Safety and efficacy profile of mogamulizumab (Poteligeo) in the treatment of cancers: an update evidence from 14 studies

Background CC chemokine receptor 4 (CCR4), the receptor for CCL22 and CCL17, is expressed on the surface of effector Tregs that have the highest suppressive effects on antitumor immune response. CCR4 is also widely expressed on the surface of tumor cells from patients with adult T-cell leukemia/lymphoma (ATL), peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL). Mogamulizumab is a humanized, IgG1 kappa monoclonal antibody that is directed against CCR4. By reducing the number of CCR4-positive Tregs and tumor cells, the mogamulizumab can reduce tumor burden and boost antitumor immunity to achieve antitumor effects. Methods We examined the PubMed and ClinicalTrials.gov until 1 February 2020. Considering variability in different studies, we selected the adverse events (AEs), overall survival (OS), progression-free survival (PFS), objective responses rate (ORR) and Hazard Ratio (HR) for PFS to evaluate the safety and efficacy profile of mogamulizumab. Results When patients were treated with mogamulizumab monotherapy, the most common all-grade AEs were lymphopenia, infusion reaction, fever, rash and chills while the most common grade ≥ 3 AEs were lymphopenia, neutropenia and rash. When patients were treated with combined therapy of mogamulizumab and other drugs, the most common all-grade AEs were neutropenia, anaemia, lymphopenia and gastrointestinal disorder, while the most common grade ≥ 3 AEs was lymphopenia. For patients treated with mogamulizumab monotherapy, the pooled ORR and mean PFS were 0.430 (95% CI: 0.393–0.469) and 1.060 months (95% CI: 1.043–1.077), respectively. For patients treated with combined therapy of mogamulizumab and other drugs, the pooled ORR was 0.203 (95% CI: 0.022–0.746) while the pooled PFS and OS were 2.093 months (95% CI: 1.602–2.584) and 6.591 months (95% CI: 6.014–7.167), respectively. Conclusions Based on present evidence, we believed that mogamulizumab had clinically meaningful antitumor activity with acceptable toxicity which is a novel therapy in treating patients with cancers.

Background CC chemokine receptor 4 (CCR4) is the receptor for two CC chemokine ligands (CCLs)-CCL22 (also called macrophage-derived chemokine) and CCL17 (thymus activation-regulated chemokine) [1]. By binding with its ligands, CCR4 is implicated in lymphocyte trafficking to the skin and migration of CCR4-positive Tregs [2][3][4]. CCR4 is predominantly expressed on the surface of effector Tregs that have the highest suppressive effects on antitumor immune response. CCR4 is also widely expressed on surface of tumor cells of most patients with adult T-cell leukemia/lymphoma (ATL) and is selectively expressed in approximately 40% of patients with other subtypes of peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) [5][6][7][8][9][10]. Mogamulizumab (also named as KW-0761, poteligeo) is a humanized, IgG1 kappa monoclonal antibody that is directed against CCR4 [10][11][12]. Previous studies have demonstrated that mogamulizumab can highly enhance antitumor effects by reducing CCR4-positive leukemic cells and inducing Tregs depletion [1]. So far, a series of phase I/II/III trials on mogamulizumab for various cancers have been completed. From these trials, we suppose that cancer patients treated with mogamulizumab can achieve significant treatment responses. We also focus on the adverse events of mogamulizumab or mogamulizumab-related therapies. However, there is no evidence-based systematic review on the safety and efficacy of mogamulizumab in treating patients with cancer. It is urgent and important to summarize those results, offering evidence-based references to direct clinical decisions. In this meta-analysis, we focus on the safety and efficacy of mogamulizumab in the treatment of various cancers based on selected clinical trials.

Literature search and selection
We followed the guidelines of PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) to complete the meta-analysis. The trials were identified through PubMed and ClinicalTrials.gov without any language restrictions until 1 February 2020. The keywords included "KW-0761", "mogamulizumab" and "poteligeo". After duplicates eliminating, two authors screened the studies independently. When there were disagreements, we referred to the opinions of a third author. Full texts of selective trials were downloaded and assessed in strict accordance with the following criteria for eligibility. Additionally, we screened the references of selected trials for potentially relevant trials.

