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.

Abstract

436 Background: Inhibition of the PD-1 pathway has demonstrated clinical benefit in metastatic urothelial carcinoma (mUC); however, response rates of 15% to 29% highlight the need for more effective therapies, especially for PD-L1- patients. Eganelisib is a first-in-class, novel, oral agent which selectively inhibits PI3K-γ, with the goal of improving the immune response to checkpoint inhibitors (CPI). Methods: Eligible patients (pts) with mUC who progressed on > 1 platinum-based chemotherapy regimen and were CPI naïve were enrolled. Pts were randomized 2:1 to receive eganelisib in combination with nivolumab (EN) or placebo with nivolumab (PN). Pts were stratified by baseline circulating monocytic myeloid derived suppressor cells (mMDSC) level. The primary endpoint was objective response rate (ORR) per RECIST v1.1 in pts with high baseline mMDSC levels. Other endpoints included ORR, progression free survival (PFS) and overall survival (OS) in all pts and PD-L1 +/- pts. Results: We report preliminary data (as of 9/1/2020) for the first 49 pts with 33 randomized to receive EN and 16 PN. Preliminary ORR/PFS is presented in the table below. Except for the mMDSC high subgroup, ORR and PFS were improved in the EN arm compared to the PN arm. The duration of exposure was a median of 15 weeks for EN and 11 for PN. Most common all-Gr AEs (EN vs PN %) were pyrexia (33 vs 0), decreased appetite (30 vs 19), pruritis (24 vs 6), rash (24 vs 6), asthenia (21 vs 31), and transaminase elevation (21 vs 6). Most common Gr≥3 AEs (EN vs PN %) include hepatotoxicity (15 vs 0), transaminase elevation (12 vs 6), and rash (9 vs 0). Following an early safety review, eganelisib dose was reduced from 40 to 30 mg, resulting in a reduction of hepatic AEs. Conclusions: Preliminary data demonstrates that the combination of eganelisib, once reduced to 30 mg, and nivolumab was well tolerated with hepatic and skin-related toxicities more common in the EN arm. When compared to PN, the combination demonstrated an improved ORR and PFS, especially in the PD-L1- subset. Updated efficacy, including PFS and OS, safety and translational data will be presented. Clinical trial information: NCT03980041 . [Table: see text]

Molecular Targeting of the Phosphoinositide-3-Protein Kinase (PI3K) Pathway across Various Cancers

“…Eganelisib (IPI 549) is a first-in-class, selective oral PI3Kγ inhibitor that has shown antitumor activity alone or in combination with programmed cell death protein 1/ligand 1 (PD-1/PD-L1) inhibitors in preclinical studies [165]. PI3K inhibition can cause a reduction in the number of regulating T (T reg) cells, intra-tumoral infiltration of CD4+ and CD8+ T cells, and the production of immunostimulatory cytokines in the tumor microenvironment, thus stimulating anticancer immunity [166].…”

Emerging strategies in targeting tumor-resident myeloid cells for cancer immunotherapy

“…Finally, translational biopsy data documented increased PD-L1 expression at 2 months post-treatment, resulting in 5 out of 8 sampled PD-L1-negative tumors and surrounding immune cells converting to a PD-L1 positive status. Additional eganelisib trials remain underway, including MARIO-275, a phase II trial comparing nivolumab monotherapy to combination therapy in urothelial cancer, with initial data reporting an ORR of 30.3% (10/33) in the experimental arm versus 25% (4/16) with nivolumab alone and no notable difference in mPFS between arms at this time (9.1 vs. 8.0 months, HR 0.79, 95% CI 0.39–1.60) [ 269 ].…”

Targeted Therapies in Advanced and Metastatic Urothelial Carcinoma

“…Because of the effect on the immune response, eganelisib is designed to increase the efficacy of nivolumab. Notably PD-L1+ patients demonstrated an ORR of 80%, although this was in a small subset of five patients [ 31 ]. Eganelisib is currently FDA approved for the treatment of triple negative breast cancer.…”