Abstract
Introduction Mogamulizumab (moga), a monoclonal antibody targeting chemokine receptor 4 (CCR4), is approved for relapsed/refractory mycosis fungoides/Sézary syndrome (MF/SS) after ≥1 prior systemic therapy with a dosing schedule of 1.0 mg/kg weekly (Q1W) in cycle (C) 1 (28 days) then every 2 weeks (Q2W) until disease progression (PD). A lower-frequency dosing schedule option could benefit some patients (pts) by reducing the number of clinic/infusion center visits. Safety and efficacy of a 2.0 mg/kg every 4 weeks (Q4W) dosing schedule was assessed in a phase 2 study in stage IB–IV MF/SS after ≥1 prior systemic therapy (NCT04745234).
Methods The primary objective was to assess the safety and tolerability of a 1.0 mg/kg Q1W in C1 followed by a 2.0 mg/kg Q4W dosing regimen. Secondary objectives included pharmacokinetics/pharmacodynamics evaluation and efficacy evaluation by MF/SS consensus response criteria: overall response rate (ORR: global complete response [CR]/partial response lasting ≥4 weeks), duration of response (DOR), disease compartmental response, time to global response (TTR), and progression-free survival (PFS). Exploratory objectives included characterizing immunophenotypic, gene expression, and mutational profiles, and identifying specific genetic alterations in lesional skin and blood samples, pre- and post-moga treatment, which are associated with clinical response, resistance, or drug eruption. Descriptive statistics for continuous variables, frequency, and percentages for discrete variables were used.
Results As of the April 18, 2025 data cut,study enrollment and follow-up are completed in 34 pts (median age 64.0 years; 64.7% male) in the United States (US) and Europe. At baseline (BL): 28 pts (82%) presented with MF at stages IB–IIA (n=8, 24%), IIB (n=12, 35%), IIIA–IIIB (n=7, 21%), and IVB (n=1, 3%), and 6 pts (18%) with SS at stages IIIA (n=1, 3%) and IVA1 (n=5, 15%). Median follow-up (min, max) was 21.1 (2.8, 35.2) months (mo).
Treatment-emergent adverse events (TEAEs) occurred in all 34 pts. Serious adverse events occurred in 26.5% of pts, with 17.6% deemed drug-related. Drug-related TEAEs occurred in 76.5% of pts (majority Grades 1/2), most frequently drug eruption (38.2%), infusion-related reaction (23.5%), diarrhea, and fatigue (both 14.7%). Thirteen pts (38.2%) discontinued due to TEAEs; 11 [32.3%] due to drug-related TEAEs. Five pts completed the 2-year protocol-prescribed treatment. There were no drug-related deaths.
The efficacy-evaluable set comprised 32 pts who completed C1 and received at least one 2.0 mg/kg dose in C2. ORR was 37.5% for all pts (12/32; CR: 2 pts), 30.8% for pts with MF (8/26; CR: 0 pts), and 66.7% for pts with SS (4/6; CR: 2 pts). For compartmental responses, ORR was 40.6% in skin (13/32 pts; CR: 2 pts), 100.0% in blood (9/9 pts; CR: 8 pts) and 0.0% in viscera (0/1 pts; CR: 0 pts). Median (min, max) TTR was 1.8 (1.0, 3.7) mo, median (min, max) DOR 13.4 (2.8, 22.7) mo, and median (min, max) PFS was 6.3 (1.7,23.6) mo (not Kaplan–Meier adjusted). Drug eruption occurred in 13 pts (38.2%), 7 (53.8%) of whom were responders.
Moga concentration increased with repeated doses, reaching a steady state by C3 (mean±SD concentration on C3 Day 1: 17,005.4±8,077.4 ng/mL). Flow cytometry showed a strong, sustained reduction in circulating malignant T cells and almost complete depletion of CCR4+ T cells. Evaluation of blood CCR4+T-cell counts of US pts showed B1/B2 pts had a higher BL count compared to B0 pts, which correlated with better moga treatment response; however, correlation between response and BL CCR4 expression in tumor, skin, and disease stage was not seen. Integrated genomic analysis of gene expression and mutational changes, including single-nucleotide polymorphisms in skin and/or blood at BL and post-treatment revealed distinct immune regulatory and skin-homing profiles associated with treatment response and drug eruptions.
Conclusions Results show a similar safety profile for the Q4W dosing schedule relative to the 1.0 mg/kg Q2W dosing schedule in a patient population that included a higher proportion of pts with MF vs the pivotal MAVORIC study (Kim 2018, Lancet Oncol). Although an increased rate of drug eruption relative to other trials was seen, this may have resulted from improved investigator experience discerning rash from PD since initial trials. Exploratory data on mutational profiles and immune response may allow for optimizing patient selection and management.
