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First in Human Phase 1/2 ICONIC Trial of the ICOS agonist vopratelimab alone and with nivolumab: ICOS high CD4 T cell populations and predictors of response.

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.