Eganelisib, a First-in-Class PI3K-γ 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 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.

Patients and methods: 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).

Results: 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.

Conclusions: 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.

 

Comments:

The purpose of the study you mentioned, called the MAcrophage Reprogramming in Immuno-Oncology-1 (MARIO-1; NCT02637531) study, was to evaluate the safety and tolerability of eganelisib (IPI-549) as a monotherapy and in combination with nivolumab in patients with solid tumors. Eganelisib is a first-in-class, orally administered, highly selective phosphoinositide-3-kinase (PI3K)-γ inhibitor with anti-tumor activity. PD-1/PD-L1 inhibitors are a type of immunotherapy used in cancer treatment.

The study included dose-escalation cohorts in which patients received different doses of eganelisib. The monotherapy group consisted of 39 patients who received eganelisib alone at doses ranging from 10 to 60 mg. The combination group included 180 patients who received eganelisib at doses of 20 to 40 mg in combination with nivolumab.

The primary endpoints of the study were the incidence of dose-limiting toxicities (DLTs) and adverse events (AEs). DLTs refer to severe side effects that limit the ability to increase the dose of the drug. The results showed that no DLTs occurred in the first 28 days of the study. However, in later treatment cycles, toxicities meeting DLT criteria, mainly grade 3 reversible hepatic enzyme elevations, were observed with the highest dose of eganelisib (60 mg).

The most common treatment-related grade ≥3 toxicities observed with eganelisib monotherapy were increased levels of liver enzymes, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST), as well as alkaline phosphatase. In the combination group, the most common treatment-related grade ≥3 toxicities were increased AST, increased ALT, and rash.

Treatment-related serious adverse events occurred in 5% of patients receiving eganelisib monotherapy and 13% of patients receiving the combination. These events included grade 4 bilirubin and hepatic enzyme increases in the monotherapy group, and pyrexia (fever), rash, cytokine release syndrome, and infusion-related reaction in the combination group.

Despite the observed toxicities, anti-tumor activity was observed in the combination group, including patients who had previously progressed on PD-1/PD-L1 inhibitors.

Based on the safety profile observed in the study, the doses of eganelisib chosen for further investigation in the phase 2 study were 30 mg and 40 mg once daily in combination with PD-1/PD-L1 inhibitors.

Related Products

Cat.No.	Product Name	Information
S8330	Eganelisib (IPI-549)	Eganelisib (IPI-549) is a potent inhibitor of PI3K-γ with >100-fold selectivity over other lipid and protein kinases. The biochemical IC50 for PI3K-γ is 16 nM.

Related Targets

PI3K