The U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation for brentuximab vedotin (Adcetris®; Seattle Genetics) for the treatment of patients with CD30-expressing mycosis fungoides (MF) and primary cutaneous anaplastic large cell lymphoma (pcALCL) who require systemic therapy and have received one prior systemic therapy.
Mycosis fungoides and primary cutaneous anaplastic large cell lymphoma or pcALCL are the most common subtypes of cutaneous T-cell lymphoma (CTCL), accounting for more than 75% of the disease.
Categories of 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 (NHL) that primarily involve the skin.
The most recent estimates by the American Cancer Society suggest that, for all types of non-Hodgkin lymphoma (NHL), there will be 72,580 (40,170 in men; 32,410 in women) new cases in the United States for 2016. The estimate further estimate that there will 20,150 (11,520 in men; 8,630 in women) deaths from the disease. 
Lymphomas of the skin are relatively uncommon, accounting for only about 5% of all non-Hodgkin lymphomas, the rate of skin lymphomas has been rising over the past few decades, although it seems to have leveled off in recent years. The reasons for this are not known.
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 tumor formation, ulceration and exfoliation, complicated by itching and infections.
Most CTCLs typically fall into the category of indolent (i.e. chronic) lymphomas – treatable, but not curable and usually not life-threatening.
Advanced stages are defined by involvement of lymph nodes, peripheral blood and internal organs. According to published literature, CD30 is expressed on skin lesions in approximately 50% of CTCL patients.
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% objective response rates (ORR), with low complete response rates.
The Breakthrough Therapy Designation further reinforces our belief that [this agent] represents a meaningful advance in the treatment of CD30-expressing cutaneous T-cell lymphoma…
Brentuximab vedotin has been evaluated in CD30-expressing CTCL in investigator- and corporate-sponsored clinical trials, including the phase III Alcanza study. Positive topline results of the Alcanza trial were announced in August 2016 and an abstract was accepted for oral presentation at the upcoming annual meeting of the American Society of Hematology (ASH), to be held in December 3-6, 2016 in San Diego, CA (abstract #182).
Mechanism of Action
Brentuximab vedotin is an antibody-drug conjugate or ADC that delivers an antineoplastic agent that results in apoptotic cell death selectively in CD30-expressing tumor cells. The drug consists of three components including cAC10, a recombinant chimeric immunoglobulin G1 (IgG1) produced by recombinant DNA technology in Chinese Hamster ovary cells specific for human CD30, the microtubule disrupting agent monomethyl auristatin E or MMAE, and a protease-cleavable linker that covalently attaches MMAE to cAC10 antibody. 
According to the available, nonclinical, data the biological activity of brentuximab vedotin results from a multi-step process. Following the binding of the antibody-drug conjugate, to CD30 on the cell surface, the ADC-CD30 complex is internalized. The complex then traffics to the lysosomal compartment. Within the cell where the single defined active species, monomethyl auristatin E, is released via proteolytic cleavage. Binding of monomethyl auristatin E to tubulin disrupts the microtubule network within the cell, induces cell cycle arrest and results in apoptotic death of the CD30-expressing tumour cell. 
CD30 which is expressed on skin lesions in approximately 50% of patients with cutaneous T-cell lymphoma, is currently not approved for the treatment of this disease.
Breakthrough Therapy Designation
The FDA’s Breakthrough Therapy Designation is intended to expedite the development and review of promising drug candidates for serious or life-threatening conditions. It is based upon clinical evidence of substantial improvement over existing therapies on one or more clinically significant endpoints.
“The decision by the FDA to grant brentuximab vedotin Breakthrough Therapy Designation further reinforces our belief that [this agent] represents a meaningful advance in the treatment of CD30-expressing CTCL,” noted Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics.
“The Breakthrough Therapy Designation supports our goal to expedite the review and approval process to make brentuximab vedotin available to patients in this setting who may benefit. We look forward to presenting the data from our phase III Alcanza trial in an oral session at the upcoming annual meeting of the American Society of Hematology and intend to submit a supplemental Biologics License Application (BLA) to the FDA in the first half of 2017 for approval in this setting,” Siegall added.
This Breakthrough Therapy Designation was based on data from the phase III Alcanza clinical trial. This trial evaluated brentuximab vedotin in CD30-expressing CTCL and met its primary endpoint, demonstrating a highly statistically significant improvement in the rate of objective response lasting at least four months (ORR4). This randomized trial, which received a Special Protocol Assessment (SPA) agreement from the FDA and scientific advice from the European Medicines Agency (EMA), compared the use of single-agent brentuximab vedotin to a control arm of investigator’s choice of standard therapies, methotrexate or bexarotene, in 131 patients with CD30-expressing CTCL who received prior systemic or radiation therapy.
The trial enrolled 131 patients at 50 sites globally. To participate in the trial, patients with primary cutaneous anaplastic large cell lymphoma must have received at least one prior systemic or radiation therapy and patients with mycosis fungoides must have received at least one prior systemic therapy. As part of the trial, these patients received brentuximab vedotin every three weeks versus investigator’s choice for up to approximately one year. [Note]
[Note:] The international multi-center trial has been conducted in North and South America, Europe and Australia under operational responsibility of Takeda Pharmaceuticals.