ATLANTA — A new investigational agent, mogamulizumab (Kyowa Kirin), holds promise as a new treatment option for cutaneous T-cell lymphoma (CTCL), according to results of a large phase 3 trial.
The results from this trial, known as MAVORIC, have already been submitted for US Food and Drug Administration (FDA) approval, and were presented here at the American Society of Hematology (ASH) 2017 Annual Meeting.
Mogamulizumab is a humanized monoclonal antibody directed against CC chemokine receptor 4, which is frequently expressed on leukemic cells of certain hematologic malignancies including CTCL.
The drug is already approved in Japan for another rare disease, adult T-cell leukemia lymphoma.
In the study, mogamulizumab achieved a median progression-free survival (PFS) of 7.7 months, which is significantly longer than the 3.1 months for those treated with vorinostat (Zolinza, Merck & Co), which is an FDA-approved standard-of-care treatment for patients with CTCL (hazard ratio, 0.53; P < .0001).
"This is the first report of a randomized phase 3 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," said lead author Youn H. Kim, MD, professor of dermatology and director of the Multidisciplinary Cutaneous Lymphoma Program at the Stanford University School of Medicine in California. "Mogamulizumab demonstrated significantly superior efficacy outcomes compared to vorinostat in patients with previously treated CTCL."
"This study supports mogamulizumab as a valuable new therapeutic option in patients with CTCL," Dr Kim noted.
CTCL is a group of lymphoproliferative disorders characterized by localization of neoplastic T lymphocytes to the skin; collectively, CTCL is classified as a type of non-Hodgkin lymphoma.
"We don't think a lot about CTCL because it is one of the rare forms of lymphoma that we treat," commented Laurie Sehn, MD, chair, Lymphoma Tumour Group, BC Cancer Agency, British Columbia, Canada. "But it is an extremely debilitating type of lymphoma. They have lesions that are highly visible to themselves and others, they are highly symptomatic, and as time goes on, the disease progresses."
She noted that most of the chemotherapy regimens used in other types of lymphomas are not very effective for this subtype. "We have few effective options, and this is a very morbid condition," she commented at a press briefing held during the meeting. "Doctors and patients are looking forward to more effective therapies, like the one we saw in this study."
New Therapies for CTCL
At last year's ASH meeting, Dr Kim presented the results for another CTCL therapy. Among patients with CD30 expressing CTCL, treatment with the CD30-targeting antibody brentuximab vedotin (Adcetris, Seattle Genetics) was superior to physician's choice of therapy (methotrexate or bexarotene) in the phase 3 head-to-head-comparator ALCANZA study.
Last month the FDA approved brentuximab vedotin for CTCL patients who have received prior systemic therapy, based on the results of the ALCANZA study. Specifically, it was approved for patients with primary cutaneous anaplastic large cell lymphoma or CD30-expressing mycosis fungoides, which are the most common subtypes of CTCL.
In an earlier US-based phase 1/2 study in CTCL, Dr Youn explained, mogamulizumab demonstrated a tolerable safety profile and promising efficacy, with a 37% overall response rate (ORR) and a 95% response rate. These results led to the development of the current MAVORIC trial, which looked at the efficacy and safety of mogamulizumab vs vorinostat in previously treated patients with CTCL.
In August, the FDA granted breakthrough therapy designation status to mogamulizumab, which is being developed for the treatment of both mycosis fungoides and Sézary syndrome in adult patients who have received at least one prior systemic therapy.
Significantly Improved PFS
The MAVORIC Trial was conducted in 59 centers across 11 countries, and randomly assigned 372 patients with mycosis fungoides (stage 1B-IVB) or Sézary syndrome (B2) who had failed one or more systemic therapies to either mogamulizumab 1.0 mg/kg (weekly for the first 4-week cycle and then every 2 weeks) or vorinostat (400 mg daily). Patients randomly assigned to vorinostat had the option of crossing over to the investigational product if they experienced disease progression or intolerable toxicity.