Inclusion and excluded criteria
All eligible studies had to satisfy the following criteria: (i) the studies were clinical trials containing the efficacy or safety data of mogamulizumab or mogamulizumabrelated therapies; (ii) the patients enrolled in these trials were suffering from cancers; (iii) the studies reported any of the following information: adverse events (AEs), overall survival (OS), progression-free survival (PFS), objective responses rate (ORR), and Hazard Ratio(HR) for PFS; (iiii) the studies used mogamulizumab as a single drug or in combination with other drugs. The exclusion criteria were: (i) the studies were not clinical trials; (ii) the studies lacked available data or the full texts were inaccessible.

Data extraction
Data extraction was performed independently by two authors and disagreements were adjudicated by a third author. In this meta-analysis, we extracted basic information including first author's name, clinical trial registration number, year, study phase, total number of patients, gender, age, treatment regime, tumor type and assessment. The AEs (all grades and grades ≥3), OS, PFS, ORR and HR for PFS were needed to assess the efficacy and safety of mogamulizumab. For safety endpoints, the data we extracted from the eligible trials were grade ≥ 3 and all-grade AEs according to Common Terminology Criteria for Adverse Events (CTCAE). For efficacy endpoints, we collected the OS and PFS directly in each included study while we collected the ORR directly or calculated based on the accessible data. The HR and 95% confidence interval (CI) for PFS were extracted following Wan's method [13].

Study selection
Through a comprehensive search, we found 213 articles in PubMed and 7 trials in ClinicalTrials.gov. After duplicate, there were 73 articles and 1 trial left. By screening the titles and abstracts, we excluded 44 articles on the basis of exclusion criteria. Then we viewed the full texts of remained studies, and finally, 13 articles and 1 trial were involved according to the inclusion and exclusion criteria [14][15][16][17][18][19][20][21][22][23][24][25][26][27]. The overall filter procedures and results were shown in Fig. 1.

Study characteristics
The basic information of eligible studies was listed on Table 1. The trials were conducted from 2010 to 2019, including 5 phase I trials, 1 phase I-II trial, 6 phase II trials, 1 phase III trial and 1 unspecified trial. Among them, patients in 2 phase I trials administered mogamulizumab intravenously at a dose of 0.01, 0.1, 0.5, 1.0 mg/kg [18,22]. Patients in 3 phase I trials and 2 phase II trials received mogamulizumab in combination with other drugs [16,[24][25][26][27]. And the rest received mogamulizumab monotherapy at a dose of 1.0 mg/kg [14-17, 19-21, 23].
There were total 1290 patients enrolled in these studies, including patients with ATL, PTCL, CTCL, ect.

Assessment of study quality and publication bias
We used Review Manager 5.3 (Copenhagen, Sweden) to measure quality assessment of involved studies. Figure 5 indicated the risk of bias graph and risk of bias summary of all those eligible trials. Overall, the quality of the studies was satisfactory.

