Mogamulizumab Forecast: Clearer patients, with a slight chance of immune mayhem

Abstract

Mogamulizumab, approved by the FDA for relapsed or refractory mycosis fungoides and Sézary syndrome, improves progression-free survival compared to vorinostat in the largest trial to date in cutaneous T-cell lymphoma, with particular efficacy in leukemic disease, but carries a risk of immune-mediated toxicities with concomitant depletion of regulatory T-cells.

In this issue of Clinical Cancer Research, Kasamon and colleagues report on the findings of the MAVORIC trial that led to FDA approval of mogamulizumab for relapsed or refractory mycosis fungoides (MF) and Sézary syndrome (SS) and provide regulatory insights on the FDA deliberation.(1) The MAVORIC trial, the largest randomized controlled trial in cutaneous T-cell lymphoma (CTCL) to date, exemplifies the latest standard set by the FDA in trial design for this disease.(2) It is notable for its rigorous assessment of response at more frequent intervals, utilization of a global composite response score, use of a comparator arm, and selection of progression-free survival (PFS) as the primary endpoint. However, the worse than expected performance of the comparator drug, vorinostat, potential early censoring in the mogamulizumab arm, and data quality problems with the patient-reported outcomes are potential caveats of the study. The modest overall response rate (ORR) in CTCL of 28% reflects the difficulty of showing efficacy in all anatomic compartments captured in the composite response score. This challenge may be overcome if mogamulizumab can be safely combined with other therapies. Immune-related adverse events were reported, and the severity, nature of autoimmune events, and long-term impact are unknown and require further study. Lastly, mogamulizumab performed better in SS than MF. Biologics that function through antibody-dependent cellular cytotoxicity (ADCC) may have greater efficacy in SS and may be less efficacious in treating non-recirculating (MF) lymphoma cells in skin.

Mogamulizumab, a defucosylated IgG1κ antibody, binds to C-C motif chemokine receptor 4 (CCR4)(Figure 1).(2) Defucosylation of the Fc portion of mogamulizumab specifically enhances ADCC.(2) Mogamulizumab does not inhibit CCR4, nor does it induce complement-dependent cytotoxicity.(3) CCR4, important for lymphocyte-specific chemotaxis to the skin, is predominately expressed in activated skin tropic and regulatory T-cells (T_regs).(4) Not surprisingly, T-cells in CTCL skin and blood largely express CCR4.(2) MAVORIC provides the largest assessment of CCR4 expression in cutaneous lesions of MF and SS. The receptor was detected in skin biopsies of all 290 evaluable patients (median CCR4 expression = 80%), but skin CCR4 levels did not correlate with response.(2) In fact, a significant portion of non-responders had expression of CCR4 in greater than 80% of lymphocytes in the skin.(1) While in the phase I/II trial, CCR4 expression in peripheral blood lymphoma cells did not correlate with response in MF or SS, patients with higher CCR4 expression in circulating malignant T-cells had faster clearance in the blood and residual leukemic cells had a lower percentage of CCR4 expression.(3,5) CCR4 expression in leukemic disease may be a more relevant biomarker for response in the blood, which is obfuscated when combined in the composite score.

Figure 1.

Effect of Mogamulizumab on T cells and risk for immune-mediated skin toxicity. A) MF T-cells and T_regs exhibit skin homing marker CLA. SS cells, have a T_CM phenotype, characterized by CD27. SS cells also express skin homing marker CCR4 and markers L Selectin and CCR7, which allow for recirculation between blood and lymph nodes. T_regs are present in skin and blood and suppress cytotoxic T-cells (T_C). Their effect on malignant T-cells is less well understood. B) Mogamulizumab binds to CCR4 and is enhanced to potentiate NK cell ADCC. C) Mogamulizumab clears leukemic disease more effectively than skin disease. Depletion of T_regs by mogamulizumab removes the breaks on cytotoxic T cells, and may result in immune-mediated toxicities, most commonly in the skin (e.g. drug eruption).

