Eganelisib combined with immune checkpoint inhibitor therapy and chemotherapy in frontline metastatic triple-negative breast cancer triggers macrophage reprogramming, immune activation and extracellular matrix reorganization in the tumor microenvironment.

Background: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a poor prognosis particularly in the metastatic setting. Treatments with anti-programmed cell death protein-1/programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors (ICI) in combination with chemotherapies have demonstrated promising clinical benefit in metastatic TNBC (mTNBC) but there is still an unmet need, particularly for patients with PD-L1 negative tumors. Mechanisms of resistance to ICIs in mTNBC include the presence of immunosuppressive tumor-associated macrophages (TAMs) in the tumor microenvironment (TME). Eganelisib is a potent and selective, small molecule PI3K-γ inhibitor that was shown in preclinical studies to reshape the TME by reducing myeloid cell recruitment to tumors and reprogramming TAMs from an immune-suppressive to an immune-activating phenotype and enhancing activity of ICIs. These studies provided rationale for the clinical evaluation of eganelisib in combination with the anti-PD-L1 atezolizumab and nab-paclitaxel in firstline mTNBC in the phase 2 clinical trial MAcrophage Reprogramming in Immuno-Oncology-3 (MARIO-3, NCT03961698). We present here for the first time, in-depth translational analyses from the MARIO-3 study and supplemental data from eganelisib monotherapy Ph1/b study in solid tumors (MARIO-1, NCT02637531).
Methods: Paired pre-treatment and post-treatment tumor biopsies were analyzed for immunophenotyping by multiplex immunofluorescence (n=11), spatial transcriptomics using GeoMx digital spatial profiling (n=12), and PD-L1 immunohistochemistry, (n=18). Peripheral blood samples were analyzed using flow cytometry and multiplex cytokine analysis.
Results: Results from paired tumor biopsies from MARIO-3 revealed gene signatures of TAM reprogramming, immune activation and extracellular matrix (ECM) reorganization. Analysis of PD-L1 negative tumors revealed elevated ECM gene signatures at baseline that decreased after treatment. Gene signatures of immune activation were observed regardless of baseline PD-L1 status and occurred in patients having longer progression-free survival. Peripheral blood analyses revealed systemic immune activation.
Conclusions: This is the first report of translational analyses including paired tumor biopsies from a phase 2 clinical study of the first-in-class PI3K-γ inhibitor eganelisib in combination with atezolizumab and nab-paclitaxel in frontline mTNBC. These results support the mechanism of action of eganelisib as a TAM-reprogramming immunotherapy and support the rationale for combining eganelisib with ICI and chemotherapy in indications with TAM-driven resistance to ICI.
Competing Interests: Competing interests: BCO, RI, CH, NZ, JLK and SP were employees, stockholders and consultant advisors for Infinity Pharmaceuticals. DF was an employee and stockholder of Infinity Pharmaceuticals. BCO is an inventor for PCT International, application number 18/265915 filed on June 7, 2023. AE was issued the following grants: NCI LAPS, DOD CTRA, DOD Clinical Extension Grant. MAC received royalties from Exact Science (formerly Genomic Health) for contribution to invention of Oncotype DX assay and participated in a safety monitoring board for Advarra. DJ received grants from Novartis, Genentech, Syros, Eisai, Pfizer, Takeda, Amgen, InventisBio, Arinas, Blueprint, AstraZeneca, and Ribon Therapeutics as well as personal fees from Vibliome, PIC therapeutics, MapKure, and Relay Therapeutics. JV was a consultant advisor for Infinity Pharmaceuticals and received grants, reagents, and tissue material for preclinical work and biomarker studies related to MARIO-1 study NCT02637531 from Infinity Pharmaceuticals. EH is a consultant advisor for Accutar Biotechnology, AstraZeneca, Daiichi Sankyo, Entos, Fosun Pharma, Gilead Sciences, Greenwich LifeSciences, Jazz Pharmaceuticals, Eli Lilly, Medical Pharma Services, Mersana, Novartis, Olema Pharmaceuticals, Orum Therapeutics, Pfizer, Roche Genentech, Stemline Therapeutics, Theratechnologies, Tubulis, Verascity Science and Zentalis Pharmaceuticals and is an investigator on multiple clinical trials including Infinity Pharmaceuticals study NCT03961698. HS is a consultant for Novartis, AstraZeneca, Seattle Genetics, Puma, Eli Lilly, and received payment from Merck for a speaking engagement. MAC, DJ, KHRT, AE, AL, SD, EH, and HS were investigators on Infinity Pharmaceuticals clinical trial NCT 03961698.
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