Loncastuximab Tesirine Plus Glofitamab Shows Early Safety and Efficacy in R/R DLBCL

Loncastuximab tesirine (Zynlonta) paired with glofitamab-gxbm (Columvi) showcased an acceptable toxicity profile and elicited responses in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), according to initial data from the phase 1b LOTIS-7 study (NCT04970901) presented during the 2025 SOHO Annual Meeting.1

The findings, which were previously shared as an oral presentation at the 18th International Conference on Malignant Lymphoma and presented as a poster at the 2025 EHA Congress, indicated that the combination did not lead to any grade 5 treatment-emergent adverse effects (TEAEs) and was associated with low rates of cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS).

Any-grade CRS was less frequent in those who received loncastuximab tesirine at a starting dose of 150 µg/kg vs 120 µg/kg. One patient in the 120-µg/kg starting dose group experienced grade 3 CRS. No grade 4 CRS events occurred, nor were grade 3 or higher ICANS events observed.

At all dose levels in the efficacy-evaluable population (n = 30), the regimen elicited an overall response rate (ORR) of 93.3%, which comprised a complete response (CR) rate of 86.7% and a partial response (PR) rate of 6.7%. The median duration of response (DOR) was not estimable. The time to first response had a median of 42.0 days, and the median time to first CR was 70.5 days. Notably, the median time to first CR was shorter in the 150-µg/kg starting dose group vs the 120-µg/kg starting dose group, at 42.0 days vs 80.0 days.

“Based on the shorter time to CR and lower rates of CRS in the loncastuximab tesirine 150-µg/kg starting dose group, current expansion is undergoing at this dose level,” Juan Pablo Alderuccio, MD, an associate profession of clinical medicine in the Division of Hematology at Sylvester Comprehensive Cancer Center and University of Miami Leonard M. Miller School of Medicine, in Miami, Florida, said in an oral presentation of the data.

What Is the Design of the LOTIS-7 Trial?

The open-label, multinational, multi-arm, phase 1b trial was designed to examine the use of loncastuximab tesirine in combination with glofitamab and other anticancer agents like polatuzumab vedotin-piiq (Polivy) and mosunetuzumab-axgb (Lonsumio) in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (B-NHL).2

Those included in the study had an ECOG performance status ranging from 0 to 2 and measurable disease by 2014 Lugano Classification.1 Those who previously underwent autologous stem cell transplantation or received CAR T-cell therapy over 100 days before trial enrollment were permitted; those with clinically significant third-space fluid accumulation were excluded.

Part 1 of the study, the dose-escalation portion, included patients with relapsed or refractory DLBCL, high-grade B-cell lymphoma (HGBCL), transformed follicular lymphoma (trFL), follicular lymphoma (FL), or marginal zone lymphoma who had received at least 2 previous lines of treatment. Part 2, the dose-optimization portion, included those with relapsed or refractory de novo DLBCL, HGBCL, trFL, or grade 3b FL who had received at least 1 prior line of therapy.

Patients underwent a screening period of no longer than 28 days prior to treatment. In part 1, patients received escalating doses of loncastuximab tesirine plus glofitamab every 3 weeks. Those in part 2 received loncastuximab tesirine at a starting dose of 120 µg/kg or 150 µg/kg for cycles 1 and 2. For cycles 3 and beyond, they received loncastuximab tesirine at 75 µg/kg plus 30-mg step-up dosing of glofitamab every 3 weeks.

In his presentation, Alderuccio offered a deeper dive into the treatment sequence. He noted that for cycle 1, obinutuzumab (Gpt) was given at a dose of 1000 mg on day 1, followed by loncastuximab tesirine for days 2 and 3, glofitamab at 2.5 mg on day 8, and glofitamab at 10 mg on day 15. “Starting on cycle 2, patients received on the same day loncastuximab tesirine and glofitamab, with loncastuximab for up to 8 doses, 8 cycles, and glofitamab [for] up to 12 cycles,” Alderuccio explained. For cycles 9 to 12, glofitamab was administered at a dose of 30 mg on day 1.

The primary end points of the study were safety and tolerability, and identification of the maximum tolerated dose and/or the recommended dose for expansion. Secondary end points comprised ORR, DOR, CR rate, progression-free survival, relapse-free survival, and overall survival. Pharmacokinetics (PK) and immunogenicity will also be evaluated. Key exploratory end points will examine the glofitamab concentration in circulation, as well as biomarker and PK correlations with clinical outcomes.

