The Food and Drug Administration (FDA) granted approval to Adcetris (brentuximab vedotin) to treat patients with cutaneous T-cell lymphoma (CTCL) who previously received systemic therapy, according to Seattle Genetics, which codevelops the drug with Takeda.
The approval is specifically for patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) and CD30-expressing mycosis fungoides (MF). MF and pcALCL are the most common subtypes of CTCL.
The FDA considered data from the phase 3 ALCANZA trial, in which Adcetris induced responses lasting at least 4 months in 56.3 percent of patients versus 12.5 percent in patients receiving physician’s choice of standard therapies.
“These data, along with data from investigator-sponsored clinical trials, led to the FDA approval of Adcetris 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 Adcetris as the foundation of care in CD30-expressing lymphomas and this approval represents our fourth FDA-approved indication,” Clay Siegall, Ph.D., president and CEO of Seattle Genetics, said in a statement.
The international, open-label phase 3 ALCANZA trial included 131 patients with CD30-expressing (at least 10 percent of infiltrate by central review) MF or pcALCL, the two 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 one prior systemic therapy and those with pcALCL were required to have prior radiation therapy or at least one systemic therapy. Patient characteristics were generally well balanced at baseline. The median age was 62 years in the Adcetris 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 percent of patients in both arms had an ECOG performance status of 0 to 1. In the Adcetris arm, there were more pcALCL patients with extracutaneous disease (44 percent vs 27 percent).
Patients were randomized in a 1-1 ratio to the anti-CD30 antibody-drug conjugate Adcetris (64 patients) or physician’s choice of the standard treatments methotrexate or bexarotene (64 patients). Adcetris was administered intravenously at 1.8 mg/kg once every three 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 four or more 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 Adcetris versus 3.5 months with physician’s choice. The ORR was 67 percent (43 patients) versus 20 percent (13 patients), with CR rates of 16 percent versus 2 percent (P = .0046), in the Adcetris and control arms, respectively. Symptom reduction, as measured by Skindex-29, was significantly better with Adcetris versus physician’s choice (-27.96 vs -8.62).
Among patients with MF who received Adcetris, the ORR4 was 50 percent versus 10 percent with physician’s choice. The ORR and CR rates were 65 percent versus 16 percent and 10 percent versus 0, respectively. In patients with pcALCL who received Adcetris, the ORR4 was 75 percent versus 20 percent with physician’s choice. The ORR and CR rates were 75 percent versus 33 percent and 31 percent versus 7 percent, respectively.
In patients with pcALCL in the skin only who received Adcetris, the ORR4 was 89 percent versus 27 percent with physician’s choice. The ORR and CR rates were 89 percent versus 45 percent and 44 percent versus 9 percent, respectively. Among pcALCL patients with extracutaneous disease who received Adcetris, the ORR4 was 57 percent versus 0 with physician’s choice. The ORR and CR rates were 57 percent versus 0 and 14 percent versus 0, respectively.
The median number of treatment cycles with Adcetris, 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 percent of the patients in the Adcetris arm and 90 percent of patients in the control arm. Grade 3 or higher AEs were observed in 41 percent versus 47 percent of the two arms, respectively. Serious AEs were also observed in 29 percent of patients in each arm.
Peripheral neuropathy occurred in 67 percent of patients in the Adcetris arm (9 percent, grade 3) versus 6 percent in the control arm. Other common all-grade AEs included nausea (36 percent vs 13 percent), diarrhea (29 percent vs 6 percent), fatigue (29 percent vs 27 percent), vomiting (17 percent vs 5 percent), alopecia (15 percent vs 3 percent), pruritus (17 percent vs 13 percent), pyrexia (17 percent vs 18 percent), decreased appetite (15 percent vs 5 percent) and hypertriglyceridemia (2 percent vs 18 percent).
AE-related discontinuations occurred in 24 percent of patients in the Adcetris arm and 8 percent of patients in the physician’s choice arm. There were four patient deaths in the Adcetris arm, three of which were considered unrelated to treatment. No patients died on-study in the control arm.
Adcetris 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, Adcetris 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.