1313MO - Safety and preliminary efficacy of AZD7789, a bispecific antibody targeting PD-1 and TIM-3, in patients (pts) with stage IIIB–IV non-small-cell lung cancer (NSCLC) with previous anti-PD-(L)1 therapy

Background

AZD7789 is a monovalent, bispecific, humanised IgG1 that blocks PD-1 and T cell immunoglobulin and mucin domain 3 (TIM-3), receptors that regulate antitumour T cell activity and myeloid activation. Dual blockade of PD-1 and TIM-3 may overcome or delay anti-PD-(L)1 resistance. Here we report dose escalation results from a phase 1/2a, first-in-human, multicentre, open-label trial of AZD7789 monotherapy in pts with stage IIIB–IV NSCLC with ≥1 prior line of systemic therapy including ≥1 anti-PD-(L)1 agent.

Methods

Eligible pts were ≥18 yr old with ECOG PS 0–1. Dose cohorts ranged from 2–2000 mg IV Q3W: 2–225 mg in an accelerated titration design, and 750–2000 mg using mTPI-2. The primary objective was safety, including dose-limiting toxicities (DLTs). Secondary/exploratory objectives included efficacy, pharmacokinetics (PK), PD-1 receptor occupancy (RO), and immunogenicity. Data cutoffs were 13 Feb 2023 for safety and 11 Jan 2023 for efficacy.

Results

In total, 39 pts received AZD7789 2–2000 mg; median age 66 yr, 56% male, 36% PD-L1 status <1%, 33% PD-L1 1–49%, and 28% PD-L1 ≥50%, and 80% had acquired resistance to prior anti-PD-(L)1 therapy (≥6 mo of treatment exposure). Treatment emergent AEs (TEAEs) occurred in 82% of pts and were Grade (Gr) ≥3 in 23%. The most common TEAE was increased blood creatinine (18%); no TEAE led to discontinuation. Treatment related AEs (TRAEs) occurred in 41% of pts; the most common was asthenia (8%). There were no DLTs or Gr ≥3 TRAEs. On-treatment scans were available for 19 pts: 7 had stable disease, including 2 with unconfirmed partial responses, 11 had progression, and 1 was not evaluable. Target lesion shrinkage was observed in 8 pts. PK was generally dose proportional, with t_½ ∼7 days; antidrug antibodies had limited impact on PK. Doses ≥225 mg led to durable PD-1 RO >90% on peripheral T cells. As of 13 Feb 2023, 24 pts remained on AZD7789; updated data will be presented.

Conclusions

AZD7789 has manageable safety and shows preliminary efficacy at tolerable doses. Evaluation is ongoing in immunotherapy-naive pts with NSCLC and pts with acquired resistance to immunotherapy.

Clinical trial identification

NCT04931654; June 18, 2021.

Editorial acknowledgement

Medical writing support for this abstract was provided by Eric Exner of Ashfield MedComms (Milwaukee, WI, USA), an Inizio company, and was funded by AstraZeneca.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

