Phase IB Study of GITR Agonist Antibody TRX518 Singly and in Combination with Gemcitabine, Pembrolizumab or Nivolumab in Patients with Advanced Solid Tumors
Mené sur 109 patients atteints d'une tumeur solide de stade avancé, cet essai de phase IB évalue la dose maximale tolérée de TRX518-003 (un anticorps anti-GITR), en monothérapie et en combinaison avec la gemcitabine, le pembrolizumab ou le nivolumab, puis analyse ses caractéristiques pharmacocinétiques et pharmacodynamiques
Purpose: TRX518 is a monoclonal antibody engaging the glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR). This open-label, phase I study (TRX518-003) evaluated the safety and efficacy of repeated dose TRX518 monotherapy and combination with gemcitabine, pembrolizumab or nivolumab in advanced solid tumors. Experimental Design: TRX518 monotherapy was dose-escalated (Part A) and expanded (Part B) up to 4 mg/kg load, 1 mg/kg Q3W. Parts C-E included dose-escalation (2mg/kg and 4 mg/kg loading followed by 1mg/kg) and dose-expansion (4mg/kg load) phases with gemcitabine (Part C), pembrolizumab (Part D) or nivolumab (Part E). Primary endpoints included incidence of dose-limiting toxicities (DLTs), serious adverse events (SAEs), and pharmacokinetics. Secondary endpoints were efficacy and pharmacodynamics. Results:109 patients received TRX518: 43 (Parts A+B), 30 (Part C), 26 (Part D), and 10 (Part E) respectively. 67% of patients in Parts D+E had received prior anti-PD(L)1 or anti-CTLA-4. No DLTs, treatment-related SAEs and/or G4/5 AEs were observed with TRX518 monotherapy. In Parts C-E, no DLTs were observed, although TRX518-related SAEs were reported in 3.3% (Part C) and 10.0% (Part E) respectively. Objective response rate was 3.2%, 3.8%, 4% and 12.5% in Parts A+B, C, D and E respectively. TRX518 affected peripheral and intratumoral regulatory T cells (Tregs) with different kinetics depending on the combination regimen. Responses with TRX518 monotherapy+anti-PD1 combination were associated with intratumoral Treg reductions and CD8 increases and activation after treatment. Conclusions:TRX518 showed an acceptable safety profile with pharmacodynamic activity. Repeated dose TRX518 monotherapy and in combination resulted in limited clinical responses associated with immune activation.