First‐in‐human phase 1 study of MK‐1248, an anti–glucocorticoid‐induced tumor necrosis factor receptor agonist monoclonal antibody, as monotherapy or with pembrolizumab in patients with advanced solid tumors

Abstract

BACKGROUND: Ligation of glucocorticoid-induced tumor necrosis factor receptor (GITR) decreases regulatory T cell-mediated suppression and enhances T-cell proliferation, effector function, and survival. MK-1248 is a humanized immunoglobulin G4 anti-GITR monoclonal antibody agonist. METHODS: In patients with advanced solid tumors, MK-1248 (starting dose, 0.12 mg) was tested alone and with pembrolizumab (200 mg) according to a 3 + 3 dose escalation design (ClinicalTrials.gov identifier NCT02553499); both treatments were administered intravenously every 3 weeks for ≤4 and ≤35 cycles, respectively. The safety and tolerability, maximum tolerated dose, and pharmacokinetics/pharmacodynamics were explored. RESULTS: Twenty patients received MK-1248 monotherapy; 17 received combination therapy. The most frequent tumor types were colorectal cancer (n = 8), melanoma (n = 6), and renal cell carcinoma (n = 4). MK-1248 was generally well tolerated at the maximum tested doses of 170 (monotherapy) and 60 mg (combination). No dose-limiting toxicities (DLTs) or treatment-related deaths occurred. Adverse events (AEs) occurred in 36 of the 37 patients (97%); the most common were vomiting (n = 13 [35%]), anemia (n = 10 [27%]), and decreased appetite (n = 10 [27%]). Grade 3 to 5 AEs occurred in 19 of the 37 patients (51%). Treatment-related AEs occurred in 18 of the 37 patients (49%): 9 of the 20 patients (45%) on monotherapy and 9 of the 17 patients (53%) on combination therapy. Among the 17 patients receiving combination therapy, 1 achieved a complete response and 2 achieved a partial response, for an objective response rate of 18%; no patients achieved an objective response with monotherapy. The disease control rate (stable disease or better) was 15% with monotherapy and 41% with combination therapy. CONCLUSIONS: MK-1248 was generally well tolerated at doses up to 170 (monotherapy) and 60 mg (combination), with no DLTs or treatment-related deaths. Combination therapy provided limited antitumor responses. Cancer 2020;126:4926-4935.

Engineering murine GITRL for antibody-mediated delivery to tumor-associated blood vessels

“…Similarly, a lack of clinical benefit was reported for a number of GITR agonistic antibodies such as TRX518 38 , AMG228 45 , BMS-986156 46 and MK-1248 47 . Thus…”

Immunotherapies targeting stimulatory pathways and beyond

“…In the monotherapy cohort, the ORR was 0% and the DCR was 15%. There were no CR or PR [ 42 ]. Three patients had SD.…”

“…In the combination cohort, the ORR was 18% and the DCR was 47%. There was 1 patient with CR, 2 with PR and 3 patients with SD [ 42 , 43 ]. No DLTs were identified in the dose-escalation phase of the trial.…”

“…The majority of patients (36/37 or 97%) developed at least 1 AE. Nineteen patients (51%) experienced grade 3–5 toxicities including anaphylactoid reactions and mucositis [ 42 ]. All other AEs were low-grade and included gastrointestinal toxicities, fatigue, and fever [ 43 ].…”

“…It is overall well tolerated. The authors did notice an increased prevalence of lymphocytes within the TME among responders [ 42 ]. Future efforts could identify biomarkers that help select patients more likely to benefit from this therapy.…”