Frontline Brentuximab Vedotin Extends PFS in Hodgkin Lymphoma

Dirk Huebner, MD

Frontline brentuximab vedotin (Adcetris) was associated with improved progression-free survival (PFS) compared with standard chemotherapy in patients with advanced classical Hodgkin lymphoma, according to results from the phase III ECHELON-1 clinical trial.

The 2-year modified PFS rate for brentuximab vedotin plus AVD (adriamycin, vinblastine, dacarbazine) was 82.1% percent compared with 77.2% for patients receiving ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). The brentuximab vedotin combination reduced the risk of disease progression or death by 23% (HR, 0.770; P = .035).

Interim analysis of overall survival (OS) also showed a trend favoring the brentuximab arm. Investigators plan to present more data at the 2017 ASH Annual Meeting in December.

Brentuximab vedotin is an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent. Takeda Pharmaceutical Company and Seattle Genetics, co-developers of the antibody-drug conjugate, announced the results in a press release.

“We are excited about the positive result which shows a statistically significant improvement in the primary endpoint of modified PFS,” said Dirk Huebner, MD, executive medical director, Oncology Therapeutic Area Unit, Takeda Pharmaceutical Company. “The results of this trial signify an important step forward in the development of Adcteris and have the potential to change the treatment approach of frontline advanced Hodgkin lymphoma.”

ECHELON-1 is a global, multicenter trial of 1334 patients with a histologically-confirmed diagnosis of stage III or IV classical Hodgkin’s 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 anticancer 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.

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%, 65%), anemia (20%, 12%), febrile neutropenia (20%, 8%), and pulmonary toxicity (24%, 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.

Takeda and Seattle Genetics plan to submit the phase III ECHELON-1 results to support regulatory approval in this patient population. The FDA has already approved brentuximab vedotin for 2 indications in Hodgkin lymphoma and 1 indication for systemic anaplastic large cell lymphoma.

References

1. Ansell SM, Connors JM, Park SI, O’Meara MM, Younes A. Frontline therapy with brentuximab vedotin combined with ABVD or AVD in patients with newly diagnosed advanced stage Hodgkin Lymphoma. Blood. 2012 120:798.
2. Connors JM, Ansell S, Park SI, et al. Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed advanced stage Hodgkin lymphoma: long term outcomes. Blood. 2014; 124: 292.