Elsevier

The Lancet

Volume 390, Issue 10094, 5–11 August 2017, Pages 555-566
The Lancet

Articles
Brentuximab vedotin or physician's choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial

https://doi.org/10.1016/S0140-6736(17)31266-7Get rights and content

Summary

Background

Cutaneous T-cell lymphomas are rare, generally incurable, and associated with reduced quality of life. Present systemic therapies rarely provide reliable and durable responses. We aimed to assess efficacy and safety of brentuximab vedotin versus conventional therapy for previously treated patients with CD30-positive cutaneous T-cell lymphomas.

Methods

In this international, open-label, randomised, phase 3, multicentre trial, we enrolled adult patients with CD30-positive mycosis fungoides or primary cutaneous anaplastic large-cell lymphoma who had been previously treated. Patients were enrolled across 52 centres in 13 countries. Patients were randomly assigned (1:1) centrally by an interactive voice and web response system to receive intravenous brentuximab vedotin 1·8 mg/kg once every 3 weeks, for up to 16 3-week cycles, or physician's choice (oral methotrexate 5–50 mg once per week or oral bexarotene 300 mg/m2 once per day) for up to 48 weeks. The primary endpoint was the proportion of patients in the intention-to-treat population achieving an objective global response lasting at least 4 months per independent review facility. Safety analyses were done in all patients who received at least one dose of study drug. This trial was registered with ClinicalTrials.gov, number NCT01578499.

Findings

Between Aug 13, 2012, and July 31, 2015, 131 patients were enrolled and randomly assigned to a group (66 to brentuximab vedotin and 65 to physician's choice), with 128 analysed in the intention-to-treat population (64 in each group). At a median follow-up of 22·9 months (95% CI 18·4–26·1), the proportion of patients achieving an objective global response lasting at least 4 months was 56·3% (36 of 64 patients) with brentuximab vedotin versus 12·5% (eight of 64) with physician's choice, resulting in a between-group difference of 43·8% (95% CI 29·1–58·4; p<0·0001). Grade 3–4 adverse events were reported in 27 (41%) of 66 patients in the brentuximab vedotin group and 29 (47%) of 62 patients in the physician's choice group. Peripheral neuropathy was seen in 44 (67%) of 66 patients in the brentuximab vedotin group (n=21 grade 2, n=6 grade 3) and four (6%) of 62 patients in the physician's choice group. One of the four on-treatment deaths was deemed by the investigator to be treatment-related in the brentuximab vedotin group; no on-treatment deaths were reported in the physician's choice group.

Interpretation

Significant improvement in objective response lasting at least 4 months was seen with brentuximab vedotin versus physician's choice of methotrexate or bexarotene.

Funding

Millennium Pharmaceuticals Inc (a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd), Seattle Genetics Inc.

Introduction

Cutaneous T-cell lymphomas are a rare group of non-Hodgkin lymphomas with heterogeneous characteristics, severe pruritus, and recurrent infectious complications. The most common forms are mycosis fungoides and Sézary syndrome.1, 2 Cutaneous T-cell lymphomas have an annual incidence in the USA of about 7·5 per million people.2 Advanced stage mycosis fungoides or Sézary syndrome (IIB–IVB) manifests as cutaneous tumours, erythroderma, or extracutaneous disease, and is associated with inferior quality of life and shortened survival compared with early-stage disease (IA–IIA).3, 4 Uniform expression of the cell-surface antigen CD30 defines a subset of cutaneous T-cell lymphomas known as the CD30-positive T-cell lymphoproliferative disorders, including primary cutaneous anaplastic large-cell lymphoma (pcALCL).1, 5 Mycosis fungoides often expresses CD30, albeit heterogeneously.6

In early-stage disease, skin-directed therapy often controls symptoms.7 For advanced-stage disease, no curative therapies exist. No randomised trials have established a preferred systemic therapy. Retinoids and methotrexate are consistently recommended for mycosis fungoides or pcALCL by standard of care guidelines worldwide, including the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology,8 the European Society for Medical Oncology,7 and the European Organisation for Research and Treatment of Cancer.5, 9 Bexarotene is standard of care in all geographic areas participating in this trial10 and the only treatment approved by both the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) to treat skin manifestations of advanced stage cutaneous T-cell lymphoma in patients refractory to one or more systemic treatments. Histone deacetylase inhibitors (eg, vorinostat and romidepsin) are FDA-approved but not EMA-approved in cutaneous T-cell lymphoma, and are not available as standard of care options in cutaneous T-cell lymphoma (mycosis fungoides or pcALCL) in many non-US regions. The proportions of patients achieving an objective response for most monotherapies are 20–35%, lasting approximately 4–6 months.11, 12, 13, 14 Multidrug chemotherapy regimens have similarly short-lived responses and are reserved for patients who have not responded to single-drug systemic therapies or have substantial nodal or visceral disease.7, 11

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.

Brentuximab vedotin is an anti-CD30 antibody–drug conjugate that has received regulatory approval in more than 65 countries for the treatment of relapsed or refractory Hodgkin lymphoma15 and systemic anaplastic large-cell lymphoma.16

In a phase 2 trial of 48 patients with CD30-positive relapsed or refractory cutaneous T-cell lymphomas, brentuximab vedotin showed notable activity, with 35 (73%) of 48 patients achieving an objective response, 17 (35%) of 48 achieving a complete response, and a median progression-free survival of 1 year. Activity was reported in 15 (54%) of 28 patients with mycosis fungoides who achieved an objective response irrespective of CD30 expression levels, and an objective response was achieved in 12 (100%) patients with CD30-positive pcALCL or lymphomatoid papulosis, or both.17 Another phase 2 trial in 32 patients with relapsed or refractory mycosis fungoides or Sézary syndrome reported 21 (70%) of 30 patients achieving an objective response, with activity noted at all levels of CD30 expression.18

These results support the rationale for ALCANZA, which aims to investigate the efficacy and safety of brentuximab vedotin versus physician's choice of methotrexate or bexarotene in previously treated patients with CD30-positive cutaneous T-cell lymphoma. This is, to our knowledge, the largest reported phase 3 trial of a new systemic drug against standard therapy in patients with cutaneous T-cell lymphoma.

Section snippets

Study design and patients

This was an international, open-label, randomised, phase 3, multicentre study of brentuximab vedotin versus conventional therapy for previously treated patients with CD30-positive cutaneous T-cell lymphoma. The trial was done in 52 academic centres in 13 countries in accordance with the International Conference on Harmonization guidelines for Good Clinical Practice, and appropriate regulatory requirements. Local ethics committees or institutional review boards approved the protocol.

Adult

Results

Between Aug 13, 2012, and July 31, 2015, we enrolled and randomly assigned 131 patients (66 to brentuximab vedotin and 65 to physician's choice; appendix p 12, figure 1). In total, 128 patients were included in the intention-to-treat population (64 in each group); three patients were excluded because of insufficient CD30 expression (appendix p 8).

Baseline characteristics were generally balanced between groups (table 1), with the exception of more patients with stage IVB mycosis fungoides and

Discussion

This international, open-label, randomised, phase 3, multicentre trial met its primary endpoint, showing significant improvement in the proportion of previously treated patients with mycosis fungoides or pcALCL achieving an objective global response lasting at least 4 months with brentuximab vedotin than with physician's choice of methotrexate or bexarotene. Specifically, treatment with brentuximab vedotin showed a 43·8% (95% CI 29·1–58·4) absolute improvement in ORR4 (56·3% [36 of 64 patients]

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    Both authors contributed equally to this Article

    Both authors contributed equally to this Article

    All ALCANZA study investigators are listed in the appendix

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