Abstract 740P
Background
Ipilimumab (IPI; anti–CTLA-4) ± NIVO (anti–PD-1) has demonstrated clinical activity across many tumor types. BMS-986249, a peptide-masked version of IPI unmasked by tumor-associated proteases, has a differentiated pharmacologic profile compared to IPI in preclinical studies, consistent with the mechanism of action of the Probody® therapeutic technology platform (Pb-Tx, CytomX Therapeutics; Engelhardt et al. AACR 2020. Abstract 4551). We present safety, efficacy, pharmacokinetic (PK), and pharmacodynamic (PD) data from a first-in-human, phase 1/2 study of BMS-986249 ± NIVO in pts with advanced cancer (NCT03369223).
Methods
Anti–CTLA-4 naive pts with advanced cancer and ECOG PS of 0–1 received BMS-986249 240–2400 mg Q4W or 1600 mg Q8W as monotherapy (mono), or 240–1200 mg Q4W or 800–1600 mg Q8W + NIVO 480 mg Q4W (combo). Combo pts were also anti–PD-(L)1 naive.
Results
Pts with various (> 12) tumor types received mono (n = 39) or combo (n = 64); 100% and 91%, respectively, had received prior systemic therapy. Any-grade/grade 3/4 treatment-related adverse events (TRAEs) were reported in 62%/23% of mono pts and 86%/38% of combo pts. The most common any-grade TRAEs were diarrhea (23%) and fatigue (15%) in mono pts, and fatigue (27%) and diarrhea (20%) in combo pts. The most common grade 3/4 TRAEs were diarrhea in mono pts (15%) and diarrhea and colitis in combo pts (8% each). TRAEs leading to discontinuation occurred in 13% of mono pts and 19% of combo pts. TRAEs were dose-dependent, and both Q4W and Q8W were tolerable. One grade 5 TRAE was reported (sepsis; 1600 mg Q8W + NIVO). Objective response and disease control rates (complete/partial response, stable disease) with mono were 0% and 26%, respectively, and with combo were 16% and 38%, respectively, including responses in tumor types typically insensitive to immuno-oncology drugs. Tumor PK showed dose-dependent increases in unmasked BMS-986249 concentrations. Peripheral and tumor PD markers were increased and were consistent with historical data for IPI ± NIVO.
Conclusions
BMS-986249 demonstrated a tolerable safety profile with no unexpected signals and promising preliminary activity. PK and PD supported unmasking at the tumor site.
Clinical trial identification
NCT03369223.
Editorial acknowledgement
Professional medical writing and editorial assistance was provided by David Buist, PhD, and Matthew Weddig, BA, of Spark Medica Inc, funded by Bristol Myers Squibb.
Legal entity responsible for the study
Bristol Myers Squibb.
Funding
Bristol Myers Squibb.
Disclosure
M. Gutierrez: Financial Interests, Personal, Invited Speaker: Guardant Health; Financial Interests, Personal, Stocks/Shares: COTA Healthcare; Financial Interests, Institutional, Invited Speaker: Merck, BMS, Incyte, NexCure, Pfizer, Roche/Genentech, Boehringer Ingelheim, GSB Pharma, Moderna, Eisai, Silenseed, Seattle Genetics, Regeneron, Sanofi, Johnson & Johnson, MedImmune, Checkpoint Therapeutics, Acerta Pharmaceuticals, Arcus Biosciences, Array BioPharma, Bayer, Celgene, Compass Therapeutics, Constellation Pharmaceuticals, Cyter, EMD Sereno, Fate Therapeutics, GlaxoSmithKline, Infinity, Pharmacyclics, Synlogic, Tesaro, Vedanta. C.F. Friedman: Non-Financial Interests, Personal, Advisory Board, compensation waived: Merck, Genentech; Non-Financial Interests, Personal, Principal Investigator: Daiichi, Bristol Myers Squibb, Genentech/Roche, Merck, AstraZeneca; Financial Interests, Personal, Personal fees: Bristol Myers Squibb, Arch Oncology. G.V. Long: Financial Interests, Personal, Consultant Advisor: Agenus Inc, Amgen Inc, Array Biopharma Inc, Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Evaxion Biotech A/S, Hexal AG , Highlight Therapeutics S.L, Merck Sharpe & Dohme (Australia) Pty Limited , Novartis Pharma AG, OncoSec Medical Australia , Pierre Fabre, Provectus Australia , Qbiotics Group Limited , Regeneron Pharmaceuticals Inc . P.A. Ascierto: Financial Interests, Personal, Advisory Role: Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, AstraZeneca, Sun Pharma, Sanofi, Idera, Sandoz, Immunocore, 4SC, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, Seagen, iTeos. 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, CatalYm GmbH, BioLineRx, Boston Pharma, Janssen, Hookipa Pharma, HotSpot Therapeutics, Inc., ImmuneSensor Therapeutics, Inc., Monopteros Therapeutics; Financial Interests, Personal, Consultant: Pharma Mar; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Roche, BMS, Genmab, Alligator. 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. P. Conkling: Financial Interests, Institutional, Clinical investigator: Bristol Myers Squibb, Pfizer, Bayer-LOXO, Arcus, Aptose, Janssen. B.R. Corr: Financial Interests, Institutional, Advisory Board: GSK, Merck, Novocure, AstraZeneca, Immunogen; Financial Interests, Institutional, Research Grant: Clovis. A.M. Kim: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb. L. Zhu: Financial Interests, Institutional, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Institutional, Stocks/Shares: Bristol Myers Squibb. A. Hammell: Financial Interests, Personal and Institutional, Full or part-time Employment: Bristol Myers Squibb. D. Perumal: Financial Interests, Personal and Institutional, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal and Institutional, Stocks/Shares: Bristol Myers Squibb. A. Chouzy: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb. A. Hannah: Financial Interests, Institutional, Member of the Board of Directors: Neogenomics, Rigel Therapeutics ; Financial Interests, Institutional, Full or part-time Employment: CytomX Therapeutics; Financial Interests, Institutional, Stocks/Shares: CytomX Therapeutics. D.T. Le: Financial Interests, Personal, Honoraria, consulting, research funding: Merck; Financial Interests, Personal, Consulting, Research Funding: Bristol Myers Squibb, Nouscom; Financial Interests, Personal, Consulting: Janssen; Financial Interests, Personal, Research funding: Aduro Biotech, Medivir, Curegenix. All other authors have declared no conflicts of interest.