Cutaneous T-cell lymphomas (CTCL) are a class of T-cell malignancies in which skin is the primary site of involvement. CTCLs are classified as non-Hodgkin lymphomas and are quite rare, affecting approximately nine people per 1 million in the U.S. Mycosis fungoides (MF) and Sézary syndrome (SS) are the two most common subtypes of CTCL. Treating patients with advanced stages of these malignancies can be quite challenging, requiring systemic therapy, which often results in short-lived responses associated with disease progression and treatment resistance. Currently, the only curative option for patients with advanced MF or SS is allogeneic hematopoietic stem cell transplantation.
In the recent MAVORIC phase III clinical trial (NCT01728805), treatment with mogamulizumab, the anti-C-C chemokine receptor 4 (CCR4) monoclonal antibody, was compared with vorinostat, an FDA-approved histone deacetylase inhibitor, in previously treated patients with MF or SS. The lead investigator that participated in this study was Youn Kim, MD, Professor of Dermatology and Director of the Multidisciplinary Cutaneous Lymphoma Clinic/Program at Stanford University School of Medicine.
“To our knowledge, the MAVORIC trial is the largest randomized study of systemic therapy in CTCL and the first to evaluate systemic therapies using progression-free survival (PFS) as a primary endpoint, testing a new agent against an FDA-approved therapy.” A report containing the results from this important study was recently published (Lancet Oncol 2018;19:1192-1204).
In August 2018, citing the results obtained in the MAVORIC trial, the FDA granted approval to mogamulizumab for the treatment of MF and SS patients who had at least one prior line of systemic therapy.
CTCL Subtypes & Treatment Options
As previously stated, CTCLs are a group of diverse and rare non-Hodgkin lymphomas that have skin-based components to their pathologies. MF, which is the most common form of CTCL, is a neoplasm that is characterized by indolent behavior and varying severity and extent of skin disease (e.g., patches, plaques, tumors, or erythroderma). However, those with extracutaneous disease have a significant shortened life span. SS, which is a more aggressive form of CTCL, is much less common and is characterized by the presence of erythroderma, lymphadenopathy, and blood involvement with malignant T cells (Sézary cells). Combined, these two forms of the disease comprise more than two-thirds of all CTCL cases.
While skin-directed therapies are employed to treat early-stage (IA-IIA) MF patients, systemic therapies are often required for those having treatment-refractory early-stage MF, advanced stage MF, or SS. Among the systemic therapies used in MF/SS are the following: retinoids, methotrexate, interferons, histone deacetylase inhibitors (e.g., vorinostat and romidepsin), brentuximab vedotin, or cytotoxic chemotherapeutic agents.
When queried if there were other trials exploring different therapies for CTCL, Kim replied, “The ALCANZA trial (NCT01578499), also a randomized controlled trial, evaluated brentuximab vedotin against standard therapy choice of methotrexate or bexarotene in patients with CD30-positive MF and primary cutaneous anaplastic large cell lymphoma (Lancet 2017;390:555-566).”
“Mogamulizumab is an infusion-delivered monoclonal antibody that specifically targets CCR4, a surface molecule that is highly and consistently expressed by malignant T cells,” noted Kim regarding the investigative therapy in this trial. “Mogamulizumab is a type of an immune therapy and, in addition to directly killing the cancer cell by antibody-dependent cell-mediated cytotoxicity, it can also activate the body's immune system activity against the cancer cells by depleting regulatory T-cells (Tregs).
“In contrast,” she noted, “vorinostat is an orally dosed daily pill which has the common histone deacetylase (HDAC) inhibitor mechanism of action and side effects that can be challenging to tolerate. Vorinostat is not immune enhancing, but is likely more immunosuppressive; however, given that it is an oral agent, there is a convenience factor.
“In 2012, mogamulizumab was approved in Japan for the treatment of relapsed or refractory CCR4-positive adult T-cell leukemia-lymphoma (ATLL), while in 2014, also in Japan, approval was given for peripheral T-cell lymphoma and CTCL,” Kim commented.
This phase III study is an international, open-label, and randomized trial performed at 61 cancer treatment centers in the U.S., western Europe, Japan, and Australia. Patients were deemed eligible if they met the following criteria: histologically confirmed, relapsed or refractory MF or SS (stage IB-IVB); minimum age of 18 years (20 years or older in Japan); failed one prior systemic therapy (progression or toxicity); ECOG performance score ≥ 1; and adequate blood, liver, and kidney functioning.
Notably, patients already taking low- to intermediate-potency topical steroids or low-dose systemic steroids were allowed to continue that therapy; however, steroid treatment initiation was not allowed while in the trial, with the exception of topical steroids for managing drug-related rash.
