Eganelisib, a First-in-Class PI3Kg Inhibitor, in Patients with Advanced Solid Tumors: Results of the Phase 1/1b MARIO-1 Trial

Purpose: Eganelisib (IPI-549) is a first-in-class, orally adminis-tered, highly selective PI3Ky inhibitor with antitumor 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-Oncol-ogy-1 (NCT02637531) study evaluated the safety and tolerability of once-daily eganelisib as monotherapy and in combination with nivolumab in patients with solid tumors. Patients and Methods: Dose-escalation cohorts received egane-lisib 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 (DLT) and adverse events (AE). Results: The most common treatment-related grade >= 3 toxi-cities 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 revers-ible hepatic enzyme elevations) occurred with eganelisib 60 mg in later treatment cycles. In combination, the most common treat-ment-related grade >= 3 toxicities were increased AST (13%) and increased ALT and rash (10%). Treatment-related serious AEs 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). Antitumor activity was observed in combination, including patients who had pro-gressed on PD-1/PD-L1 inhibitors. Conclusions: On the basis of the observed safety profile, ega-nelisib doses of 30 and 40 mg once daily in combination with PD-1/ PD-L1 inhibitors were chosen for phase 2 study.