Impressive Brentuximab Vedotin Data May Change Practice in CTCL

Youn H. Kim, MD

Brentuximab vedotin (Adcetris) induced responses lasting at least 4 months in 56% of patients with cutaneous T-cell lymphoma (CTCL) versus 13% in patients receiving physician’s choice of standard therapies (P <.0001), according to findings from the phase III ALCANZA trial presented at the 2016 ASH Annual Meeting.

“These compelling results have potential practice-changing implications for the use of brentuximab vedotin in managing CD30-expressing CTCL in patients who require systemic therapy,” lead study author Youn H. Kim, MD, Stanford University School of Medicine, said when presenting the results at ASH.

The international, open-label phase III ALCANZA trial included 131 patients with CD30-expressing (≥10% of infiltrate by central review) mycosis fungoides (MF) or primary cutaneous anaplastic large cell lymphoma (pcALCL), the 2 most common subtypes of 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. The median age was 62 years (range, 22-83) in the brentuximab vedotin arm and 59 years (range, 22-83) in the control arm, and the median number of prior systemic therapies in each arm was 2. At least 95% of patients in both arms had an ECOG performance status of 0 to 1. In the brentuximab vedotin arm, there were more pcALCL patients with extracutaneous disease (44% vs 27%).

Patients were randomized in a 1:1 ratio to the anti-CD30 antibody-drug conjugate 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 lasting ≥4 months (ORR4), 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).

Among patients with MF who received brentuximab vedotin, the ORR4 was 50% versus 10% with physician’s choice. The ORR and CR rates were 65% versus 16% and 10% versus 0, respectively. In patients with pcALCL who received brentuximab vedotin, the ORR4 was 75% versus 20% with physician’s choice. The ORR and CR rates were 75% versus 33% and 31% versus 7%, respectively.

In patients with pcALCL in the skin only who received brentuximab vedotin, the ORR4 was 89% versus 27% with physician’s choice. The ORR and CR rates were 89% versus 45% and 44% versus 9%, respectively. Among pcALCL patients with extracutaneous disease who received brentuximab vedotin, the ORR4 was 57% versus 0 with physician’s choice. The ORR and CR rates were 57% versus 0 and 14% versus 0, respectively.

“The data from the ALCANZA trial presented at this year’s ASH meeting provide evidence of the potential benefit of Adcetris in treating patients with CD30-positive CTCL. For patients with CTCL, there is a significant need for additional treatment options that increase the opportunity to achieve durable responses," Dirk Huebner, MD, executive medical director, Oncology Therapeutic Area Unit, at Takeda, which codevelops brentuximab vedotin with Seattle Genetics, said in a statement.

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). All-grade adverse events (AEs) occurred in 95% of the patients in the brentuximab vedotin arm and 90% of patients in the control arm. Grade ≥3 AEs were observed in 41% versus 47% of the 2 arms, respectively. 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. Other common all-grade AEs included nausea (36% vs 13%), diarrhea (29% vs 6%), fatigue (29% vs 27%), vomiting (17% vs 5%), alopecia (15% vs 3%), pruritus (17% vs 13%), pyrexia (17% vs 18%), decreased appetite (15% vs 5%), and hypertriglyceridemia (2% vs 18%).

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. No patients died on-study in the control arm.

“The data from the phase 3 ALCANZA clinical trial presented at ASH highlight improvements in the efficacy measurements experienced by the Adcetris-treated patients with CD30-expressing CTCL over the standard of care agents methotrexate or bexarotene utilized in the control arm," Jonathan Drachman, MD, chief medical officer and executive vice president, Research and Development, Seattle Genetics, said in a statement.

“The ALCANZA clinical trial represents the fourth consecutive registrational trial with a positive outcome for Adcetris, which we are evaluating broadly as the foundation of care for CD30-expressing lymphomas. Based on the results of this trial, the FDA has granted breakthrough therapy designation and we plan to submit a supplemental biologics license application in the first half of 2017 for approval in this setting."

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. Presented at: 58th Annual ASH Annual Meeting; December 3-6, 2016; San Diego, CA. Abstract 182.

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