1. Fuerst, Mark L.

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ATLANTA-The targeted monoclonal antibody mogamulizumab more than doubled progression-free survival (PFS) as compared to standard care with vorinostat in previously treated cutaneous T-cell lymphoma (CTCL) patients, according to a new study.

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The results of a large, international, randomized phase III trial showed patients who received the investigational targeted drug mogamulizumab not only had significantly better PFS, but also had better response rate and quality of life than patients who received vorinostat, an FDA-approved standard-of-care treatment for patients with CTCL. The adverse events observed with mogamulizumab treatment were generally mild to moderate in severity.


"This is the first report of a randomized phase III study evaluating PFS as a primary endpoint in CTCL to compare a new systemic therapy against an FDA-approved agent, utilizing the consensus comprehensive global response criteria," stated lead author Youn H. Kim, MD, Professor of Dermatology and Director of the Multidisciplinary Cutaneous Lymphoma Program at the Stanford University School of Medicine. "Mogamulizumab, a novel CCR4-targeting antibody therapy, demonstrated significantly superior efficacy outcomes compared to vorinostat in patients with previously treated CTCL."


Kim presented the results at the 2017 American Society of Hematology Annual Meeting (Abstract 817).


A Look at CTCL

CTCL, a rare form of non-Hodgkin lymphoma, often leads to reduced quality of life from intractable itching and recurrent infections, and advanced stages have a poor prognosis. CTCL primarily occurs in the skin, caused when T cells begin to grow uncontrollably and build up in the skin. CTCL can also involve the blood, lymph nodes, and internal organs. Mogamulizumab is a monoclonal antibody directed against chemokine receptor 4 (CCR4), which is overexpressed on malignant T cells.


In a phase I/II study in CTCL, mogamulizumab demonstrated a tolerable safety profile with a 37 percent overall response rate (ORR), Kim noted. Based on these results, researchers initiated MAVORIC, an open-label, multinational, randomized, phase III study, to compare mogamulizumab to vorinostat in previously treated CTCL.


In late November 2017, the FDA granted a priority review to a biologics license application for mogamulizumab for the treatment of patients with CTCL who have received at least one prior systemic therapy. The FDA is scheduled to make its final decision on this application by mid-2018.


The MAVORIC study included 372 patients with histologically confirmed stage IB to IVB mycosis fungoides (MF) or Sezary syndrome (SS) who had failed at least one systemic therapy. Patients were randomized to 1 mg/kg of mogamulizumab weekly for the first 4-week cycle and then every 2 weeks, or vorinostat at 400 mg daily. Crossover to mogamulizumab was allowed for patients receiving vorinostat who progressed or had intolerable toxicity.


Patient characteristics in the two arms were well-balanced, she said. Median age was 64 years, ECOG performance status of 0 or 1 in virtually all patients, and stage III/IV disease in about two-thirds of patients. The patients had a median of three prior systemic therapies.


Among the 372 patients, the investigator-assessed median PFS was 7.7 months in the mogamulizumab arm and 3.1 months in the vorinostat arm. By independent review, the median PFS was 6.7 months versus 3.8 months, respectively. The PFS benefit with mogamulizumab was observed across predefined subgroups, including disease type and disease stage.


The ORR was 28 percent with mogamulizumab versus 4.8 percent with vorinostat. Among patients with MF and SS, the ORR was 21.0 percent versus 7.1 percent and 37.0 percent versus 2.3 percent, respectively. Mogamulizumab also improved ORR in patients with stage III disease at 22.7 percent versus 0, and stage IV disease at 36.5 percent versus 3.1 percent. Among patients assigned to vorinostat who crossed over to mogamulizumab, the ORR was 30.1 percent.


The median time to response was shorter with mogamulizumab (3.32 months) as compared to vorinostat (5.1 months). The median duration of response was longer with mogamulizumab (14.1 months) than with vorinostat (9.1 months).


Trial Results

"We found that mogamulizumab has convincing clinical activity, not just in skin, but also in clearing malignant T cells in the blood and lymph nodes," Kim explained. "PFS and overall global response outcomes are clearly superior, the side effects are tolerable, and we see measurable improvements in quality of life with mogamulizumab compared with vorinostat. Taken together, these findings represent a durable and clinically meaningful benefit for patients with CTCL."


Adverse effects such as diarrhea, nausea, altered taste, decreased appetite, increased blood creatinine levels, and decreased platelet counts occurred more than twice as frequently in patients treated with vorinostat than in those treated with mogamulizumab, she noted. By contrast, the adverse effects seen most frequently in patients treated with mogamulizumab were drug rash and infusion-related reactions, such as chills and flushing.


Grade 1/2 treatment-emergent adverse events (TEAEs) were experienced by 54.9 percent of patients receiving mogamulizumab; 42.4 percent of patients experienced grade 3 to 5 TEAEs. TEAEs occurring in more than 20 percent of patients that were more common with mogamulizumab versus vorinostat included infusion-related reactions (33.2% vs. 0.5%) and skin eruptions due to drug (23.9% vs. 0.5%).


Patient-reported outcomes (Skindex-29 and FACT-G) demonstrated significant improvement with mogamulizumab, Kim said.


The next step in the research will be to learn more about biomarkers to predict treatment outcome, and to test whether clinical benefit can be further improved by combining mogamulizumab with skin-directed or other systemic therapies that have different mechanisms of action, she said.


"We are very excited and we hope that this drug will be approved early next year to add to the limited options that we have in this patient population," Kim concluded.


Mark L. Fuerst is a contributing writer.