The FDA has awarded brentuximab vedotin (Adcetris) a breakthrough therapy designation for the first-line treatment of patients with classical Hodgkin lymphoma.
Clay Siegall, PhD
The FDA has awarded brentuximab vedotin (Adcetris) a breakthrough therapy designation for the first-line treatment of patients with classical Hodgkin lymphoma, Seattle Genetics, the company developing the antibody-drug conjugate, announced today.
Brentuximab vedotin is an antibody-drug conjugate directed to CD30, a defining marker of the disease. The designation is based on phase III results from the ECHELON-1 clinical trial, which were released in June.
The 2-year rate of modified progression-free survival (PFS) for brentuximab vedotin plus AVD (adriamycin, vinblastine, dacarbazine) was 82.1% compared with 77.2% for patients receiving ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). The experimental combination reduced the risk of disease progression or death by 23% (HR, 0.770; P = .035). An interim analysis of 2-year overall survival (OS) also showed a trend favoring the brentuximab arm.
“The phase III ECHELON-1 study that supports the breakthrough therapy designation for [brentuximab vedotin] in combination with chemotherapy showed superior activity versus the standard of care chemotherapy regimen in the treatment of frontline advanced classical Hodgkin lymphoma patients,” Clay Siegall, PhD, president and CEO of Seattle Genetics, said in a press release. “The decision by the FDA to grant this designation recognizes the need for new options that can change the care of people with newly diagnosed advanced Hodgkin lymphoma. The designation supports our goal to make Adcetris available to patients in this setting as soon as possible.”
The company plans to present full data at the 2017 ASH Annual Meeting in December.
ECHELON-1 is a global, multicenter trial of 1334 patients with a histologically confirmed diagnosis of stage III or IV classical Hodgkin lymphoma who had not been previously treated with systemic chemotherapy or radiotherapy. Study sites included medical facilities on every continent except Antarctica.
The primary endpoint is modified PFS per independent review facility assessment using the Revised Response Criteria for Malignant Lymphoma. Modified PFS is defined as the time to progression, death, or receipt of additional anti-cancer therapy for patients who are not in complete response after completion of frontline therapy.
The combination of brentuximab vedotin and AVD showed promising objective response rates (ORR) in phase I results from 47 patients presented at the 2012 ASH Annual Meeting.1 Long-term follow-up data presented at the 2014 ASH Annual Meeting demonstrated 3-year OS was 100% and 3-year failure-free survival was 96%.2
In the 2012 results, patients (N = 51) received doses of 0.6, 0.9, or 1.2 mg/kg of brentuximab vedotin with standard doses of ABVD or 1.2 mg/kg of brentuximab vedotin with AVD, depending upon cohort assignment. The combination regimens were administered on days 1 and 15 of each 28-day cycle for up to 6 cycles of therapy. At baseline, 45% of all patients had stage IV Hodgkin lymphoma, 25% had an IPS score ≥4, and all patients with available ECOG status had a score of 0 or 1.
Six patients received 0.6 mg/kg of brentuximab vedotin, 13 received 0.9 mg/kg, and 6 received 1.2 mg/kg with ABVD. Twenty-six patients received 1.2 mg/kg brentuximab vedotin with AVD. There was no dose-limiting toxicity observed in either regimen up to a dose of 1.2 mg/kg to brentuximab vedotin.
Each regimen was evaluated for a dose-limiting toxicity period, defined as any cycle 1 toxicity requiring a delay of ≥7 days in standard ABVD or AVD therapy. Determination of antitumor activity was based on investigator assessment of objective response according to the Revised Response Criteria for Malignant Lymphoma. FDG-PET interpretation for cycle 2 was performed by a central review per Deauville criteria with uptake above liver background considered positive.
The overall ORR was 96%. At the end of frontline therapy, 95% of patients assigned to brentuximab vedotin plus ABVD had complete response (CR) and 92% of those assigned to brentuximab vedotin plus AVD patients had a CR. One patient in the brentuximab vedotin plus AVD arm had a partial response and 1 had progressive disease.
One patient in the brentuximab vedotin plus ABVD arm died of hyponatremia and pulmonary toxicity. Overall, 7 patients discontinued brentuximab vedotin due to an adverse event (AE; 5 in the ABVD arm and 2 in the AVD arm).
Common AEs (≥20% patients overall) in the ABVD and AVD groups, respectively, included nausea (76%, 77%), neutropenia (80%, 69%), peripheral sensory neuropathy (72%, 65%), vomiting (60%, 38%), fatigue (44%, 46%), and constipation (48%, 31%).
Common grade ≥3 AEs (>10% of patients) observed in the brentuximab vedotin plus ABVD and brentuximab vedotin plus AVD cohorts, respectively, included neutropenia (80% vs 65%), anemia (20% vs 12%), febrile neutropenia (20% vs 8%), and pulmonary toxicity (24% vs 0%).
In the ABVD cohort, 44% of patients experienced pulmonary toxicity, interstitial lung disease, or pneumonitis that led to discontinuation of bleomycin. Two of these events led to death. Of these patients, 7 completed treatment with AVD and brentuximab vedotin. In general, these events occurred between cycles 3 and 6.
Investigators did not observe any pulmonary toxicity in the brentuximab vedotin plus AVD cohort. The incidence of neuropathy was similar between the ABVD (72%) and AVD (73%) regimens, and none of these events were grade ≥4 in severity.