Eganelisib, a First-in-Class PI3K-γ Inhibitor, in Patients with Advanced Solid Tumors: Results of the Phase 1/1b MARIO-1 Trial
David S Hong 1, Michael Postow 2, Bartosz Chmielowski 3, Ryan Sullivan 4, Amita Patnaik 5, Ezra E W Cohen 6, Geoffrey Shapiro 7, Conor Steuer 8, Martin Gutierrez 9, Heather Yeckes-Rodin 10, Robert Ilaria 11, Brenda O’Connell 12, Joanna Peng 12, Guangbin Peng 13, Nora Zizlsperger 12, Anthony Tolcher 14, Jedd D Wolchok 2

Purpose: Eganelisib (IPI-549) is really a first-in-class, orally administered, highly selective phosphoinositide-3-kinase (PI3K)-|? inhibitor with anti-tumor activity alone and in conjunction with programmed cell dying 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 security and tolerability of once-daily eganelisib as monotherapy and in conjunction with nivolumab in patients with solid tumors.

Patients and techniques: Dose-escalation cohorts received eganelisib 10-60 mg as monotherapy (n=39) and 20-40 mg when coupled with nivolumab (n=180). Primary endpoints incorporated incidence of dose-restricting toxicities (DLTs) and adverse occasions (AEs).

Results: The most typical treatment-related grade ?Y3 toxicities with monotherapy were elevated alanine aminotransferase (ALT 18%), aspartate aminotransferase (AST 18%), and alkaline phosphatase (5%). No DLTs happened within the first 4 weeks however, toxicities meeting DLT criteria (mostly grade 3 reversible hepatic enzyme elevations) happened with eganelisib 60 mg in later treatment cycles. Together, the most typical treatment-related grade ?Y3 toxicities were elevated AST (13%) and elevated ALT and rash (10%). Treatment-related serious adverse occasions happened in fivePercent of monotherapy patients (grade 4 bilirubin and hepatic enzyme increases in a single patient each) and 13% together (pyrexia, rash, cytokine release syndrome, and infusion-related reaction in ?Y2 patients each). Anti-tumor activity was noticed in combination, including patients who’d progressed on PD-1/PD-L1 inhibitors.

Conclusions: In line with the observed safety profile, eganelisib doses of 30 mg and 40 mg once daily in conjunction with PD-1/PD-L1 inhibitors were selected for phase 2 study.