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Mogamulizumab superior to vorinostat for cutaneous T-cell lymphoma
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ATLANTA — Mogamulizumab demonstrated significantly superior PFS, overall response rate and quality of life compared with vorinostat among patients with previously treated cutaneous T-cell lymphoma, according to results of the phase 3 MAVORIC clinical trial presented at the ASH Annual Meeting and Exposition.
“This study supports mogamulizumab [Kyowa Hakko Kirin Co. Ltd.] as a valuable new therapeutic option in patients with cutaneous T-cell lymphoma,” Youn H. Kim, MD, Joanne and Peter Haas Jr., Professor for Cutaneous Lymphoma Research at Stanford University, and director of the Stanford Multidisciplinary Cutaneous Lymphoma Clinic, said during her presentation. “Were very excited and hope this drug will be approved early next year to add to limited options we have in this patient population.”
Mogamulizumab is a humanized monoclonal antibody directed against CC chemokine receptor 4, which often is expressed on leukemic cells of certain hematologic malignancies, including cutaneous T-cell lymphoma.
In a previous U.S.-based phase 1/2 study, mogamulizumab demonstrated a tolerable safety profile and promising efficacy with a 37% ORR and a 95% response rate in blood.
Based on results from this study, the FDA in November granted priority review to mogamulizumab for the treatment of patients with cutaneous T-cell lymphoma who underwent at least one prior systemic therapy.
In the trial, researchers randomly assigned 372 patients with mycosis fungoides or Sézary syndrome — the most common subtypes of cutaneous T-cell lymphoma — to 1 mg/kg IV mogamulizumab (n = 186; median age, 63.5 years; 63.4% stage III-IV disease) weekly for the first 4-week cycle and then every 2 weeks, or 400 mg vorinostat (Zolinza, Merck; n = 186; median age, 65 years; 61.3% stage III-IV disease) daily. All patients had failed at least one prior systemic therapy.
Investigator-assessed PFS using the global composite response according to the International Society for Cutaneous Lymphomas and EORTC consensus guidelines served as the primary endpoint. Secondary endpoints included ORR, duration of response and quality of life.
The median dose intensity was 97.5% for mogamulizumab and 95.7% for vorinostat, representing similar treatment in both arms. Patients assigned mogamulizumab had longer treatment exposure than those who received vorinostat (median, 170 days vs. 84 days).
Median PFS was 7.7 months (95% CI, 5.7-10.3) in the mogamulizumab arm and 3.1 months (95% CI, 2.9-4.1) in the vorinostat arm (HR = 0.53; 95% CI, 0.41-0.69).
“[This] is a strikingly impressive superior result in mogamulizumab with a P value of .0001,” Kim said.
Independent review also showed improvement in PFS (6.7 months vs. 3.8 months; HR = 0.64; 95% CI, 0.49-0.84).
The PFS benefit associated with mogamulizumab persisted among predefined subgroups, including patients with stage III or IV disease (HR = 0.36; 95% CI, 0.26-0.51) and Sézary syndrome (HR = 0.32; 95% CI, 0.21-0.49).
A significantly higher proportion of patients treated with mogamulizumab achieved global ORR compared with patients assigned vorinostat (28% vs. 4.8%; P < .0001).
Researchers observed significant improvement in ORR among patients treated with mogamulizumab among those with mycosis fungoides (21% vs. 7.1%; P = .0042) and Sézary syndrome (37% vs. 2.3%; P < .0001), which was higher than expected, Kim said.
Patients who crossed over from mogamulizumab treatment to vorinostat achieved an ORR of 30.1%.
“These are all confirmed global composite responses ... [and] not just skin responses,” Kim said.
Patient-reported outcomes showed significantly greater symptom reduction and improved functional status with mogamulizumab in early cycles and throughout treatment (P < .05).
The most common treatment-related adverse events that occurred more frequently in the mogamulizumab arm — with more than 15% difference compared with the vorinostat arm — included infusion-related reactions (33.2% vs. 0.5%) and skin eruptions due to drug (23.9% vs. 0.5%).
