Henry M. Prince

The phase 2, multicohort, ongoing ELM-2 study evaluates odronextamab, a CD20×CD3 bispecific antibody, in patients with relapsed/refractory (R/R) B cell non-Hodgkin lymphoma after ≥2 lines of therapy. Here primary analysis of the diffuse large B cell lymphoma (DLBCL) cohort is reported. Patients received intravenous odronextamab in 21-day cycles until progression or unacceptable toxicity, with cycle 1 step-up dosing to mitigate cytokine release syndrome (CRS) risk. The primary endpoint was objective response rate (ORR). Secondary endpoints included complete response (CR) rate, duration of response, progression-free survival (PFS) and overall survival. A total of 127 patients were enrolled. At the 29.9-month efficacy follow-up, the ORR was 52.0% and CR rate was 31.5%. Median durations of response and CR were 10.2 and 17.9 months, respectively. Undetectable minimal residual disease at cycle 4 day 15 was associated with PFS benefit. With a step-up of 0.7 to 4 to 20 mg (n = 60), CRS was the most common treatment-emergent adverse event (53.3% (grade ≥3, 1.7%)). No immune effector cell-associated neurotoxicity syndrome was reported. Infections were reported in 82/127 (64.6%) patients (grade ≥3, 38.6%; coronavirus disease 2019, 18.1% (grade ≥3, 12.6%)). In conclusion, odronextamab showed encouraging efficacy in heavily pretreated R/R DLBCL and generally manageable safety with supportive care. Clinical trial registration: NCT03888105.

Patients with relapsed/refractory B-cell non-Hodgkin lymphoma (B-NHL) have a poor median survival rate when treated with traditional salvage therapies. Bispecific antibodies (BsAbs) are an emerging class of 'off-the-shelf' immunotherapies that show promising efficacy in this population. Odronextamab is a CD20×CD3 targeting bispecific antibody that is being investigated in multiple subtypes of relapsed/refractory B-NHL. This article describes the development of odronextamab from pre-clinical work through to ongoing clinical trials in relapsed/refractory B-NHL. The structure, safety, efficacy, and administration of odronextamab are discussed. Studies were selected for inclusion by performing a search in PubMed, EMBASE, Cochrane Library, and relevant conference abstracts from 2014 to 2024. The clinicaltrials.gov website and reference lists of the included studies were also reviewed. Odronextamab has demonstrated manageable safety and promising efficacy in multiple subtypes of relapsed/refractory B-NHL. The low rates of immune effector cell-associated neurotoxicity syndrome (ICANS) and high response rates in rare aggressive subtypes of B-NHL are particularly noteworthy. High rates of severe infections remain a challenge with BsAbs, with further prophylactic efforts required to reduce the risk. Clinical trials of combination therapies with odronextamab are required to improve the utility of this BsAb across a wider range of settings and subtypes of B-NHL.

There is no standard of care in relapsed/refractory T-cell/natural killer-cell lymphomas. Patients often cycle through cytotoxic chemotherapy (CC), epigenetic modifiers (EM) or small molecule inhibitors (SMI) empirically. Ideal therapy at each line remains unknown. We conducted a retrospective, multiple intervention, 'target-trial' using the PETAL global cohort. Patients received front-line CC, then second and third line (2L and 3L) with either CC again, EM or SMI (12 possible treatment scenarios). Overall survival (OS; 2L or 3L to death) was compared across treatment sequences using Cox, reinforcement learning and synthetic intervention methods adjusting for age, histology, primary refractory disease, prognostic index for T-cell lymphoma (PIT) score, response to 2L, and receipt of 2L transplant consolidation. Five hundred and forty received 2L (EM = 101, SMI = 45, CC = 394), and 290 received 3L (EM = 65, SMI = 44, CC = 181). 2L SMI then 3L EM improved OS (adjusted hazard ratio [aHR]: 0.29, 95% confidence interval [CI]: 0.11-0.74; p = 0.010) versus 2L-3L CC-CC, and consistently across most other sequential strategies. In 2L stability analyses, benefit was notable with 2L SMI in angioimmunoblastic T-cell lymphoma (vs. CC: aHR: 0.23, 95% CI: 0.10-0.4; p < 0.001); vs. EM: aHR: 0.32, 95% CI: 0.12-0.82; p = 0.020), and both SMI and EM in PIT-stratified high-risk groups (SMI: aHR: 0.40, 95% CI: 0.21-0.76; p = 0.005; EM: aHR: 0.60, 95% CI: 0.39-0.92; p = 0.020) versus 2L CC. Results were consistent across all other independent stability and causal inference analyses providing a treatment selection framework.

