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3072 Strategies to Develop Anti-KIR Mab Lacutamab in Patients with Peripheral T-Cell Lymphoma: Preliminary Monotherapy Clinical Data and Pre-Clinical Combinability Data

Program: Oral and Poster Abstracts
Session: 624. Hodgkin Lymphomas and T/NK cell Lymphomas: Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
clinical trials, Research, Lymphoid Leukemias, Biological therapies, Antibody Therapy, adult, Fundamental Science, Lymphomas, Clinical Research, T Cell lymphoma, drug development, Diseases, Therapies, Immunotherapy, Lymphoid Malignancies, Infusion, Monoclonal Antibody Therapy, Study Population, Human
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Swami P. Iyer, MD1, Sabarish R. Ayyappan, MD2, Irl Brian Greenwell, MD3, Won Seog Kim, MD, PhD4*, Seung Tae Lee, MD5, Jin Seok Kim, MD, PhD6*, Won-Sik Lee7*, Youngwoo Jeon, MD8*, William Johnson9*, Utpal P. Dave, MD10, Sung-Soo Yoon, MD, PhD11, Ka-Won Kang12*, Florent Carrette13*, Julien Viotti13*, A.J. Leyco, RN14*, Marianna Muller, MD13* and Steven M. Horwitz, MD9

1MD Anderson, Houston, TX
2Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA
3Hollings Cancer Center, Medical University of South Carolina, Charleston, SC
4Samsung Medical Center, Seoul, KOR
5University of Maryland, Baltimore, MD
6Division of Hematology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea, Republic of (South)
7Inje Univ. Busan Baik-Hospital, Busan, KOR
8The Catholic University of Korea, Yeouido St. Mary`s Hospital, Seoul, KOR
9Memorial Sloan Kettering Cancer Center, New York, NY
10Vanderbilt University Medical Center, Indianapolis, IN
11Department of Hemato-Oncology, Seoul National University Hospital, Seoul, Korea, Republic of (South)
12Division of Hematology-Oncology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea, Republic of (South)
13Innate Pharma, Marseille, France
14Innate Pharma, Rockville, MD

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.

Disclosures: Iyer: Yingli: Consultancy, Research Funding; CRISPR: Consultancy, Research Funding; Innate: Research Funding; Acrotech: Consultancy, Research Funding; Legend: Research Funding; Astra Zeneca: Research Funding; Ono: Research Funding; Pfizer: Research Funding; Salarius: Consultancy; Drenbio: Research Funding; Merck: Research Funding; American Society of Transplant and Cellular Therapy: Speakers Bureau; CuraBio: Speakers Bureau; American Society of Hematology: Speakers Bureau; Seagen: Consultancy, Research Funding. Kim: Sanofi, Beigene, Boryong, Roche, Kyowa-kirin, Donga: Research Funding. Jeon: Catholic University of Korea (10-2018-0112511, 10-1718380): Patents & Royalties; Janssen, F. Hoffmann-La Roche Ltd, Antengene, Celltrion, Vigencell: Consultancy; Korean research fundings: Research Funding; Korean Society of Experimental Hematology: Membership on an entity's Board of Directors or advisory committees; Catholic University of Korea, Yeouido ST. Mary hospital: Current Employment. Johnson: Myeloid Therapeutics: Consultancy. Viotti: Innate Pharma: Current Employment. Muller: Innate Pharma: Current Employment. Horwitz: Celgene: Research Funding; Trillium Therapeutics: Consultancy, Research Funding; ADC Therapeutics: Research Funding; Auxilius Pharma: Consultancy; Abcuro Inc.: Consultancy; Cimieo Therapeutics: Consultancy; Kyowa Hakko Kirin: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; ONO Pharmaceuticals: Consultancy; Tubulis: Consultancy; Yingli Pharma Limited: Consultancy; Affimed: Research Funding; Crispr Therapeutics: Research Funding; Shoreline Biosciences, Inc.: Consultancy; SecuraBio: Consultancy; Millenium: Research Funding; Verastem/SecuraBio: Research Funding; Seattle Genetics: Research Funding; Takeda: Consultancy, Research Funding.

*signifies non-member of ASH