MAVORIC included MF and SS patients, the two most common subtypes of CTCL and revealed better responses in SS (ORR 37%) compared to MF (ORR 21%). While included in the same staging paradigm for historical reasons, they are now considered distinct diseases based on clinical presentation, genomic features and molecular T-cell markers.(6,7) MF, characterized by fixed, well-defined patches or plaques in early stages, expresses surface markers characteristic of non-recirculating skin resident memory T-cells (T_RM).(6,8) SS, characterized by leukemic disease and erythroderma, exhibits markers of central memory T-cells (T_CM), a recirculating T-cell population (Figure 1).(6,8,9) The different migratory properties of malignant T-cells in MF and SS may explain the superior effect of mogamulizumab in leukemic disease, as is the case for alemtuzumab, an anti-CD52 antibody that induces ADCC used in CTCL.(8,9) Following treatment with alemtuzumab, CTCL patients had depletion of benign and malignant T_CM from skin but not T_RM, the non-migratory population(8), suggesting that ADCC is not as effective in skin. Interestingly, there is a striking difference in efficacy of mogamulizumab in the blood (ORR 68%) compared to the skin (ORR 42%).(2) Furthermore, as with alemtuzumab, the time to response in the skin is delayed compared to the blood.(2) Taken together, this suggests that mogamulizumab’s efficacy in the skin is dependent on malignant T-cell recirculation from the skin to blood. Ineffective ADCC in the skin may also explain the lack of correlation between drug response and cutaneous CCR4 expression. As noted previously, this finding stands in contrast to the correlation between blood clearance and circulating malignant T-cell CCR4 expression.

The ability of mogamulizumab to deplete T_regs may serve as another mechanism of drug action independent of lymphoma cell CCR4 expression.(3) Most circulating T_regs express CCR4 and many express the skin homing marker CLA (Figure 1).(4) Because mogamulizumab depletes circulating T_regs, patients with active autoimmune diseases were excluded from MAVORIC. While T_regs are generally associated with poor prognosis in cancer, their role in CTCL is less well understood, as it is possible that T_regs may function not only to dampen the anti-tumor immune response but also to suppress malignant T-cells. For example, elevated levels of tumor infiltrating T_regs in skin lesions of early stage CTCL have been associated with improved survival.(10)

Not surprisingly, given depletion of T_regs by mogamulizumab, immune-related adverse events (irAE) have become evident (Figure 1). As with immune checkpoint inhibitors (ICI), dermatologic toxicities are the most common irAE (25% of patients), which is particularly challenging in these patients with pre-existing skin disease. Up to 18% of patients discontinued therapy due to rash or drug eruption. Other reported irAEs included myositis, myocarditis, polymyositis, hepatitis, pneumonitis, hypothyroidism, and a variant of Guillain-Barré syndrome. In contrast to ICI toxicities, and perhaps related to differential effects in different organ compartments, colitis was notably absent. To date, post market cases of photosensitivity and Steven’s Johnson Syndrome/Toxic epidermal necrolysis have been reported with mogamulizumab in patients with T-cell lymphoma. The conceptual framework for management of irAE remains the same as with ICI with a notable exception. While controversial in the management of ICI-induced irAEs in those with solid tumors, corticosteroids are used extensively in the management of CTCL, and we feel high dose corticosteroids should be implemented early and used liberally for life-threatening or severe mogamulizumab toxicity. Importantly, as with ICI-induced irAEs, it appears that these toxicities may persist long after the drug has stopped; awareness of and counselling on delayed and persistent toxicities is critical.(11)

The persistence of drug, the attendant T_reg depletion and the potential for delayed irAEs has led to significant concern about severe and refractory GVHD after hematopoietic stem cell transplantation (HSCT). HSCT prior to 50 days from last dose carries a considerable risk of severe and potentially fatal GVH that exceeds the mortality from MF/SS.(12) While mogamulizumab can be removed via plasma exchange, the recovery of T_regs may not be rapid enough to prevent irAEs, including GVHD. Thus, the greater the interval from mogamulizumab cessation without relapse to transplant, the better. This makes transplant planning and coordination logistically critical, but challenging.

Overall, mogamulizumab is a welcome addition to the therapeutic armamentarium, and is a particularly attractive therapy for patients with leukemic disease. The majority of approved therapies used in CTCL are limited by poor response rates, short duration of response, dose limiting toxicities, or lack efficacy across disease compartments. Durable responses are elusive, save for allogeneic HSCT, which carries with it significant morbidity and mortality. There remains an unmet need for many patients with advanced CTCL: a therapy that is relatively well tolerated and prevents disease progression. Mogamulizumab may help bridge this gap.