Seattle Genetics has submitted a supplemental Biologics License Application or BLA to the U.S. Food and Drug Administration (FDA) for brentuximab vedotin (Adcetris®) for the treatment of patients with Cutaneous T-Cell Lymphoma,(CTCL). The application is based on data from the phase III ALCANZA trial and two phase II investigator-sponsored trials of brentuximab vedotin in patients with cutaneous T-cell lymphoma.

Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Cutaneous lymphomas are a category of non-Hodgkin lymphoma that primarily involve the skin. According to the Cutaneous Lymphoma Foundation, CTCL is the most common type of cutaneous lymphoma and typically presents with red, scaly patches or thickened plaques of skin that often mimic eczema or chronic dermatitis. Progression from limited skin involvement may be accompanied by skin tumor formation, ulceration and exfoliation, complicated by itching and infections. Advanced stages are defined by involvement of lymph nodes, peripheral blood and internal organs.

Illustration: The ALCANZA study is a randomized, open-label, phase III Trial of brentuximab vedotin (SGN-35) versus Physician’s Choice (methotrexate or bexarotene) in Patients With CD30-Positive Cutaneous T-Cell Lymphoma (NCT01578499).

The standard treatment for systemically pretreated CTCL includes skin-directed therapies, radiation and systemic therapies.

The systemic therapies currently approved for treatment have demonstrated 30 to 45 percent objective response rates, with low complete response rates.

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A new direction
“The submission of the supplemental BLA requesting label expansion for [brentuximab vedotin] as a treatment in CTCL patients who require systemic therapy is an important milestone. CTCL is an incurable and disfiguring disease in need of new therapeutic options, particularly those that achieve durable responses,” explained Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development of Seattle Genetics.

“Results from the phase III ALCANZA trial demonstrated that CTCL patients treated with [brentuximab vedotin] had superior outcomes across all primary and secondary endpoints compared to patients in the control arm who were treated with either methotrexate or bexarotene standard of care agents. In addition to the ALCANZA results, data from two investigator-sponsored trials also support [brentuximab vedotin] use in this disease setting. We believe these data are clinically meaningful and support a label expansion for [brentuximab vedotin] in CTCL, which would be the fourth indication for this program.”

Preliminary analysis
In November 2016, based on preliminary analysis of ALCANZA, the FDA granted [brentuximab vedotin] Breakthrough Therapy Designation (BTD) for the treatment of patients with CD30-expressing mycosis fungoides and primary cutaneous anaplastic large cell lymphoma who require systemic therapy and have received one prior systemic therapy. These represent the most common subtypes of CTCL. Based on discussions with the FDA following the BTD, additional data from investigator-sponsored phase II trials have been incorporated into the supplemental BLA to support the potential for a broader label in CTCL.

The supplemental BLA is primarily based on positive results from a phase III trial called ALCANZA that were presented during the 58th annual meeting of the American Society of Hematology (ASH) annual meeting in December 2016 and published in the Lancet in June 2017.

A total of 131 patients were enrolled in the ALCANZA trial. The intend-to-treat population included in 128 patients (97 mycosis fungoides, 31 primary cutaneous Anaplastic Large Cell Lymphoma; 3 excluded for insufficient CD30 expression) assigned to brentuximab vedotin (n=66) or physician’s choice (n=65). Baseline characteristics were generally balanced between arms with the exception of more patients with extracutaneous disease in the brentuximab vedotin arm. In brentuximab vedotin vs physician’s choice arms, respectively, median age was 62 (22–83) vs 58 (22–83) years; ECOG performance status 0–1 was 95% vs 97%. Patients in each arm had a median of 2 prior systemic therapies. [1][2]

The trial achieved its primary endpoint with the brentuximab vedotin treatment arm demonstrating a highly statistically significant improvement in the rate of objective response lasting at least four months (ORR4) versus the control arm as assessed by an independent review facility. ORR4, as assessed by Global

Response Score, was 56.3%  in the brentuximab vedotin arm compared to 12.5% in the control arm (p-value <0.0001).

Key secondary endpoints specified in the protocol, including complete response rate, progression-free survival and reduction in the burden of symptoms during treatment (Skindex-29), were all highly statistically significant in favor of the brentuximab vedotin arm.

The safety profile associated with brentuximab vedotin from the ALCANZA trial was generally consistent with the existing prescribing information. The most common adverse events of any grade include: peripheral neuropathy, nausea, diarrhea, fatigue, vomiting, alopecia, pruritis, pyrexia, decreased appetite and hypertriglyceridemia.

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