Response to Nivolumab in Metastatic Urothelial Cancer Is Enhanced by Eganelisib

February 11, 2021
Brielle Benyon

High response rates with novel eganelisib plus PD-1 inhibition is reported in patients with metastatic urothelial carcinoma, especially those with low PD-L1 expression.

Eganelisib (IPI 549), a novel PI3K-y inhibitor, induced promising response rates when added to nivolumab (Opdivo) for the treatment of patients with metastatic urothelial carcinoma (mUC), according to results of a phase 2 trial.

“PD-1 inhibitors have demonstrated clinical benefit in metastatic urothelial carcinoma. However, clinical benefit remains low, particularly in PD-L1—low patients, who have [an average] overall response rate of only 16%,” study author Piotr Tomczak, of the Poznan University of Medical Sciences in Poznan, Poland, said in a presentation at the 2021 Genitourinary Cancers Symposium where the data were read out.

The MARIO-275 study (NCT03980041) included 49 patients with mUC who progressed on 1 or more platinum-based chemotherapy regimens and had no prior treatment with a checkpoint inhibitor. Study participants were stratified by baseline circulating monocytic myeloid suppressor cells (mMDSC) levels and randomized 2:1 to receive eganelisib plus nivolumab (EN) or placebo plus nivolumab (PN).

Objective response rate (ORR) per RECIST v1.1 in patients with high baseline mMDSC levels (22.3) was the primary endpoint, and the investigators also examined overall ORR, progression-free survival (PFS), and overall survival.

Duration of exposure was a median of 15 weeks for patients treated with EN and 11 weeks for the placebo arm.

While no mMDSC-high patients responded to EN treatment, there was a higher response rate in the overall population with EN (30.3%; 95% CI, 16%-9%) compared with PN (25%; 95% CI, 7%-52%). Additionally, there was a 38.5% (95% CI, 20%-59%) ORR in mMDSC-low patients who received EN versus 23.1% in the mMDSC-low patients (95% CI, 5%-54%).

There were 5 PD-L1–positive patients (tumor proportion score [TPS] >1%) in the EN group, 4 (80%) of whom responded to EN therapy (95% CI, 28%-100%) compared with 2 of 4 (50%; 95% CI, 7%-93%) in the placebo group who responded. In PD-L1–negative patients (TPS <1%), 6 out of 23 patients (26.1%; 95% CI, 10%-48%) responded to EN versus 1 of 7 (14.3%; 95% CI, 0%-58%) in the PN group.

“The combination demonstrated improved ORR, disease control rates, and PFS when compared to the control, especially in the PD-L1–negative patients, who represent approximately 70% of the patient population,” Tomczak said.

The median PFS was 9.1 months in the EN therapy group versus 7.9 months with PN, with a hazard ratio of 0.54.

Common all-grade adverse events (AEs) were pyrexia (33% with EN vs 0% with PN), decreased appetite (30% vs 19%, respectively), pruitis (24% vs 6%), asthenia (21% vs 31%), and transaminase elevation (21% vs 6%).

The most common grade 3 or higher AEs were hepatotoxicity (15% in EN vs 0% in PN), transaminase elevation (12% vs 6%, respectively), and rash (9% vs 0%). After a safety review, the eganelisib dose was reduced from 40 mg to 30 mg, which lowered the rate of hepatic AEs.

“Importantly, nivolumab monotherapy in the control arm of MARIO-275 demonstrated clinical activity consistent with monotherapy with nivolumab in CheckMate-275, further adding to our confidence in interpreting the contribution of eganelisib [with] nivolumab in the controlled study,” Tomczak said.

Based on these findings, a larger study is being planned in the future to further evaluate eganelisib in PD-L1–low patients.

“Given the magnitude of unmet need in the PD-L1—low patient [population], Infinity is planning a registration and labeling study exploring the potential benefit of eganelisib for PD-L1—low patients, more broadly in other indications,” Tomczak said.


Tomczak T, Popovic L, Barthelemy P, et al. Preliminary analysis of a phase II, multicenter, randomized, active-control study to evaluate the efficacy and safety of eganelisib (IPI 549) in combination with nivolumab compared to nivolumab monotherapy in patients with advanced urothelial carcinoma. J Clin Oncol. 2020;39(suppl 6):436