Abstract 627P
Background
B7-H3, a member of the B7 superfamily, is highly expressed (relative to PD-L1 and PD-L2) in prostate cancer, and is associated with rapid biochemical recurrence and early metastases. Enoblituzumab (MacroGenics, Inc.) is an investigational humanized Fc-optimized B7-H3–targeting antibody that induces antibody-dependent cellular cytotoxicity (ADCC).
Methods
In this phase II single-arm neoadjuvant trial (NCT02923180), men with operable intermediate- and high-risk localized prostate cancer (Grade Groups 3-5) were enrolled to evaluate the safety, anti-tumor efficacy, and immunogenicity of enoblituzumab when given prior to prostatectomy. Patients received enoblituzumab (15 mg/kg IV weekly x 6) prior to surgery. Prostate glands were harvested 2 weeks after the last enoblituzumab dose, and were examined for pathologic and immunologic endpoints. The co-primary outcomes were safety and PSA0 at 1 year post-op.
Results
A total of 32 patients were enrolled. Grade 3/4 drug-related adverse events occurred in 12% of patients; there was no surgical delay due to AEs. One patient developed a grade-3 infusion reaction, and one had immune myocarditis that improved with steroids. Pre-prostatectomy PSA declines of >10% were observed in 34% of patients (95% CI: 20-52%). PSA0 at 1 year post-op was seen in 66% of men (95% CI: 48-80%). Median time to PSA recurrence was not reached (95% CI: 9.4 months – NE). Gleason grade group upgrade, no change, and downgrade was observed in 12.5%, 37.5%, and 50% of patients respectively. Exploratory tumor microenvironment profiling by NanoString GeoMx spatial proteomics and PanCancer IO 360 mRNA expression analysis revealed evidence of post-treatment upregulation of CD8+ T cells, PD-1/PD-L1, and immune activation (granzyme B, IFN signaling, myeloid inflammation).
Conclusions
In this neoadjuvant trial, inhibition of B7-H3 with enoblituzumab demonstrated favorable safety and encouraging activity in prostate cancer patients. Preliminary data suggest robust intratumoral induction (adaptive upregulation) of immune checkpoints, T cell activation, and myeloid inflammation.
Clinical trial identification
NCT02923180 (Posted October 4th 2016).
Editorial acknowledgement
Legal entity responsible for the study
Emmanuel Antonarakis, Johns Hopkins University.
Funding
Macrogenics, Prostate Cancer Foundation, American Society of Clinical Oncology Conquer Cancer Foundation, Department of Defense.
Disclosure
E. Shenderov: Financial Interests, Institutional, Principal Investigator: Macrogenics; Financial Interests, Personal, Ownership Interest, Patent assigned to LifeImmune: LifeImmune. A. De Marzo: Financial Interests, Institutional, Sponsor/Funding: Janssen R&D; Financial Interests, Personal, Advisory Role: Cephied. T. Lotan: Financial Interests, Institutional, Sponsor/Funding: Roche; Financial Interests, Institutional, Sponsor/Funding: DeepBio. F. Chen: Financial Interests, Personal, Stocks/Shares, Employee: Macrogenics. P. Moore: Financial Interests, Personal and Institutional, Stocks/Shares, Employed by, leadership: Macrogenics. J. Muth: Financial Interests, Personal and Institutional, Stocks/Shares, Employed by: Macrogenics. K. Sorg: Financial Interests, Personal, Full or part-time Employment, Stock ownership: Nanostring Technologies. A.M. White: Financial Interests, Personal, Stocks/Shares, Employee: Nanostring Technologies. S.E. Church: Financial Interests, Personal, Stocks/Shares, Employee: Nanostring Technologies. T. Bivalacqua: Financial Interests, Personal, Other, Consultant: Feregene; Financial Interests, Personal, Other, Consultant: Biogenesis; Financial Interests, Personal, Other, Consultant: Aura. A.E. Ross: Financial Interests, Personal, Invited Speaker: Janssen R&D; Financial Interests, Personal, Invited Speaker: Bayer; Financial Interests, Personal, Invited Speaker: Myovant; Financial Interests, Personal, Invited Speaker: GenomeDx; Financial Interests, Personal, Invited Speaker: Tempus; Financial Interests, Personal, Advisory Role: Astellas. C.P. Pavlovich: Financial Interests, Personal, Advisory Role: Dendreon. C.G. Drake: Financial Interests, Personal, Full or part-time Employment: Janssen R&D; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Advisory Role, Patent licensed from Johns Hopkins University: BMS; Financial Interests, Personal, Advisory Role: Compugen; Financial Interests, Personal, Advisory Role: F-Star; Financial Interests, Personal, Advisory Role: Genocea; Financial Interests, Personal, Advisory Role, Patent licensed from Johns Hopkins University: Janssen; Financial Interests, Personal, Advisory Role: Kleo; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Merck-Serono; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Pierre Fabre; Financial Interests, Personal, Advisory Role: Roche / Genentech; Financial Interests, Personal, Advisory Role: Shattuck Labs; Financial Interests, Personal, Advisory Role: Tizona; Financial Interests, Personal, Advisory Role: Werewolf. D. Pardoll: Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Advisory Role: Dynavax; Financial Interests, Personal, Advisory Role: Enara; Financial Interests, Personal, Advisory Role: FLX Bio; Financial Interests, Personal, Advisory Role: Immunomic Therapeutics; Financial Interests, Personal, Advisory Role: Janssen; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Rock Springs Capital; Financial Interests, Personal, Advisory Role: Tizona; Financial Interests, Personal, Advisory Role: Trieza; Financial Interests, Personal, Member of the Board of Directors: DNAtrix; Financial Interests, Personal, Advisory Board: ImmununeOncia Therapeutics; Financial Interests, Personal, Advisory Board: RAPT Therapeutics; Financial Interests, Personal, Advisory Board: WindMil; Financial Interests, Personal, Advisory Board: Dracen; Financial Interests, Personal, Advisory Board: Camden Partners; Financial Interests, Personal, Advisory Board: Astellas; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: Compugen; Financial Interests, Personal, Other, Consultant and Founder: Aduro Biotech; Financial Interests, Personal, Other, Founder: ManaT Bio. E.S. Antonarakis: Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Personal, Advisory Role: Astellas; Financial Interests, Personal and Institutional, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Institutional, Sponsor/Funding: Bristol Myers-Squibb; Financial Interests, Institutional, Sponsor/Funding: Celgene; Financial Interests, Personal and Institutional, Sponsor/Funding: Dendreon; Financial Interests, Personal, Advisory Role: Eli Lilly and Co.; Financial Interests, Personal, Advisory Role: ESSA; Financial Interests, Institutional, Sponsor/Funding: Genentech; Financial Interests, Personal, Advisory Role: GlaxoSmithKline; Financial Interests, Personal and Institutional, Advisory Role: Janssen; Financial Interests, Institutional, Sponsor/Funding: Johnson&Johnson; Financial Interests, Personal, Advisory Role: Medivation; Financial Interests, Personal and Institutional, Invited Speaker: Merck; Financial Interests, Institutional, Advisory Role: Novartis; Financial Interests, Institutional, Advisory Role: Qiagen; Financial Interests, Personal and Institutional, Advisory Role: Sanofi; Financial Interests, Institutional, Sponsor/Funding: Tokai. All other authors have declared no conflicts of interest.