Abstract P5-16-02: Updated efficacy, safety and translational data from MARIO-3, a phase II open-label study evaluating a novel triplet combination of eganelisib (IPI-549), atezolizumab (atezo), and nab-paclitaxel (nab-pac) as first-line (1L) therapy for locally advanced or metastatic triple-negative breast cancer (TNBC)
Authors: Hatem Soliman , Hargis Jeffrey , Elias Anthony , Lee Arielle , Swart Rachel , Dahkil Shaker , Drakaki Alexandra , Phan Vu , Kass Frederic , Cobleigh Melody , Babu Sanil , Tkaczuk Katherine , O'Connell Brenda , Roberts Jennifer , Zizlsperger Nora , Hamilton Erika 
Published: March 2022

Abstract
Background: Eganelisib is a first-in-class, oral, immuno-oncology macrophage reprogramming agent. The IMpassion130 randomized trial in 1L advanced TNBC has demonstrated improved efficacy with the addition of atezo to nab-pac in patients with PD-L1+ tumors. Adding eganelisib to the approved doublet of atezo and nab-pac is expected to improve patient benefit regardless of PD-L1 status. Methods: Eligible patients (pts) had measurable unresectable locally advanced or metastatic TNBC and no prior systemic therapy for advanced disease. A safety run-in assessed the safety of the triplet of oral eganelisib 30 mg daily in combination with IV nab-pac 100 mg/m2 given on days 1, 8, & 15, and IV atezo 840 mg given on days 1 & 15 of a 28 day cycle. After establishing tolerability and confirmation of the 30 mg dose in the safety run-in (n=6), the expansion phase of the phase II study was initiated to enroll approximately 60 pts (30 PD-L1+ and 30 PD-L1-). Cycles are repeated until loss of clinical benefit, unacceptable toxicity or consent withdrawal. The primary efficacy endpoint is confirmed complete response (CR) rate per RECIST v1.1. Secondary endpoints include the overall response rate (ORR), progression free survival and safety assessment. Results: As of 6/26/2021, data from the safety run-in and the expansion cohorts are reported for 43 pts evaluable for safety and 38 evaluable for efficacy defined as having at least one post-baseline tumor assessment. 2 CRs (2/38), 19 PRs (19/38), and 11 SDs (11/38) were observed with an ORR of 55.3% (21/38) and a disease control rate (DCR) of 84.2% (32/38). Responses were seen irrespective of PD-L1 status; in PD-L1+ pts, ORR is 66.7% (8/12) and DCR is 91.7% (11/12), and in PD-L1- pts, ORR is 47.8% (11/23) and DCR is 78.3% (18/23). The most common all-grade adverse events were nausea (51.2%), fatigue (48.8%), alopecia (32.6%), diarrhea (32.6%), rash maculo-papular (30.2%), ALT increased (27.9%), and AST increased (25.6%). The most common grade ≥3 adverse events were ALT increased (18.6%), AST increased (14.0%), neutrophil count decreased (9.3%) and rash maculo-papular (9.3%). The safety profile is acceptable and in line with expectations of component drugs with no additive or new safety signals. Translational data from paired biopsies show a shift in tumor associated macrophages towards an immune activated state as well as an increase in cytotoxic T cells. In addition, a subset of tumors with baseline PD-L1 negative status show conversion to PD-L1 positive status post treatment. Consistent with immune activation, increased interferon gamma signature, increased proinflammatory cytokines and T cell invigoration were observed in peripheral blood cells. Conclusions: The novel triplet regimen of eganelisib, atezo, and nab-pac shows promising anti-tumor activity (ORR 55.3% and DCR 84.2%) irrespective of PD-L1 status and has manageable toxicity. . Translational data from paired biopsies and peripheral blood show evidence of immune activation regardless of PD-L1 status as well as conversion from PD-L1 negative to PD-L1 positive subtype within a subset of patients treated with the triplet regimen. The expansion phase of the phase II study is currently enrolling. At the time of presentation, we will have updated efficacy, safety and translational data.
Citation Format: Soliman Hatem, Jeffrey Hargis, Anthony Elias, Arielle Lee, Rachel Swart, Shaker Dahkil, Alexandra Drakaki, Vu Phan, Frederic Kass, Melody Cobleigh, Sanil Babu, Katherine Tkaczuk, Brenda O'Connell, Jennifer Roberts, Nora Zizlsperger, Erika Hamilton. Updated efficacy, safety and translational data from MARIO-3, a phase II open-label study evaluating a novel triplet combination of eganelisib (IPI-549), atezolizumab (atezo), and nab-paclitaxel (nab-pac) as first-line (1L) therapy for locally advanced or metastatic triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-16-02.