FDA Grants Brentuximab Vedotin Breakthrough Designation in CTCL

Clay Siegall, PhD

Brentuximab vedotin (Adcetris) has received an FDA breakthrough therapy designation for the treatment of patients with CD30-positive mycosis fungoides (MF) or primary cutaneous anaplastic large cell lymphoma (pcALCL) following at least 1 prior systemic therapy, according to Seattle Genetics, the manufacturer of the anti-CD30 antibody-drug conjugate.

The designation, which will expedite the development and review of brentuximab vedotin for use in these 2 most common subtypes of cutaneous T-cell lymphoma (CTCL), is based on data from the phase III ALCANZA trial. In the study, the rate of objective responses lasting ≥4 months was 56% in patients treated with brentuximab vedotin, compared with 13% in patients receiving physician’s choice of standard therapies (P <.0001).

“The decision by the FDA to grant Adcetris breakthrough therapy designation further reinforces our belief that Adcetris represents a meaningful advance in the treatment of CD30-expressing CTCL,” Clay Siegall, PhD, president and CEO of Seattle Genetics, said in a statement. “The breakthrough therapy designation supports our goal to expedite the review and approval process to make ADCETRIS 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 ASH annual meeting and intend to submit a supplemental biologics license application to the FDA in the first half of 2017 for approval in this setting.”

The international, open-label phase III ALCANZA trial included 131 patients with CD30-expressing (≥10% of infiltrate by central review) CTCL. The intent-to-treat population comprised 128 patients, 97 with MF and 31 with pcALCL. Three patients were excluded because their CD30 expression level was too low.

Patients with MF had to have received at least 1 prior systemic therapy and those with pcALCL were required to have prior radiation therapy or at least 1 systemic therapy. Patient characteristics were generally well balanced at baseline; however, in the brentuximab vedotin arm, there were more patients with extracutaneous disease.

The median age was 62 (range, 22-83) in the brentuximab vedotin arm and 58 (range, 22-83) in the control arm. Almost all patients in each arm had an ECOG performance status of 0 or 1, and the median number of prior systemic therapies in each arm was 2.

Patients were randomized in a 1:1 ratio to single-agent brentuximab vedotin (n = 64) or physician’s choice of the standard treatments methotrexate or bexarotene (n = 64). Brentuximab vedotin was administered intravenously at 1.8 mg/kg once every 3 weeks and for up to 48 weeks (16 cycled). Methotrexate was dosed at 5 to 50 mg once weekly and bexarotene was administered orally at 300 mg/m2 once daily. Treatments were administered until disease progression or unacceptable toxicity.

Beyond the primary endpoint of objective response rate (ORR) lasting ≥4 months, secondary outcome measures included complete response (CR) rate, progression-free survival (PFS), and reduction in the burden of symptoms during treatment.

At a median follow-up of 17.5 months, the median PFS was 16.7 months with brentuximab vedotin versus 3.5 months with physician’s choice (HR, 0.270; 95% CI, 0.169-0.430; P <.0001). The ORR was 67% (n = 43) versus 20% (n = 13; P <.0001), with CR rates of 16% versus 2% (P = .0046), in the brentuximab vedotin and control arms, respectively. Symptom reduction, as measured by Skindex-29, was significantly better with brentuximab vedotin versus physician’s choice (-27.96 vs -8.62; P <.0001).

The median number of treatment cycles with brentuximab vedotin, bexarotene, and methotrexate, was 12 (range, 1-16), 5.5 (range, 1-16) and 3 (range, 1-16). Drug-related grade 3/4 adverse events (AEs) were observed in 29% of patients in each arm. Serious AEs were also observed in 29% of patients in each arm.

Peripheral neuropathy occurred in 67% of patients in the brentuximab vedotin arm (9%, grade 3) versus 6% in the control arm. At the time the abstract was submitted to ASH, 82% of the peripheral neuropathy incidents in the brentuximab vedotin arm had been improved or resolved.

AE-related discontinuations occurred in 24% of patients in the brentuximab vedotin arm and 8% of patients in the physician’s choice arm. There were 4 patient deaths in the brentuximab vedotin arm, 3 of which were considered unrelated to treatment.

Kim YH, Whittaker S, Horwitz SM, et al. Brentuximab vedotin demonstrates significantly superior clinical outcomes in patients with CD30-expressing cutaneous T cell lymphoma versus physician's choice (methotrexate or bexarotene): the phase 3 ALCANZA study. To be presented at 2016 ASH Annual Meeting; December 3-6, 2016; San Diego, CA. Abstract 182.