Paclitaxel plus Eftilagimod Alpha, a Soluble LAG-3 Protein, in Metastatic, HR+ Breast Cancer: Results from AIPAC, a Randomized, Placebo Controlled Phase IIb Trial

Abstract

Purpose: Eftilagimod alpha (efti), a soluble lymphocyte activation gene (LAG-3) protein and MHC class II agonist, enhances innate and adaptive immunity. Active Immunotherapy PAClitaxel (AIPAC) evaluated safety and efficacy of efti plus paclitaxel in patients with predominantly endocrine-resistant, hormone receptor-positive, HER2-negative metastatic breast cancer (ET-resistant HR+ HER2- MBC).

Patients and methods: Women with HR+ HER2- MBC were randomized 1:1 to weekly intravenous paclitaxel (80 mg/m2) and subcutaneous efti (30 mg) or placebo every 2 weeks for six 4-week cycles, then monthly subcutaneous efti (30 mg) or placebo maintenance. Primary endpoint was progression-free survival (PFS) by blinded independent central review. Secondary endpoints included overall survival (OS), safety/tolerability, pharmacokinetics/pharmacodynamics, and quality of life. Exploratory endpoints included cellular biomarkers.

Results: 114 patients received efti and 112 patients received placebo. Median age was 60 years (91.6% visceral disease, 84.1% ET-resistant, 44.2% with previous CDK4/6 inhibitor treatment). Median PFS at 7.3 months was similar for efti and placebo. Median OS was not significantly improved for efti (20.4 vs. 17.5 months; HR, 0.88; P = 0.197) but became significant for predefined exploratory subgroups. EORTC QLQC30-B23 global health status was sustained for efti but deteriorated for placebo. Efti increased absolute lymphocyte, monocyte and secondary target cell (CD4, CD8) counts, plasma IFNγ and CXCL10 levels.

Conclusions: Although the primary endpoint, PFS, was not met, AIPAC confirmed expected pharmacodynamic effects and demonstrated excellent safety profile for efti. OS was not significantly improved globally (2.9-month difference), but was significantly improved in exploratory biomarker subgroups, warranting further studies to clarify efti's role in patients with ET-resistant HER2- MBC.

Figure 1.

A, PFS by BICR and (B) OS in the efficacy evaluable population by treatment arm.

Figure 2.

Treatment effect by subgroup (A) PFS by BICR. B, OS.

Figure 3.

A, Mean of peripheral blood CD8⁺ T-cell count over time from randomization stage immuno-monitoring subject subset and (B) observed correlation between CD8⁺ T-cell count at baseline, 3 and 6 months and OS among patients in the 30 mg efti plus paclitaxel and placebo plus paclitaxel treatment arms. C, Mean change from baseline in ALC over time by OS status and treatment arm in randomization stage. Timepoints with ≥ 8 patients per subgroup are displayed. D and E, Kaplan–Meier plot of OS of subgroup of efti (D) and placebo (E) treatment arms by ALC change from baseline (cutoff = 0.2×10⁹/L of blood within 9 weeks of treatment). Median OS = 18.2 months. * indicates significant (P < 0.05) difference between treatment arms (black) and between OS status in eftilagimod arm (red).