Maturing data from the pivotal Phase II LOTIS 2 study (NCT04384484), a clinical trial of loncastuximab tesirine (formerly ADCT-402) being developed by ADC Therapeutics, shows an overall high response rate in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), including an overall response rate of 48.3%, a complete response rate of 24.1%. The pivotal study, which enrolled 145-patients, also confirmed manageable toxicity.

ADC Therapeutics (Lausanne; Biopôle, Switzerland) also announced interim results from LOTIS 3, a Phase I/II clinical trial of loncastuximab tesirine in combined with ibrutinib (Imbruvica®; Pharmacyclics/Janssen Biotech). According to the researchers involved in this study, these results highlight the potential of loncastuximab tesirine to advance into earlier lines of therapy in combination with other therapies.

Investigational agent
Loncastuximab tesirine is an antibody-drug conjugate (ADC) composed of a humanized monoclonal antibody directed against human CD19 and conjugated through a linker to a potent pyrrolobenzodiazepine (PBD) dimer cytotoxin.

Once bound to a CD19-expressing cell, the investigational drug is designed to be internalized by the cell, after which the cytotoxic payload is released.

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The payload is designed to bind irreversibly to DNA to create highly potent interstrand cross-links that block DNA strand separation, thus disrupting essential DNA metabolic processes such as replication and ultimately resulting in cell death. CD19 is a clinically validated target for the treatment of B-cell malignancies.

Virtual EHA congress
The data were presented in an oral presentation and ePoster at the virtual 25th Congress of the European Hematology Association, held June 11 – June 21, 2020.

“Our two presentations at EHA25 highlight loncastuximab tesirine’s potential as both a single agent and in combination with other therapies for patients with non-Hodgkin lymphoma,” noted Jay Feingold, M.D., Ph.D., Senior Vice President and Chief Medical Officer of ADC Therapeutics.

“In LOTIS 2, loncastuximab tesirine demonstrated important anti-tumor activity and durability, as well as manageable toxicities, across a broad population of hard-to-treat, relapsed, or refractory DLBCL patients, including patients with poor prognosis, those who never responded to prior therapy and those who received prior stem cell transplant,” Feingold added.

Biologics License Application
“We are pleased to be on track to file a Biologics License Application (BLA) with the U.S. Food and Drug Administration for Lonca for the treatment of relapsed or refractory DLBCL in the second half of 2020,” said Chris Martin, Chief Executive Officer of ADC Therapeutics.

“If approved, we look forward to launching loncastuximab tesirine in mid-2021. We are also planning to initiate LOTIS 5, a post-marketing confirmatory clinical trial of loncastuximab tesirine in combination with rituximab, which we believe will support a supplemental BLA for Lonca to be used as second-line therapy for the treatment of relapsed or refractory DLBCL.”

Tesirine (SG3249) is a cathepsin B-cleavable valine-alanine pyrrolobenzodiazepine (PBD) dimer and an antibody-drug conjugate (ADC) payload. Tesirine (SG3249) was designed to combine potent antitumor activity with desirable physicochemical properties such as favorable hydrophobicity and improved conjugation characteristics.
Tesirine (SG3249) is a cathepsin B-cleavable valine-alanine pyrrolobenzodiazepine (PBD) dimer and an antibody-drug conjugate (ADC) payload. Tesirine (SG3249) was designed to combine potent antitumor activity with desirable physicochemical properties such as favorable hydrophobicity and improved conjugation characteristics.

Lotus 2: Initial Results
LOTIS 2, a Phase 2, multi-center, open-label, single-arm clinical trial, is evaluating the efficacy and safety of Lonca in patients with relapsed or refractory DLBCL following ≥2 lines of prior systemic therapy. [1]

Participating patients received 30-minute intravenous infusions of loncastuximab tesirine once every three weeks (Q3W) at a dose of 150 μg/kg for the first two cycles, followed by 75 μg/kg for subsequent cycles for up to one year or until disease progression, unacceptable toxicity, or other discontinuation criteria, whichever occurred first. As of the data cut-off date of April 6, 2020, 145 patients were enrolled and received a mean of 4.3 cycles of Lonca (range: 1-15).

Key data
Loncastuximab tesirine achieved an overall response rate (ORR) of 48.3% (70/145 patients) and a complete response rate (CRR) of 24.1% (35/145 patients), compared to an ORR of 45.5% (66/145 patients) and CRR of 20.0% (29/145 patients) in the previous data cut (October 14, 2019). Patients refractory to first-line or last-line prior therapy had ORRs of 37.9% and 36.9%, respectively.

The observed clinical success of SG3199 stems from its potent cytotoxicity, showing activity across a wide range of both solid tumor and hematological cancers. This high potency an important advantage in ADCs utilizing payload tesirine, allowing to treat tumors with low copy number antigen targets.

