ECHELON-2: Brentuximab Vedotin Combination Outperforms CHOP for Peripheral T-Cell Lymphomas

Results from the phase III ECHELON-2 trial showed that brentuximab vedotin added to a combination of cyclophosphamide, doxorubicin, and prednisone (BV+CHP) nearly doubled progression-free survival (PFS) for patients with peripheral T-cell lymphomas (PTCLs), compared with treatment involving a standard regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).

Steven Horwitz, MD, from the Memorial Sloan Kettering Cancer Center in New York, presented the results at the 2018 ASH Annual Meeting.

“CHOP and CHOP-like regimens are the most common frontline treatments of PTCL, but these regimens do not produce a durable remission in the majority of [PTCL] subtypes, including ALK-positive systemic anaplastic large cell lymphoma (sALCL) and other CD30-positive PTCLs,” Dr. Horwitz explained. “ECHELON-2 is the first prospective trial in peripheral T-cell lymphoma to show an overall benefit over CHOP, [with a] 29-percent reduction in the risk of disease progression and a 34-percent reduction in the risk of death.”

Based on these data, the U.S. Food and Drug Administration expanded brentuximab vedotin’s indication in November 2018 to include the firstline treatment of adult patients with PTCLs– marking the first approval for this indication.

The double-blind, randomized, multicenter ECHELON-2 trial enrolled 452 patients from 132 sites in 17 countries. All participants had newly diagnosed, CD30-positive PTCLs and an Eastern Cooperative Oncology Group performance status score of ≤2. People with a history of other primary invasive malignancy or progressive multifocal leukoencephalopathy were excluded from the trial.

After stratifying patients according to histologic subtype and International Prognostic Index score, investigators randomly assigned patients to receive six to eight 21-day cycles of either:

  • BV+CHP: brentuximab vedotin 1.8 mg/kg plus cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and prednisone 100 mg on days 1-5 (n=226)
  • CHOP: cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2, and prednisone 100 mg on days 1-5 (n=226)

The researchers reported that baseline characteristics were similar between both arms: The median age was 58 years (range not reported) and most patients had stage III/IV disease. sALCL was the most common PTCL subtype (70%), followed by PTCL-not otherwise specified (16%) and angio-immunoblastic T-cell lymphoma (12%).

As of August 15, 2018 (data cutoff), 449 of the 452 randomized patients received at least one dose of study treatment. Most of the patients –85 percent and 79 percent of patients in the BV+CHP and CHOP groups, respectively – completed treatment. In the BV+CHP group, discontinuation was most often related to adverse events (AEs; 7%) or disease progression (3%); in the CHOP group, most patients discontinued due to disease progression (12%) and AEs (7%).

After a median follow-up of 36.2 months (range not reported), 83 percent of BV+CHP-treated participants responded, compared with 72 percent of CHOP-treated participants (p=0.003), and complete responses were more common in the BV+CHP group (68% vs. 56%; p=0.007). “The superiority of [BV+CHP] is not due to the poor response of CHOP, as the CHOP curves were better than anticipated or historically reported,” Dr. Horwitz clarified.

The median PFS (primary endpoint) was 48.2 months (range = 35.2 months to not evaluable) in the BV+CHP group and 20.8 months (range = 12.7-47.6 months) in the CHOP group. This translated to a 29-percent lower risk of disease progression or death with BV+CHP (hazard ratio = 0.71; 95% CI 0.54-0.93; p=0.01).

The rate of three-year PFS also appeared to be higher in the BV+CHP group (57% vs. 44%; p value not provided).

Median overall survival (OS; secondary endpoint) also appeared to be higher in the BV+CHP group (not reached vs. 17.5 months; ).

The incidence of AEs was consistent between groups, and with the known safety profiles of each treatment regimen, the researchers added. Nearly all patients in each arm experienced an AE (99% for BV+CHP and 98% for CHOP). The most common treatment-related AEs were nausea (46% for BV+CHP and 38% for CHOP), peripheral sensory neuropathy (45% and 41%), and neutropenia (38% in each arm). Grade ≥3 AEs reported in the BV+CHP group included neutropenia (33%), febrile neutropenia (17%), and anemia (12%).

AEs were fatal for seven patients (3%) on the brentuximab vedotin arm and nine (4%) on the CHOP arm.

Patients with ALK-positive sALCL generally saw the greatest improvement in PFS and OS with BV+CHP over CHOP, Dr. Horwitz reported, but he noted the study was not powered to compare efficacy among individual subtypes, which may be a limitation of the analysis.

The authors reported financial relationships with Seattle Genetics, which sponsored the trial.


Reference

Horwitz S, O’Connor O, Pro B, et al. The ECHELON-2 trial: results of a randomized, double-blind, active-controlled phase 3 study of brentuximab vedotin and CHP (A+CHP) versus CHOP in the frontline treatment of patients with CD30+ peripheral T-cell lymphomas. Abstract #997. Presented at the 2018 ASH Annual Meeting, December 3, 2018; San Diego, CA.

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