Mogamulizumab Forecast: Clearer Patients, with a Slight Chance of Immune Mayhem Cecilia Larocca, Thomas S

Published OnlineFirst October 15, 2019; DOI: 10.1158/1078-0432.CCR-19-2742

CCR Translations Clinical Cancer Research Mogamulizumab Forecast: Clearer Patients, with a Slight Chance of Immune Mayhem Cecilia Larocca, Thomas S. Kupper, and Nicole R. LeBoeuf

Mogamulizumab, approved by the FDA for relapsed or particular efﬁcacy in leukemic disease, but carries a risk of refractory mycosis fungoides and Sezary syndrome, improves immune-mediated toxicities with concomitant depletion of progression-free survival compared with vorinostat in the regulatory T cells. largest trial to date in cutaneous T-cell lymphoma, with See related article by Kasamon et al., p. 7275

In this issue of Clinical Cancer Research, Kasamon and collea- (Treg; ref. 4). Not surprisingly, T cells in CTCL skin and blood gues report on the findings of the MAVORIC trial that led to FDA largely express CCR4 (2). MAVORIC provides the largest assess- approval of mogamulizumab for relapsed or refractory mycosis ment of CCR4 expression in cutaneous lesions of mycosis fun- fungoides and Sezary syndrome and provide regulatory insights goides and Sezary syndrome. The receptor was detected in skin on the FDA deliberation (1). The MAVORIC trial, the largest biopsies of all 290 evaluable patients (median CCR4 expression ¼ randomized controlled trial in cutaneous T-cell lymphoma 80%), but skin CCR4 levels did not correlate with response (2). In (CTCL) to date, exemplifies the latest standard set by the FDA fact, a significant portion of nonresponders had expression of in trial design for this disease (2). It is notable for its rigorous CCR4 in greater than 80% of lymphocytes in the skin (1). While in assessment of response at more frequent intervals, utilization of a the phase I/II trial, CCR4 expression in peripheral blood lym- global composite response score, use of a comparator arm, and phoma cells did not correlate with response in mycosis fungoides selection of progression-free survival as the primary endpoint. or Sezary syndrome, patients with higher CCR4 expression in However, the worse than expected performance of the comparator circulating malignant T cells had faster clearance in the blood and drug, vorinostat, potential early censoring in the mogamulizu- residual leukemic cells had a lower percentage of CCR4 expres- mab arm, and data quality problems with the patient-reported sion (3, 5). CCR4 expression in leukemic disease may be a more outcomes are potential caveats of the study. The modest overall relevant biomarker for response in the blood, which is obfuscated response rate (ORR) in CTCL of 28% reflects the difficulty of when combined in the composite score. showing efficacy in all anatomic compartments captured in the MAVORIC included patients with mycosis fungoides and composite response score. This challenge may be overcome if Sezary syndrome, the two most common subtypes of CTCL and mogamulizumab can be safely combined with other therapies. revealed better responses in Sezary syndrome (ORR 37%) com- Immune-related adverse events (irAE) were reported, and the pared with mycosis fungoides (ORR 21%). While included in the severity, nature of autoimmune events, and long-term impact same staging paradigm for historical reasons, they are now are unknown and require further study. Finally, mogamulizumab considered distinct diseases based on clinical presentation, geno- performed better in Sezary syndrome than mycosis fungoides. mic features, and molecular T-cell markers (6, 7). Mycosis fun- Biologics that function through antibody-dependent cellular goides, characterized by fixed, well-defined patches or plaques in cytotoxicity (ADCC) may have greater efficacy in Sezary syndrome early stages, expresses surface markers characteristic of non- and may be less efficacious in treating non-recirculating (mycosis recirculating skin resident memory T cells (TRM; refs. 6, 8). Sezary fungoides) lymphoma cells in skin. syndrome, characterized by leukemic disease and erythroderma, Mogamulizumab, a defucosylated IgG1k antibody, binds to C- exhibits markers of central memory T cells (TCM), a recirculating T- C motif chemokine receptor 4 (CCR4; Fig. 1; ref. 2). Defucosyla- cell population (Fig. 1; refs. 6, 8, 9). The different migratory tion of the Fc portion of mogamulizumab specifically enhances properties of malignant T cells in mycosis fungoides and Sezary ADCC (2). Mogamulizumab does not inhibit CCR4, nor does it syndrome may explain the superior effect of mogamulizumab in induce complement-dependent cytotoxicity (3). CCR4, impor- leukemic disease, as is the case for alemtuzumab, an anti-CD52 tant for lymphocyte-specific chemotaxis to the skin, is predom- antibody that induces ADCC used in CTCL (8, 9). Following inately expressed in activated skin tropic and regulatory T cells treatment with alemtuzumab, patients with CTCL had depletion of benign and malignant TCM from skin but not TRM, the non- migratory population (8), suggesting that ADCC is not as effective Department of Dermatology, Brigham and Women's Hospital, and Dana Farber in skin. Interestingly, there is a striking difference in efficacy of Cancer Institute, Boston, Massachusetts. mogamulizumab in the blood (ORR 68%) compared with the Corresponding Author: Thomas S. Kupper, Brigham and Women's Hospital, skin (ORR 42%; ref. 2). Furthermore, as with alemtuzumab, the Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Suite 671, Boston, MA time to response in the skin is delayed compared with the 02115. Phone: 617-525-5550; Fax: 617-525-5571; E-mail: [email protected] blood (2). Taken together, this suggests that mogamulizumab's efficacy in the skin is dependent on malignant T-cell recirculation – Clin Cancer Res 2019;25:1 3 from the skin to blood. Ineffective ADCC in the skin may also doi: 10.1158/1078-0432.CCR-19-2742 explain the lack of correlation between drug response and cuta- 2019 American Association for Cancer Research. neous CCR4 expression. As noted previously, this finding stands

