Primary efficacy results from AIPAC: A double-blinded, placebo controlled, randomized multinational phase IIb trial comparing weekly paclitaxel plus eftilagimod alpha (soluble LAG-3 protein) vs. weekly paclitaxel plus placebo in HR-positive metastatic breast cancer patients

Abstract

Background:Eftilagimod alpha (efti, IMP321),a soluble LAG-3 protein (LAG-3Ig) that binds to a subset of MHC class II molecules, mediates antigen-presenting cell (APC) activation followed by CD8 T-cell activation. AIPAC (Active Immunotherapy PAClitaxel; NCT02614833) investigatedcombinations of the APC activator efti + weekly paclitaxel compared to paclitaxel + placebo in metastatic breast carcinoma (MBC) patients (pts). Methods:The placebo-controlled, double-blinded, 1:1 randomized, multinational, phase IIb trial enrolled pts with measurable disease, hormone receptor-positive (HR+) MBC with indications for first line weekly paclitaxel without indication for HER2/neu targeted therapy. Pts received paclitaxel (80 mg/m² IV at D1, D8, D15 plus efti (30 mg) or placebo at D2, D16 (injected SC every 2 weeks) for 6 cycles (1 cycle = 4 weeks). Maintenance phase followed in which pts benefitting from treatment received efti or placebo for an additional 52 weeks. Primary endpoint was progression-free survival (PFS) (RECIST1.1) determined by blinded independent central read (BICR). Secondary endpoints included local read PFS, RECIST 1.1 tumor response, pharmacodynamic effects, quality of life and overall survival. The study was powered (80 %) to detect 0.667 hazard ratio (HR) based on 5% one-sided alpha and planned to enroll 226 pts. Results: From Jan 2017-Jul 2019, 227 pts were randomized. All except 1 received ≥ 1 treatment and were included in the full analysis set [(efti (n = 114); placebo (n = 112)]. Data cut-off was 10th Jan 2020 with 12 month median follow-up. HR for PFS assessed by BICR was 0.93 [95 % CI 0.67-1.30], p =0.341. In the efti group 63 % (95% CI 52- 71%) were progression free at 6 months compared to 54 % (95% CI 43-63%) in the placebo group. ORR was 48.3 % in the efti group compared to 38.4 % in the placebo group as assessed by BICR (p=0.118). Efti increased numbers of PBMCs and T cells (CD4 and CD8) significantly compared to placebo. In predefined subgroups such as pts with low monocytes at baseline, luminal B subtype or age <65 years, clinically meaningful improvement in PFS was observed. TEAE rates leading to death (or discontinuation) in the two groups were similar, at 1.8 % (5.3 %) and 2.7 % (6.3 %) for the efti and placebo groups, respectively. Three pts (1.3 %) were withdrawn from treatment due to grade 3-4 immediate hypersensitivity reactions to efti, while 4 pts (1 in efti group vs. 3 in placebo group) were withdrawn from the study due to grade 2-3 hypersensitivity to paclitaxel. The most frequent (≥10%) TEAEs ≥ grade 3 were gamma-glutamyl transferase increase (19.3% vs 29.5%), aspartate aminotransferase increase (8.8% vs 10.7%) and neutropenia (15.8% vs 14.3%) reported in the efti and placebo group, respectively. Injection site reaction (34.2% vs 3.6%) and injection site erythema (30.7% vs 1.8%) were more frequent in efti versus placebo arms. Conclusion: Efti did not prolong overall median PFS in women with HR+ MBC receiving first line chemotherapy. Tested in a randomized setting against placebo in pts receiving paclitaxel, efti is well tolerated and did not add clinically significant toxicity while inducing a sustained, significant increase in CD8 T cells in blood and clinical benefits in some predefined subgroups. Relevant subgroups and overall survival will be investigated.