Phase I study of MK-4166, an anti-human glucocorticoid-induced tnf receptor antibody, alone or with pembrolizumab in advanced solid tumors

Kyriakos P. Papadopoulos, Karen Autio, Talia Golan, Konstantin Dobrenkov, Elliot Chartash, Qiusheng Chen, Richard Wnek, Georgina V. Long

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: In this first-in-human phase I study (NCT02132754), we explored MK-4166 [humanized IgG1 agonist mAb targeting glucocorticoid-induced TNF receptor (GITR)] with and without pembrolizumab in advanced solid tumors. Patients and Methods: MK-4166 was tested alone (0.0015. 900 mg i.v. every 3 weeks for four doses) or with pembrolizumab (200 mg i.v. every 3 weeks for ≤35 doses) in patients with metastatic solid tumors (dose escalation/confirmation) and advanced melanoma (expansion). Primary objectives were to evaluate the safety and tolerability and establish the MTD of MK-4166. Exploratory endpoints were objective response rate (ORR) and T cell-inflamed gene expression profile (GEP) analysis using RNA from baseline tumor samples. Results: A total of 113 patients were enrolled [monotherapy, n = 48; combination therapy, n = 65 (20 in the expansion)]. Fortysix patients (40.7%) had grade ≥3 adverse events, 9 (8.0%) of which were treatment related. No treatment-related deaths were observed. One dose-limiting toxicity event with monotherapy (bladder perforation in patient with neobladder) was considered related to study drug. MTD was not reached. MK-4166 pharmacodynamics showed decreased GITR availability on circulating T cells with increasing doses. One objective response (ORR, 2.2%) was achieved with combination therapy in the dose escalation/confirmation (n=45). In the expansion, 8 of 13 patients with immune checkpoint inhibitor (ICI)-naive melanoma achieved a response (ORR, 62%; 95% confidence interval, 32.86; 5 complete responses and 3 partial responses). None of the ICI-pretreated patients (n=7) responded. Highresponse rates were observed in ICI-naive patients irrespective of GEP status. Conclusions: MK-4166 900 mg i.v. every 3 weeks as monotherapy and with pembrolizumab was tolerable. Responses were observed with combination therapy, mostly in patients with ICI-naïve melanoma.

Original languageEnglish
Pages (from-to)1904-1911
Number of pages8
JournalClinical Cancer Research
Volume27
Issue number7
DOIs
StatePublished - Apr 2021

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