B. Besse: Financial Interests, Institutional, Funding: 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Celgene, Cergentis, Cristal Therapeutics, Daiichi Sankyo, Eli Lilly, GSK, Janssen, Onxeo, Ose Immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Tolero Pharmaceuticals; Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical, Eisai, Genzyme Corporation, Inivata, Ipsen, Turning Point Therapeutics. A. Italiano: Financial Interests, Personal, Advisory Board: Bayer, Roche, Philips, Chugai, GSK; Financial Interests, Institutional, Coordinating PI: Bayer, AstraZeneca, Roche, MSD, Ipsen, Merck. S. Cousin: Financial Interests, Personal, Advisory Board: BMS, AstraZeneca, MSD, Takeda. G. Ruiter: Financial Interests, Personal and Institutional, Principal Investigator: AstraZeneca, AbbVie, Daiichi Sankyo, Cullinan Oncology, Boehringer Ingelheim, Merus, Bayer. E. Felip: Financial Interests, Personal, Advisory Board: AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Gilead, GSK, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Peptomyc, Regeneron, Sanofi, Takeda, Turning Point, Pfizer; Financial Interests, Personal, Invited Speaker: Amgen, Daiichi Sankyo, Genentech, Janssen, Medical Trends, Medscape, Merck Serono, PeerVoice, Pfizer, Sanofi, Takeda, Touch Oncology, AstraZeneca, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Merck Sharp & Dohme; Financial Interests, Personal, Member of Board of Directors, Independent member: Grifols; Financial Interests, Institutional, Local PI, Clinical Trial: AstraZeneca AB, AbbVie, Amgen, Bayer Consumer Care AG, BeiGene, Boehringer Ingelheim GmbH, Bristol Myers Squibb International Corporation, Daiichi Sankyo Inc., Exelixis Inc., F. Hoffmann-La Roche Ltd., Genentech Inc., GSK Research and Development Limited, Janssen Cilag International NV, Merck Sharp & Dohme Corp, Merck KGAA, Mirati Therapeutics Inc, Novartis Pharmaceutica SA, Pfizer, Takeda Pharmaceuticals International; Non-Financial Interests, Leadership Role, President (2021-2023): SEOM (Sociedad Espanola de Oncologia Medica); Non-Financial Interests, Member, Member of Scientific Committee: ETOP (European Thoracic Oncology Platform); Non-Financial Interests, Member, Member of the Scientific Advisory Committee: CAC Hospital Universitari Parc Taulí. E. Castanon Alvarez: Financial Interests, Personal, Advisory Board: MSD, Roche, BMS; Financial Interests, Personal, Invited Speaker: GSK; Non-Financial Interests, Principal Investigator: AZ, BMS, Roche, MSD, GSK, ARC. S.S. Ramalingam: Financial Interests, Personal, Other, Editor in Chief, CANCER journal: American Cancer Society; Financial Interests, Research Grant: Merck, AstraZeneca, Advaxis, BMS, Amgen, Takeda, Genmab, GSK. C.D. Rolfo: Financial Interests, Personal, Invited Speaker, Egypt event: AstraZeneca; Financial Interests, Personal, Invited Speaker, Foundation One Liquid Biopsy: Roche; Financial Interests, Personal, Invited Speaker, Middle East: MSD; Financial Interests, Personal, Advisory Board, NGS Lung: Inivata, Archer; Financial Interests, Personal, Advisory Board, Lung: Boston Pharmaceuticals, Novartis; Financial Interests, Personal, Advisory Board, Lung pipeline: MD Serono; Financial Interests, Institutional, Invited Speaker, Lung: COR2ED, Daiichi Sankyo, Physicians Education Resource; Financial Interests, Institutional, Advisory Board, Lung: Regeneron, Intellisphere, CEA, Bayer U.C. LLC, General Dynamics, MedStar, Imagene; Financial Interests, Institutional, Coordinating PI, Empower me study Grant by LCRF and Pfizer: Pfizer- Lung Cancer research Foundation; Financial Interests, Institutional, Coordinating PI, Global PI LUNG itrapid@024 trial: MD Serono; Non-Financial Interests, Institutional, Other, Analysis of Liquid Biopsies in Lung Cancer Trial: Guardant Health; Non-Financial Interests, Other, Faculty ESMO NSCLC Metastatic 2021-2025: ESMO; Non-Financial Interests, Leadership Role, Vice-President: ISLB International Society of Liquid Biopsy; Non-Financial Interests, Leadership Role, Scientific Board member: ESO European School of Oncology; Non-Financial Interests, Leadership Role, Deputy Chair Educational Committee: IASLC International Association for Study of Lung Cancer; Non-Financial Interests, Leadership Role, Educational chair: OLA Oncology Latin American Association; Non-Financial Interests, Other, Editor in Chief of the Journal: CROH Critical Reviews in Oncology Hematology; Non-Financial Interests, Other, Associate Editor: ESMO Open. D.R. Spigel: Financial Interests, Institutional, Other, Consulting: AstraZeneca, BeiGene, Bristol Myers Squibb, Evidera, GSK, Ipsen Biopharmaceuticals, Janssen, Jazz Pharmaceuticals, Lilly, Molecular Templates, Monte Rosa Therapeutics, Novartis, Pfizer, Regeneron, Sanofi-Aventis, AbbVie, Novocure, Roche/Genentech; Financial Interests, Institutional, Research Grant, Serve as PI: Amgen, Aeglea Biotherapeutics, Agios, Arrys Therapeutics, Astellas, AstraZeneca, Bayer, BeiGene, BIND Therapeutics, Blueprint Medicine, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celldex Therapeutics, Clovis, Daiichi Sankyo, Eisai, Lilly, Genentech/Roche, G1 Therapeutics, Gilead Sciences, GSK, GRAIL, Hutchinson MediPharma, ImClone Systems, Ipsen, Janssen, Loxo, MacroGenics, MedImmune, Merck, Nektar, Neon Therapeutics, Novartis, Novocure, Rgenix, SeaGen, Taiho Oncology, Tarveda, Tizona Therapeutics, Transgene, UT Southwestern, Verastem, Arcus Biosciences, Molecular Template, Cyteir Therapeutics, BioNTech, Apollomics, Pure Tech Health, Elevation Oncology, Repare Therapeutics, Razor Genomics, Denovo Biopharma, Erasca, Kronos Bio, Zai Laboratory, Faeth Therapeutics, Ascendis Pharma, Lyell Immunopharma, Synthekine, Shenzhen Chipscreen Biosciences, AbbVie, AnHeart Therapeutics, Calithera, Endeavor, FujiFilm Pharmaceuticals, Incyte, Jazz Pharmaceuticals, Millennium Pharmaceuticals, Moderna, Monte Rosa Therapeutics, Peloton Therapeutics, Stemline Therapeutics, Tango Therapeutics, Tesaro. D. Andrew, S. Cho, T. Collins, R. Kurek, N. Ceaicovscaia, M. Petruzzelli, E.J. Dean: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. A. Hansen: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. G. Hawkins: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca; Financial Interests, Personal, Member: AstraZeneca; Financial Interests, Personal, Advisory Role: AstraZeneca. A. Sacher: Financial Interests, Institutional, Coordinating PI: Genentech-Roche, BMS, AstraZeneca; Financial Interests, Institutional, Local PI: Amgen, Iovance, CRISPR Therapeutics, Merck, Pfizer, GSK, Spectrum, Lilly.