Initial results from first-in-human study of IPI-549, a tumor macrophage-targeting agent, combined with nivolumab in advanced solid tumors.

3013 Background: IPI-549 is a potential first-in-class, oral, selective PI3K-γ inhibitor that in preclinical studies reprograms macrophages from an immune-suppressive to an immune-activating phenotype and can overcome resistance to checkpoint inhibitors. Methods: Ph 1/1b study IPI-549-01 (NCT02637531) is evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunomodulatory activity of IPI-549 to determine its recommended Ph 2 dose (RP2D) and preliminary efficacy, as monotherapy and combined with nivolumab (nivo), in advanced solid tumor pts. Pre- and on-treatment blood samples were obtained for flow cytometry, gene expression, and serum analysis. Results: Initial combination dose-escalation results are reported. 31 pts (30 evaluable), median age 57 yrs and median 4 prior therapies (8 with prior anti PD-(L)1 therapy), received IPI-549 20, 30, and 40 mg QD + nivo 240 mg Q2W in a 6+6 design. IPI-549 PK/PD were unaffected by nivo. The MTD was not reached. Most treatment-emergent adverse events (TEAEs) were Gr 1-2. The most common (≥ 2 pts) treatment-related TEAEs included rash (23%); pruritus (10%); and nausea, anemia, ALT increase, AST increase, and pyrexia (6% each), with no treatment-related deaths. 2 DLTs each occurred at IPI-549 30 mg (Gr 3 rash) and 40 mg QD (Gr 3 rash; Gr 3 ALT/AST increase). 2 pts demonstrated partial responses at first assessment (8 wks): 1 with adrenocortical carcinoma and 1 with microsatellite-stable gallbladder carcinoma receiving IPI-549 30 and 40 mg QD, respectively. 40% of pts (n = 12) remained on study ≥ 12 wks and 6 pts were ongoing at the 05 Feb data cutoff. Based on safety + PK/PD data, the RP2D was IPI-549 40 mg QD + nivo 240 mg Q2W. On-treatment blood samples show evidence of immune activation and reduced immune suppression, including upregulation of IFNg-responsive factors, such as PD-L1 and CXCL9/10, and dose-dependent re-invigoration/proliferation of exhausted PD1+CD8+CD45RA- T cells, evidenced by Ki67 increases. Conclusions: IPI-549 + nivo demonstrates favorable tolerability, early signs of clinical activity, and evidence of immune modulation. Combination expansion cohorts are enrolling at the RP2D. Clinical trial information: NCT02637531.