FDA Approval Sought for Brentuximab Vedotin in CTCL

Jonathan Drachman, MD

A supplemental Biologics License Application (sBLA) has been submitted to the FDA for brentuximab vedotin (Adcetris) as a treatment for patients with cutaneous T-cell lymphoma (CTCL), according to Seattle Genetics, which codevelops the antibody-drug conjugate with Takeda.

The sBLA is primarily based on the phase III ALCANZA trial, in which brentuximab vedotin induced responses lasting at least 4 months in 56.3% of patients versus 12.5% in patients receiving physician’s choice of standard therapies (P <.0001).

“The submission of the supplemental BLA requesting label expansion for Adcetris as a treatment in CTCL patients who require systemic therapy is an important milestone. CTCL is an incurable and disfiguring disease in need of new therapeutic options, particularly those that achieve durable responses,” said Jonathan Drachman, MD, Chief Medical Officer and Executive Vice President, Research and Development of Seattle Genetics.

“Results from the phase 3 ALCANZA trial demonstrated that CTCL patients treated with Adcetris had superior outcomes across all primary and secondary endpoints compared to patients in the control arm who were treated with either methotrexate or bexarotene standard of care agents. In addition to the Adcetris results, data from 2 investigator-sponsored trials also support Adcetris use in this disease setting. We believe these data are clinically meaningful and support a label expansion for Adcetris in CTCL, which would be the fourth indication for this program.”

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 in the brentuximab vedotin arm and 59 years in the control arm, and the median number of prior systemic therapies overall was 4 (range, 2-6). 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 cycles). 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 22.9EC 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 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.

Brentuximab consists of the anti-CD30 monoclonal antibody SGN-30 conjugated to the cytotoxic agent monomethyl auristatin E (MMAE) via a valine-citrulline peptide linker. The treatment is internalized by CD30 expressing tumor cells, causing the release of MMAE into the cytosol through the enzymatic cleavage of the linker.

In November 2016, brentuximab vedotin received an FDA breakthrough therapy designation for the treatment of patients with CD30-positive MF or pcALCL following at least 1 prior systemic therapy.

The drug has FDA-approved indications for Hodgkin lymphoma and systemic anaplastic large cell lymphoma.

References

1. 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.
2. Prince HM, Kim YH, Horwitz SM, et al. Brentuximab vedotin or physician's choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial [published online June 6, 2017]. Lancet. 2017 doi: 10.1016/S0140-6736(17)31266-7.