Abstract 171P
Background
CM 8KX is a phase 1/2 study of an SC NIVO formulation with a permeation enhancer, recombinant human hyaluronidase PH20 enzyme (rHuPH20), developed to allow rapid delivery and reduced treatment burden compared with intravenous (IV) NIVO administration. We report PD biomarker changes in the tumor microenvironment and peripheral blood from CM 8KX and key PD biomarker comparisons between SC and IV NIVO.
Methods
Patients were checkpoint inhibitor–naive, ≥ 18 years of age, ECOG performance status 0–1, with metastatic/unresectable solid tumors and measurable disease. Patients received SC NIVO 720 mg ± rHuPH20, SC NIVO 960 mg ± rHuPH20, or SC NIVO 1200 mg + rHuPH20. Paired baseline and on-treatment tumor biopsies were assessed for CD8+ tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 expression on tumor cells (TC PD-L1) by immunohistochemistry. Soluble PD-1 (sPD-1), interferon gamma (IFNγ), CXCL9, and CXCL10 were assessed in serum from cycle (C) 1 day (D) 1 to C2D1. sPD-1 changes were compared with unpublished data from IV NIVO 3 mg/kg Q2W administration in CM 038; other biomarkers were compared with published data.
Results
As previously reported, SC NIVO ± rHuPH20 resulted in numerical mean increases from baseline to C1D15 in CD8+ TILs (5.0% [95% CI, −17.5 to 27.5]) and TC PD-L1 (2.8% [95% CI, −12.8 to 18.4]), which are surrogates for tumoral IFNγ activity. These observations were consistent with those published for IV NIVO in several indications. sPD-1 increased significantly following SC NIVO across dose cohorts, similar to increases observed in CM 038. Early increases in IFNγ and CXCL9 were observed following SC NIVO ± rHuPH20, with significant cycle-day effects but no apparent dose dependence. Numerical increases in CXCL10 were also observed. These increases are consistent with published IV NIVO data from CM 038.
Conclusions
Increases in tumor biomarkers and changes in key peripheral PD markers demonstrate immune activation post-SC NIVO. Despite the limitations of cross-trial comparisons, PD effects are consistent with historical IV NIVO data from CM 038. The results support further evaluation of SC NIVO + rHuPH20 in phase 3 studies.
Clinical trial identification
NCT03656718 and NCT01621490.
Editorial acknowledgement
Editorial support was provided by Sandra Page, PhD, of Spark Medica Inc.
Legal entity responsible for the study
Bristol Myers Squibb.
Funding
Bristol Myers Squibb.
Disclosure
C.G.C.A. Jackson: Non-Financial Interests, Personal, Advisory Role: Merck Sharp & Dohme; Financial Interests, Institutional, Funding: Athenex. D. Perumal: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. I. Lugowska: Financial Interests, Personal, Funding: Roche, MSD, AstraZeneca, Boehringer Ingelheim, Janssen, Pfizer, Amgen, Incyte, Macrogenics, RyVu, Rhizen, Agenus. A. O’Donnell: Other, Institutional, Full or part-time Employment: Capital and Coast Health, Bowen Icon Cancer Centre. R.T. North: Non-Financial Interests, Institutional, Principal Investigator: BOP Clinical Trials Unit. P.A. Calvo Ferrandiz: Non-Financial Interests, Personal, Full or part-time Employment: Hospital Universitario Gregorio Marañón. L.M. Latten-Jansen: Non-Financial Interests, Personal and Institutional, Principal Investigator: Maastricht University Medical Center+. A. Santoro: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Servier, Gilead, Pfizer, Eisai, Bayer, Merck Sharp & Dohme, Incyte; Financial Interests, Personal, Advisory Role: Sanofi; Financial Interests, Personal, Speaker’s Bureau: Takeda, Bristol Myers Squibb, Roche, AbbVie , Amgen, Celgene, Servier, Gilead, AstraZeneca, Pfizer, Lilly, Sandoz, Eisai, Novartis, Bayer, Merck Sharp & Dohme. L. Li: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb. K. Sidik: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. T. Tang: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. J.S. Deutsch: Financial Interests, Personal, Other, Application No: 63/313,548: Patent pending. J. Taube: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Merck Sharpe & Dohme, AstraZeneca, Replimune; Financial Interests, Personal, Research Grant: Bristol Myers Squibb; Financial Interests, Personal and Institutional, Stocks/Shares: Akoya Biosciences; Financial Interests, Personal and Institutional, Advisory Board: Akoya Biosciences; Financial Interests, Personal and Institutional, Research Grant: Akoya Biosciences; Non-Financial Interests, Institutional, Other, Equipment loan: Akoya Biosciences; Non-Financial Interests, Institutional, Other, Reagent provision: Akoya Biosciences. C. Horak: Financial Interests, Personal, Full or part-time Employment: Palleon Pharmaceuticals; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. S. Ravimohan: Financial Interests, Institutional, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. S. Lonardi: Financial Interests, Personal, Advisory Board: Amgen, Merck Serono, Lilly, Servier, AstraZeneca, MSD, Incyte, Daiichi Sankyo, Bristol Myers Squibb, Mirati; Financial Interests, Personal, Invited Speaker: Pierre-Fabre, GlaxoSmithKline, Roche; Financial Interests, Institutional, Invited Speaker: Amgen, Merck Serono, Bayer, Roche, Lilly, AstraZeneca, Bristol Myers Squibb. All other authors have declared no conflicts of interest.