Elsevier

The Lancet Oncology

Volume 19, Issue 9, September 2018, Pages 1192-1204
The Lancet Oncology

Articles
Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC): an international, open-label, randomised, controlled phase 3 trial

https://doi.org/10.1016/S1470-2045(18)30379-6Get rights and content

Summary

Background

Cutaneous T-cell lymphomas are rare non-Hodgkin lymphomas with substantial morbidity and mortality in advanced disease stages. We compared the efficacy of mogamulizumab, a novel monoclonal antibody directed against C-C chemokine receptor 4, with vorinostat in patients with previously treated cutaneous T-cell lymphoma.

Methods

In this open-label, international, phase 3, randomised controlled trial, we recruited patients with relapsed or refractory mycosis fungoides or Sézary syndrome at 61 medical centres in the USA, Denmark, France, Italy, Germany, the Netherlands, Spain, Switzerland, the UK, Japan, and Australia. Eligible patients were aged at least 18 years (in Japan, ≥20 years), had failed (for progression or toxicity as assessed by the principal investigator) at least one previous systemic therapy, and had an Eastern Cooperative Oncology Group performance score of 1 or less and adequate haematological, hepatic, and renal function. Patients were randomly assigned (1:1) using an interactive voice web response system to mogamulizumab (1·0 mg/kg intravenously on a weekly basis for the first 28-day cycle, then on days 1 and 15 of subsequent cycles) or vorinostat (400 mg daily). Stratification was by cutaneous T-cell lymphoma subtype (mycosis fungoides vs Sézary syndrome) and disease stage (IB–II vs III–IV). Since this study was open label, patients and investigators were not masked to treatment assignment. The primary endpoint was progression-free survival by investigator assessment in the intention-to-treat population. Patients who received one or more doses of study drug were included in the safety analyses. This study is ongoing, and enrolment is complete. This trial was registered with ClinicalTrials.gov, number NCT01728805.

Findings

Between Dec 12, 2012, and Jan 29, 2016, 372 eligible patients were randomly assigned to receive mogamulizumab (n=186) or vorinostat (n=186), comprising the intention-to-treat population. Two patients randomly assigned to mogamulizumab withdrew consent before receiving study treatment; thus, 370 patients were included in the safety population. Mogamulizumab therapy resulted in superior investigator-assessed progression-free survival compared with vorinostat therapy (median 7·7 months [95% CI 5·7–10·3] in the mogamulizumab group vs 3·1 months [2·9–4·1] in the vorinostat group; hazard ratio 0·53, 95% CI 0·41–0·69; stratified log-rank p<0·0001). Grade 3–4 adverse events of any cause were reported in 75 (41%) of 184 patients in the mogamulizumab group and 76 (41%) of 186 patients in the vorinostat group. The most common serious adverse events of any cause were pyrexia in eight (4%) patients and cellulitis in five (3%) patients in the mogamulizumab group; and cellulitis in six (3%) patients, pulmonary embolism in six (3%) patients, and sepsis in five (3%) patients in the vorinostat group. Two (67%) of three on-treatment deaths with mogamulizumab (due to sepsis and polymyositis) and three (33%) of nine on-treatment deaths with vorinostat (two due to pulmonary embolism and one due to bronchopneumonia) were considered treatment-related.

Interpretation

Mogamulizumab significantly prolonged progression-free survival compared with vorinostat, and could provide a new, effective treatment for patients with mycosis fungoides and, importantly, for Sézary syndrome, a subtype that represents a major therapeutic challenge in cutaneous T-cell lymphoma.

Funding

Kyowa Kirin.

Introduction

Cutaneous T-cell lymphomas are a rare and heterogeneous group of extranodal T-cell lymphomas characterised by skin involvement, with an overall US incidence of 7·5 cases per 1 million people.1 The most common type of cutaneous T-cell lymphoma is mycosis fungoides, an indolent neoplasm characterised by variable type and extent of skin disease (patches, plaques, tumour-type, and erythroderma), with a subset of patients either presenting with or developing extracutaneous disease. Sézary syndrome is a much rarer but more aggressive type of cutaneous T-cell lymphoma, characterised by erythroderma, lymphadenopathy, and blood involvement with neoplastic T cells. Together, mycosis fungoides and Sézary syndrome account for about two-thirds of all cutaneous T-cell lymphomas.2 With substantial clinical and biological overlap, both disease types can cause lifelong morbidity, decreased quality of life due to chronic skin impairment with intractable itching, recurrent infections, disfiguring skin lesions, sleep disturbance, and psychosocial problems.3 The burden of disease in skin and the presence of extracutaneous disease are primary determinants of survival.4, 5, 6, 7 Patients with advanced-stage mycosis fungoides and Sézary syndrome (stages IIB–IVB disease) have a median overall survival of approximately 5 years.6