The median duration of response has increased to 10.25 months in the more mature data cut, compared to 6.7 months in the previous data cut (October 14, 2019). All patients had received a median of 3 prior lines of therapy

Adverse events
The toxicity profile was manageable and no new safety concerns were identified
The most common grade ≥3 treatment-emergent adverse events in ≥10% of patients were: neutropenia (25.5%) with a low incidence of febrile neutropenia (3.4%), thrombocytopenia (17.9%), GGT increased (16.6%) and anemia (10.3%)

“Despite recent advances in DLBCL treatment, outcomes for patients with relapsed or refractory disease remain poor,” said Carmelo Carlo-Stella, MD, Professor of Hematology, Humanitas University, Section Chief, Lymphoid Malignancies, Humanitas Cancer Center, and an investigator for the trial.

“The substantial single-agent anti-tumor activity Lonca has demonstrated in patients with relapsed or refractory DLBCL who failed established therapies underscores the potential of this CD19-targeted, PBD-based ADC to fill a critical unmet need,” Carlo-Stella added.

Loncastuximab tesirine + ibrutinib: Interim Results
LOTIS 3, a Phase I/II open-label, single-arm dose-escalation and dose-expansion clinical trial, is evaluating the safety and efficacy of Lonca in combination with ibrutinib in patients with relapsed or refractory DLBCL or mantle cell lymphoma (MCL). Lonca is administered as 30-minute intravenous infusions using a standard 3+3 dose-escalation design at doses of 60 or 90 μg/kg.[2]

In this trial, patients received loncastuximab tesirine every three weeks for the first two doses, with concurrent fixed-dose ibrutinib (560 mg/day, oral) for up to one year. As of the data cut-off date of April 6, 2020, 25 patients have been enrolled, including 23 patients with DLBCL and two patients with MCL, and 18 patients were evaluable for antitumor activity. The trial continues to enroll patients.

Key data

  • Across both Lonca dose levels of 60 and 90 μg/kg, the combination with ibrutinib has demonstrated an ORR of 66.7% and a CRR of 50.0%;
  • At the recommended Phase 2 Lonca dose of 60 μg/kg, the combination with ibrutinib has demonstrated an ORR of 75.0% and CRR of 58.3%;
  • The combination has a manageable toxicity profile;
  • The most common grade ≥3 treatment-emergent adverse events in ≥10% of patients were thrombocytopenia (20%) and anemia (12%);
  • Patients had received a median of 2 prior lines of therapy;
  • Pharmacokinetic profiles demonstrate good exposure throughout the dosing interval.

“As patients with relapsed or refractory DLBCL or MCL have a poor prognosis and limited salvage treatment options, it is important to explore the potential for combinations of drugs with different mechanisms of action to increase clinical activity compared to either agent alone,” said Julien Depaus, MD, Department of Hematology, CHU UCL Namur.

“Based on synergies demonstrated in preclinical research and the interim results of the Phase 1 portion of this clinical trial, I believe the combination of Lonca and ibrutinib warrants further evaluation as a treatment option for patients with relapsed or refractory DLBCL or MCL,” Depaus concluded.

Clinical trials
Safety and Efficacy Study of Loncastuximab Tesirine + Ibrutinib in Diffuse Large B-Cell or Mantle Cell Lymphoma – NCT03684694
Study to Evaluate Loncastuximab Tesirine With Rituximab Versus Immunochemotherapy in Participants With Relapsed or Refractory Diffuse Large B-Cell Lymphoma (LOTIS 5) – NCT04384484
Study to Evaluate the Efficacy and Safety of Loncastuximab Tesirine in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma – NCT03589469
Study of ADCT-402 in Patients With Relapsed or Refractory B-cell Lineage Acute Lymphoblastic Leukemia (B-ALL) – NCT02669264
Safety and Antitumor Activity Study of Loncastuximab Tesirine and Durvalumab in Diffuse Large B-Cell, Mantle Cell, or Follicular Lymphoma – NCT03685344
Study of ADCT-402 in Patients With Relapsed or Refractory B-cell Lineage Non-Hodgkin Lymphoma (B-NHL) – NCT02669017

Reference
[1] Carlo-Stella C, Luigi Zinzani P, Kahl B, Caimi P, Solh M, Ardeshna K, Stathis A, Hamadani M, Ai W, et al. Initial results of a phase 2 study of loncastuximab tesirine, a novel pyrrolobenzodiazepine-based antibody-drug conjugate, in patients with relapsed or refractory diffuse large B-cell lymphoma. EHA Library. Carlo-Stella C. 06/12/20; 295053; S233 [Abstract]
[2] Depaus J, Ervin-Haynes A, Bryan L, Magagnoli M, Gritti G, Chao G, Boni J, Dautaj I, Wagner-Johnston N. Interim results of a Phase I/II study of loncastuximab tesirine (Lonca) combined with ibrutinib in advanced diffuse large B-cell lymphoma (DLBCL) o mantle cell lymphoma (MCL). EHA Library. Depaus J. 06/12/20; 293773; EP1284 [Abstract]