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.

PURPOSE: The first-in-human phase I/II ICONIC trial evaluated an investigational inducible costimulator (ICOS) agonist, vopratelimab, alone and in combination with nivolumab in patients with advanced solid tumors. PATIENTS AND METHODS: In phase I, patients were treated with escalating doses of intravenous vopratelimab alone or with nivolumab. Primary objectives were safety, tolerability, MTD, and recommended phase II dose (RP2D). Phase II enriched for ICOS-positive (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 I established 0.3 mg/kg every 3 weeks 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-high (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 that 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 II non-small cell lung cancer trial. See related commentary by Lee and Fong, p. 3633.

Specialty trainee-led intensive care unit induction.

BACKGROUND: Junior doctors from varied medical specialties are increasingly undertaking placements in intensive care units (ICUs). They may have minimal previous experience in the provision of advanced organ support, yet may have high levels of clinical responsibility. Traditional ICU induction has been consultant led, and has focused on local procedures and policies. A survey of trainees highlighted low levels of preparedness and confidence at managing advanced organ support, and dissatisfaction with the existing induction format. METHODS: Based on survey feedback and personal experience, a focus group of specialty trainees identified five core topics to be covered in a half-day of interactive lecture-based teaching presentations and a trainee handbook. A systems-based approach to advanced organ support and ICU emergencies was adopted. In cycle 2, formal written pre- and post-induction exams provided a more objective assessment of knowledge. RESULTS: Two cycles of the new induction programme were delivered during consecutive junior doctor intakes, and yielded improved satisfaction and improved self-assessed confidence in routine and emergency management of advanced organ support and in the understanding of the principles of advanced organ support. DISCUSSION: Specialty trainee-led induction may be better tailored to the needs of incoming junior doctors. This study demonstrated increased trainee satisfaction with induction and provided a legacy of teaching opportunity within the department, highlighting the potential for our near-peer model of induction. Safe and effective induction is paramount in the high-stakes ICU environment, but the principles described may also be transferrable to other clinical specialties. Traditional ICU induction has been consultant let, and has focused on local procedures and policies.