Research in context

Evidence before this study

We searched PubMed, Embase, and Cochrane Library for phase 2 and phase 3 clinical trials in patients with cutaneous T-cell lymphoma done in the past 20 years (between Jan 1, 1998, and Jan 17, 2018) with the following search string: (“cutaneous T-cell lymphoma” OR “CTCL” OR “mycosis fungoides” OR “Sézary syndrome”), with no language restrictions. In the previous two decades, most prospective phase 2 or 3 clinical trials of systemic agents were either non-randomised (67 studies in total) or randomised to compare one or more doses of an agent, with or without a placebo or observational arm (five studies in total). Two non-randomised mogamulizumab trials were identified in our search—one phase 1/2 trial and one phase 2 trial. One phase 3 randomised trial published in 2017 (n=131; ALCANZA) compared systemic drugs (brentuximab vedotin vs physician's choice of methotrexate or bexarotene) in previously treated patients with CD30-positive mycosis fungoides or primary cutaneous anaplastic large-cell lymphoma—with exclusion of patients with Sézary syndrome—and used objective global response lasting at least 4 months as the primary endpoint. In published studies, the proportion of patients who achieved an objective response was determined by a range of methods, with trials before 2011 generally using less comprehensive assessments.

Added value of this study

Previous studies of systemic agents in cutaneous T-cell lymphoma that included Sézary syndrome as a major subtype were single-arm trials that mostly used the proportion of patients achieving an overall response as the primary endpoint. Although both overall response and progression-free survival are clinically relevant endpoints in cutaneous T-cell lymphoma, progression-free survival also captures the duration of disease control (absence of disease progression) with treatment, and therefore might more broadly reflect the overall clinical benefit in patients with cutaneous T-cell lymphoma, who often have a chronic disease course. To our knowledge, the phase 3 MAVORIC trial is the largest randomised study of systemic therapy in cutaneous T-cell lymphoma and the first to compare systemic therapies using progression-free survival as a primary endpoint. Our results show that mogamulizumab was superior to vorinostat for investigator-assessed median progression-free survival, the study's primary efficacy endpoint, and also for the proportion of patients who achieved an overall response and for quality-of-life outcomes, with a manageable safety profile consistent with previous studies.

Implications of all the available evidence

Our MAVORIC study found that, in patients with previously treated mycosis fungoides or Sézary syndrome, treatment with mogamulizumab, a first-in-class anti-CC chemokine receptor 4 monoclonal antibody, resulted in superior progression-free survival, a higher proportion of patients achieving an overall response, and better patient-reported outcomes than vorinostat, a US Food and Drug Administration-approved histone deacetylase inhibitor. Therefore, mogamulizumab could be a valuable new therapeutic option for patients with cutaneous T-cell lymphoma.

Patients with early-stage mycosis fungoides (IA–IIA) are treated primarily with skin-directed therapies, whereas those with treatment-resistant early-stage mycosis fungoides, advanced-stage mycosis fungoides, or Sézary syndrome require systemic drugs, including retinoids, methotrexate, interferons, histone deacetylase inhibitors (eg, vorinostat and romidepsin), brentuximab vedotin, or cytotoxic chemotherapeutic drugs.8, 9 Many of these drugs were approved on the basis of small, single-arm or non-randomised trials with varied response criteria. The largest phase 3 trial comparing systemic therapies reported so far included 131 patients.10 Except for allogeneic haemopoietic stem cell transplantation, there are no curative options for cutaneous T-cell lymphoma. Patients with cutaneous T-cell lymphoma often experience disease progression on therapy or become resistant to existing treatments, resulting in a need for newer therapies that target all disease compartments (skin, blood, lymph nodes, and viscera) and provide a durable response.

