The combination of eganelisib and nivolumab demonstrated promising activity and was well tolerated in a phase 2 trial of patients with advanced urothelial cancer.
The combination of the PI3K-gamma inhibitor eganelisib (IPI-549) and the PD-1 inhibitor nivolumab (Opdivo) was well tolerated and showed promising efficacy in patients with advanced, metastatic urothelial cancer enrolled in the phase 2 MARIO-275 trial.1
The phase 2 trial randomized patients with platinum-refractory, immunotherapy-naïve disease to nivolumab plus either eganelisib or placebo. Infinity Pharmaceuticals, Inc., the manufacturer of eganelisib, reported in a press release that the data from MARIO-275 will be shared at an upcoming medical conference. The tolerability and activity updates in the press release were based on the first 49 patients enrolled in the study.
"The MARIO-275 study provided Infinity with important insights to shape the future of eganelisib in urothelial cancer," Adelene Perkins, chief executive officer and chair, Infinity, stated in the press release. "The data from the 49 patients enrolled in the study are very encouraging. The combination was well tolerated at the 30 mg dose of eganelisib and provided patient benefit relative to the placebo controlled arm on important response rate and progression free survival measures, particularly in urothelial cancer patients with low levels of PD-L1 expression who respond poorly to checkpoint inhibitors alone.
We are leveraging the clinical and translational learnings from MARIO-275 in planning a new, registration-enabling study of eganelisib in patients with advanced urothelial cancer. We look forward to presenting our data from MARIO-275, which support our clinical strategy, at a major medical meeting in Q1 2021, with details for our new, planned trial to follow in the coming months after discussions with regulatory authorities."
Overall, the global phase 2 MARIO-275 trial (NCT03980041) is randomizing patients with advanced urothelial carcinoma in a 2:1 ratio to eganelisib /nivolumab or placebo/nivolumab. Prior immune checkpoint-inhibitor therapy is not allowed and patients must have progressed or recurred following treatment with platinum-based chemotherapy. The targeted enrollment for the study is 160 patients. The primary end point is objective response rate, with secondary end points including time to response, duration of response, and progression-free survival.
In the March 2020, the FDA granted a Fast Track Designation to eganelisib for use in combination with nivolumab (Opdivo) for the treatment of patients with advanced urothelial cancer. The designation is intended to expedite the development and review of eganelisib in this setting.
Data from a phase I/Ib trial (NCT02637531) of eganelisib plus nivolumab in solid tumors were presented at the 2018 ASCO Annual meeting.2 The study included 30 evaluable patients with advanced solid tumors. The median age was 57 years and the median number of prior therapies was 4.
In a 6+6 design, patients were administered eganelisib at 20-, 30-, or 40-mg daily in combination with nivolumab at 240 mg every 2 weeks. The maximum-tolerated dose was not reached. The investigators reported that the pharmacokinetics and pharmacodynamics of eganelisib were not affected by nivolumab.
Partial responses were observed in 2 patients at the first assessment, which occurred 8 weeks after treatment. One occurred in a patient with adrenocortical carcinoma who received a 30-mg dose of eganelisib. The other occurred in a patient with microsatellite-stable gallbladder carcinoma who was treated with the 40-mg dose. Twelve (40%) patients were still on study at ≥12 weeks’ follow-up.
The majority of treatment-emergent adverse events (TEAEs) were grade 1/2. The most common TEAEs across all grades were rash (23%); pruritus (10%); and nausea, anemia, ALT increase, AST increase, and pyrexia (6% each). Dose-limiting toxicities occurred at eganelisib 30 mg (grade 3 rash) and eganelisib 40 mg (grade 3 rash; grade 3 ALT/AST increase). There were no treatment-related deaths.
1. Infinity Pharmaceuticals Provides Update for Eganelisib in Patients with Metastatic Urothelial Cancer. Posted online January 6, 2021. https://yhoo.it/3bfXjqw. Accessed January 6, 2021.2. Sullivan RJ, Hong DS, Tolcher AW, et al. J Clin Oncol 36, 2018 (suppl; abstr 3013) doi: 10.1200/JCO.2018.36.15_suppl.3013.