Initial results from LOTIS-7: a phase 1B study of Loncastuximab Tesirine plus Glofitamab in patients with Relapsed/Refractory (R/R) Diffuse Large B-cell Lymphoma (DLBCL)

Juan Pablo Alderuccio;Craig Okada;Crochet, Gilles;Emily Ayers;Pier Luigi Zinzani;et.al.
(2025) 18th international conference on malignant lymphoma — Location: Lugano, Switzerland (17.June.2025)

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HematologicalOncology-2025-Alderuccio-78INITIALRESULTSFROMLOTIS7APHASE1BSTUDYOFLONCASTUXIMABTESIRINE.pdf
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Authors
  • Juan Pablo Alderuccio
    Author
  • Craig Okada
    Author
  • Crochet, Gillesorcid-logoUCLouvain
    Author
  • Emily Ayers
    Author
  • Depaus, JulienUCLouvain
    Author
  • Reyes Rodríguez, RubénUCLouvain
    Author
  • Pier Luigi Zinzani
    Author
  • et. al.
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Abstract
Introduction: Loncastuximab tesirine (Lonca), a CD19-targeted, antibody–drug conjugate, and glofitamab (Glofit), a CD20×CD3 bispecific engager, are FDA/EMA-approved for R/R DLBCL as ≥ 3rd line therapy. LOTIS-7 (NCT04970901), an open-label, multicenter, phase 1b trial, evaluates Lonca+Glofit in R/R DLBCL. Eligible patients (pts) have histologically confirmed R/R B-NHL (DLBCL, FL, and MZL) and ≥ 1 prior systemic therapy. Primary objective is to characterize safety/tolerability of Lonca+Glofit and identify maximum tolerated/recommended expansion dose. Secondary objectives evaluate antitumor effects, pharmacokinetics (PK), and anti-drug antibodies (ADAs). Exploratory objective investigates correlations between tumor tissue/biomarkers/PK and clinical activity. Methods: LOTIS-7 evaluated Lonca at 90, 120, and 150 μg/kg (part 1, dose escalation) and 120 or 150 μg/kg (part 2, dose expansion) Q3W for a fixed duration ≤ 8 cycles; doses 120 and 150 μg/kg were reduced to 75 μg/kg for cycles ≥ 3 per label. Glofit was dosed 30 mg Q3W with step-up dosing ≤ 12 cycles. PK of Lonca and its analytes were assessed using parameters from a noncompartmental analysis. ADAs were evaluated with a tiered strategy. Circulating immune cells/cytokines were assessed longitudinally. Immune phenotypes were analyzed by flow cytometry, and plasma cytokines by multiplex immunoassay. Results: As of 17Jan2025, 31 pts received ≥ 1 Lonca dose. Median age was 73; 45.2% had DLBCL, 16.1% HGBCL, 61.3% received ≥ 2 prior therapies, and 19.4% had prior CAR-T therapy. A subset was refractory to primary (45.2%) and/or last (61.3%) therapy. Most common TEAE grade (Gr) ≥ 3 was neutropenia (32.3%). Gr 1/2 instances of CRS (29.0%/9.7%) and ICANS (0%/6.5%) were observed, but no Gr ≥ 3. Gr 3/4 TEAEs of interest included generalized edema, pericardial effusion, photosensitivity reaction, rash, sepsis, and pneumonia (each 3.2%). In the efficacy evaluable population ORR was 95.5% (21/22), CRR was 90.9% (20/22), and median DOR was not reached (Table 1). Of responders (n = 21), 20 remained in response (CR). Lonca+Glofit versus Lonca showed comparable exposure (AUClast) but lower maximum concentration (Cmax), with moderate to high PK variability (cycles 1/2). Only 4.7% of pts had ADAs. As of 4Oct2024, T-cell margination was appreciable, circulating activated CD4+ and CD8+ T cells increased during treatment. Amount of circulating monocytes and NK cells were also modulated and showed a trend of increase over time. Cytokine profiles indicated immune activation; when present, IL-6 induction was relatively modest in most pts. Conclusions: Lonca+Glofit in R/R B-NHL showed a manageable safety profile consistent with each drug and encouraging efficacy in heavily pretreated aggressive lymphoma pts. Lonca+Glofit induced T-cell margination, and sustained circulating CD4+ and CD8+ T-cell activation was noted. Results support that Lonca complements Glofit’s mechanism and provides additive efficacy. Updated data will be presented.
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Juan Pablo Alderuccio, Craig Okada, Crochet, G., Emily Ayers, Marie Hu, Silvia Ferrari, Paolo Caimi, Mehdi Hamadani, Depaus, J., Enrico Derenzini, Jose Sandoval-Sus, Reyes Rodríguez, R., Andrzej Urban, Erica Rave, Adina Graf, Eva Tiecke, Marie Toukam, Pier Luigi Zinzani, & et al. (2025). Initial results from LOTIS-7: a phase 1B study of Loncastuximab Tesirine plus Glofitamab in patients with Relapsed/Refractory (R/R) Diffuse Large B-cell Lymphoma (DLBCL). 18th international conference on malignant lymphoma, Lugano, Switzerland. https://hdl.handle.net/2078.5/273223