www.aacrjournals.org OF1

Larocca et al.

ABC

TC CLA MF CCR4 Treg Drug eruption CCR4 MF CLA T C Mogamulizumab TC NK Treg NK TC ? TC Skin

CLA CCR4 T CCR4 Treg L selectin reg SS CCR7 NK SS CD27 NK Blood

Figure 1. Effect of mogamulizumab on T cells and risk for immune-mediated skin toxicity. A, Mycosis fungoides T cells and Tregs exhibit skin homing marker CLA. Sezary syndrome cells have a TCM phenotype, characterized by CD27. Sezary syndrome cells also express skin homing marker CCR4 and markers L Selectin and CCR7, which allow for recirculation between blood and lymph nodes. Tregs are present in skin and blood and suppress cytotoxic T cells (TC). Their effect on malignant T cells is less well understood. B, Mogamulizumab binds to CCR4 and is enhanced to potentiate natural killer (NK) cell ADCC. C, Mogamulizumab clears leukemic disease more effectively than skin disease. Depletion of Tregs 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).

in contrast to the correlation between blood clearance and cir- controversial in the management of ICI-induced irAEs in those culating malignant T cell CCR4 expression. with solid tumors, corticosteroids are used extensively in the The ability of mogamulizumab to deplete Tregs may serve as management of CTCL, and we feel high dose corticosteroids another mechanism of drug action independent of lymphoma should be implemented early and used liberally for life- cell CCR4 expression (3). Most circulating Tregs express CCR4 and threatening or severe mogamulizumab toxicity. Importantly, as many express the skin homing marker CLA (Fig. 1; ref. 4). Because with ICI-induced irAEs, it appears that these toxicities may persist mogamulizumab depletes circulating Tregs, patients with active long after the drug has stopped; awareness of and counselling on autoimmune diseases were excluded from MAVORIC. While Tregs delayed and persistent toxicities is critical (11). are generally associated with poor prognosis in cancer, their role in The persistence of drug, the attendant Treg depletion, and the CTCL is less well understood, as it is possible that Tregs may potential for delayed irAEs has led to significant concern about function not only to dampen the antitumor immune response but severe and refractory graft-versus-host disease (GVHD) after also to suppress malignant T cells. For example, elevated levels of hematopoietic stem cell transplantation (HSCT). HSCT prior to tumor-infiltrating Tregs in skin lesions of early stage CTCL have 50 days from last dose carries a considerable risk of severe and been associated with improved survival (10). potentially fatal GVH that exceeds the mortality from mycosis Not surprisingly, given depletion of Tregs by mogamulizumab, fungoides/Sezary syndrome (12). While mogamulizumab can be irAEs have become evident (Fig. 1). As with immune checkpoint removed via plasma exchange, the recovery of Tregs may not be inhibitors (ICI), dermatologic toxicities are the most common rapid enough to prevent irAEs, including GVHD. Thus, the greater irAE (25% of patients), which is particularly challenging in these the interval from mogamulizumab cessation without relapse to patients with preexisting skin disease. Up to 18% of patients transplant, the better. This makes transplant planning and coor- discontinued therapy due to rash or drug eruption. Other reported dination logistically critical, but challenging. irAEs included myositis, myocarditis, polymyositis, hepatitis, Overall, mogamulizumab is a welcome addition to the ther- pneumonitis, hypothyroidism, and a variant of Guillain-Barre apeutic armamentarium, and is a particularly attractive therapy syndrome. In contrast to ICI toxicities, and perhaps related to for patients with leukemic disease. The majority of approved differential effects in different organ compartments, colitis was therapies used in CTCL are limited by poor response rates, short notably absent. To date, post market cases of photosensitivity and duration of response, dose-limiting toxicities, or lack of efficacy Steven's Johnson Syndrome/Toxic epidermal necrolysis have across disease compartments. Durable responses are elusive, save been reported with mogamulizumab in patients with T-cell for allogeneic HSCT, which carries with it significant morbidity lymphoma. The conceptual framework for management of irAE and mortality. There remains an unmet need for many patients remains the same as with ICI with a notable exception. While with advanced CTCL: a therapy that is relatively well-tolerated and

OF2 Clin Cancer Res; 25(24) December 15, 2019 Clinical Cancer Research

Mogamulizumab Forecast

prevents disease progression. Mogamulizumab may help bridge Acknowledgments this gap. T.S. Kupper is supported by the NIH (R01 CA210372, R01 AI127654, and R01 AR065807). Disclosure of Potential Conflicts of Interest C. Larocca is an employee/paid consultant for Kyowa Kirin. N.R. LeBoeuf is an employee/paid consultant for Bayer and Seattle Genetics. No potential conflicts of interest were disclosed by the other author. Received September 12, 2019; revised September 26, 2019; accepted October 10, 2019; published first October 15, 2019.

