Phase IB study of GITR agonist antibody TRX518 singly and in combination with gemcitabine, pembrolizumab, or nivolumab in patients with advanced solid tumors Journal Article
| Authors: | Davar, D.; Zappasodi, R.; Wang, H.; Naik, G. S.; Sato, T.; Bauer, T.; Bajor, D.; Rixe, O.; Newman, W.; Qi, J.; Holland, A.; Wong, P.; Sifferlen, L.; Piper, D.; Sirard, C. A.; Merghoub, T.; Wolchok, J. D.; Luke, J. J. |
| Article Title: | Phase IB study of GITR agonist antibody TRX518 singly and in combination with gemcitabine, pembrolizumab, or nivolumab in patients with advanced solid tumors |
| Abstract: | Purpose: TRX518 is a mAb engaging the glucocorticoid-induced TNF receptor-related protein (GITR). This open-label, phase I study (TRX518-003) evaluated the safety and efficacy of repeated dose TRX518 monotherapy and in combination with gemcitabine, pembrolizumab, or nivolumab in advanced solid tumors. Patients and Methods: TRX518 monotherapy was dose esca-lated (Part A) and expanded (Part B) up to 4 mg/kg loading, 1 mg/kg every 3 weeks. Parts C-E included dose-escalati on (2 and 4 mg/kg loading followed by 1 mg/kg) and dose-expansion (4 mg/kg loading) phases with gemcitabine (Part C), pembroli-zumab (Part D), or nivolumab (Part E). Primary endpoints included incidence of dose-limiting toxicities (DLT), serious adverse events (SAE), and pharmacokinetics. Secondary end-points were efficacy and pharmacodynamics. Results: A total of 109 patients received TRX518: 43 (Parts A+B), 30 (Part C), 26 (Part D), and 10 (Part E), respectively. A total of 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 grade 4 or 5 AEs were observed with TRX518 mono-therapy. 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 (Treg) with different kinetics depending on the combination regimen. Responses with TRX518 monotherapy+anti-PD1 com-bination 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. |
| Keywords: | carcinoma; pd-1; modulation; expression; t-cells; expansion; engagement; suppression; induced tnf receptor; glucocorticoid-induced tnfr |
| Journal Title: | Clinical Cancer Research |
| Volume: | 28 |
| Issue: | 18 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2022-09-15 |
| Start Page: | 3990 |
| End Page: | 4002 |
| Language: | English |
| ACCESSION: | WOS:000861182400001 |
| DOI: | 10.1158/1078-0432.Ccr-22-0339 |
| PROVIDER: | wos |
| PMCID: | PMC9475244 |
| PUBMED: | 35499569 |
| Notes: | Article -- Source: Wos |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work