Research in context
Evidence before this study
Cutaneous T-cell lymphoma is incurable and, unlike systemic lymphomas, multidrug systemic chemotherapy is ineffective, generally achieving responses lasting 3–6 months. Moreover, recently approved drugs such as bexarotene, vorinostat, romidepsin, and pralatrexate achieve a response in approximately 30% of patients and the associated phase 2 studies have shown that response duration is often short and progression-free survival is about 6–8 months. Methotrexate and bexarotene are the most frequently used systemic therapies worldwide for the treatment of cutaneous T-cell lymphoma.
CD30 is frequently expressed in cutaneous T-cell lymphoma subtypes, in particular mycosis fungoides and primary cutaneous anaplastic large-cell lymphoma (pcALCL). The safety and efficacy of brentuximab vedotin for the treatment of patients with other CD30-expressing haematological malignancies has been shown for Hodgkin's lymphoma and systemic ALCL.
We searched the scientific literature to identify reports of patients with cutaneous T-cell lymphoma, including mycosis fungoides and pcALCL, treated with brentuximab vedotin. We searched MEDLINE for studies published in English between database inception and Jan 16, 2017. Search terms included “CTCL”, “cutaneous T-cell lymphoma”, “mycosis fungoides”, “primary cutaneous CD30-positive T-cell lymphoma”, and “primary cutaneous anaplastic large cell lymphoma”. We identified two phase 2 studies using single-drug brentuximab vedotin, one for the treatment of mycosis fungoides or Sézary syndrome, and the second in CD30-positive cutaneous T-cell lymphoma and lymphomatoid papulosis. We identified six case reports or series on the use of brentuximab vedotin in patients with mycosis fungoides and six case reports or series on the use of brentuximab vedotin in patients with pcALCL. These studies and reports showed single-drug activity of brentuximab vedotin in cutaneous T-cell lymphoma. We did not identify any phase 3 studies of brentuximab vedotin for cutaneous T-cell lymphoma.
Added value of this study
This is the first randomised study of a new systemic drug against standard therapy and the largest reported phase 3 trial in patients with cutaneous T-cell lymphoma, and unlike many previous studies, uses the present international consensus response criteria incorporating skin, nodal, visceral, and blood responses. The study shows impressive activity of brentuximab vedotin in patients with cutaneous T-cell lymphoma who require systemic therapy. The proportion of patients achieving an objective response lasting 4 months or longer was 56·3% with brentuximab vedotin versus 12·5% with physician's choice (p<0·0001). This endpoint captures the proportion of patients with a response and duration of response as a single measurement and reflects a more appropriate and stringent measure of treatment success than the proportion of patients with a response alone in a patient population for whom short clinical responses do not necessarily correspond with meaningful benefit. Improvement in progression-free survival was striking (16·7 months vs 3·5 months). Moreover, the proportions of patients achieving a complete response and improvement in symptom burden were all significantly improved in the brentuximab vedotin group and activity was consistent across key subgroups, including skin-only and extracutaneous disease subgroups. Treatment with brentuximab vedotin was not associated with any new or unexpected toxicities compared with the established safety profile.
Implications of all the available evidence
This study reports the first finding of benefit in a randomised phase 3 trial of a novel systemic drug versus an active standard comparator for the treatment of cutaneous T-cell lymphoma. We consider these results to be potentially practice changing and as a consequence approval is being sought from the US Food and Drug Administration and European Medicines Agency for the use of brentuximab vedotin in the treatment of patients with cutaneous T-cell lymphoma who require systemic therapy.