Treatment with mogamulizumab improved progression-free survival (PFS), compared with vorinostat in patients with previously treated cutaneous T-cell lymphoma (CTCL), according to results from a phase III study presented at the 2017 ASH Annual Meeting.
Lead author Youn H. Kim, MD, from Stanford University in California, shared findings from the open-label, international MAVORIC trial, the largest randomized trial and the first pivotal trial to use PFS as a primary endpoint in CTCL.
Mogamulizumab is a monoclonal antibody directed against chemokine receptor 4 (CCR4), which is overexpressed on malignant T-cells, the authors explained. In previous phase I/II studies, the agent had an acceptable safety profile and a 37 percent overall response rate (ORR), paving the way for the phase III randomized trial.
On November 28, 2017, the U.S. Food and Drug Administration granted priority review to a biologics license application of mogamulizumab for the treatment of patients with CTCL who have received at least one prior systemic therapy, based on results from the MAVORIC trial.
Investigators compared the safety and efficacy of mogamulizumab with vorinostat in 372 adult patients with histologically confirmed mycosis fungoides (MF) or Sézary syndrome (SS), two subtypes of CTCL, who had previously received at least one systemic therapy. People were stratified by disease type (MF or SS) and stage (IB/II or III/IV), then randomized 1:1 to receive either mogamulizumab 1.0 mg/kg (weekly for the first 4-week cycle and then every 2 weeks; n=186) or vorinostat 400 mg daily (n=186).
People randomized to the vorinostat arm were allowed to crossover to mogamulizumab if they had disease progression or intolerable toxicity.
Characteristics were similar between each treatment group. Patients had received a median of three prior systemic treatments (range not provided) across both arms, and most patients had stage III/IV disease (118 [63.4%] in the mogamulizumab group and 114 [61.3%] in the vorinostat group). Median age was 63.5 years (range = 25-101 years) in the mogamulizumab group and 65.0 years (range = 25-89 years) in the vorinostat group. Diagnoses of MF or SS also were equally represented between the treatment groups (105 [56.5%] and 99 [53.2%] patients, respectively, had MF, and 81 [43.5%] and 87 [46.8%] patients had SS).
Treatment with mogamulizumab resulted in a significant improvement in median PFS (defined as composite response on skin, lymph nodes, and viscera according to the International Society for Cutaneous Lymphomas/European Organization of Research and Treatment of Cancer consensus guidelines), compared with vorinostat: 7.7 months (range = 5.7-10.3 months) versus 3.1 months (range = 2.9-4.1 months), for a 47 percent lower risk of disease progression (hazard ratio [HR] = 0.53; 95% CI 0.41-0.69; p<0.0001).
Mogamulizumab also outperformed vorinostat in secondary endpoints, such as ORR and duration of response, including in patients who crossed over from the vorinostat arm. Dr. Kim reported that the agent “has convincing clinical activity, not just in skin, but also in clearing malignant T cells in the blood and lymph nodes.” (See TABLE for secondary endpoints.)
People treated with mogamulizumab also reported greater reduction in CTCL symptom burden (measured by the Skindex-29 questionnaire; p<0.05) and functional quality of life (measured by the Functional Assessment of Cancer Therapy – General scale; p<0.05).
The safety profile was consistent with previous reports for each agent, the researchers wrote. The most common treatment-related adverse events (AEs; >20%) in the entire study population included diarrhea, nausea, infusion-related reactions (IRRs), skin eruptions, and thrombocytopenia. Both IRRs and skin eruptions related to treatment occurred more frequently in the mogamulizumab arm (33.2% vs. 0.5% and 23.9% vs. 0.5%, respectively). Most of these AEs were mild to moderate (grade 1/2 = 55%; grade 3/4 = 42.4%).
“PFS and overall global response outcomes are superior, the side effects are tolerable, and we see measurable improvements in quality of life with mogamulizumab, compared with vorinostat,” Dr. Kim concluded. “Taken together, these findings represent a durable and clinically meaningful benefit for patients with CTCL.”
The open-label design and the use of investigator-assessed PFS as a primary endpoint may have limited the study’s findings by introducing bias. Also, because CCR4 expression level was not an eligibility criterion for inclusion, future trials will need to investigate how this factor affects response to mogamulizumab, Dr. Kim noted.
The authors report financial relationships with Kyowa Kirin, the manufacturer of mogamulizumab.
Kim YH, Bagot M, Pinter-Brown L, et al. Anti-CCR4 monoclonal antibody, mogamulizumab, demonstrates significant improvement in PFS compared to vorinostat in patients with previously treated cutaneous T-cell lymphoma: results from the phase 3 MAVORIC study. Abstract #817. Presented at the 2017 American Society of Hematology Annual Meeting, December 11, 2017; Atlanta, GA.