The combination of brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (A+CHP) more than doubled progression-free survival (PFS) as well as improved overall survival (OS) in patients with CD30-expressing peripheral T-cell lymphoma compared with a combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), according to results of the phase III ECHELON-2* trial.

“A+CHP provided clinically meaningful improvement in PFS and OS vs CHOP with a 29 percent reduction in the risk of a progression event and a 34 percent reduction in the risk of death,” said study author Dr Steven Horwitz from the Memorial Sloan Kettering Cancer Center in New York City, New York, US.

“ECHELON-2 [is also the] first prospective trial in peripheral T-cell lymphoma to show OS benefit over CHOP,” he added.

Participants in this international, double-blind study were adults (median age, 58 years) with previously untreated CD30-expressing peripheral T-cell lymphoma who were randomized 1:1 to receive A+CHP (brentuximab vedotin [1.8 mg/kg], cyclophosphamide [750 mg/m²], and doxorubicin [50 mg/m²] on day 1, and prednisone [100 mg on days 1–5]; n=226, 59 percent male) plus placebo or CHOP (cyclophosphamide [750 mg/m²], doxorubicin [50 mg/m²], and vincristine [1.4 mg/m²] on day 1, and prednisone [100 mg on days 1–5]; n=226, 67 percent male) plus placebo Q3W for 6–8 21-day cycles. Eighty percent of patients had stage 3–4 disease and 72 and 68 percent of A+CHP and CHOP recipients, respectively, had systemic anaplastic large cell lymphoma (sALCL), with 50 and 46 percent, respectively, having ALK-negative sALCL.

After a median follow up of 36.2 months, PFS was more than doubled among A+CHP compared with CHOP recipients (median, 48.2 vs 20.8 months, hazard ratio [HR], 0.71, 95 percent confidence interval [CI], 0.54–0.93; p=0.0110; 3-year PFS, 57 percent vs 44 percent). [ASH 2018, abstract 997; Lancet 2018;doi:10.1016/S0140-6736(18)32984-2]

PFS was also superior among the A+CHP vs CHOP recipients with sALCL (HR, 0.59, 95 percent CI, 0.42–0.84; p=0.0031).

At a median follow up of 42.1 months, A+CHP recipients demonstrated superior OS over CHOP recipients, with 51 compared with 73 deaths (median OS not reached in either group, HR, 0.66, 95 percent CI, 0.46–0.95; p=0.0244).

“For T-cell lymphoma, this has really been unprecedented as we have no studies that show an OS benefit over standard therapies so that’s really a big step forward,” said Horwitz.

The objective response rate was higher in A+CHP vs CHOP recipients (83 percent vs 72 percent; p=0.0032), as was the complete remission rate (68 percent vs 56 percent; p=0.0066).

Adverse event (AE) incidence was comparable between A+CHP and CHOP recipients (99 percent vs 98 percent), specifically grade ≥3 AEs (66 percent vs 65 percent), serious AEs (39 percent vs 38 percent), and AE-related deaths (3 percent vs 4 percent). Neutropenia was the most frequent grade ≥3 AE in A+CHP and CHOP recipients (35 percent vs 34 percent) followed by anaemia (13 percent vs 10 percent). Treatment-emergent peripheral neuropathy occurred in 117 and 124 A+CHP and CHOP recipients, respectively, with resolution rates of 50 and 64 percent. At the most recent follow up, 52 and 36 percent of A+CHP and CHOP recipients, respectively, still had peripheral neuropathy.

Eighty-five and 79 percent of A+CHP and CHOP recipients, respectively, discontinued therapy, with disease progression the primary reason among CHOP recipients (12 percent vs 3 percent [A+CHP recipients]). Discontinuation due to AEs was comparable between A+CHP and CHOP recipients (6 percent vs 7 percent).

“Importantly, [the] improvements in survival came without an observed increase in toxicity. A+CHP was well tolerated, with a manageable safety profile compared with CHOP, although the median time to resolution of peripheral neuropathy was longer with A+CHP [17.0 weeks] than with CHOP [11.4 weeks],” said Horwitz and co-authors.

Positioning A+CHP in the treatment regimen

CHOP has been the most common first-line treatment in this patient population for decades, with “attempts to improve upon CHOP … largely unsuccessful, said the authors.

“We consider [the ECHELON-2] results to be potentially practice-changing,” they said. “[T]he ECHELON-2 trial … supports the potential for A+CHP to become a new standard of care for many patients with CD30-positive peripheral T-cell lymphoma.”

“This data led to a … US FDA** approval [in November 2018] for brentuximab vedotin in combination with CHP for adults with previously untreated sALCL and other CD30-expressing peripheral T-cell lymphomas, including angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma not otherwise specified,” said Horwitz.

“Regulatory approval is being sought from additional health authorities worldwide for the use of A+CHP in the treatment of patients with previously untreated CD30-positive peripheral T-cell lymphoma,” the authors said.

“The next step is to understand who the true patients are who benefit [from this treatment],” said Horwitz.