15th ICML: Loncastuximab Tesirine Shows Significant Activity in R/R Diffuse Large B-cell Lymphoma

Loncastuximab tesirine (ADCT‐402), an anti‐CD19 antibody‐drug conjugate (ADC) conjugated via a protease cleavable linker to SG3199, a highly cytotoxic DNA minor groove interstrand cross-linking pyrrolobenzodiazepine (PDB) dimer (PMID 29298756), shows significant activity in the treatment of patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). This is the conclusion based on presentations during the 15th International Conference on Malignant Lymphoma (15-ICML) in Lugano, Switzerland.

The investigational agent’s target is CD19, a 95-kDa type I membrane glycoprotein in the immunoglobulin superfamily. CD19 is an ideal target for an ADC approach because it is highly expressed in the majority of B-cell malignancies, including leukemias and non-Hodgkin lymphomas of B-cell origin, while its expression in healthy, non cancer, tissue is restricted.

Once bound to a CD19-expressing cell, loncastuximab tesirine is internalized into the cell where enzymes release the PBD-based payload.

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Loncastuximab tesirine is currently investigated in phase II clinixal trials as single agent for patients with relapsed/refractory diffuse large B‐cell lymphoma (DLBCL) (NCT03589469) and in phase I clinical trials in different combination, including a combination with ibrutinib in patients with R/R DLBCL or MCL (NCT03684694) and a Phase I trial in combination with durvalumab in patients with R/R DLBCL, MCL or follicular lymphoma (NCT03685344).

Loncastuximab tesirine continues to demonstrate an acceptable safety profile and strong single-agent anti-tumor activity in patients with relapsed or refractory diffuse large B-cell lymphoma.

15-ICML
During the 15th ICML data were presented from Phase I clinical trial (Abstract 054) subgroup analyses of response to loncastuximab tesirine at doses  ≥120 μg/kg in 129 patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). As of the October 16, 2018 data cutoff, 129 patients were evaluable for safety and 127 patients were evaluable for efficacy.[1]

Key findings from the oral presentation included:

  • Older patients had a higher overall response rate (ORR) than younger patients (≥ 75 years: 59.1%; 65-74 years: 52.8%; <65 years: 33.3%)
  • Patients with transformed disease had a higher ORR than those with de novo DLBCL (54.8% vs 39.6%)
  • Median duration of response (DoR) was longer for refractory patients than relapsed patients, and median DoR was comparable for patients to their most recent therapy vs relapsed patients
  • No difference in ORR was observed between patients who had received ≤3 lines vs >3 lines of prior therapy
  • The most common grade ≥3 treatment-emergent adverse events were: gamma-glutamyltransferase increased (20.2%), neutropenia (17.8%), neutrophil count decreased (14%), anaemia (11.6%), thrombocytopenia (11.6%) and platelet count decreased (10.9%)

Results from a separate, preclinical trial (Abstract 084), which evaluated the activity of loncastuximab tesirine as a single agent and in combination with approved drugs in lymphoma cell lines, support the continued evaluation of ADCT-402 in ongoing clinical trials in patients with R/R DLBCL and other types of non-Hodgkin lymphoma.[2]

Key findings from the oral presentation include:

  • Loncastuximab tesirine demonstrated significant activity in vitro in a wide panel of lymphoma cell lines and sensitivity to loncastuximab tesirine was higher in B-cell lymphomas than T-cell lymphomas
  • Loncastuximab tesirine in vitro activity correlated with CD19 expression at both the cell surface and RNA level
  • When tested in combination with other drugs, loncastuximab tesirine demonstrated strong synergy with BCL2 inhibitor venetoclax (4/4 cell lines), PI3K-delta inhibitor idelalisib (4/4 cell lines) and chemotherapy agent bendamustine (3/4 cell lines)

“The data for loncastuximab tesirine data presented at 15-ICML demonstrate its signficant anti-tumor activity and manageable tolerability profile at doses greater than or equal to 120 μg /kg in patients with relapsed or refractory diffuse large B-cell lymphoma ,” said John Radford, MD, FRCP, FMedSci, Professor of Medical Oncology at The University of Manchester and Director of Research at The Christie NHS Foundation Trust, Manchester, UK.

“It is particularly encouraging to see the responses in older patients and patients with transformed or primary refractory disease, as in many cases these are very frail and sick patients who have not responded to multiple previous therapies. I believe loncastuximab tesirine has the potential to become an important part of the treatment paradigm for patients with relapsed or refractory DLBCL, if approved, and look forward to the forthcoming interim results of the pivotal Phase II trial,” Radford said.

Orphan drug designation
The U.S. Food and Drug Administration has granted orphan drug designation to loncastuximab tesirine for the treatment of diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL).

“On the heels of these encouraging data, we look forward to completing enrollment in the pivotal 140-patient Phase II trial of ADCT-402 in patients with relapsed or refractory DLBCL and, if successful, preparing to file a potential Biologics License Application in the second half of 2020,” Said Chris Martin, PhD, Chief Executive Officer of ADC Therapeutics.

Clinical trial
Study to Evaluate the Efficacy and Safety of Loncastuximab Tesirine in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma – NCT03589469

Safety and Antitumor Activity Study of Loncastuximab Tesirine + Ibrutinib in Diffuse Large B-Cell or Mantle Cell Lymphoma – NCT03684694

Safety and Antitumor Activity Study of Loncastuximab Tesirine and Durvalumab in Diffuse Large B-Cell, Mantle Cell, or Follicular Lymphoma – NCT03685344

Reference
[1] Radford J, Kahl B, Hamadani M, Carlo-Stella C, O’Connor OA, Ardeshna KM, Feingold J, et al. Analysis of Efficacy and Safety of Loncastuximab Tesirine (ADCT-402) by Demographic and Clinical Characteristics in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (Abstract 054). Presented during the 15th International Conference on Malignant Lymphoma, June 18–22, 2019, Lugano, Switzerland [PowerPoint Slides]
[2] The Antibody-Drug Conjugate (ADC) Loncastuximab Tesirine (ADCT-402) Targeting CD19 Shows Strong In Vitro Anti-Lymphoma Activity Both as Single Agents and In Combination (Abstract 084) Tarantelli C, Presented during the 15th International Conference on Malignant Lymphoma, June 18–22, 2019, Lugano, Switzerland [PowerPoint Slides]