Phase I, first-in-human trial of programmed cell death receptor-1 (PD-1) inhibitor, JTX-4014, in adult patients with advanced, refractory, solid tumors

Kyriakos P Papadopoulos,Nehal Lakhani,Gosia Riley,Gilad Gordon,Johan Baeck,Judy S Wang,Karen S Brown,Gerald S Falchook,Lidya Le

doi:10.1007/s00262-020-02730-5

Abstract

BackgroundInhibition of programmed cell death receptor protein-1 (PD-1) has proven to be a highly effective strategy for immunotherapy of cancer. Approvals of both PD-1 and PD-L1 inhibitors [PD-(L)1i] in multiple tumor types are evidence of the durable benefits they provide to patients with cancer. In this first-in-human trial, we assessed the safety and tolerability of JTX-4014, a fully human antibody targeting PD-1.MethodsJTX-4014 was administered to 18 patients with multiple solid tumor types who had not previously received a PD-(L)1i. The primary objectives were to evaluate the safety and tolerability of JTX-4014 and determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). Secondary objectives included evaluation of the pharmacokinetics (PK) of JTX-4014, anti-drug antibodies (ADA) against JTX-4014, and clinical activity.ResultsJTX-4014 was well tolerated and no new safety signals were identified as compared with other PD-1is. The MTD was not reached and the RP2D was selected, based on PK modelling and supportive safety data, to be 500 mg every 3 weeks or 1000 mg every 6 weeks. Clinical activity, based on RECIST v1.1 criteria, demonstrated an overall response rate of 16.7% (n = 3) with one complete and two partial responses and a disease control rate of 44.4% (n = 8). The responses occurred at different doses in patients with PD-L1 positive tumors and in tumor types that are not typically PD-1i responsive.ConclusionsFurther development of JTX-4014 is warranted as a monotherapy or in combination with other innovative cancer therapies.Trial registration numberNCT03790488, December 31 2018.

Highlights

The approvals of progressive disease (PD)-1 inhibitors (PD-1is), including pembrolizumab and nivolumab, have caused a paradigm shift in immuno-oncology therapeutics, providing durable remissions for many patients with cancer [1,2,3,4]
JTX-4014 binds to PD-1 and augments antitumor activity by blocking the interaction between PD-1 and its ligands, PD-L1 and PD-L2
JTX-4014 is being developed in combination with other therapies for the treatment of cancer in which inhibition of PD-1 may be of benefit

Summary

Introduction

The approvals of PD-1 inhibitors (PD-1is), including pembrolizumab and nivolumab, have caused a paradigm shift in immuno-oncology therapeutics, providing durable remissions for many patients with cancer [1,2,3,4]. JTX-4014 is being developed in combination with other therapies for the treatment of cancer in which inhibition of PD-1 may be of benefit This phase I first-in-human (FIH) trial was designed to evaluate the safety and tolerability of JTX-4014, along with its maximum tolerated dose (MTD) and recommended phase II dose (RP2D), to provide the foundation for future clinical development. Inhibition of programmed cell death receptor protein-1 (PD-1) has proven to be a highly effective strategy for immunotherapy of cancer Approvals of both PD-1 and PD-L1 inhibitors [PD-(L)1i] in multiple tumor types are evidence of the durable benefits they provide to patients with cancer. In this first-in-human trial, we assessed the safety and tolerability of JTX-4014, a fully human antibody targeting PD-1.

Methods

Results

Conclusion