Eganelisib（IPI-549）是一种口服高度选择性磷脂酰肌醇-3-激酶（PI3K）-γ抑制剂，在临床前研究中具有单独和与程序性细胞死亡蛋白1/配体1（PD-1 / PD-L1）抑制剂联用的抗肿瘤活性。该1 / 1b人用初步研究MAcrophage Reprogramming in Immuno-Oncology-1（MARIO-1; NCT02637531）评估了一次日常口服eganelisib单药和与尼伏单抗联用时对固体肿瘤患者的安全性和耐受性。剂量逐步增加队列接受eganelisib 10-60 mg单药治疗（n = 39）和20-40 mg联用尼伏单抗治疗（n = 180）。主要终点包括剂量限制性毒性（DLTs）和不良事件（AE）的发生率。单药治疗的最常见相关级别≥3的毒性是丙氨酸氨基转移酶（ALT;18％），天门冬氨酸氨基转移酶（AST;18％）和碱性磷酸酶（5％）增加。前28天内没有发生DLTs;然而，晚期治疗周期中，eganelisib 60 mg出现符合DLT标准的毒性（大多数是3级可逆性肝酶升高）。在联用时，最常见的相关级别≥3的毒性是AST升高（13％）和ALT和皮疹增加（10％）。单药治疗患者出现与治疗相关的严重不良事件的发生率为5％（一个患者分别出现4级胆红素和肝酶升高），联用组为13％（pyrexia，皮疹，细胞因子释放综合征和输注相关反应，每个≥2个患者）。联用中观察到了抗肿瘤活性，包括已经在PD-1 / PD-L1抑制剂上进展的患者。根据观察到的安全性资料，选择一天一次与PD-1 / PD-L1抑制剂联用的eganelisib剂量为30mg和40mg进行第2阶段研究。

Eganelisib (IPI-549) is a first-in-class, orally administered, highly selective phosphoinositide-3-kinase (PI3K)-γ inhibitor with anti-tumor activity alone and in combination with programmed cell death protein 1/ligand 1 (PD-1/PD-L1) inhibitors in preclinical studies. This phase 1/1b first-in-human, MAcrophage Reprogramming in Immuno-Oncology-1 (MARIO-1; NCT02637531) study evaluated the safety and tolerability of once-daily eganelisib as monotherapy and in combination with nivolumab in patients with solid tumors.Dose-escalation cohorts received eganelisib 10-60 mg as monotherapy (n=39) and 20-40 mg when combined with nivolumab (n=180). Primary endpoints included incidence of dose-limiting toxicities (DLTs) and adverse events (AEs).The most common treatment-related grade ≥3 toxicities with monotherapy were increased alanine aminotransferase (ALT; 18%), aspartate aminotransferase (AST; 18%), and alkaline phosphatase (5%). No DLTs occurred in the first 28 days; however, toxicities meeting DLT criteria (mostly grade 3 reversible hepatic enzyme elevations) occurred with eganelisib 60 mg in later treatment cycles. In combination, the most common treatment-related grade ≥3 toxicities were increased AST (13%) and increased ALT and rash (10%). Treatment-related serious adverse events occurred in 5% of monotherapy patients (grade 4 bilirubin and hepatic enzyme increases in one patient each) and 13% in combination (pyrexia, rash, cytokine release syndrome, and infusion-related reaction in ≥2 patients each). Anti-tumor activity was observed in combination, including patients who had progressed on PD-1/PD-L1 inhibitors.Based on the observed safety profile, eganelisib doses of 30 mg and 40 mg once daily in combination with PD-1/PD-L1 inhibitors were chosen for phase 2 study.