The approval of brentuximab vedotin (Adcetris®; Seattle Genetics) for the treatment of adult patients with primary cutaneous anaplastic Large cell lymphoma or pcALC, which is part of a group of rare non-Hodgkin lymphomas that arise from the T-cell type lymphocytes, and CD30-Expressing Mycosis Fungoides or MF, who have received prior systemic therapy, is a fourth indication for the anticancer agent.

The FDA approval is based on Clinical Trial Results from the Phase III ALCANZA and Phase II Investigator-Sponsored Studies in CTCL.[1]

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).

Generally used as a 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.

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Cutaneous lymphomas are a category of non-Hodgkin lymphoma that primarily involve the skin.

Presentation
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, which are, in turn, considered the most most common subtypes of cutaneous T-cell lymphoma.


“Cutaneous T-cell lymphoma is a blood cancer of the skin with no known cure and few new treatment options. It is a disfiguring disease in dire need of more effective and durable treatment options to help keep this debilitating and painful disease at bay…”


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.

Furthermore, according to the American Cancer Society and the Leukemia and Lymphoma Society, CTCL represents approximately four percent of non-Hodgkin lymphoma, which is about 2,800 patients.

Not all newly diagnosed patients require systemic therapy. 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, with low complete response rates.

“Cutaneous T-cell lymphoma is a blood cancer of the skin with no known cure and few new treatment options. It is a disfiguring disease in dire need of more effective and durable treatment options to help keep this debilitating and painful disease at bay,” said Susan Thornton, cutaneous lymphoma patient and chief executive officer of the Cutaneous Lymphoma Foundation (CLF).

Approval
The approval of the label expansion is based on data from the phase III ALCANZA trial and two phase II investigator-sponsored trials. The phase III ALCANZA study was designed to compare brentuximab vedotin monotherapy administered every three weeks versus physician’s choice of representative standard of care options, methotrexate or bexarotene.

Photo 1.0: Intermediate magnification micrograph of cutaneous T-cell lymphoma or CTCL. (Hematoxylin and eosin stain/H&E stain). Features include: Nests of lymphocytes in the epidermis (Pautrier microabscesses); Single lymphocytes in epidermis (lymphocyte exocytosis) and short linear arrays of lymphocytes along the basal layer of the epidermis (epidermotropism). Courtesy: © Michael Bonert/Nephron. This file is licensed under the Creative Commons Attribution-Share Alike 3.0 Unported licenses.

Results from the ALCANZA trial in 128 pcALCL and CD30-expressing MF patients requiring systemic therapy met 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, known as ORR4, versus the control arm as assessed by an independent review facility.

ORR4, as assessed by Global Response Score, was 56.3% (95% CI: 44.1, 68.4) in the brentuximab vedotin arm compared to 12.5% (95% CI: 4.4, 20.6) in the control arm (p-value <0.001). The most common adverse reactions (≥ 20%) were: anemia, peripheral sensory neuropathy, nausea, diarrhea, fatigue and neutropenia. Furthermore,

  • The Complete Response or CR rate in the brentuximab vedotin arm was 15.6% (95% CI: 7.8, 26.9) compared to 1.6% (95% CI: 0, 8.4) in the control arm (p-value = 0.0066).
  • The median Progression Free Survival of PFS in the brentuximab vedotin arm was 16.7 months (95% CI: 14.9, 22.8) compared to 3.5 months (95% CI: 2.4, 4.6) in the control arm (HR 0.270; 95% CI, 0.169, 0.430; p-value <0.001).
  • The safety profile associated with brentuximab vedotin from the ALCANZA trial was generally consistent with the existing prescribing information. The most common adverse events occurring in 20 percent or more of patients of any grade include: anemia, peripheral sensory neuropathy, nausea, diarrhea, fatigue and neutropenia.

Additional data from two investigator-sponsored phase II trials evaluating brentuximab vedotin in 73 MF patients were also incorporated into the supplemental BLA representing a broader spectrum of CD30-expression levels than that of the ALCANZA trial.

“Our phase III ALCANZA clinical trial evaluating brentuximab vedotin in patients with primary cutaneous anaplastic large cell lymphoma and mycosis fungoides, which are the most common types of cutaneous T-cell lymphoma, demonstrated superior efficacy with durable responses for long-term disease management when compared to standard of care treatment options methotrexate and bexarotene,” noted Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics.

“As both a patient and representative of the cutaneous lymphoma community, we welcome the FDA approval of brentuximab vedotinas a new treatment option for the most common subtypes of cutaneous T-cell lymphoma in patients who require systemic therapy and we look forward to sharing this important milestone with patients and physicians,” Cutaneous Lymphoma Foundation’s Thornton added.

Fourth indication
This is the fourth FDA-approved indication for brentuximab vedotin. In the United States the agent is also indicated for the treatment of classical Hodgkin lymphoma (cHL) patients who fail autologous hematopoietic stem cell transplantation (auto-HSCT) or who fail at least two prior multi-agent chemotherapy regimens and are not auto-HSCT candidates, as well as treatment of patients with cHL at high risk of relapse or progression as post-auto-HSCT consolidation, and treatment of systemic anaplastic large cell lymphoma (sALCL) patients who fail at least one prior multi-agent chemotherapy regimen.

Accelerated approval in the sALCL indication is based on overall response rate, and continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

“These data, along with data from investigator-sponsored clinical trials, led to the FDA approval of brentuximab vedotin as a treatment for patients with pcALCL or CD30-expressing MF, which represent the most common subtypes of CTCL. This FDA approval, which was granted more than a month in advance of the PDUFA date, represents a significant milestone for the lymphoma community. Our goal is to establish brentuximab vedotin as the foundation of care in CD30-expressing lymphomas and this approval represents our fourth FDA-approved indication,” Siegall added.

Regulatory milestones
In November 2016, the FDA granted Breakthrough Therapy Designation (BTD) for the treatment of patients with pcALCL and CD30-expressing MF who require systemic therapy and have received one prior systemic therapy. The FDA also granted Priority Review for the supplemental Biologics License Application (BLA), and the Prescription Drug User Fee Act (PDUFA) target action date was December 16, 2017.

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