Response rates in patients with metastatic urothelial carcinoma were boosted when the novel PI3K-y inhibitor eganelisib was added to nivolumab, according to recent research presented during the American Society of Clinical Oncology 2021 Genitourinary Cancers Symposium.
Response rates in patients with metastatic urothelial carcinoma (mUC) were boosted when the novel PI3K-y inhibitor eganelisib (IPI 549) was added to nivolumab (Opdivo), according to recent research presented during the American Society of Clinical Oncology (ASCO) 2021 Genitourinary Cancers Symposium.
“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%,” said study author Piotr Tomczak, of the Poznan University of Medical Sciences in Poznan, Poland.
The phase II 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 cell (mMDSC) levels and randomized 2:1 to receive eganelisib plus nivolumab or placebo plus nivolumab.
Objective response rate (ORR) per RECIST v1.1 in patients with high baseline mMDSC levels (≥22.3) was the primary end point, and researchers also examined overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).
Duration of exposure was a median of 15 weeks for patients treated with – and 11 weeks for the placebo arm.
While no mMDSC-high patients responded to treatment with eganelisib, there was a higher response rate in the overall population treated with the combination regimen, compared to placebo ([30.3%; 95% CI, 16-9] vs [25%; 95% CI, 7-52], respectively). Additionally, there was a 38.5% ORR in mMDSC-low patients who received eganelisib (95% CI, 20-59), compared to 23.1% in the mMDSC-low patients who received placebo (95% CI, 5-54).
There were 5 PD-L1–positive patients (TPS >1%) in the combination treatment group, of which 4 (80%) responded to the addition of eganelisib to nivolumab (95% CI, 28-100), compared to 2 of 4 (50%) in the placebo group (95% CI, 7-93). In PD-L1–negative patients (TPS <1%) 6 out of 23 patients (26.1%) responded to to the combination regimen (95% CI, 10-48), versus 1 of 7 (14.3%) in the placebo group (95% CI, 0-58).
“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.
When it came to PFS, 9.1% of patients responded on the combination therapy, compared to 8% on the placebo arm.
Common all-grade adverse events (AEs) in the eganelisib and placebo arms were pyrexia (33% vs 0%, respectively), decreased appetite (30% vs 19%), 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% vs 0%, respectively), transaminase elevation (12% vs 6%), 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. Presented at: 2021 Genitourinary Cancers Symposium; February 11-13, 2021; Virtual. Abstract 436.