Discussion
Although various advanced or metastatic malignancies remain incurable, the application of mogamulizumab  does benefit the patients. In this meta-analysis, we selected 14 prospective trials with 1290 patients and systematically assess the safety and efficacy of mogamulizumab. The integrated results of the data analysis confirm the role of mogamulizumab in various cancers. This is the first time to evaluated the safety and efficacy of mogamulizumab independently and systematically. This meta-analysis reveals that mogamulizumab is a novel therapy in treating various cancers, offering powerful evidence for clinical decision.
With regard to the safety, we analyzed the AEs of patients administered mogamulizumab by intravenous infusion. According to our analysis, the most common all-grade AEs in low, medium and high doses were lymphopenia, and event rates of lymphopenia were all higher than 70%. Besides, lymphopenia was also the most common grade ≥ 3 AEs which happened in nearly half of the participants. For combination therapies, neutropenia was the most common AEs which happened in more than 80% patients while lymphopenia was the most  The mogamulizumab, having a defucosylated Fc region, has increased binding affinity to the Fcγ receptor on effector cells such as NK cells which can enhance ADCC. By strongly activating NK cells, mogamulizumab can induce NK cells to release cytokines and related cytotoxic molecules which might be the mechanism of infusion reaction [15,28,29]. Mogamulizumab can reduce the level of CCR4-positive malignant T cells locally and systematically, and can also eliminate CCR4-positive Tregs leading to Tregs depletion, which contributes to the enhancement of antitumor effects and the immunotherapeutic effect of activating the host immune response [18,30]. However, mogamulizumab induced Tregs depletion can cause alteration of the immune balance, which may unleash various undesirable infections [22,31]. Skin-related AEs were another frequent nonhematologic AEs because CCR4 can promote skin-specific homing of lymphocytes, while mogamulizumab was a monoclonal antibody directed against CCR4 [32,33]. Mogamulizumab induced Tregs depletion may abrogate a peripheral checkpoint which is controlled by Tregs and induce the production of autoantibodies. These autoantibodies can combine with keratinocytes and melanocytes which play an essential role in the pathogenesis of skin-related AEs [34,35]. In addition, some studies revealed the mogamulizumab treatment could provoke homeostatic CD8-positive T-cell proliferation predominantly of newly emerging clones, some of which may also play an important role in the pathogenesis of skin-related AEs [35][36][37]. For combination therapies, most of the AEs showed similar trends to those in monotherapy which was consist with previous studies.
In combination therapy of mogamulizumab and nivolumab treating solid tumors, the profile of AEs was not substantially different from that seen in mogamulizumab or nivolumab monotherapy [25]. With regard to the efficacy, we analyzed the ORR, PFS, OS and HR for PFS of included trials. Approximately 43% of participants reached complete response or partial response in monotherapy. This is a particularly promising result since the response rate of patients with ATL, PTCL, CTCL ect, to conventional chemotherapy with a single agent is reportedly extremely low. The mogamulizumab is a humanized, IgG1 kappa monoclonal antibody directed against CCR4 which can highly enhance antitumor effects by reducing the number of CCR4-positive leukemic cells and Tregs leading to Tregs depletion [38]. The mechanism of the decline of CCR4positive leukemic cells is that mogamulizumab has increased binding affinity to the Fc receptor on effector cells such as NK cells which can enhance ADCC [29,   ]. The mechanism of Tregs depletion is that mogamulizumab prevents the binding of CCR4 and CCL22 so that the Tregs cannot be activated and recruited [38]. So the mechanism of antitumor activity is that the mogamulizumab can reduce the number of CCR4-positive leukemic cells, boost antitumor immunity by reducing CCR4-positive Tregs and influence tumor microenvironment to reduce tumor escape [40]. Patients administered mogamulizumab stabilized the disease more than 1 month and the overall patient survival time ranged from 4.9 months to 17.6 months which were longer than existing standard therapies. The analysis of HR for PFS in eligible trials also indicated that mogamulizumab can prolong the PFS of cancer patients compared to other chemotherapeutics. In the combination therapy of mogamulizumab and mLSG15 treating ATL, the pooled ORR was higher than that of mogamulizumab monotherapy, which was related to the different mechanism of antitumor effects. However, in combination therapy of mogamulizumab and nivolumab or utomilumab treating solid tumors, the pooled ORR was relatively low, which was related to the characteristics of the treated tumors. But mogamulizumab combined with nivolumab or utomilumab were more effective than nivolumab or utomilumab alone in treating solid tumors [24,25,41]. These results above demonstrated that mogamulizumab is a novel therapy in treating patients with cancers either as a single drug or in combination with other drugs. However, there are several limitations to this study. Firstly, the data of this meta-analysis is limited and some included studies even miss partial data. More experiments with larger sample size and more comparisons with other drugs are required. Second, the deficiencies in the experimental design of the selective studies cannot be eliminated from our analysis. Third, some patients might receive different prior systemic chemotherapy regimens, which could affect the results of the present study. Besides, there are diversities in the study design of different experiments such as experiment duration. Finally, the cancer types are different, so the heterogeneity of the enrolled patients might have affected the results.

Conclusions
Based on the current evidence, this meta-analysis elucidates that mogamulizumab has clinically meaningful antitumor activity in patients with an acceptable toxicity profile which is a novel therapy in treating patients with cancers.