Among the key exclusion criteria were prior allogeneic transplant; prior vorinostat or mogamulizumab therapy (brief vorinostat exposure without evidence of progression or toxicity on treatment was permitted at sponsor's discretion); CTCL skin-directed therapy within 2 weeks or systemic therapy within 4 weeks of randomization. Additionally, the following conditions rendered one ineligible for participation in this study: presence of large cell transformation at study entry; central nervous system metastases; active autoimmune disease; ongoing clinically significant uncontrolled illness.
Investigator-assessed PFS in the intent-to-treat population was considered the primary endpoint. Safety analyses utilized those patients who received one or more dose of study treatment. Although enrollment is complete, this study is ongoing.
“We chose vorinostat as our comparator drug,” Kim explained, “because it is an FDA-approved standard of care option for cutaneous T-cell lymphoma treatment with proven activity across disease compartments. Additionally, vorinostat was not used for first-line systemic treatment of MF or SS, unlike other standards of care such as bexarotene.”
Patients were randomized in a 1:1 manner to either mogamulizumab or vorinostat. Those in the mogamulizumab group were treated at 1.0 mg/kg IV over 1 hour on days 1, 8, 15, and 22 of the initial 28-day cycle, and on days 1 and 15 of each subsequent treatment cycle. Dose reductions were not allowed for those in the mogamulizumab group. Vorinostat was orally dosed at 400 mg QD with food.
Treatment could be continued until disease progression, drug intolerance, unacceptable toxicity, or any other criteria for treatment discontinuation were met. If a global complete response was noted for an individual (defined as a complete response in the skin, and complete response or no involvement in the other three disease compartments [lymph nodes, blood, and viscera]), then treatment could be continued for up to 12 months or until disease progression, whichever occurred first.
“Crossover was allowed only after discussion with the medical monitor and receipt of sponsor approval,” Kim noted. “This was done to ensure that patients on vorinostat did not prematurely discontinue that therapy and protocol criteria for crossover were met.”
From December 2012 to January 2016, the 372 patients who comprised the intent-to-treat population were enrolled and randomized to either mogamulizumab (n=186) or vorinostat (n=186). As of the data cutoff date (Dec. 31, 2016), 27 patients in the mogamulizumab group and 10 in the vorinostat group were still receiving their respective study drug.
Primary analysis showed that the investigator-assessed median PFS was 7.7 months (95% CI: 5.7-10.3 months) for mogamulizumab patients and 3.1 months (95% CI: 2.9-4.1 months) for vorinostat patients, affording a hazard ratio (HR) of 0.53 (95% CI: 0.41-0.69; p<0.0001).
Independently reviewed analyses afforded median PFS values of 6.7 months (95% CI: 5.6-9.4 months) and 3.8 months (95% CI: 3.0-4.7 months) for the mogamulizumab and vorinostat groups, respectively, providing a HR of 0.64 (95% CI: 0.49-0.84; p<0.0007).
“Our results show that for the investigator-assessed median PFS, the study's primary efficacy endpoint, mogamulizumab was superior to vorinostat,” Kim said. “Superiority was also noted for mogamulizumab with regards to the proportion of patients who achieved an overall response and for patient-reported quality-of-life outcomes, with a manageable safety profile that was consistent with previous studies.”
Stating what she felt were the most significant findings from the MAVORIC study, Kim said, “Mogamulizumab met all primary (PFS) and secondary endpoints and displayed superior PFS and ORR to vorinostat, a previously FDA-approved drug.” “This difference was most significant in the subset of CTCL patients with SS.”
In summarizing how the results from MAVORIC would affect the future treatment of CTCL, Kim stated, “Mogamulizumab was demonstrated to be a new and effective option for patients with the MF or SS subtype of CTCL (the specific patient population enrolled in this study), and an especially great therapy for patients with the SS type with leukemic disease.”
Regarding the outcomes for this therapy, “Side effects of mogamulizumab are usually mild to moderate and very manageable; in addition to the objective efficacy and safety outcome measures, patient-reported outcome data showed their quality of life was also improved with this treatment,” she noted.
“As a consequence, we may elect to use mogamulizumab for those with high-risk blood disease (SS) over previously available options given that it has impressive efficacy in these leukemic patients with overall great tolerability.”
When asked about the next steps for evaluating mogamulizumab, Kim replied, “I expect there to be more studies utilizing combination approaches in order to enhance ORR and further improve PFS/DOR (duration of response)—there are numerous possibilities.
“Since mogamulizumab does best in the blood compartment, we can combine it with treatments that have stellar performance in the skin compartment (such as total skin electron beam therapy) to give improved combined outcome; other combinations can utilize synergy data in preclinical models.”
In discussing other knowledge gaps within the treatment of patients with mogamulizumab, Kim noted, “We need to understand who responds to mogamulizumab better and what the escape/resistance mechanisms are for patients with disease that does not respond to this therapy.
“There is new evidence in ATLL that the patients having malignant cells with an activating CCR4 mutation may have superior clinical outcomes than those without; this type of data needs to be validated in CTCL so we can enrich those patients that would likely benefit from mogamulizumab therapy.”
Richard Simoneaux is a contributing writer.