Phase 1 study of MK-4166, an anti-human glucocorticoid-induced tumor necrosis factor receptor (GITR) antibody, as monotherapy or with pembrolizumab (pembro) in patients (pts) with advanced solid tumors.

person Kyriakos P. Papadopoulos South Texas Accelerated Research Therapeutics, San Antonio, TX info_outline Kyriakos P. Papadopoulos, Karen A. Autio, Talia Golan, Konstantin Dobrenkov, Elliot Chartash, Xiaoyun Nicole Li, Richard Wnek, Georgina V. Long

Authors person Kyriakos P. Papadopoulos South Texas Accelerated Research Therapeutics, San Antonio, TX info_outline Kyriakos P. Papadopoulos, Karen A. Autio, Talia Golan, Konstantin Dobrenkov, Elliot Chartash, Xiaoyun Nicole Li, Richard Wnek, Georgina V. Long Organizations South Texas Accelerated Research Therapeutics, San Antonio, TX, Memorial Sloan Kettering Cancer Center, New York, NY, The Oncology Institute, Sheba Medical Center at Tel-Hashomer, Tel Aviv University, Tel Aviv, Israel, Merck & Co., Inc., Kenilworth, NJ, Melanoma Institute Australia, The University of Sydney, and Royal North Shore and Mater Hospitals, Sydney, Australia Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Background: Ligation of GITR on immune cells decreases T reg -mediated suppression and enhances T cell proliferation. MK-4166 is a humanized IgG1 agonist monoclonal antibody targeting GITR. Data from the first-in-human phase 1 study (NCT02132754) of MK-4166 as monotherapy (mono) or in combination with pembro (combo) are presented. Methods: MK-4166 was tested alone (0.0015 mg IV-900 mg Q3W ×4 doses) or with pembro (fixed dose 200 mg IV Q3W up to 35 doses) in the absence of toxicity or progression. Study included a dose escalation/confirmation cohort (metastatic solid tumors) and an expansion cohort (treatment-naive and pretreated melanoma). A T cell?inflamed gene expression profile (GEP) was assessed using RNA from baseline tumor samples. End points ? primary: safety/tolerability, maximum tolerated dose (MTD) of MK-4166; secondary: pharmacokinetics (PK), pharmacodynamics (PD); exploratory: objective response rate (ORR) per irRECIST1.1. Results: Of 113 pts, 48 received mono and 65 combo; 20 were in the melanoma expansion. Common AEs ( > 20%) were fatigue, infusion-related reaction, nausea, abdominal pain, and pruritus; 43 pts had grade ≥3 AEs (38.1%); 6 (5.3%) were treatment-related. One dose-limiting toxicity (bladder perforation in a urothelial pt with a neobladder) possibly related to study drug was observed with mono. MTD was not reached. No treatment-related deaths were observed. MK-4166 PK/PD showed target-mediated drug disposition concomitant with decreased GITR availability on T cells in blood with increasing doses. Four objective responses (4/45; ORR, 9%) were seen with combo in dose escalation. For ICI-naive melanoma pts (n = 13) in expansion, ORR was 69% (95% CI, 38-91), including 4 CRs and 5 PRs. No response was observed in 7 pts previously treated with ICI. High ORRs were observed in noninflamed and inflamed ICI-naive melanoma pts. Conclusions: MK-4166 at a dose up to 900 mg as monotherapy and in combination with pembro was well tolerated, with dose-related evidence of target engagement. Responses were observed with MK-4166 900 mg plus pembro, particularly in pts with melanoma naive to ICIs. Clinical trial information: NCT02132754