The CCR4-directed monoclonal antibody mogamulizumab has been shown to significantly improve progression-free survival and overall response rate compared with vorinostat in adults with relapsed/refractory mycosis fungoides (MF) and Sézary syndrome (SS). One of the most common adverse events seen with mogamulizumab in MF/SS patients is rash. Because of the protean nature of MF/SS and the variable clinical and histopathological features of mogamulizumab-associated rash, healthcare providers may have difficulty distinguishing rash from disease, and may not be aware of appropriate treatment strategies for this generally manageable adverse event. The objective of this report was to combine results from published literature with experiences and recommendations from multiple investigators and institutions into clinical best practice recommendations to assist healthcare providers in identifying and managing mogamulizumab-associated rash. Optimal management, which includes biopsy confirmation and steroid treatment, requires a multidisciplinary approach among oncology, dermatology, and pathology practitioners. Infographic
Background In response to the increased use of combination checkpoint inhibitors (CPIs) and the resulting increased cutaneous adverse events (CAEs), this study reviewed patients with melanoma treated with combination CPIs to characterize CAE features and their clinical impact, correlation to adverse events in other organs, and correlation to tumor response. Methods Patients from the authors' institutional database who received at least 1 dose of ipilimumab in combination with either nivolumab or pembrolizumab between January 1, 2012, and December 31, 2017, for stage IV or unresectable stage III melanoma were identified. The time to next treatment (TTNT) was calculated from the start of CPI therapy to the start of the next treatment or death, and the development of CAEs was tested in a time‐dependent Cox regression to identify associations with TTNT. Results Eighty‐one patients (52.3%) experienced a total of 92 CAEs, including eczematous dermatitis (25.0%), morbilliform eruption (22.8%), vitiligo (12.0%), and pruritus without rash (8.7%). The median times to the onset and resolution of CAEs were 21 days (range, 0‐341 days) and 50 days (range, 1‐352 days), respectively. Most CAEs resolved after patients entered the CPI maintenance phase and treatment with oral antihistamines with or without topical steroids. CPI discontinuation occurred in 4 patients (2.6%) because of CAEs, in 49 (31.6%) because of other immune‐related adverse events, and in 20 (12.9%) because of melanoma progression or death. For patients definitively treated with CPIs (n = 134; 86.5%), TTNT was significantly longer with CAEs than without CAEs (hazard ratio, 0.567; 95% CI, 0.331‐0.972; P = .039). Conclusions CAEs were mostly reversible and rarely required therapy discontinuation. The development of CAEs was associated with a longer TTNT, and this suggested a possible clinical benefit.
Background: Cobomarsen (MRG-106) is an inhibitor of miR-155, a microRNA with a strong link to cutaneous T cell lymphoma (CTCL) pathogenesis. The goals of this first in human study are to evaluate the safety, tolerability, pharmacokinetics, and efficacy of cobomarsen in mycosis fungoides (MF) patients. Methods: This Phase 1 trial evaluated cobomarsen given via intralesional injection (75 mg/dose), subcutaneous (SC), IV rapid bolus injection, or 2-hour IV infusion (300, 600 or 900 mg/dose). Patients must have MF stage I-III with plaques and/or tumors and could remain on concurrent stable CTCL therapy. Patients received 6 doses, either subcutaneous or intravenous, in the first 26 days of the study followed by weekly or bi-monthly doses. Safety was monitored by physical exams, clinical lab tests, and reported adverse events (AEs). Efficacy was assessed by CAILS and by the modified Severity Weighted Assessment Tool (mSWAT). The effect of cobomarsen on quality of life was assessed by Skindex-29. Results: 38 subjects receiving IV or SC treatment (25 male/13 female, median age 59 years) have been on study for up to 22 months. As of the data cut off, no serious AEs have been attributed to cobomarsen. The most common AEs reported in greater than 15% of subjects were: fatigue, neutropenia, injection site pain, nausea, pruritus, and headache. Two AEs were deemed dose limiting toxicities (DLTs): Grade 3 worsening pruritus and Grade 3 tumor flare. The maximum tolerated dose (MTD) has not yet been reached. In the subcutaneous and IV cohorts, 29 out of 32 (91%) evaluable subjects had improvement in mSWAT score. Skin improvements were observed as early as the first assessment (Day 17). The best improvements were observed after more than 1 month of treatment. Eleven out of twenty-one (52%) patients receiving more than one month of dosing (6 doses) achieved greater than 50% reduction in mSWAT score. The mean duration of response (n=11) was 213 days, as of data cut off. Eight patients achieved a partial response meeting the criteria for ORR4, an objective response rate lasting at least four months in duration. The overall skin response in patients who received cobomarsen as monotherapy or cobomarsen with concurrent stable therapy were not significantly different. Improvement in quality of life (QOL), as measured by the Skindex-29 total score, correlated with reductions in mSWAT score during the treatment phase. Conclusions: These results demonstrate that cobomarsen is well-tolerated, has clinical activity, and has the potential to impact MF quality of life. These encouraging data support the continued investigation of cobomarsen in the CTCL population. The study is expanded to enroll patients with other hematologic malignancies in which miR-155 is elevated and relevant, including chronic lymphocytic leukemia (CLL), diffuse large B cell lymphoma (DLBCL), and adult T cell lymphoma/leukemia (ATLL). Final safety and efficacy data on CTCL mycosis fungoides will be presented. Disclosures Foss: Seattle genetics: Consultancy; Miragen: Consultancy, Speakers Bureau; Spectrum: Consultancy; Mallinkrodt: Consultancy.
