As reported by Youn H. Kim, MD, of Stanford Cancer Institute, Stanford University School of Medicine, and colleagues in The Lancet Oncology, the phase III MAVORIC trial showed that the anti-C-C chemokine receptor 4 (CCR4) monoclonal antibody mogamulizumab (Poteligeo) significantly improved progression-free survival vs vorinostat (Zolinza) among patients with previously treated cutaneous T-cell lymphomas.¹ The trial supported the recent U.S. Food and Drug Administration (FDA) approval of mogamulizumab in this setting.

Study Details

In the open-label trial, 372 adult patients with relapsed or refractory mycosis fungoides or Sézary syndrome at 61 sites in the United States, Denmark, France, Italy, Germany, the Netherlands, Spain, Switzerland, the UK, Japan, and Australia were randomized between December 2012 and January 2016 to receive mogamulizumab at 1.0 mg/kg intravenously weekly for the first 28-day cycle and then on days 1 and 15 of subsequent cycles (n = 186) or vorinostat at 400 mg daily (n = 186). Treatment was continued until disease progression or unacceptable toxicity. Patients had to have failed to respond to at least one previous systemic therapy. Randomization was stratified by disease subtype (mycosis fungoides vs Sézary syndrome) and disease stage (IB–II vs III–IV). The primary endpoint was progression-free survival on investigator assessment in the intention-to-treat population. Patients in the vorinostat group could cross over to mogamulizumab treatment upon disease progression or intolerable toxicity.

For the mogamulizumab vs vorinostat groups, the median age was 64 vs 65 years (47% vs 52% aged ≥ 65 years); 59% vs 58% were male; 67% vs 73% were white; all but 2 patients had an Eastern Cooperative Oncology Group performance status of 0 or 1; the median time since diagnosis was 41 vs 35 months; 56% vs 53% had mycosis fungoides and 44% vs 47% had Sézary syndrome; 36% vs 38% had stage IB to II disease and 64% vs 62% had stage III to IV disease; and the median number of prior systemic therapies was 3 in both groups.

Progression-Free Survival

At data cutoff, 27 patients receiving mogamulizumab and 10 receiving vorinostat remained on study treatment; 31 patients in the vorinostat group who crossed over to mogamulizumab also remained on treatment. The median duration of follow-up was 17.0 months in the randomized phase of the study.

Mogamulizumab significantly prolonged progression-free survival compared with vorinostat and could provide a new, effective treatment for patients with mycosis fungoides and Sézary syndrome.

— Youn H. Kim, MD, and colleagues

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The median progression-free survival was 7.7 months (95% confidence interval [CI] = 5.7–10.3 months) in the mogamulizumab group vs 3.1 months (95% CI = 2.9–4.1 months) in the vorinostat group (hazard ratio [HR] = 0.53, P < .0001). On independent review, the median progression-free survival was 6.7 months (95% CI = 5.6–9.4 months) vs 3.8 months (95% CI = 3.0–4.7 months; HR = 0.64, P < .0007). In a subgroup analysis, hazard ratios favored mogamulizumab in patients with mycosis fungoides (HR = 0.72, 95% CI = 0.51–1.01), Sézary syndrome (HR = 0.32, 95% CI = 0.21–0.49), stage IB to II disease (HR = 0.88, 95% CI = 0.58–1.35), and stage III to IV disease (HR = 0.36, 95% CI = 0.26–0.51). 

Overall response by global assessment occurred in 28% vs 5% of patients (P < .0001). A total of 136 patients treated with vorinostat (73%) crossed over to mogamulizumab therapy (109 due to disease progression, 27 due to toxicity). A post hoc analysis showed that the median progression-free survival was 8.4 months among the 319 patients who were either randomized to or crossed over to mogamulizumab. An exploratory analysis of overall survival showed that the median survival was not reached in the mogamulizumab group vs 43.9 months in the vorinostat group (HR = 0.93, P = .9439).

Toxicity

The most common adverse events of any grade in the mogamulizumab group were infusion-related reactions (32% grade 1–2, 2% grade 3), drug rash (20% grade 1–2, 4% grade 3), diarrhea (23% grade 1–2, 1% grade 3), and fatigue (22% grade 1–2, 2% grade 3). Grade 3 or 4 adverse events occurred in 41% of the mogamulizumab group vs 41% of the vorinostat group, with the most common in the mogamulizumab group being pneumonia (5%), drug eruption (4%), and hypertension (4%) and the most common in the vorinostat group being thrombocytopenia (7%), fatigue (6%), and hypertension (6%). Serious adverse

events occurred in 38% vs 25% of patients, with the most common in the mogamulizumab group being pyrexia (4%) and cellulitis (3%) and the most common in the vorinostat group being cellulitis (3%), pulmonary embolism (3%), and sepsis (3%). Adverse events led to discontinuation of treatment in 19% vs 23% of patients, with the most common causes being drug rash in the mogamulizumab group (7%) and fatigue in the vorinostat group (4%). Adverse events considered related to treatment resulted in death in two patients in the mogamulizumab group (due to sepsis and polymyositis) and three patients in the vorinostat group (two due to pulmonary embolism and one due to bronchopneumonia).

The investigators concluded: “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.” ■

DISCLOSURE: The study was funded by Kyowa Hakko Kirin. For full disclosures of the study authors, visit www.thelancet.com.

REFERENCE

1. Kim YH, Bagot M, Pinter-Brown L, et al: Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC).. Lancet Oncol. August 9, 2018 (early release online).