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Treatment with mogamulizumab improved progressionfree survival ( PFS ), compared with vorinostat in patients with previously treated cutaneous T-cell lymphoma ( CTCL ), according to results from a phase III study presented at the 2017 ASH Annual Meeting .

Lead author Youn H . Kim , MD , from Stanford University in California , shared findings from the open-label , international MAVORIC trial , the largest randomized trial and the first pivotal trial to use PFS as a primary endpoint in CTCL .

Mogamulizumab is a monoclonal antibody directed against chemokine receptor 4 ( CCR4 ), which is overexpressed on malignant T-cells , the authors explained . In previous phase I / II studies , the agent had an acceptable safety profile and a 37 percent overall response rate ( ORR ), paving the way for the phase III randomized trial .

On November 28 , 2017 , the U . S . Food and Drug Administration granted priority review to a biologics license application of mogamulizumab for the treatment of patients with CTCL who have received at least one prior systemic therapy , based on results from the MAVORIC trial .

Investigators compared the safety and efficacy of mogamulizumab with vorinostat in 372 adult patients with histologically confirmed mycosis fungoides ( MF ) or Sézary syndrome ( SS ), two subtypes of CTCL , who had previously received at least one systemic therapy . People were stratified by disease type ( MF or SS ) and stage ( IB / II or III / IV ), then randomized 1:1 to receive either mogamulizumab 1.0 mg / kg ( weekly for the first 4-week

— YOUN H . KIM , MD

TABLE 1 . Measures of Response by Investigator Assessment

Mogamulizumab ( n = 186 ) cycle and then every 2 weeks ; n = 186 ) or vorinostat 400 mg daily ( n = 186 ).

People randomized to the vorinostat arm were allowed to crossover to mogamulizumab if they had disease progression or intolerable toxicity .

Characteristics were similar between each treatment group . Patients had received a median of three prior systemic treatments ( range not provided ) across both arms , and most patients had stage III / IV disease ( 118 [ 63.4 %] in the mogamulizumab group and 114 [ 61.3 %] in the vorinostat group ). Median age was 63.5 years ( range = 25-101 years ) in the mogamulizumab group and 65.0 years ( range = 25-89 years ) in the vorinostat group . Diagnoses of MF or SS also were equally represented between the treatment groups ( 105 [ 56.5 %] and 99 [ 53.2 %] patients , respectively , had MF , and 81 [ 43.5 %] and 87 [ 46.8 %] patients had SS ).

Treatment with mogamulizumab resulted in a significant improvement in median PFS ( defined as composite response on skin , lymph nodes , and viscera according to the International Society for Cutaneous Lymphomas / European Organization of Research and Treatment of Cancer consensus guidelines ), compared with vorinostat : 7.7 months ( range = 5.7-10.3 months ) versus 3.1 months ( range = 2.9-4.1 months ), for a 47 percent lower risk of disease progression ( hazard ratio [ HR ] = 0.53 ; 95 % CI 0.41-0.69 ; p < 0.0001 ).

Mogamulizumab also outperformed vorinostat in secondary endpoints , such as ORR and duration of response , including in patients who crossed over from the vorinostat arm . Dr . Kim reported that the agent “ has convincing clinical activity , not just in skin , but also in clearing malignant T cells in the blood and lymph nodes .” ( See TABLE 1 for secondary endpoints .)

People treated with mogamulizumab also reported greater reduction in CTCL symptom burden ( measured by the Skindex-29 questionnaire ; p < 0.05 ) and functional quality of life ( measured by the Functional Assessment of Cancer Therapy - General scale ; p < 0.05 ).

The safety profile was consistent with previous reports for each agent , the researchers wrote . The most common treatment-related adverse events ( AEs ; > 20 %) in the entire study population included diarrhea , nausea , infusion-related reactions ( IRRs ), skin eruptions ,

Vorinostat ( n = 186 )

and thrombocytopenia . Both IRRs and skin eruptions related to treatment occurred more frequently in the mogamulizumab arm ( 33.2 % vs . 0.5 % and 23.9 % vs . 0.5 %, respectively ). Most of these AEs were mild to moderate ( grade 1 / 2 = 55 %; grade 3 / 4 = 42.4 %).

“ PFS and overall global response outcomes are superior , the side effects are tolerable , and we see measurable improvements in quality of life with mogamulizumab , compared with vorinostat ,” Dr . Kim concluded . “ Taken together , these findings represent a durable and clinically meaningful benefit for patients with CTCL .”

The open-label design and the use of investigatorassessed PFS as a primary endpoint may have limited the study ’ s findings by introducing bias . Also , because CCR4 expression level was not an eligibility criterion for inclusion , future trials will need to investigate how this factor affects response to mogamulizumab , Dr . Kim noted .

The authors report financial relationships with Kyowa Kirin , the manufacturer of mogamulizumab .

REFERENCE

Kim YH , 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 : results from the phase 3 MAVORIC study . Abstract # 817 . Presented at the 2017 American Society of Hematology Annual Meeting , December 11 , 2017 ; Atlanta , GA .

In November 2017 , the U . S . Food and Drug Administration ( FDA ) approved once-weekly dosing of the recombinant bispecific monoclonal antibody emicizumab for patients with hemophilia A with inhibitors . The decision was based on results from the phase III HAVEN 1 and HAVEN 2 trials that showed emicizumab reduced bleeding rates by 87 percent ( compared with standard bypassing agents ).

At the 2017 ASH Annual Meeting , investigators shared preliminary results from the ongoing , multicenter , open-label , phase III HAVEN 4 study that suggest once-monthly emicizumab dosing is feasible and may prevent bleeding episodes .

Lead author Víctor Jiménez-Yuste , PhD , of La Paz University Hospital in Madrid , Spain , and researchers examined the pharmacokinetic profile of emicizumab 6 mg / kg ( delivered every 4 weeks for at least 24 weeks ) in seven patients included in the run-in phase of the HAVEN 4 trial . ( The FDA-approved dosing for this patient population is emicizumab 3 mg / kg by subcutaneous injection once-weekly for the first 4 weeks , followed by 1.5 mg / kg once-weekly .)

Patients included in this analysis were > 12 years old and had been receiving on-demand treatment with factor VIII replacement therapy or bypassing agents . By April 10 , 2017 ( data cutoff ), seven patients with severe hemophilia A were enrolled in the pharmacokinetic run-in cohort ; four patients did not have inhibitors .

Investigators measured pharmacokinetics and peak concentration levels of emicizumab after a minimum follow-up of six weeks ( median = 8 weeks ; range not provided ), then compared those measurements with a pharmacokinetic model based on clinical data from patients receiving 1.5 mg / kg once-weekly dosing .

All individual observed pharmacokinetic profiles were within the 95 percent prediction interval computed by this model , and “ emicizumab 6 mg / kg exhibited a pharmacokinetic behavior that was consistent with prior predictions , leading to an expected steady-state concentration average

30 ASH Clinical News January 2018 Annual Meeting Edition