Background MAVORIC was a phase 3, open-label, multi-center, randomized controlled trial that evaluated the safety and efficacy of mogamulizumab compared with vorinostat in patients with relapsed/refractory mycosis fungoides (MF) or Sézary syndrome (SS) (NCT01728805). Mogamulizumab-associated rash was the second most common TEAE of any cause or grade in the mogamulizumab treatment arm and the most common TEAE leading to treatment discontinuation, resulting in a discontinuation rate of 7% (13/184). Grade 1-2 and 3 drug rashes occurred in 20% (36/184) and 4% (8/184) of mogamulizumab-treated patients, respectively. The objectives of this analysis were to describe histopathological and other characteristics of drug rash in patients who received mogamulizumab in MAVORIC. Methods In MAVORIC, 372 patients were randomized 1:1 to receive either intravenous mogamulizumab at 1.0 mg/kg once weekly for Cycle 1 (28 days) and then on days 1 and 15 of subsequent cycles or oral vorinostat at 400 mg daily. Confirmed overall response rate (ORR; complete response + partial response) was based on a global composite response involving all four disease compartments and verified at two consecutive visits. Guidance to investigators was provided in the protocol for evaluation and management of new drug rash on mogamulizumab treatment. Patients with an initial Grade 1 drug rash were allowed to continue treatment with use of topical steroids as needed. For patients with Grade ≥2 drug rash, mogamulizumab was temporarily stopped, and treatment of the drug rash with topical steroids was advised. Use of systemic steroids was prohibited during the study. Treatment could resume if the drug rash resolved to Grade ≤1 within 2 weeks. Biopsies were evaluated by an on-site pathologist, and a central blinded review was also conducted. Results This analysis included 44 patients who were treated with mogamulizumab and experienced drug rash during MAVORIC. Pathologically, central review assessed rashes as granulomatous, histiocytic spongiotic, lichenoid, eosinophilic, psoriasiform, or a combination of these patterns with no clear predominant histological pattern. Among the 44 patients with drug rash, 59.1% (26/44) were ≥65 years of age, and more patients with SS [56.8 (25/44)] than MF [43.2% (19/44]) experienced drug rash. Median (Q1, Q3) exposure among patients with drug rash was 344 days (162, 652) in patients with SS and 185 days (85, 463) in patients with MF. Mogamulizumab did not result in any cases of anaphylaxis or SJS/toxic epidermal necrolysis (TEN). Concomitant or immediate prior CTCL therapies that may make patients prone to drug rash were examined, and no trend toward increased incidence of drug rash was observed with any particular agent or class. The proportion of SS responders with drug rash was significantly higher than responders without rash (P=0.02; Figure 1); the proportion of MF responders with drug rash did not differ from responders without rash (P=0.21). Overall, the median (Q1, Q3) time to onset of drug rash was 106 days (36, 254). Initial drug rash occurred after response to mogamulizumab in 70% (14/20) of patients who experienced both. Thirty-five patients (80%) in the drug rash cohort resumed treatment with mogamulizumab upon resolution of initial drug rash per-protocol. After these patients resumed treatment, the median (Q1, Q3) duration of exposure to mogamulizumab was 183 days (58, 332). Conclusions Mogamulizumab-associated rashes displayed heterogeneous histopathology without one predominant feature; therefore, close correlation of suspected drug rash with clinical features is advised to differentiate it from disease progression. A trend toward higher rate of drug rash was observed in patients with SS, the group more likely to respond to mogamulizumab. Therefore, drug rash may be attributable to increased exposure, but rash may also involve underlying disease characteristics or treatment-induced immune alterations; further investigations are warranted. Nevertheless, the observation that 80% of patients on trial were able to continue mogamulizumab for >6 months following resolution of their initial rash suggests that appropriate evaluation, identification, and management of these reactions may prevent premature discontinuation. Disclosures Musiek: Kyowa Kirin: Honoraria; Helsinn: Honoraria; miRagen: Other: Investigator; Elorac: Other: Investigator; Soligenix: Other: Investigator. Horwitz:ASTEX: Consultancy; Affirmed: Consultancy; Vividion Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Corvus: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Portola: Consultancy, Research Funding; Beigene: Consultancy; C4 Therapeutics: Consultancy; Daiichi Sankyo: Research Funding; GlaxoSmithKline: Consultancy; Janssen: Consultancy; ADCT Therapeutics: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Kura Oncology: Consultancy; Miragen: Consultancy; Myeloid Therapeutics: Consultancy; Aileron: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Bagot:Helsinn/Recordati: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Huen:Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Galderma: Other: Travel expense reimbursement, Research Funding; miRagen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Helsinn: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Research Funding; Rhizen: Consultancy, Research Funding. Fisher:Dana-Farber Cancer Institute: Current Employment; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees. Haun:Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Karger, Inc.: Patents & Royalties: Textbook royalties. Vermeer:Kyowa Kirin: Consultancy, Research Funding; Takeda: Research Funding; PIQUR: Research Funding; Innate Pharma: Consultancy. Ito:Kyowa Kirin Pharmaceutical Development, Inc.: Current Employment. Dwyer:Kyowa Kirin Pharmaceutical Development, Inc.: Current Employment. Herr:Kyowa Kirin, Inc.: Current Employment. Kim:Elorac: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Corvus: Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; Kyowa-Kirin Pharma: Research Funding; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Research Funding; Galderma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon Pharma: Consultancy, Research Funding; miRagen: Research Funding; Merck: Research Funding; Solingenix: Research Funding; Trillium: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Neumedicine: Consultancy, Research Funding; Portola: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.
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