The majority of treatment-related adverse events with mogamulizumab were mild to moderate in severity (grade 1-2, 54.9%; grade 3-5, 42.4%). Common treatment-related adverse events reported more often with vorinostat than mogamulizumab included diarrhea (61.8% vs. 23.4%), nausea (42.5% vs. 15.2%), thrombocytopenia (30.6% vs. 11.4%), dysgeusia (29% vs. 3.3%) and increased blood creatinine (28.0% vs. 3.3%).
Kim said an application is pending with the FDA for approval mogamulizumab, which is approved in Japan for cutaneous T-cell lymphoma and other hematologic malignancies.
“PFS and overall global response outcomes are clearly superior, the side effects are tolerable and we see measurable improvements in quality of life with mogamulizumab compared with vorinostat,” Kim said in a press release. “Taken together, these findings represent a durable and clinically meaningful benefit for patients with CTCL.” – by Melinda Stevens
Reference:
Kim YH, et al. Abstract 817. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta.
Disclosures: Kim reports financial relationships with Eisai, Forty Seven Inc., Horizon Pharma, Innate Pharma, Kyowa-Kirin-Pharma, Medivir, Merck, Millennium Pharmaceuticals, miRagen, Neumedicine, Portola, Seattle Genetics, Soligenix and Tetralogic. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Sunita Nasta, MD, FACP
The MAVORIC study is an important step forward in the treatment of cutaneous T-cell lymphoma. This rare disease entity within non-Hodgkin lymphoma is a particularly problematic one; when oncologists see these patients, theyve had significant prior therapy and cytotoxic therapy has traditionally been very unsuccessful. Patients receiving chemotherapy do not tolerate it because of baseline immunosuppression with high risk for infection. T-cell targeted therapies such as histone deacetylase inhibitors, including vorinostat, have had some success. However, the medications have significant associated adverse events, including hematologic and gastrointestinal toxicity. Although we have seen success with prior antibody approaches with brentuximab vedotin (Adcetris, Seattle Genetics), the population with CD30 expression is much more limited.
This particular therapy approach uses an antibody to chemokine receptor 4, which is overexpressed on malignant T cells. In the original phase 1/phase 2 study, researchers reported a good safety profile with about a 30% to 40% ORR.
In this open-label trial, Kim and colleagues compared mogamulizumab to the oral histone deacetylase inhibitor vorinostat. These patients all had advanced disease and had failed more than one prior systemic therapy. The trial was stratified by stage of disease and randomized in a 1:1 fashion.
What is very interesting in this trial is the significant improvement in ORR as well as PFS. The mogamulizumab arm had a PFS on the order of about 4 months longer. It also was much better tolerated with regard to side effects and quality of life, along with amelioration of disease-related symptoms. Given that there is no fixed endpoint to therapy, you want patients to be able to stay on therapy as long as possible. The side effect profile noted for this drug appeared fairly mild, with primarily some GI side effects as well as some hematologic side effects.
This will be an excellent new option for patients. I would like to see it moved closer to the frontline of systemic therapy for this group. There also is good potential for use in a combination given its excellent side effects profile. Patients had improved symptoms and improved functional status, and that is critical in this population.
Perspective
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Laurie Sehn, MD
Cutaneous T-cell lymphoma is a disease that has been described as one we don’t think a lot about because it is a rare form of lymphoma, but it is an extremely debilitating type of lymphoma. Patients have incredible skin lesions that are highly visible to themselves and to other people. They are highly symptomatic to those skin lesions and, as time goes on, the disease progresses. So far, most of the chemotherapies we use for other lymphomas don’t seem to work against this unique kind of lymphoma. Although drugs approved in recent years have demonstrated some progress, they all have quite significant limitations in their ability as well. There are relatively few effective drugs for cutaneous T-cell lymphoma, and it is still a morbid condition for patients. Mogamulizumab has shown benefit against one of the very common standard therapies used in practice. I think doctors and patients are looking forward to more effective therapies like mogamulizumab.
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