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.

Conflict of interest statement

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

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

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Catherine Thieblemont

Honoraria: Celgene, AbbVie, Bayer, Janssen, Roche, Incyte, Novartis, Gilead Sciences

Research Funding: Roche

Travel, Accommodations, Expenses: Roche, Janssen-Cilag, Kite/Gilead, Novartis, AbbVie

Tycel Phillips

Honoraria: Seattle Genetics, Lymphoma & Myeloma Connect

Consulting or Advisory Role: Seattle Genetics, Pharmacyclics, Incyte, Genentech, Bayer, Gilead Sciences, Curis, Kite/Gilead, Celgene, Genmab, TG Therapeutics, ADC Therapeutics, Lilly

Research Funding: AbbVie, Pharmacyclics/Janssen, Bayer, Genentech

Herve Ghesquieres

Honoraria: Gilead Sciences, Roche, Takeda

Consulting or Advisory Role: Gilead Sciences, Roche

Travel, Accommodations, Expenses: AbbVie

Chan Y. Cheah

Honoraria: Roche/Genentech, Janssen-Cilag, TG Therapeutics, Loxo/Lilly, AstraZeneca, Bristol Myers Squibb, Gilead Sciences, BeiGene, Novartis

Consulting or Advisory Role: Janssen-Cilag, Roche/Genentech (Inst), TG Therapeutics, Loxo/Lilly, Gilead Sciences, AstraZeneca, Bristol Myers Squibb, Ascentage Pharma, Merck

Research Funding: Roche/Genentech (Inst), Bristol Myers Squibb (Inst), AbbVie (Inst), Merck (Inst)

Travel, Accommodations, Expenses: Roche

Michael Roost Clausen

Consulting or Advisory Role: AbbVie, Janssen, Kite, a Gilead company, Genmab

Speakers' Bureau: AbbVie, Janssen

Travel, Accommodations, Expenses: AstraZeneca/Merck, Janssen, Genmab, AbbVie

David Cunningham

Stock and Other Ownership Interests: OVIBIO

Consulting or Advisory Role: OVIBIO

Research Funding: Celgene (Inst), MedImmune (Inst), Bayer (Inst), 4SC (Inst), Clovis Oncology (Inst), Lilly (Inst), Roche (Inst), Leap Oncology (Inst)

Tatyana Feldman

Honoraria: Seattle Genetics, Pharmacyclics/Janssen, AbbVie, Bristol Myers Squibb, Kite, a Gilead company, Bayer, Takeda

Consulting or Advisory Role: Seattle Genetics, Bristol Myers Squibb, Genmab, ADC Therapeutics, AstraZeneca

Speakers' Bureau: Seattle Genetics, Kite, a Gilead company

Research Funding: Bristol Myers Squibb (Inst), Seattle Genetics (Inst), Portola Pharmaceuticals (Inst), Eisai (Inst), Kyowa Hakko Kirin (Inst), Amgen (Inst), Viracta Therapeutics (Inst), Cell Medica (Inst), Roche (Inst), Trillium Therapeutics (Inst), Pfizer (Inst)

Travel, Accommodations, Expenses: Seattle Genetics, Takeda

Robin Gasiorowski

Honoraria: MSD, AbbVie, Astellas Pharma, Janssen, Novartis, Otsuka

Wojciech Jurczak

Consulting or Advisory Role: Roche, AstraZeneca, BeiGene

Research Funding: Acerta Pharma, TG Therapeutics, Sandoz-Novartis, Roche, Takeda, Epizyme, Janssen-Cilag, BeiGene, MorphoSys, MEI Pharma

Tae Min Kim

Consulting or Advisory Role: Hanmi, AstraZeneca/MedImmune, Janssen Oncology, Novartis, Takeda, Yuhan

Speakers' Bureau: Takeda, Roche/Genentech

Research Funding: AstraZeneca

Uncompensated Relationships: AstraZeneca/MedImmune, Novartis, Bayer, Sanofi, Boryung, Roche/Genentech

David John Lewis

Consulting or Advisory Role: Janssen Oncology, Kite/Gilead, BeiGene

Travel, Accommodations, Expenses: Kite, a Gilead company

Marjolein van der Poel

Consulting or Advisory Role: Takeda

Travel, Accommodations, Expenses: Jazz Pharmaceuticals, Daiichi Sankyo, AbbVie

Mariana Cota Stirner

Employment: AbbVie

Stock and Other Ownership Interests: AbbVie

Travel, Accommodations, Expenses: AbbVie

Nurgul Kilavuz

Employment: ADC Therapeutics, Genmab

Stock and Other Ownership Interests: Bristol Myers Squibb/Celgene, Genmab, ADC Therapeutics

Christopher Chiu

Employment: Janssen Research & Development, Genmab

Stock and Other Ownership Interests: Genmab

Patents, Royalties, Other Intellectual Property: Related to Daratumumab with Janssen, Related to Epcoritamab with Genmab

Menghui Chen

Employment: Genmab, Janssen

Stock and Other Ownership Interests: Genmab, Merck/Schering Plough

Mariana Sacchi

Employment: Genmab

Leadership: Genmab

Stock and Other Ownership Interests: Genmab

Brian Elliott

Employment: Genmab, Novartis

Stock and Other Ownership Interests: Novartis, Genmab

Patents, Royalties, Other Intellectual Property: Patents pending related to Genmab development of epcoritamab

Travel, Accommodations, Expenses: Genmab, Novartis

Tahamtan Ahmadi

Employment: Genmab

Leadership: Genmab

Stock and Other Ownership Interests: Genmab

Martin Hutchings

Consulting or Advisory Role: Takeda, Roche, Genmab, Janssen, AbbVie

Research Funding: Celgene (Inst), Genmab (Inst), Roche (Inst), Takeda (Inst), Novartis (Inst), Janssen (Inst), Merck (Inst), AbbVie (Inst), AstraZeneca (Inst)

Pieternella J. Lugtenburg

Consulting or Advisory Role: Takeda, Roche/Genentech, Genmab, Celgene, Regeneron, Incyte, AbbVie, Y-mAbs Therapeutics

Research Funding: Takeda (Inst), Servier (Inst)

Travel, Accommodations, Expenses: Celgene

No other potential conflicts of interest were reported.

Figures

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.