Lacutamab in Patients with Relapsed and/or Refractory Sézary Syndrome: Translational Analysis from the Tellomak Phase 2 Trial
Authors: Battistella Maxime , Gru Alejandro A. , Moins-Teisserenc Hélène , Bagot Martine , Kim Youn-H H. , Geskin Larisa J , Ortiz-Romero Pablo L , Kim Ellen , Mehta-Shah Neha , Dereure Olivier , Oro Saskia , Sokol Lubomir , Beylot-Barry Marie , Dalle Stéphane , Jacobsen Eric D. , Lansigan Frederick , Ram-Wolff Caroline , Khodadoust Michael S. , Zinzani Pier Luigi , Viotti Julien , Magrez David , Boyer Chammard Agnes , Vagne Constance , Carraguel Flavien , Assante Miranda Laura , Peri Valentine , Bokobza Sivan , Thibult Marie-Laure , Bonnafous Cécile , Carrette Florent , Porcu Pierluigi 
Published: December 2024

Introduction
Cutaneous T-cell lymphoma (CTCL) is a form of non-Hodgkin lymphoma, which includes Sézary Syndrome (SS), a rare, aggressive and advanced type of CTCL characterized by erythroderma, significant blood involvement, and lymphadenopathy. SS is associated with poor prognosis with a median patient survival of approximately 5 years. KIR3DL2, is expressed on circulating tumor cells (CTCs) of all SS patients and in the skin of more than 85% of SS patient. Lacutamab is a first-in-class monoclonal antibody designed to deplete KIR3DL2-expressing cells via antibody-dependent cell-cytotoxicity (ADCC) and phagocytosis (ADCP). TELLOMAK is an international, open-label, multi-cohort Phase 2 trial investigating the safety and efficacy of single agent lacutamab in patients with relapsed/refractory (R/R) CTCL (NCT03902184). Here we report the results of translational analysis of the SS cohort exploring the association between biomarkers and clinical outcomes.
Methods
Blood and skin samples were collected at baseline and on treatment to evaluate biomarkers association with clinical outcomes and to inform lacutamab mechanism of action through several exploratory objectives. Association between baseline and longitudinal frequency and counts of KIR3DL2-expressing cells or other biomarkers and clinical activity, as well as impact of treatment on KIR3DL2-expressing cells and on other biomarkers were explored using flow cytometry (blood) and multiplex imaging (skin), and are presented here. Additional translational data may be presented.
Results
At DCO of May 1, 2023, 56 SS pts were enrolled, treated and evaluated. Analysis of blood samples by flow cytometry revealed that all patients expressed KIR3DL2 on their CTCs as measured by flow-cytometry, with a median of 92.2% [0.6-99.6] KIR3DL2-expressing CTCs. Among 55 patients evaluable for translational analysis, lacutamab treatment resulted in depletion of KIR3DL2-expressing CTCs in 48/55 pts, with 15/55 patients reaching a depletion ≥99%. Importantly, depletion of KIR3DL2-expressing CTCs occurred as early as week 5 of treatment. Response to lacutamab in blood was observed regardless of the baseline CTC burden, as blood response was observed for patients with CTCs ranging from 311 to 74634 cells /µl.
In the skin, using a threshold of ≥1% among mononucleated cells, KIR3DL2 expression was observed in 87.5% patients, consistent with the literature. Skin responses were observed irrespective of KIR3DL2 expression in baseline biopsies. A decrease of KIR3DL2 expressing cells in skin is observed as early as week 5, prior to the clinical skin response (median time to response in skin of 2.8 months; range 1-10 months) determined by modified Severity-Weighted Assessment Tool (mSWAT). Imaging analysis of skin biopsies at baseline revealed a higher infiltration by CD68+ macrophages than NK cells. Importantly, a higher baseline skin density of cells expressing the Fc receptor CD16, especially CD68+ macrophages were associated with better skin responses to lacutamab (p=0.027 and p=0.007, respectively).
Conclusion
Lacutamab monotherapy shows promising clinical activity in a R/R SS population previously treated with 2 or more prior systemic therapies including mogamulizumab. The exploratory translational data from the Tellomak SS cohort demonstrate rapid and deep depletion of KIR3DL2-expressing CTCs, irrespective of the baseline blood tumor burden. In skin, while no association was observed between response to lacutamab and KIR3DL2-expression in biopsies or KIR3DL2+ cell density at baseline, higher baseline infiltration by CD16-expressing cells, in particular CD16-expressing CD68+ macrophages was associated with better response in this compartment, consistent with lacutamab mechanism of action. These data confirm at a translational level the activity of lacutamab in the clinical trial setting, and its potential as a compelling future treatment option for CTCL patients with unmet need.