The anti-CCR4 antibody mogamulizumab delays disease progression compared to vorinostat in patients with previously treated cutaneous T-cell lymphoma

Patients with previously treated cutaneous T-cell lymphoma (CTCL) who received the investigational anti-CCR4 humanized antibody mogamulizumab in the phase III MAVORIC study had a significantly longer progression-free survival (PFS) than patients who received vorinostat. Moreover, also the response rate and the quality of life (QoL) were superior with mogamulizumab. The adverse events observed with mogamulizumab treatment were generally mild to moderate in severity.

Cutaneous T- cell lymphoma (CTCL) is a rare form of non-Hodgkin lymphoma. Patients with CTCL have a reduced QoL due to intractable itching and recurrent infections. Patients with advanced stage CTCL have a poor prognosis. Mogamulizumab is a monoclonal antibody directed against chemokine receptor 4 (CCR4), a protein that is frequently overexpressed on malignant T-cells. In a previously reported phase I/II study in CTCL, mogamulizumab demonstrated a favourable safety profile with a 37% overall response rate (ORR). These data formed the basis for the large, phase III MAVORIC trial. In this open-label, multinational, randomized, Phase III study, mogamulizumab was compared to the histone deacytelase inhibitor vorinostat in previously treated CTCL.

The study enrolled a total of 372 adult patients with histologically confirmed mycosis fungoides (MF) or Sézary syndrome (SS) who had failed at least 1 systemic therapy. Patients in the trial were stratified by  disease type (MF or SS) and disease stage (IB/II or III/IV), and were randomized (1:1) to receive either mogamulizumab (1.0 mg/kg weekly for the first 4-week cycle and then every 2 weeks) or vorinostat (400 mg daily). Patients in the randomized vorinostat arm were allowed to cross over to mogamulizumab upon disease progression or intolerable toxicity. The primary study endpoint was investigator-assessed PFS, while secondary objectives included ORR, duration of response (DoR) and QoL.

The median age of patients in the study was 64 years and almost all patients had an ECOG performance status of 0-1 (99%). Approximately two thirds of patients had stage III/IV disease and the median number of prior systemic treatments for both study arms was 3. The median PFS was 7.7 months for patients treated with mogamulizumab, compared with 3.1 months for those treated with vorinostat (HR[95%CI]: 0.53[0.41-0.69]; p< 0.0001). This PFS benefit in favour of mogamulizumab was also demonstrated by independent review (median PFS: 6.7 vs. 3.8 months; HR[95%CI]:0.64[0.49,0.84],p= 0.0007).

Also the secondary endpoints were significantly better with mogamulizumab. In fact, the ORR was 28% in the experimental arm compared to 4.8% with vorinostat (p< 0.001). The median DoR with mogamulizumab was 14.1 months, while this was 9.1 months with vorinostat (p< 0.05). Looking at specific subgroups of patients, significant improvements in ORR were found with mogamulizumab vs. vorinostat in patients with both MF (21.0% vs. 7.1%; p=0.0042) and SS (37.0% vs. 2.3%; p<0.0001). An ORR of 30.1% was observed in mogamulizumab treated patients who crossed over from vorinostat.

The most common treatment-emergent adverse events (TEAEs; >20%) that were more frequent (>15% difference) in the mogamulizumab vs. vorinostat arm included infusion-related reactions (33.2% vs. 0.5%) and drug-related skin eruptions (23.9% vs. 0.5%). The majority of TEAEs with mogamulizumab were mild to moderate in severity (grade I/II, 54.9%; grade III/IV/V, 42.4%). Diarrhoea (61.8% vs. 23.4%), nausea (42.5% vs. 15.2%), dysgeusia (29.0% vs. 3.3%), thrombocytopenia (30.6% vs. 11.4%), and increased blood creatinine (28.0% vs. 3.3%) occurred more than twice as frequently in patients treated with vorinostat than in those treated with mogamulizumab.

Patient-reported outcomes, as measured by the Skindex-29 and FACT-G, showed significantly greater symptom reduction and improved functional status in favour of mogamulizumab. This effect was seen early on in the treatment and persisted throughout the treatment (p<0.05).

In this first report of a randomized Phase III study evaluating PFS as primary endpoint in CTCL, mogamulizumab, a novel CCR4-targeting antibody therapy, demonstrated significantly superior PFS and ORR compared to vorinostat in patients with previously treated CTCL. The side effects with mogamulizumab were tolerable, and a measurable improvement in quality of life was observed with mogamulizumab.  

Reference

Kim Y, Bagot M, Pinter-Brown L, et al. Anti-CCR4 Monoclonal Antibody, Mogamulizumab, Demonstrates Significant Improvement in PFS Compared to Vorinostat in Patients with Previously Treated Cutaneous T-Cell Lymphoma (CTCL): Results from the Phase III MAVORIC Study. Presented at ASH 2017; Abstract #817.