TOKYO—Kyowa Hakko Kirin Co. Ltd. (Kyowa Kirin) announced mid-August that results of the global Phase 3 MAVORIC study investigating the use of mogamulizumab (Poteligeo) in patients with cutaneous T cell lymphoma (CTCL) have been published in Lancet Oncology.
As Dr. Jeffrey S. Humphrey, president of Kyowa Kirin Pharmaceutical Development Inc., tells DDNews, “Mogamulizumab is a humanized immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that utilizes the body’s existing immune mechanism to recognize and destroy tumor cells, targeting CC chemokine receptor 4 (CCR4), for the treatment of the most common subtypes of cutaneous T cell lymphoma (CTCL), mycosis fungoides (MF) and Sézary syndrome (SS). Unlike most other drugs directed at G protein-coupled receptors, mogamulizumab doesn’t alter signaling through its target receptor. It instead binds CCR4 on the surface of tumor cells, catalyzing a form of immune defense known as antibody-dependent cellular cytotoxicity (ADCC). This process relies on natural killer cells in the immune system to recognize the tail of target-engaged antibodies and destroy the bound cells.”
MAVORIC (Mogamulizumab anti-CCR4 Antibody Versus ComparatOR In CTCL) was the open-label, randomized, multi-center Phase 3 trial that evaluated mogamulizumab versus vorinostat for treatment of adult patients with relapsed or refractory MF or SS after at least one prior systemic therapy. MF and SS are the most common subtypes of CTCL, a rare type of non-Hodgkin’s lymphoma, characterized by localization of malignant T lymphocytes to the skin. Depending on the stage, the disease may involve skin, blood, lymph nodes and viscera.
“The discovery of mogamulizumab was initially inspired by a finding that reduced fucose content in the carbohydrate side-chain on the tail of monoclonal antibodies enhanced antibody-dependent cellular cytotoxicity (ADCC). Kyowa Hakko Kirin learned how to manufacture pharmaceutical-grade monoclonal antibodies with reduced fucose content using a proprietary technology known as POTELLIGENT. Mogamulizumab was created using POTELLIGENT technology to enhance ADCC,” Humphrey continues.
MAVORIC is the first pivotal trial to use progression-free survival (PFS) as a primary endpoint, and the largest randomized study to compare systemic therapies in CTCL. Secondary endpoints included proportion of patients achieving an overall response (ORR), duration of response (DOR) and safety. It was the pivotal study included in the Biologics License Application that was recently approved by the U.S. Food and Drug Administration.
“Progression-free survival captures the duration of disease control with treatment based on the composite response assessment of each disease compartment—skin, blood, lymph nodes and viscera—and may more broadly reflect the overall impact of new therapies,” said Youn Kim, lead investigator and professor of dermatology/medicine and director of the Multidisciplinary Cutaneous Lymphoma Program at Stanford University School of Medicine and Stanford Cancer Institute. “Progression-free survival is more informative about the duration of overall clinical benefit for patients with a chronic course as in CTCL compared to using the overall response rate as a primary endpoint.”
“Patients with MF and SS may face years of disease management, and the goal of treatment is to improve PFS. Current treatment options for CTCL include skin-directed therapies consisting of phototherapy, radiation (local and entire skin surface), topical therapy and systemic therapies (affecting the entire body), including biologics, immune therapies and chemotherapies. Mogamulizumab is the first CCR4-targeting monoclonal antibody for the treatment of MF and SS,” notes Humphrey.
“The pivotal trial for mogamulizumab, MAVORIC, had PFS as the primary endpoint and looked at disease progression in all four compartments (skin, blood, lymph nodes and viscera),” he adds. “This was a unique and comprehensive endpoint for a CTCL study. In MAVORIC, mogamulizumab demonstrated significantly superior PFS and durable overall response rates compared to vorinostat in patients with previously treated MF and SS. By demonstrating response across three of the four disease compartments of CTCL (skin, blood and lymph nodes), mogamulizumab answers the need for a targeted therapy that helps patients manage their disease.”
In MAVORIC, 372 patients across 61 centers in 11 countries were randomized 1:1 to mogamulizumab or vorinostat, and stratified by CTCL subtype (MF or SS) and disease stage (IB/II or III/IV). Once enrolled, patients received either mogamulizumab 1.0 mg/kg or vorinostat 400 mg, and each treatment cycle was 28 days. Patients on vorinostat who demonstrated confirmed disease progression or experienced intolerable toxicity after two cycles, despite dose reduction and appropriate management of side effects, could cross over to treatment with mogamulizumab.
The results showed that mogamulizumab demonstrated significantly superior PFS at a median of 7.7 months [95 percent CI, 5.7, 10.3] compared to 3.1 months with vorinostat [95 percent CI, 2.9, 4.1; hazard ratio 0.53, 95 percent CI 0.41– 0.6969; p<0.0001]. In addition to meeting the primary endpoint, ORR [28 percent; 95 percent CI, 21.6, 35.0 vs. 4.8 percent; 95 percent CI, 2.2, 9.0], median DOR [14.1 months, IQR 8.4-19.2 vs. 9.1 months (IQR 5.6 – not estimable)] and response by disease compartment were higher for patients assigned to mogamulizumab than for patients assigned to vorinostat.
The safety profile of mogamulizumab was consistent with previous studies, and the most common adverse events of any grade included infusion-related reactions (33 percent) and drug rash (24 percent). Infusion-related reactions were manageable and mostly limited to early infusions. Grade 3–4 adverse events were reported in 75 (41 percent) of 184 patients in the mogamulizumab group and 76 (41 percent) of 186 patients in the vorinostat group. The most common serious adverse events were pyrexia in eight (4 percent) patients and cellulitis in five (3 percent) patients in the mogamulizumab group; and cellulitis in six (3 percent) patients, pulmonary embolism in six (3 percent) patients and sepsis in five (3 percent) patients in the vorinostat group.
“As seen on clinicaltrials.gov, Mogamulizumab is currently involved in various active trials, and some are as combination therapies, including with nivolumab and KHK2455, for various experimental cancer and tumor therapies,” Humphrey remarks. “Kyowa Kirin has also submitted a Marketing Authorization Application to the European Medicines Agency, seeking approval of mogamulizumab for the treatment of CTCL.”
“Mycosis fungoides and Sézary syndrome can be debilitating for patients and complex to treat and manage for healthcare professionals,” he concludes. “We are encouraged that these findings underscore the viability of mogamulizumab as a new treatment option for patients living with MF or SS.”