Several peripheral T-cell lymphomas (PTCL) express the tumour necrosis factor (TNF) receptor CD30, conferring cell survival and growth when activated through the NF-kB pathway. Brentuximab vedotin (BV) is an antibody-drug conjugate (ADC) comprising an anti-CD30 monoclonal antibody and a microtubule-disrupting agent, monomethyl auristatin E (MMAE). Once bound to CD30 on tumour cells, BV is internalised by endocytosis and the MMAE released into the cytosol disrupts the microtubule network causing cell death.

In the phase III, ECHELON-2 trial, 452 patients with untreated CD30-expressing PTCL were randomised 1:1 to receive BV (1.8 mg/kg IV) plus cyclophosphamide, doxorubicin, and prednisone (CHP) or cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for six or eight 21-day cycles. Adding BV to chemotherapy conferred longer progression-free survival (PFS) than chemotherapy alone (PFS: 48.2 months versus 20.8 months), reducing the risk of death or progression by 29%. Greater objective response (OR) and complete remission (CR) rates were reported in BV+CHP patients compared with CHOP (ORR: 83% versus 72%; CRR: 68% versus 56%). Durable OR was achieved at all levels of CD30 expression among BV+CHP recipients, including those with 10% CD30 expression. No clinically meaningful differences in generic or disease-specific quality of life (QoL) scores were observed between groups. Treatment-related adverse events of any grade reported in 20% or more patients in the BV+CHP versus the CHOP group were nausea, peripheral sensory neuropathy, neutropenia, diarrhoea, constipation, alopecia, pyrexia, vomiting, fatigue, and anaemia.

Overall, ECHELON-2 is the first phase 3, randomised, double-blind, active comparator study to demonstrate that adding BV to CHP increases PFS, OR and CR in previously untreated CD30-positive PTCL patients. While the PFS benefits were generally consistent across subtypes, the study was not powered to compare efficacy between individual histological subtypes and small sample sizes preclude definitively determining the treatment effect in non-systematic ALCL. No clinically meaningful differences were noted in QoL measures. The development of a clinically validated in vitro diagnostic for CD30 expression may ensure the appropriate selection of patients most likely to benefit from BV+CHP therapy. Further studies are needed to better define the efficacy of BV in non-ALCL histologies, optimal dosing to enhance disease control while limiting complications, optimal therapeutic sequence, and use as monotherapy versus in combination with immune checkpoint inhibitors or other immunomodulatory agents.