Pushing the accelerator and releasing the brake: A phase I dose escalation study evaluating a LAG-3 fusion protein (eftilagimod alpha), together with pembrolizumab in unresectable or metastatic melanoma.

Abstract

e15099 Background: Eftilagimod alpha (efti; previously named IMP321) is a recombinant LAG-3Ig fusion protein binding to MHC class II molecules and mediating antigen presenting cell (APC) activation followed by CD8 T-cell activation. The activation of the dendritic cell network and the subsequent T cell recruitment at the tumor site with efti may lead to stronger anti-tumor CD8 T cell responses than observed with pembrolizumab alone. This combination of an APC activator with an immune checkpoint inhibitor (ICI) is aiming to increase efficacy without additional toxicity. We report results of the dose escalation cohorts from a phase I trial (NCT02676869) with pembrolizumab and efti in melanoma patients (pts). Methods: In this study, melanoma pts treated with pembrolizumab and being without a complete response (CR) or symptomatic progression after 3 cycles continued pembrolizumab (2 mg/kg; IV) plus either 1, 6 or 30 mg injections SC of efti (every 2 weeks for 6 months) from cycle 5 onwards. Blood for pharmacokinetic and -dynamic assessments was withdrawn in cycle 1 and 9. Responses were assessed by immune related response criteria (irRC). Results: Between 04/16 and 12/17 18 pts (17 male, 1 female) with a median age of 66 years (range 48-85) were enrolled. The majority (83 %) of pts had visceral disease. Eight SAEs in 6 patients were reported. None of the SAEs was related to the study treatment. No dose limiting toxicities or adverse events (AEs) ≥ grade 4 were reported. No patient discontinued treatment due to an AE. Four pts experienced 4 different AEs grade 3 related to efti or pembrolizumab. PK results showed a dose proportional increase in Cmax. Sixteen (16) patients were eligible for response evaluation. In 8 (50 %) pts a tumor reduction was observed. This includes one patient with a confirmed CR after initial progression on pembrolizumab monotherapy. Conclusions: Thirty (30) mg efti SC every 2 weeks in combination with standard dose of pembrolizumab is safe. This dose is investigated in an extension cohort. The late tumor responses seen after the combination started may point out to the benefit of adding a systemic APC activator to an ICI. Clinical trial information: NCT02676869.