The European Commission has extended the current conditional marketing authorization for brentuximab vedotin (Adcetris®; Takeda/Seattle Genetics) to include the treatment of adult patients with CD30-positive cutaneous T-cell lymphoma (CTCL) after at least one prior systemic therapy.

Brentuximab vedotin is an antibody-drug conjugate or (ADC) directed to CD30, which is expressed on the surface of Hodgkin lymphoma cells and several types of non-Hodgkin lymphoma, including CTCL.

The agent includes an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), using Seattle Genetics’ proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.

MabPlex
 

The approval of brentuximab vedotin in this setting brings a much needed, effective treatment option to patients living with CTCL … who have received one prior systemic therapy…


The decision to approve brentuximab follows a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) on November 9, 2017, and is based on positive results from the phase III ALCANZA Trial which demonstrated a highly statistically significant improvement in rate of objective response lasting at least four months, median progression-free survival, and improvement in symptom burden in the trial’s brentuximab vedotin arm.

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.

The most common subtypes of CTCL include mycosis fungoides and primary cutaneous anaplastic large cell lymphoma. 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. The standard treatment for CTCL patients includes skin-directed therapies, radiation and systemic therapies. Prior to the FDA approval of brentuximab vedotin, systemic therapies approved for treatment demonstrated 30 to 45 percent objective response rates, with low complete response rates.

Debilitating and disfiguring
“CD30-positive cutaneous T-cell lymphoma or CTCL is a debilitating and disfiguring disease with few effective and durable treatment options,” said Clay Siegall, Ph.D., President and Chief Executive Officer at Seattle Genetics, Takada’s North American Partner and co-developer of brentuximab vedotin.

“[This disease] is a subtype of non-Hodgkin lymphoma that primarily involves the skin; it typically presents with red, scaly patches or thickened plaques of skin that often mimics eczema or psoriasis and can have a substantial impact on patients’ self-esteem. There are few approved CTCL treatment options with only limited efficacy, creating a significant unmet need for these patients,” explained Julia Scarisbrick, M.D., Department of Dermatology, University Hospital Birmingham, Birmingham, UK.

“The approval of brentuximab vedotin in this setting brings a much needed, effective treatment option to patients living with CTCL and I am looking forward to be able to offer this treatment to CD30-positive patients who have received one prior systemic therapy,” she added.

Collaboration
“The approval of [brentuximab vedotin] for use in the European Union in CD30-positive CTCL patients represents a meaningful advance for patients with CTCL. We are pleased that our partner Takeda is able to make this therapeutic option available to patients in Europe. Since [brentuximab vedotin] was first approved by the U.S. Food and Drug Administration (FDA) in 2011, Seattle Genetics and Takeda have made significant progress in our goal to establish [brentuximab vedotin] as the foundation of care for CD30-expressing lymphomas, and we are working together on our next milestone of securing FDA approval and European Union marketing authorization for the use of brentuximab vedotin as a treatment for frontline advanced Hodgkin lymphoma,” Siegall added.

“Today’s approval is an important milestone for the CTCL community in Europe, and further reinforces the role brentuximab vedotin may have in improving outcomes and quality of life for patients with CD30-positive malignancies,” said Jesus Gomez Navarro, M.D., Vice President, Head of Oncology Clinical Research and Development, Takeda. “The clinical data that supported this approval are exceptionally strong. We are proud to be the company to bring a novel treatment option with impressive efficacy and a manageable safety profile to appropriate CTCL patients in the European Union.”

Foundation of care
“As a distinct subset of non-Hodgkin lymphoma, cutaneous lymphoma is generally visible on the skin, and can cause significant discomfort. This can result in serious emotional distress and impacts qualify of life for patients who are afflicted,” said Susan Thornton, CEO, Cutaneous Lymphoma Foundation. “There is no known cure, and only a few new treatment options have been introduced over the last several years. This is a welcome new treatment option for cutaneous lymphoma patients in Europe.”

European Union
The marketing authorization for brentuximab vedotin is valid in 28 countries of the European Union (EU), Norway, Liechtenstein and Iceland. It is based on positive results from a phase 3 trial called brentuximab vedotin that were presented at the 58th American Society of Hematology (ASH) annual meeting in December 2016, published online in the Lancet in June 2017, and recently updated in a poster presentation at the 59th ASH annual meeting in December 2017.

Alcanza trial
Figure 1.0: The Alcanza trials is a randomized , open label, Phase III study of Brentuximab Vedotin vs. Physician’s Choice (Methotrexate or Bexarotene) in patients with CD30+ Cutaneous T-Cell Lymphoma. (Study: NCT01578499).

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. The ORR4 was 56.3 percent in the brentuximab vedotin arm compared to 12.5 percent in the control arm (p-value <0.001).

The key secondary endpoints specified in the protocol, including complete response rate, progression-free survival and reduction in skin symptom burden as measured by the Skindex-29 questionnaire, 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: anemia, peripheral sensory neuropathy, nausea, diarrhea, fatigue and neutropenia.

In November 2017, the U.S. Food and Drug Administration (FDA) approved brentuximab vedotin for the treatment of adult patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy based on the results of the phase III ALCANZA clinical trial. Together, pcALCL and CD30-expressing MF comprise approximately 70 percent of CTCL diagnoses and the majority of patients who require systemic therapy. Brentuximab vedotin is currently not approved as a frontline therapy for Hodgkin lymphoma.

Joint development
Seattle Genetics and Takeda are jointly developing brentuximab vedotin. Under the terms of the collaboration agreement, Seattle Genetics has U.S. and Canadian commercialization rights and Takeda has rights to commercialize brentuximab vedotin in the rest of the world. Seattle Genetics and Takeda are funding joint development costs for brentuximab vedotin on a 50:50 basis.  In Japan Takeda is solely responsible for development costs.