The study's primary endpoint was investigator-assessed PFS in the randomized population, using the global composite response (based on skin, blood, nodes, and viscera) according to the ISCL/EORTC consensus guidelines.
Secondary endpoints included ORR, duration of response, and quality of life.
The significant improvement in PFS for mogamulizumab vs vorinostat was also seen on independent review (hazard ratio, 0.64; P = .0007; 6.7 vs 3.8 months). Superior PFS was also observed across predefined subgroups.
For secondary endpoints, global ORR was also significantly improved in the patients who received mogamulizumab vs vorinostat, at 28.0% vs 4.8% (P < .0001). This was also true as stratified by disease subtype: In patients with mycosis fungoides, it was 21.0% vs 7.1% (P = .0042), and for Sézary syndrome, it was 37.0% vs 2.3% (P < .0001). In addition, an ORR of 30.1% was observed in crossover patients.
Time to treatment response was also superior for the investigational agent, with a median of 3.32 vs 5.10 months. The duration of response also favored mogamulizumab, at 14.1 vs 9.1 months.
There were also statistically significant differences observed in patient-reported outcomes, as measured by the Skindex-29 and FACT-G, in favor of mogamulizumab, with significantly greater symptom reduction and improved functional status (Skindex-29 Symptoms cycles 3, 5, and 7, P < .05; Functional Cycles 3 and 5, P < .05; FACT-G Functional Well-Being scale cycles 3, 5, 7, and 9, P < .05).
The majority of adverse events associated with mogamulizumab were mild to moderate, Dr Kim explained. About 55% were grade 1/2, and 42.4% were grade 3/4. The most common events that were more commonly observed in the mogamulizumab group included infusion-related reactions (33.2% vs 0.5%, respectively) and skin eruptions caused by the drug (23.9% vs 0.5%, respectively).
Established as an Effective Option
Commenting on the study, Stefan K. Barta, MD, associate professor in the Department of Hematology/Oncology at Fox Chase Cancer Center, Philadelphia, Pennsylvania, noted that randomized studies for this disease have been rare, and the "investigators have to be congratulated on completing a randomized prospective clinical trial with 372 patients receiving either oral vorinostat or the new [CC chemokine receptor 4] monoclonal antibody mogalizumab."
"In this trial, mogalizumab resulted in an approximate doubling in the median [PFS] and a nearly 6-fold improvement in response when compared to vorinostat," Dr Barta told Medscape Medical News. "This was especially [true in] patients with Sézary syndrome, who appeared to derive the greatest benefit with a response seen in 37% of patients as compared to only 2.3% treated with vorinostat."
The drug was also well tolerated, and disease-related symptoms and functional status in mogalizumab-treated patients were significantly improved. "This establishes mogalizumab as an effective option for patients with mycosis fungoides and Sézary syndrome who have received at least 1 prior systemic therapy, and especially for CTCL patients with significant blood involvement," Dr Barta commented.
Funding for this study was provided by Kyowa Kirin Pharmaceutical Development. Dr Kim reports the following disclosures: Membership on an entity's board of directors or advisory committees: Eisai, Seattle Genetics, Medivir, Kyowa-Kirin-Pharma, Forty Seven Inc, and Millennium Pharmaceuticals Inc; consultancy: Portola, Innate Pharma, and Horizon Pharma; and research funding: Eisai; Millennium Pharmaceuticals Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited; Soligenix; Seattle Genetics; Portola; Neumedicine; miRagen: Merck; Kyowa-Kirin-Pharma; Innate Pharma; Horizon Pharma; Forty Seven Inc; Tetralogic. Several coauthors also report relationships with industry.
American Society of Hematology (ASH) 2017 Annual Meeting: Abstract 817. Presented December 11, 2017.
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Cite this: Mogamulizumab: Valuable New Option for Cutaneous Lymphoma - Medscape - Dec 10, 2017.