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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.

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TPS9137 Background: Immune checkpoint inhibitors have led to durable remissions for some patients with advanced malignancies, including NSCLC; however, only a minority of patients benefit. The field of oncology is addressing this via the development of novel therapies, combinations and identification of biomarkers to select patients most likely to derive clinical benefit. ICOS, a novel therapeutic target, is a costimulatory molecule upregulated on activated T cells. Vopratelimab is an investigational IgG1 ICOS agonist monoclonal antibody that results in activation and proliferation of primed CD4 T effector cells. The preliminary efficacy of vopratelimab +/- nivolumab was assessed in the phase 1/2 ICONIC study in which durable responses were observed in a subset of patients who demonstrated on treatment emergence of peripheral ICOS hi CD4 T effector cells. Patients with peripheral ICOS hi CD4 T cells achieved significantly greater clinical benefit than patients whose CD4 T cells remained ICOS lo. An RNA based tumor inflammation signature (TIS) comprised of 18 genes associated with immune cell infiltration was previously identified as a predictive biomarker of response to anti-PD-1 therapy (Ayers et al, 2017); it was also associated with ICOS hi CD4 T cell emergence in ICONIC (ASCO-SITC 2020). The pre-treatment tumor TIS score, coupled with a specific threshold established by Jounce, referred to as TISvopra, was predictive of ICOS hi CD4 T cell emergence. TISvopra positive patients had improved RECIST response, PFS, and OS compared to those with a TISvopra negative score. Therefore, we hypothesize that patient selection by TISvopra will identify those who will display emergence of ICOS hi CD4 T cell populations and importantly, improved clinical outcomes when treated with vopratelimab in combination with JTX-4014 (a novel PD-1 inhibitor in development by Jounce) vs JTX-4014 alone. Methods: This Phase 2 open-label multicenter study is investigating JTX-4014 alone and in combination with vopratelimab in TISvopra selected patients with metastatic NSCLC after one prior platinum-containing regimen (NCT04549025). Patients must be PD-1/L1 inhibitor naïve and negative for activating EGFR mutations. TISvopra eligibility is determined using RNA isolated from a tumor sample. Eligible patients will be randomized to receive either JTX-4014 as monotherapy or in combination with one of two dose levels of vopratelimab. The primary endpoint is mean percent change from baseline tumor size of all measurable existing and new lesions averaged over 9 and 18 weeks. Secondary endpoints include ORR and PFS according to RECIST v1.1, OS, safety, and association of baseline TIS score with clinical outcomes. The study has a target enrollment goal of approximately 75 patients; the first patient was dosed October 2020. Clinical trial information: NCT04549025.

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