Mogamulizumab (KW-0761; Kyowa Kirin, Tokyo, Japan), a first-in-class defucosylated humanised IgG1 κ monoclonal antibody, selectively binds to C-C chemokine receptor 4 (CCR4) with enhanced antibody-dependent cellular cytotoxicity activity.11 CCR4, which is involved in cell trafficking of lymphocytes to skin, is consistently expressed on the surface of tumour cells in T-cell malignancies, such as cutaneous T-cell lymphoma (including mycosis fungoides and Sézary syndrome), adult T-cell leukaemia-lymphoma, and peripheral T-cell lymphoma.12, 13, 14, 15

Mogamulizumab has been approved in Japan for relapsed or refractory CCR4-positive adult T-cell leukaemia-lymphoma (2012), peripheral T-cell lymphoma (2014), and cutaneous T-cell lymphoma (2014).16 In a US-based phase 1/2 study in patients with cutaneous T-cell lymphoma, mogamulizumab showed an acceptable safety profile and promising efficacy, with 37% of patients achieving an overall response, and 95% achieving a response in the blood compartment.17 These encouraging results led to the development of our phase 3 MAVORIC study, which compared mogamulizumab to vorinostat, a US Food and Drug Administration (FDA)-approved drug with established clinical activity,18, 19 in previously treated patients with mycosis fungoides or Sézary syndrome. Both the proportion of patients achieving an overall response and progression-free survival are clinically relevant efficacy endpoints in cutaneous T-cell lymphoma. However, in contrast to the proportion of patients achieving an overall response, progression-free survival also provides information about the duration of disease control (ie, absence of disease progression) with treatment, and therefore might more broadly reflect overall meaningful clinical benefit in patients with cutaneous T-cell lymphoma, who often have a chronic disease course. Therefore, we undertook a phase 3 randomised trial comparing systemic therapies in previously treated patients with cutaneous T-cell lymphoma in which we used progression-free survival as the primary endpoint.

Section snippets

Study design and participants

MAVORIC is an open-label, international, randomised controlled phase 3 trial done at 61 medical centres in the USA, Denmark, France, Italy, Germany, the Netherlands, Spain, Switzerland, the UK, Japan, and Australia.

Eligible patients had stage IB–IVB (appendix pp 10–12),20 histologically confirmed relapsed or refractory mycosis fungoides or Sézary syndrome, were aged at least 18 years (in Japan, ≥20 years), had failed (for progression or toxicity as assessed by the principal investigator) at

Results

Between Dec 12, 2012, and Jan 29, 2016, we enrolled 372 patients and randomly assigned them to receive mogamulizumab (n=186) or vorinostat (n=186); these patients comprised the intention-to-treat population (figure 1). The total number of patients enrolled and randomly assigned to a treatment group exceeded the planned enrolment (n=317) because large numbers of participants were enrolled after sites were notified of the last day to screen, and an allowance by the sponsor for newly initiated

Discussion

In the international, randomised, controlled phase 3 MAVORIC trial in previously treated patients with relapsed or refractory mycosis fungoides or Sézary syndrome, the anti-CCR4 antibody mogamulizumab showed statistically significantly superior progression-free survival compared with vorinostat. In addition to meeting the primary endpoint of the trial, mogamulizumab was also superior to vorinostat in terms of the proportion of patients who achieved an overall response, and resulted in improved

References (30)

  • MF Demierre et al.

    Significant impact of cutaneous T-cell lymphoma on patients' quality of life: results of a 2005 National Cutaneous Lymphoma Foundation survey

    Cancer

    (2006)
  • NS Agar et al.

    Survival outcomes and prognostic factors in mycosis fungoides/Sézary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer staging proposal

    J Clin Oncol

    (2010)
  • YH Kim et al.

    Long-term outcome of 525 patients with mycosis fungoides and Sézary syndrome: clinical prognostic factors and risk for disease progression

    Arch Dermatol

    (2003)
  • JJ Scarisbrick et al.

    Cutaneous Lymphoma International Consortium study of outcome in advanced stages of mycosis fungoides and Sézary syndrome: effect of specific prognostic markers on survival and development of a prognostic model

    J Clin Oncol

    (2015)
  • R Talpur et al.

    Long-term outcomes of 1,263 patients with mycosis fungoides and Sézary syndrome from 1982 to 2009

    Clin Cancer Res

    (2012)
  • Cited by (397)

    View all citing articles on Scopus

    Members are listed in the appendix

    View full text