First-in-Human Phase I/II ICONIC Trial of the ICOS Agonist Vopratelimab Alone and with Nivolumab: ICOS-High CD4 T-Cell Populations and Predictors of Response

Abstract

Purpose: The First-in-Human Phase 1/2 ICONIC trial evaluated an investigational ICOS agonist, vopratelimab, alone and in combination with nivolumab in patients with advanced solid tumors. Experimental Design: In Phase 1, patients were treated with escalating doses of intravenous vopratelimab alone or with nivolumab. Primary objectives were safety, tolerability, maximum tolerated dose and recommended Phase 2 dose (RP2D). Phase 2 enriched for ICOS+ tumors; patients were treated with vopratelimab at the monotherapy RP2D alone or with nivolumab. Pharmacokinetics, pharmacodynamics and predictive biomarkers of response to vopratelimab were assessed. Results: ICONIC enrolled 201 patients. Vopratelimab alone and with nivolumab was well tolerated; Phase 1 established 0.3 mg/kg q3w as the vopratelimab RP2D. Vopratelimab resulted in modest objective response rates of 1.4% and with nivolumab of 2.3%. The prospective selection for ICOS+ tumors did not enrich for responses. A vopratelimab-specific peripheral blood pharmacodynamic biomarker, ICOS-hi CD4 T-cells, was identified in a subset of patients who demonstrated greater clinical benefit versus those with no emergence of these cells [overall survival (OS), p=0.0025]. A potential genomic predictive biomarker of ICOS-hi CD4 T-cell emergence was identified which demonstrated improvement in clinical outcomes, including OS (p=0.0062). Conclusions: Vopratelimab demonstrated a favorable safety profile alone and in combination with nivolumab. Efficacy was observed only in a subset of patients with a vopratelimab-specific pharmacodynamic biomarker. A potential predictive biomarker of response was identified, which is being prospectively evaluated in a randomized Phase 2 non-small cell lung cancer trial.

Analysis and Regulatory Mechanisms of Platelet-related Genes in Patients with Ischemic Stroke

“…The mechanism may be that MEDI-570 leads to a sustained reduction of ICOS+ T lymphocytes (Chavez et al 2023). The presence and persistence of this pharmacodynamic biomarker was found to confirm the agonistic effect of Vopratelimab on ICOS leading to proliferation and sustained activation of ICOS-hi CD4 T cells, including Th1, Tcm and Tfh subpopulations (Yap et al 2022).…”

Integrated systems immunology approach identifies impaired effector T cell memory responses as a feature of progression to severe dengue fever

“…In these cells, ICOS plays an important role in cell activation, maintenance, and survival [75]. Emerging research is highlighting the importance of ICOS co-stimulation to deliver efficient anti-tumour effector T cell responses [76][77][78], with various ICOS agonist antibodies currently in clinical trial showing promising results [79,80]. Targeting this co-stimulatory pathway could be also beneficial to boost adaptive immunity and improve disease outcomes in secondary dengue infections.…”

From Co-Stimulation to Co-Inhibition: A Continuum of Immunotherapy Care Toward Long-Term Survival in Melanoma

“…12,13 The ICOS agonist mAb, vopratelimab, has been investigated in combination with anti-PD-1 and anti-CTLA-4 mAb in the Phase I ICONIC trial (NCT02904226). [14][15][16] Furthermore, the first-in-human INDUCE-1 study (NCT02723955) explored the combination of the ICOS agonist mAb feladilimab with anti-PD-1, anti-TIM-3 mAb or chemotherapy, in patients with advanced solid tumors. 17,18 However, in spite of the initial results showing safety, tolerability, and clinical activity of ICOS agonists in heavily pretreated patients, more mature data failed to confirm their efficacy; thus, their therapeutic potential is being investigated further.…”