Brentuximab vedotin plus chemotherapy for CD30+ PTCL: Results from the phase III ECHELON-2 trial

On 4 December 2018, the results of the global phase III trial ECHELON-2 trial were published in The Lancet by Steven Horwitz from Memorial Sloan Kettering Cancer Center, New York, USA, and colleagues.

ECHELON-2 (NCT01777152) is a global, double-blind, active-comparator, randomized, phase III trial that investigated the efficacy and safety of brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (A+CHP) versus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in patients with CD30⁺ peripheral T-cell lymphoma (PTCL). The primary endpoint of the trial was progression-free survival (PFS) as assessed by a double-blinded Independent Central Review. Secondary endpoints included, overall survival (OS) as well as objective response rate, complete response (CR) rate, and PFS assessed by a blinded Independent Central Review.

Study design

• N = 452 patients with previously-untreated CD30⁺ PTCL, aged ≥ 18, and with an International Prognostic Index (IPI) ≥ 2 were randomized
• Patient PTCL subtypes:
  • ALK-positive systemic anaplastic large cell lymphoma
  • ALK-negative systemic anaplastic large cell lymphoma
  • Peripheral T-cell lymphoma not otherwise specified (NOS)
  • Angioimmunoblastic T-cell lymphoma
  • Adult T-cell leukemia or lymphoma
  • Enteropathy-associated T-cell lymphoma
  • Hepatosplenic T-cell lymphoma
• Patients were randomized 1:1 to A+CHP (n =226) or CHOP (n =226) in the following dosing schedules:
  • A+CHP (6 or 8, 21-day cycles): 1.8 mg/kg brentuximab vedotin, 750 mg/m² cyclophosphamide, and 50 mg/m² doxorubicin intravenously on Day 1 of each cycle. Prednisone was administered at 100 mg once daily orally on Day 1 and 5 of each cycle
  • CHOP (6 or 8, 21-day cycles): 750 mg/m² cyclophosphamide, and 50 mg/m² doxorubicin intravenously on Day 1 of each cycle. Prednisone was administered at 100 mg once daily orally on Day 1 and 5 of each cycle. Vincristine was administered at 1.4 mg/m² with a maximum of 2.0 mg/m² on Day 1 of each cycle.
• The study used a double-dummy design for brentuximab vedotin in the A+CHP arm and a placebo for vincristine in the CHOP arm
• Data cut-off: 15 August 2018
• Baseline characteristics were generally balanced between the two arms
• Overall median patient age (range): 58 (45−67) years

Key findings

• At data cut-off a total of 29 PFS events had occurs
• At median follow-up of 36.2 months (95% CI, 35.9−41.8):
  • Median PFS:
    • A+CHP: 48.2 months (95% CI, 35.2−not evaluable)
    • CHOP: 20.8 months (95% CI, 12.7−47.6)
    • Comparison: HR = 0.71; (95% CI, 0.54−0.93); P = 0.0110
    • A 29% PFS event risk reduction in the A+CHP arm compared to the CHOP arm
  • Three-year PFS:
    • A+CHP: 57.1% (95% CI, 49.9−63.7)
    • CHOP: 44.4% (95% CI, 37.6−50.9)
  • The PFS analyses for important subgroups were generally consistent with the overall results mentioned above
    • The ALK-positive systemic anaplastic large cell lymphoma subgroup had the lowest HR
    • The ALK-negative systemic anaplastic large cell lymphoma and peripheral T-cell lymphoma NOS subgroups were similar to the intention-to-treat (ITT) population
    • The angioimmunoblastic T-cell lymphoma had a HR above unity
  • Treatment with A+CHP reduced the risk of death by 34% compared with CHOP (HR = 0.66; [95% CI, 0.46−0.95]; P = 0.0244)
  • After a median follow-up of 42.1 months (95% CI, 40.4−43.8)
    • Median OS:
      • A+CHP: not reached
      • CHOP: not reached
    • OS was in favour of A+CHP for key subgroups, including both non-systemic anaplastic large cell lymphoma histological subtypes, peripheral T-cell lymphoma NOS, and angioimmunoblastic T-cell lymphoma
  • Patients with subsequent anticancer therapy for residual or progressive disease (excluding stem cell transplantation and radiotherapy):
    • A+CHP: 26% (n = 59)
    • CHOP: 42% (n = 94)
  • Patients completing treatment as intended:
    • A+CHP: 89% (n = 198)
    • CHOP: 81% (n = 184)
  • Patients receiving more than 6 treatment cycles:
    • A+CHP: 19% (n = 42)
    • CHOP: 19% (n = 44)

Safety

• A common treatment-emergent adverse event (TEAE) was diarrhea. Any grade diarrhea was more commonly observed in the A+CHP (38%) arm than the CHOP group (20%)
• Other common TEAEs (A+CHP versus CHOP) were:
  • Nausea (46% vs 38%)
  • Peripheral sensory myopathy (45% vs 41%)
  • Constipation (29% vs 30%)
  • Alopecia (26% vs 25%)
  • Pyrexia (26% vs 19%)
  • Vomiting (26% vs 17%)
  • Fatigue (24% vs 20%)
  • Anemia (21% vs 16%)
• Grade ≥ 3 events were similar between arms
• Treatment discontinuation due to AE occurred in:
  • A+CHP: 6% of patients
  • CHOP: 7% of patients
• AE leading to death occurred in:
  • A+CHP: 3% of patients
  • CHOP: 4% of patients

Conclusions

• A+CHP showed a superior survival benefit over the established standard of care CHOP in previously-untreated CD30⁺ PTCL patients
• Treatment with A+CHP reduced the risk of an event by 29% in these patients, as compared to CHOP administration
• The incidence and severity of TEAEs were similar in both arms
• According to the investigators, A+CHP should become the new standard of care for CD30⁺ PTCL patients