Mogamulizumab in Patients with Mycosis Fungoides/Sézary Syndrome: Preliminary Results from an Ongoing Phase 2, Open-Label, Multicenter, Single-Arm Study Assessing a 4-Weekly Dosing Schedule

Background: Mogamulizumab (moga) targets the CC chemokine receptor 4 (CCR4), widely expressed on malignant T cells in patients (pts) with cutaneous T-cell lymphoma (CTCL). Moga depletes tumor cells in CTCL and is approved for relapsed/refractory mycosis fungoides (MF)/Sézary syndrome (SS) after ≥1 systemic therapy. The licensed dosing schedule consists of a weekly dose for the first 28-day cycle (C1), followed by doses every 2 weeks (Q2W) at 1 mg/kg. We present preliminary results using a Q4W dosing schedule at 2 mg/kg in adult pts with MF/SS (NCT04745234).

Methods: This ongoing open-label, multicenter, single-arm phase 2 study planned to enroll 33 pts with stage IB-IV MF/SS after ≥1 systemic therapy. The primary objective of the preliminary analysis (data cut 3 Nov 2023) was to assess moga safety and tolerability. Secondary endpoints included immunogenicity (anti-drug antibodies [ADA] and neutralizing antibodies) and anti-tumor activity (overall response rate [ORR; defined as complete/partial response [CR/PR] lasting ≥4 weeks] and time to next treatment [TTNT]). Exploratory endpoints were molecular and cellular dynamics of MF/SS: matched pre- and post-treatment blood samples and lesional vs non-lesional skin biopsies were analyzed for biomarker assessment by flow cytometry (FC) and immunohistochemistry (IHC), respectively, and subjected to comprehensive transcriptome profiling (IO360+CTCL gene panel [825 genes]) and whole exome sequencing. Skin samples of moga-induced rashes were similarly assessed.

Results: 34 pts were enrolled in the study (18 in the USA, 16 in Europe), for a median follow-up of 8.6 months (mos) (range 2.8–21.5). Median age was 64.0 years, 64.7% of pts were male, and 35.3% were female. 70.6% were White, 5.9% Black/African American, 2.9% Asian, 8.8% Other, and 11.8% not reported. 82.4% of pts had MF, 17.6% SS (stage IB–IIA: 23.5% [8/34]; IIB–IIIB: 58.8% [20/34]; IVA–IVB: 17.6% [6/34]). Median number of prior therapies was 4.5; 100% of pts received prior systemic therapies (median number of prior systemic therapies 4.0, range 1–6) and 67.6% of pts received skin-directed therapies. Treatment-emergent adverse events (TEAEs) were reported in 97.1% of pts; 26.5% had serious adverse events (SAEs). Moga-related TEAEs and SAEs were reported in 73.5% and 17.6% of pts, respectively. The most frequent moga-related TEAEs were drug eruption (32.4%), infusion-related reaction (23.5%), diarrhea (14.7%), and fatigue (14.7%). Among pts who completed C1 and received ≥1 dose at 2 mg/kg (n=32), ORR was 37.5% (12/32, 1 CR). ORR was 14.3% (1/7) for pts with clinical stage IB–IIA, 40.0% (8/20) for IIB–IIIB, and 60.0% (3/5) for IVA–IVB. Median TTNT was not evaluable per Kaplan-Meier estimate. The rate (95% Confidence Interval) of pts without next treatment at 15 months was 53.6% (31.4, 71.5). Of the 32 ADA evaluable pts, the ADA status of 4 (12.5%) was positive, 27 (84.4%) negative, and 1 (3.1%) unknown. No pts were positive for anti-moga neutralizing antibodies. Moga resulted in significant cell population shifts in pts with MF/SS, with near complete depletion of CD4⁺CCR4⁺T cells (98.0%, median) and CD4⁺CD25⁺FoxP3⁺ regulatory T (Treg) cells (59.8%, median), as assessed by FC. Reductions in CCR4⁺ and FoxP3⁺ cells in response to therapy were also observed by IHC, with concomitant changes seen in other cell populations, including an increase in CD8, CD16a, CD163, and granzyme B (GrB) cells. Whole exome sequencing of pre- and post-treatment skin lesions identified hotspot mutations in STAT3, TP53, RHOA, DNMT3A, JAK3, and HLA antigens, as well as unique mutations. Preliminary results of gene expression profiles for STAT3, CCR4, CD30, TOX, and PD-1 and tumor microenvironment-related genes (CXCL13, CCL22, PD-L1, VEGF) in matched pre- and post-treatment and lesional vs non-lesional skin biopsies will be presented to demonstrate the identified intra- and intertumoral heterogeneity which may correlate with disease progression or response to therapy.

Conclusions: Preliminary results of moga treatment at 2 mg/kg Q4W showed a manageable safety profile and promising response rate in pts with relapsed/refractory MF/SS. Translational results offer insights into the moga mechanism of action and potentially identify signatures that may predict response or resistance to therapy.