There is no standard of care in relapsed/refractory T-cell/natural killer-cell lymphomas. Patients often cycle through cytotoxic chemotherapy (CC), epigenetic modifiers (EM) or small molecule inhibitors (SMI) empirically. Ideal therapy at each line remains unknown. We conducted a retrospective, multiple intervention, 'target-trial' using the PETAL global cohort. Patients received front-line CC, then second and third line (2L and 3L) with either CC again, EM or SMI (12 possible treatment scenarios). Overall survival (OS; 2L or 3L to death) was compared across treatment sequences using Cox, reinforcement learning and synthetic intervention methods adjusting for age, histology, primary refractory disease, prognostic index for T-cell lymphoma (PIT) score, response to 2L, and receipt of 2L transplant consolidation. Five hundred and forty received 2L (EM = 101, SMI = 45, CC = 394), and 290 received 3L (EM = 65, SMI = 44, CC = 181). 2L SMI then 3L EM improved OS (adjusted hazard ratio [aHR]: 0.29, 95% confidence interval [CI]: 0.11-0.74; p = 0.010) versus 2L-3L CC-CC, and consistently across most other sequential strategies. In 2L stability analyses, benefit was notable with 2L SMI in angioimmunoblastic T-cell lymphoma (vs. CC: aHR: 0.23, 95% CI: 0.10-0.4; p < 0.001); vs. EM: aHR: 0.32, 95% CI: 0.12-0.82; p = 0.020), and both SMI and EM in PIT-stratified high-risk groups (SMI: aHR: 0.40, 95% CI: 0.21-0.76; p = 0.005; EM: aHR: 0.60, 95% CI: 0.39-0.92; p = 0.020) versus 2L CC. Results were consistent across all other independent stability and causal inference analyses providing a treatment selection framework.

Objective: Denileukin diftitox (DD)-cxdl is a fusion protein comprising diphtheria toxin fragments A and B and human interleukin-2. This phase III, multicenter, open-label, single-arm registrational trial evaluated the efficacy and safety of DD-cxdl in patients with relapsed/refractory (R/R) cutaneous T-cell lymphoma (CTCL). Methods: In the main study, which followed a dose-finding lead-in, DD-cxdl was administered intravenously daily (5 days; 9 µg/kg/d once daily) every 21 days for up to eight cycles. Patients in the primary efficacy analysis set (PEAS) were required to have stage IA-IIIB CTCL (mycosis fungoides and/or Sézary syndrome) and at least ≥one previous systemic therapy. The primary efficacy end point was objective response rate (ORR) using the Global Response Score. Secondary end points were duration of response (DOR), time to response (TTR), skin tumor burden, and safety and tolerability. Results: The PEAS included 69 patients (median age, 64.0 years). The ORR was 36.2% (95% CI, 25.0 to 48.7), including 8.7% with complete response. The median DOR was 8.9 months (95% CI, 5.0 to not estimable), and the median (Q1-Q3) TTR was 1.4 (0.7-2.1) months. A total of 84.4% of patients showed decreased skin tumor burden, with 48.4% showing a ≥50% decrease. Treatment-emergent adverse events (TEAEs) of special interest, most of which were grade 1 or 2, included infusion reaction (73.9%), hypersensitivity (68.1%), hepatotoxicity (36.2%), and capillary leak syndrome (20.3% [grade ≥3, 5.8%]). Other common TEAEs were nausea (43.5%) and fatigue (31.9%). Conclusions: Efficacy and safety results show that DD-cxdl would potentially fulfill a serious, unmet medical need for patients with R/R CTCL.