Featured Image: Journal + glasses. Courtesy: © 2017 - 2019. Fotolia. Used with permission.
Featured Image: Journal + glasses. Courtesy: © 2017 - 2019. Fotolia. Used with permission.

Data from the randomized Phase III ALCANZA clinical trial evaluating brentuximab vedotin (Adcetris®)  in patients with cutaneous T-cell lymphoma (CTCL) were published in the Lancet.[1]

The data were previously presented in an oral session at the 58th American Society of Hematology (ASH) annual meeting in December 2016. Brentuximab vedotin is an antibody-drug conjugate (ADC) directed to CD30 (Ki-1, TNFRSF8), a membrane protein belonging to the tumor necrosis factor (TNF) receptor superfamily, is expressed on CTCL lesions in approximately 50% of patients with the disease.[2][3]

The agent is currently not approved for the treatment of CTCL.

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. CTCL is a chronic disease that negatively impacts Quality of Life (QoL) and, in advanced stages, has poor prognosis. [2]

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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. According to published literature, CD30 is expressed on CTCL lesions in approximately 50% of patients with the disease.

The standard treatment for systemically pre-treated CTCL includes skin-directed therapies, radiation and systemic therapies. Current systemic therapies approved for treatment have demonstrated 30% to 45% objective response rates (ORR), with low complete response rates.  But they rarely provide reliable and durable responses, and to date, no systemic agent has shown outcomes superior to standard-of-care therapy such as methotrexate or bexarotene. [2]

Diagram 1.0: The ALCANZA Trial is a randomized, open-label, phase III clinical trial of brentuximab vedotin (also known as Adcetris® | SGN-35) versus physician’s choice (methotrexate or bexarotene) in patients with CD30-Positive cutaneous T-cell lymphoma (NCT01578499). 

Positive results
“Today’s publication of the positive results of the ALCANZA trial is another milestone for our brentuximab vedotin clinical program. We plan to submit the data to regulatory bodies around the world, and if approved, brentuximab vedotinwould be a potential new treatment option for patients with CD30-positive CTCL, a rare, debilitating and often difficult to treat form of cancer,” noted Dirk Huebner, M.D., Executive Medical Director, Oncology Therapeutic Area Unit, Takeda Pharmaceutical Company.

“We are encouraged by the data we’ve seen from our robust ongoing clinical investigation program of brentuximab vedotin in CD30-positive lymphomas, and are committed to bringing this important therapy to patients,” he added.

“The ALCANZA study is the first randomized Phase III clinical trial to evaluate a novel agent versus standard of care in CTCL, an incurable and disfiguring disease with few treatment options that achieve durable responses,” explained Bob Lechleider, M.D., Senior Vice President, Clinical Development of Seattle Genetics.

“The data from the ALCANZA trial provide compelling evidence that CTCL patients treated with brentuximab vedotin had superior outcomes across the primary and all secondary endpoints assessed in the study compared to patients in the control arm who were treated with a standard of care agent. These data demonstrate the potential of brentuximab vedotin to change the treatment landscape of CTCL,” Lechleider observed.

Trial design
Brentuximab vedotin, which targets CD30, has demonstrated marked clinical activity in two phase II single-arm trials in CTCL with overall response rates (ORR) of about 70%. These results led to ALCANZA trial, a randomized, open-label Phase III study designed to evaluate single-agent brentuximab vedotin versus a control arm of investigator’s choice of the standard of care therapies methotrexate or bexarotene, in patients with CD30-positive CTCL. The ALCANZA trial is the first reported randomized phase III trial testing a new agent against standard-of-care therapy in CTCL. [2]

A total of  131 patients were randomized with 128 patients in the intent-to-treat population (97 mycosis fungoides, 31 primary cutaneous Anaplastic Large Cell Lymphoma; 3 excluded for insufficient CD30 expression) and 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]

Key findings reported
The article highlights data from the trial which 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.

At a median follow-up of 22·9 months (95% CI 18·4–26·1), the proportion of patients achieving an ORR4, as assessed by Global Response Score, was 56.3% (36 of 64 patients) in the brentuximab vedotin arm compared to 12.5% (eight of 64) in the control arm.  This resulted in a between group difference of 43·8% (95% CI 29·1–58·4; p<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.

Based on their findings, the researchers concluded that the clinical outcome of brentuximab vedotin was far superior to physician’s choice.

Safety and adverse events
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.

What’s Next
Based on the study results, Takeda plans to begin to submit data from the ALCANZA trial to regulatory agencies in its territories in 2017.

The U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation to brentuximab vedotin for the treatment of the most common subtypes of CTCL, mycosis fungoides (MF) and primary cutaneous anaplastic large cell lymphoma (pcALCL).

Seattle Genetics plans to submit these data as part of a supplemental Biologics License Application (BLA)to the FDA in mid-2017. The ALCANZA trial received a Special Protocol Assessment (SPA) agreement from the FDA and scientific advice from the European Medicines Agency (EMA).