References 1. Kasamon YL, Chen H, de Claro RA, Nie L, Ye J, Blumenthal GM, et al. FDA 7. van Doorn R, van Kester MS, Dijkman R, Vermeer MH, Mulder AA, Szuhai approval summary: mogamulizumab-kpkc for mycosis fungoides and K, et al. Oncogenomic analysis of mycosis fungoides reveals major differ- Sezary syndrome. Clin Cancer Res 2019;25:7275–80. ences with Sezary syndrome. Blood 2009;113:127–36. 2. Kim YH, Bagot M, Pinter-Brown L, Rook AH, Porcu P, Horwitz SM, et al. 8. Clark RA, Watanabe R, Teague JE, Schlapbach C, Tawa MC, Adams N, et al. Mogamulizumab versus vorinostat in previously treated cutaneous T-cell Skin effector memory T cells do not recirculate and provide immune lymphoma (MAVORIC): an international, open-label, randomised, con- protection in alemtuzumab-treated CTCL patients. Sci Transl Med 2012; trolled phase 3 trial. Lancet Oncol 2018;19:1192–204. 4:117ra7. 3. Ni X, Jorgensen JL, Goswami M, Challagundla P, Decker WK, Kim YH, et al. 9. Watanabe R, Teague JE, Fisher DC, Kupper TS, Clark RA. Alemtuzumab Reduction of regulatory T cells by mogamulizumab, a defucosylated anti-CC therapy for leukemic cutaneous T-cell lymphoma: diffuse erythema as a chemokine receptor 4 antibody, in patients with aggressive/refractory positive predictor of complete remission. JAMA Dermatol 2014;150: mycosis fungoides and Sezary syndrome. Clin Cancer Res 2015;21:274–85. 776–9. 4. Hirahara K, Liu L, Clark RA, Yamanaka K, Fuhlbrigge RC, Kupper TS. The 10. Gjerdrum LM, Woetmann A, Odum N, Burton CM, Rossen K, Skovgaard majority of human peripheral blood CD4þCD25highFoxp3þ regulatory GL, et al. FOXP3þ regulatory T cells in cutaneous T-cell lymphomas: T cells bear functional skin-homing receptors. J Immunol 2006;177: association with disease stage and survival. Leukemia 2007;21:2512–8. 4488–94. 11. Bonnet P, Battistella M, Roelens M, Ram-Wolff C, Herms F, Frumholtz L, 5. Duvic M, Pinter-Brown L, Foss F, Sokol L, Jorgensen J, Ni X, et al. Corre- et al. Association of autoimmunity and long-term complete remission in lation of target molecule expression and overall response in refractory patients with Sezary syndrome treated with mogamulizumab. Br J Der- cutaneous T-cell lymphoma patients dosed with mogamulizumab (KW- matol 2019;180:419–20. 0761), a monoclonal antibody directed against CC chemokine receptor 12. Fuji S, Inoue Y, Utsunomiya A, Moriuchi Y, Uchimaru K, Choi I, et al. type 4 (CCR4). Blood 2012;120:3697. Pretransplantation anti-CCR4 antibody mogamulizumab against adult T- 6. Campbell JJ, Clark RA, Watanabe R, Kupper TS. Sezary syndrome and cell leukemia/lymphoma is associated with signiﬁcantly increased risks of mycosis fungoides arise from distinct T-cell subsets: a biologic rationale for severe and corticosteroid-refractory graft-versus-host disease, nonrelapse their distinct clinical behaviors. Blood 2010;116:767–71. mortality, and overall mortality. J Clin Oncol 2016;34:3426–33.

www.aacrjournals.org Clin Cancer Res; 25(24) December 15, 2019 OF3

Mogamulizumab Forecast: Clearer Patients, with a Slight Chance of Immune Mayhem

Cecilia Larocca, Thomas S. Kupper and Nicole R. LeBoeuf

Clin Cancer Res Published OnlineFirst October 15, 2019.

Updated version Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-19-2742

E-mail alerts Sign up to receive free email-alerts related to this article or journal.

Reprints and To order reprints of this article or to subscribe to the journal, contact the AACR Publications Subscriptions Department at [email protected].

Permissions To request permission to re-use all or part of this article, use this link http://clincancerres.aacrjournals.org/content/early/2019/11/21/1078-0432.CCR-19-2742. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC) Rightslink site.