Strategies to Develop Anti-KIR Mab Lacutamab in Patients with Peripheral T-Cell Lymphoma: Preliminary Monotherapy Clinical Data and Pre-Clinical Combinability Data

Abstract

Peripheral T-cell Lymphoma (PTCL) is a heterogeneous group of aggressive T-cell lymphomas associated with poor prognosis. Many patients with PTCL do not respond or relapse despite responding to first line systemic therapy. Despite the common use of chemotherapies, there is no universally accepted standard of care. This highlights an urgent and significant need for innovative treatment strategies that incorporate novel mechanisms of action, particularly for patients with relapsed or refractory (R/R) PTCL. One such novel target is KIR3DL2, a killer immunoglobulin-like receptor that is expressed across different subtypes of T-cell lymphomas including approximately 50% of PTCL patients. Lacutamab is a first-in-class monoclonal antibody designed to specifically deplete KIR3DL2-expressing cells through antibody-dependent cell-cytotoxicity (ADCC) and antibody-dependent cell-phagocytosis (ADCP). It is being developed as a novel treatment for patients with R/R PTCL as a single agent or in combination. In previous trials in patients with R/R cutaneous T-cell lymphoma (CTCL), lacutamab showed acceptable safety profile with no dose limiting toxicities and promising activity. Here we provide preclinical combination data supporting anti-tumor activity and rationale for the exploration of lacutamab in combination with approved and novel therapies in patients with PTCL and we present preliminary monotherapy data from an ongoing Phase 1b study in PTCL. To further develop novel-lacutamab combinations, the combinability of lacutamab with therapies used in R/R or frontline PTCL e.g., pralatrexate or CHOP, respectively, was tested. Pralatrexate is an antineoplastic folate analog approved for the treatment of R/R PTCL. In vitro, pralatrexate was shown to induce KIR3DL2 upregulation on several tumor cell lines with endogenous or forced KIR3DL2 expression and to enhance lacutamab-induced ADCC by NK cells. Importantly, the combination of lacutamab with pralatrexate in vivo delayed tumor growth (Figure 1A) and improved survival (Figure 1B) compared to each monotherapy. CHOP-based chemotherapy is a standard of care in the frontline treatment of PTCL subtypes. In a preclinical in vivo human tumor model, lacutamab in combination with CHOP was shown to reduce tumor growth compared with CHOP or lacutamab alone. An ongoing multi-center, open-label, Phase Ib trial (NCT05321147) evaluate the safety and efficacy of lacutamab monotherapy in patients with KIR3DL2-expressing R/R PTCL who have received at least one prior line of systemic therapy. Lacutamab 750 mg is administered as an intravenous infusion weekly x 5 weeks, every 2 weeks x 10 then every 4 weeks until disease progression or unacceptable toxicity. The primary objective was to assess the safety and tolerability of lacutamab in R/R PTCL. Secondary objectives were to assess clinical activity and to characterize the pharmacokinetics and immunogenicity of lacutamab. At the data cut-off, 10 patients were treated with lacutamab. Median age was 71.0 years (range: 61-77), median prior lines of therapies was 3 (range: 1-5), and median follow-up was 1.9 months (m) (range: 0.5-8.8 m). The majority (90%) of treatment-emergent adverse events (TEAEs) were of grade 1-2 severity, grade ≥3 related TEAEs were observed in 2 (20%) patients: 1 with serum sickness, and 1 with aspartate aminotransferase elevation. No serious TEAEs were observed and none of the patients discontinued study drug due to TEAE. Overall, preliminary Phase 1b data in patients with R/R PTCL confirm the acceptable safety profile of lacutamab monotherapy. The preclinical activity profile improves when assessed in combination. These data inform the future development of lacutamab to provide additional therapeutic options that may improve outcomes for PTCL patients, including those who relapse or are refractory to available therapies. A Phase 2 study evaluating the combination of lacutamab with GemOx is ongoing (NCT04984837) based on pre-clinical observations that GemOx improves lacutamab-induced ADCC by NK cells.