A Deeper Dive Into the Analysis Population

As of the data cutoff date of April 14, 2025, a total of 47 patients with relapsed or refractory B-NHL had received at least 1 dose of loncastuximab tesirine at starting doses of 90 µg/kg, 120 µg/kg, and 150 µg/kg. The treated population included 41 patients with LBCL who received loncastuximab tesirine at starting doses of 120 µg/kg or 150 µg/kg; the efficacy population comprised 30 patients in the treated population who underwent at least 1 disease assessment.

In the overall treated population, the median patient age was 71 years (range, 26-85). Slightly more than half of patients were male (56.1%) and had an ECOG performance status of 0 (56.1%). Most patients had an Ann Arbor disease stage or III or IV (85.4%), and about half of patients (53.7%) had an International Prognostic Index score of 3 to 5. In terms of LBCL histology, most patients had de novo DLBCL (73.2%), followed by HGBCL (14.6%), trFL (9.8%), and grade 3b FL (2.4%).

The median number of prior lines of therapy received was 2, with a range of 1 to 5; 48.8% of patients had only received 1 prior line, and 51.2% of patients had received 2 or more prior lines. Moreover, 51.2% of patients had disease that was refractory to primary therapy, and 48.8% of patients had disease refractory to their last prior therapy. In terms of prior treatment, 9.8% of patients previously underwent transplant, and 19.5% of patients had prior exposure to CAR T-cell therapy.

What Were the Safety Outcomes of Loncastuximab Tesirine Plus Glofitamab in LOTIS-7?

In all 41 patients, the most common grade 3 or 4 TEAEs included neutropenia (24.4%), anemia (9.8%), increased aspartate aminotransferase levels (7.3%), increased gamma-glutamyl transferase (GGT) levels (7.3%), and thrombocytopenia (7.3%). The most common grade 3 or 4 AEs of special interest included increased GGT levels (7.3%), thrombocytopenia (7.3%), generalized edema (4.9%), febrile neutropenia (2.4%), rash (2.4%), photosensitivity reaction (2.4%), sepsis (2.4%), upper respiratory infection (2.4%), and pneumonia (2.4%). Serious TEAEs were reported in 48.8% of patients.

TEAEs led to the discontinuation of loncastuximab tesirine only for 7.3% of all treated patients. When broken down by starting dose group, loncastuximab tesirine–only discontinuation due to TEAEs occurred in 5% of those in the 120-µg/kg group (n = 20) and 9.5% of those in the 150-µg/kg group (n = 21). Of the 3 total patients who discontinued treatment, the TEAEs that led to discontinuation were pericardial effusion (n = 1); generalized edema and increased GGT levels (n = 1); and pleural effusion and erythema (n = 1). TEAEs led to glofitamab-only discontinuation for 7.3% of all treated patients; this rate was 0% in the 120-µg/kg group and 14.3% in the 150-µg/kg group. The TEAEs that led to discontinuation in this group were ICANS (n = 1), polyneuropathy (n = 1), and febrile neutropenia (n = 1).

“Neutropenia was the most common TEAE leading to dose delay of loncastuximab tesirine, at [a rate of] 12.2%, and glofitamab, at [a rate of] 17.1%,” Alderuccio noted. “There was only 1 patient who had a dose reduction of loncastuximab tesirine.”

What Were the PK and Biomarker Outcomes Observed With Loncastuximab Plus Glofitamab?

Loncastuximab tesirine exposure demonstrated a dose-dependent increase during the first 2 cycles of treatment, according to Alderuccio, who added that there was low immunogenicity with no cases of post-dose loncastuximab tesirine antidrug antibodies.

“Loncastuximab tesirine plus glofitamab produced a similar CD4-positive/CD8-positive T-cell margination and activation pattern as previously reported for glofitamab monotherapy,” he concluded. “Immune activation was evidenced by a transient increase of interferon-γ [levels] and increases in monocyte and natural killer cell [levels].”

Editor’s Note: No disclosures were listed.

References

1. Alderuccio J, Okada C, Crochet G, et al. 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. Presented at: 2025 SOHO Annual Meeting; September 3-6, 2025; Houston, TX. Abstract ABCL-777.
2. A study to evaluate the safety and anticancer activity of loncastuximab tesirine in combination with other anti-cancer agents in participants with relapsed or refractory B-cell non-Hodgkin lymphoma (LOTIS-7). ClinicalTrials.gov. Updated June 17, 2025. Accessed September 6, 2025. https://www.clinicaltrials.gov/study/NCT04970901