Abstract 745P
Background
Concurrent immune checkpoint inhibition of PD-1 and LAG-3 by monospecific antibodies can lead to significantly longer median progression-free survival in previously untreated metastatic melanoma compared with PD-1 inhibition alone (Tawbi et al. 2022). RO7247669 is a novel, PD1-LAG3 bispecific antibody which delivers dual checkpoint inhibition through monovalent high affinity binding to PD-1, and monovalent binding to LAG-3 allowing a unique avidity-mediated selectivity gain. The bispecific antibody is IgG1-based and has a silent Fc region. RO7247669 blocks the PD-1 interaction with PD-L1 and PD-L2 as well as the interaction of LAG-3 with MHCII to re-invigorate dysfunctional T-cells and overcome LAG3-mediated resistance to current checkpoint inhibitors (CPIs).
Methods
NP41300 is an open label, first in human phase I multiple ascending-dose study investigating single agent RO7274669 in patients with advanced and/or metastatic solid tumors. The dose escalation part assessed doses from 50 mg up to 2100 mg administered i.v. every 2 weeks. Primary objective was safety and tolerability. Secondary endpoints included PK, peripheral blood receptor occupancy, and preliminary anti-tumor activity according to RECIST 1.1.
Results
As of March 1, 2022, a total of 35 patients have been treated with RO7274669 during the dose escalation phase of the study. 40 % of patients had >= 3 prior lines of systemic treatment, and 34.3 % had prior CPI treatment. RO7274669 shows linear PK across the dose range (50 - 2100 mg), with ∼100 % peripheral blood receptor occupancy observed across all doses and sustained over the treatment period. Objective response rate (ORR) was 17.1 %, and disease control rate (DCR) was 51.4 %. Responses have been observed in CPI naive patients (4/23) as well as in CPI experienced patients (2/12). The majority of adverse events (AEs) were grade 1-2. Treatment related grade 3 AEs occurred in 6 patients (17.1 %). There were no treatment related grade 4-5 AEs, and no dose limiting toxicity has been observed.
Conclusions
RO7274669 has a favorable safety profile and has shown encouraging anti-tumor activity in the dose escalation phase. Expansion cohorts in CPI experienced Melanoma and NSCLC as well as CPI naive ESCC are ongoing.
Clinical trial identification
NCT04140500.
Editorial acknowledgement
Legal entity responsible for the study
F. Hoffmann-La Roche Ltd.
Funding
F. Hoffmann-La Roche Ltd.
Disclosure
K.S. Rohrberg: Financial Interests, Personal, Invited Speaker: Bayer, Amgen; Financial Interests, Institutional, Invited Speaker, Compensation for conduction of clinical trial.: Lilly, Roche/Genentech, Bristol Myers Squibb, Symphogen, Pfizer, Novartis, Alligator Bioscience, Genmab, Bioinvent, Monta Bioscience; Financial Interests, Institutional, Compensation for conduction of clinical trial.: Bayer, Incyte, Puma Biotechnology, Orion Clinical. E. Garralda: Financial Interests, Personal, Advisory Board: Genentech, F.Hoffmann/La Roche, Neomed Therapeutics1 Inc, Boehringer Ingelheim, Janssen Global Services, Alkermes, Thermo Fisher, MabDiscovery, Anaveon, Lilly, Hengrui; Financial Interests, Personal, Invited Speaker: Ellipses Pharma, Seattle Genetics, Bristol Myers Squibb, MSD, F-Star Therapeutics; Financial Interests, Institutional, Funding: Novartis, Roche, Thermo Fisher, AstraZeneca, Taiho. E. Calvo: Financial Interests, Personal, Advisory Role: Nanobiotix, Janssen-Cilag, PsiOxus Therapeutics, Seattle Genetics, Roche/Genentech, Amcure, TargImmune Therapeutics, Servier, Bristol Myers Squibb, PharmaMar, Alkermes, Amunix, Adcendo, Anaveon, AstraZeneca/MedImmune, BeiGene, Chugai Pharma, MonTa, MedSIR, MSD Oncology, Nouscom, Novartis, OncoDNA, Sanofi, Syneos Health, T-Knife, Boehringer Ingelheim; Financial Interests, Personal, President and Founder ofFoundation INTHEOS (Investigational Therapeutics in Oncological Sciences): INTHEOS; Financial Interests, Personal, Research Grant: BeiGene, START; Financial Interests, Institutional, Research Grant: Achilles; Financial Interests, Personal, Leadership Role: START; Financial Interests, Personal, Stocks/Shares: START, Oncoart Associated; Financial Interests, Personal, Full or part-time Employment: START, HM Hospitales Group; Financial Interests, Personal, Honoraria: HM Hospitales Group. V. Moreno Garcia: Financial Interests, Personal, Advisory Board: BMS, Janssen, Roche, Basilea, Bayer; Financial Interests, Personal, Full or part-time Employment: START; Non-Financial Interests, Principal Investigator, AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca Bayer Beigene BioInvent International AB, BMS, Boehringer, Boheringer, Boston, Celgene, Daichii Sankyo, Debiopharm ,Eisai, e-Terapeutics, Exelisis, Forma Therapeutics, Genmab, GSK, Harpoon, Hutchison, Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa Kirin, Lilly, Loxo, MedSir, Menarini, Merck, Merus, Millennium, MSD, Nanobiotix, Nektar, Novartis, Odonate Therapeutics, Pfizer, Pharma Mar, PharmaMar, Principia, PsiOxus, Puma, Regeneron, Rigontec, Roche, Sanofi, Sierra Oncology, Synthon, Taiho, Takeda, Tesaro, Transgene, Turning Point Therapeutics, Upshersmith.: Multiple. M. Guidi: Financial Interests, Employee without stock options: F. Hoffmann-La Roche Ltd. D.G. Kraus: Financial Interests, Employee without stock options: F. Hoffmann-La Roche Ltd.. C. McIntyre: Financial Interests, Employee with stock options: Roche Products Ltd. H. Kao: Financial Interests, Employee with stock options: F. Hoffmann-La Roche Ltd.. L. Codarri Deak: Financial Interests, Employee without stock options: Roche Glycart AG. F. Michielin: Financial Interests, Employee with stock options: F. Hoffmann-La Roche Ltd. T. Liu: Financial Interests, Employee with stock options: F. Hoffmann-La Roche Ltd. M. Muecke: Financial Interests, Invited Speaker, Employee with stock options: F. Hoffmann-La Roche Ltd. C. Markert: Financial Interests, Employee without stock options: Roche Diagnostics GmbH. I. Melero: Financial Interests, Personal, Advisory Board: Gossamer Bio, Highlight Therapeutics, MSD, Alligator Bioscience, Genmab, Numab, Noxxon Pharma AG, BMS, CRISPR Therapeutics, Genentech, AstraZeneca, Boehringer Ingelheim, EMD Serono, Roche; Financial Interests, Personal, Consultant: Pharma Mar; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Roche, BMS, Genmab, Alligator.