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