Epcoritamab, a Novel, Subcutaneous CD3xCD20 Bispecific T-Cell-Engaging Antibody, in Relapsed or Refractory Large B-Cell Lymphoma: Dose Expansion in a Phase I/II Trial

Abstract

Purpose: Epcoritamab is a subcutaneously administered CD3xCD20 T-cell-engaging, bispecific antibody that activates T cells, directing them to kill malignant CD20⁺ B cells. Single-agent epcoritamab previously demonstrated potent antitumor activity in dose escalation across B-cell non-Hodgkin lymphoma subtypes.

Patients and methods: In the dose-expansion cohort of a phase I/II study (ClinicalTrials.gov identifier: NCT03625037), adults with relapsed or refractory CD20⁺ large B-cell lymphoma and at least two prior therapy lines (including anti-CD20 therapies) received subcutaneous epcoritamab in 28-day cycles (once weekly step-up doses in weeks 1-3 of cycle 1, then full doses once weekly through cycle 3, once every 2 weeks in cycles 4-9, and once every 4 weeks in cycle 10 and thereafter) until disease progression or unacceptable toxicity. The primary end point was overall response rate by the independent review committee.

Results: As of January 31, 2022, 157 patients were treated (median age, 64 years [range, 20-83]; median of three [range, 2-11] prior therapy lines; primary refractory disease: 61.1%; prior chimeric antigen receptor (CAR) T-cell exposure: 38.9%). At a median follow-up of 10.7 months, the overall response rate was 63.1% (95% CI, 55.0 to 70.6) and the complete response rate was 38.9% (95% CI, 31.2 to 46.9). The median duration of response was 12.0 months (among complete responders: not reached). Overall and complete response rates were similar across key prespecified subgroups. The most common treatment-emergent adverse events were cytokine release syndrome (49.7%; grade 1 or 2: 47.1%; grade 3: 2.5%), pyrexia (23.6%), and fatigue (22.9%). Immune effector cell-associated neurotoxicity syndrome occurred in 6.4% of patients with one fatal event.

Conclusion: Subcutaneous epcoritamab resulted in deep and durable responses and manageable safety in highly refractory patients with large B-cell lymphoma, including those with prior CAR T-cell exposure.

FIG 1.

Efficacy results (per IRC; Lugano criteria) with epcoritamab in patients with LBCL. (A) shows best percentage change in sum-of-product perpendicular diameters of target lesions for patients with LBCL. Asterisks represent patients with prior exposure to CAR T-cell therapy. (B) shows the Kaplan-Meier curve for DOR. Results were similar in the DLBCL population (data not shown). (C) shows the Kaplan-Meier plot of PFS. A PFS ad hoc analysis using the Mantel-Byar approach showed a hazard ratio (95% CI) for patients with CR versus nonresponders of 0.11 (0.04 to 0.25) and a hazard ratio (95% CI) for patients with PR versus nonresponders of 0.47 (0.26 to 0.86). Thirty-six patients had disease progression (n = 28) or died (n = 8) within the first 6 weeks of treatment. Data cutoff: January 31, 2022. CAR, chimeric antigen receptor; CR, complete response; DLBCL, diffuse large B-cell lymphoma; DOR, duration of response; IRC, independent review committee; LBCL, large B-cell lymphoma; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease.

FIG 2.

Response (per IRC; Lugano criteria) in prespecified subgroups of patients with LBCL. (A) ORRs. (B) CR rates. Data cutoff: January 31, 2022. ^aA greater proportion of patients in North America had exposure to CAR T-cell therapy compared with other regions. ^bPer the statistical analysis plan, subgroup analyses were not performed on subgroups with fewer than 20 patients. The ORR in patients who were not refractory to prior CAR T-cell therapy (n = 15) was 80.0% (95% CI, 51.9 to 95.7). The CR rate in patients who were not refractory to prior CAR T-cell therapy (n = 15) was 53.0% (95% CI, 26.6 to 78.7). ABC, activated B-cell; ASCT, autologous stem-cell transplantation; CAR, chimeric antigen receptor; CR, complete response; CRR, complete response rate; DLBCL, diffuse large B-cell lymphoma; GCB, germinal center B-cell; IPI, International Prognostic Index; IRC, independent review committee; LBCL, large B-cell lymphoma; ORR, overall response rate.