheim, Ono, Chugai, Taiho, Pfizer, AstraZeneca, Gilead, Takeda, Eisai; Financial Interests, Personal, Steering Committee Member: Daiichi Sankyo; Non-Financial Interests, Principal Investigator, JCOG: Natera; Non-Financial Interests, Principal Investigator: Myriad. S. Gaillard: Financial Interests, Personal, Advisory Board: Verastem; Financial Interests, Personal, Advisory Role: Organon; Financial Interests, Personal, Leadership Role: NRG; Financial Interests, Personal, Other, Safety Review Committee: SignPath Pharma ; Financial Interests, Institutional, Principal Investigator: AstraZeneca, Compugen, Clovis, GOG, Tempest, Blueprint, Immunogen, MD Anderson, Volastra; Financial Interests, Institutional, Royalties: UpToDate; Non-Financial Interests, Personal, Other, United States Patent Nos 10,258,604 & 10,905,659: US Patent. V. Chung: Financial Interests, Personal, Other, Consultant: Perthera; Financial Interests, Institutional, Research Grant, Funding for investigator sponsored trial: Merck. A.A. Davis: Financial Interests, Personal, Advisory Board: Pfizer, Biotheranostics. T. Proia, A. Ayyoub, M. Kulkarni, S. Upadhyay, N. Miller: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. N. Luheshi: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Leadership Role: AstraZeneca; Financial Interests, Personal, Sponsor/Funding: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. A. Varga: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca; Financial Interests, Personal, Sponsor/Funding: AstraZeneca. D. Oh: Financial Interests, Personal, Advisory Board: AstraZeneca, Novartis, Genentech/Roche, Merck Serono, Bayer, Taiho, ASLAN, Halozyme, Zymeworks, BMS/Celgene, BeiGene, Basilea, Turning Point, Yuhan, Arcus Biosciences, IQVIA, MSD, LG Chem, Astellas, AbbVie, J-Pharma, Mirati Therapeutics, Eutilex, Moderna, Idience; Financial Interests, Institutional, Research Grant: AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, Handok. L. Mileshkin: Financial Interests, Personal, Advisory Board, Participation in Dostarlimab advisory board: GSK; Financial Interests, Institutional, Coordinating PI, Institutional funding 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. All other authors have declared no conflicts of interest.