ASH 2018 | Ibrutinib plus rituximab provide superior outcomes than FCR in naïve CLL patients: Results from the ECOG-ACRIN phase III trial E1912

On Tuesday 4 December 2018, during the 60^th Annual Meeting of the American Society of Hematology (ASH), San Diego, CA, USA, in the Late Breaking Abstracts Session, Tait Shanafelt from Stanford University, Stanford, CA, USA, presented the results of the phase III trial of the ECOG-ACRIN Cancer Research Group E1912 (#LBA-4).

E1912 (NCT02048813) is a randomized, phase III trial that compared the efficacy and safety of ibrutinib-based therapy versus fludarabine, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy for previously-untreated young chronic lymphocytic leukemia (CLL) patients. The primary endpoint of this trial was progression-free survival (PFS), with overall survival (OS) being a secondary endpoint.

Study design

• N = 529 previously-untreated CLL patients, aged ≤ 70, Eastern Cooperative Oncology Group (ECOG) performance status 0−2, who required therapy
• Patients with the 17p deletion were excluded from the study
• Patients were randomly assigned 2:1 to ibrutinib and rituximab (arm A; n = 354) versus FCR (arm B; n = 175)
  • Dosing:
    • Arm A (ibrutinib + rituximab [IR]; n = 332 eligible patients):
      • Cycle 1: 420 mg ibrutinib orally, daily on Day 1−28
      • Cycle 2: 420 mg ibrutinib orally, daily on Day 1−28 and 50 mg/m² rituximab intravenously (IV) on Day 1 and 325 mg/m² intravenously on Day 2
      • Cycles 3−7: 420 mg ibrutinib orally, daily on Day 1−28 and 500 mg/m² rituximab IV on Day 1
      • Cycle 8−until progression: 420 mg ibrutinib orally, daily on Day 1−28
    • Arm B (FCR; n = 166 eligible patients):
      • Cycles 1−6: 25 mg/m² fludarabine IV on Day 1−3, 250 mg/² cyclophosphamide IV on Day 1−3
      • Cycle 1: 50 mg/m² rituximab intravenously (IV) on Day 1 and 325 mg/m² intravenously on Day 2
      • Cycles 2−6: 500 mg/m² rituximab IV on Day 1 of each cycle
    • Data cut-off date: 24 October 2018
    • Baseline characteristics were well-balanced between the two arms
    • Total median age: 58 years
    • Sex: 32.7% female patients
    • Immunoglobulin variable region heavy chain (IGHV) unmutated (tested in 82% patients): 71.1% of patients

Key results

• At a median follow-up of 33.4 months:
  • Seventy-seven PFS events occurred
  • Fourteen deaths occurred
• Four-year PFS (intention-to-treat population [ITT]):
  • IR: 37 events/354 cases
  • FCR: 40 events/175 cases
  • Comparison: HR = 0.35; (95% CI, 0.22−5); P < 0.00001
• Four-year PFS (eligible population):
  • IR: 33 events/332 cases
  • FCR: 39 events/166 cases
  • Comparison: HR = 0.32; (95% CI, 0.20−51); P < 0.00001
• Four-year OS (ITT):
  • IR: 4 events/354 cases
  • FCR: 10 events/175 cases
  • Comparison: HR = 0.17, (95% CI, 0.05−54); P < 0.0003
• Four-year OS (eligible patients):
  • IR: 3 events/332 cases
  • FCR: 10 events/166 cases
  • Comparison: HR = 0.13, (95% CI, 0.03−46); P < 0.0001
• From PFS subgroup analysis:
  • IR was superior to FCR independent of age, sex, performance status, disease stage or the presence/absence of del11q23
  • With the current follow-up, IR was also superior to FCR in IGHV unmutated patients (HR = 0.26; [95% CI, 0.14−0.50]; P < 0.0001) but not in IGHV mutated patients (HR = 0.44; [95% CI, 0.14−0.136]; P = 0.07)

Safety

• The total number of deaths that occurred during the study were:
  • IR: n = 4/354
  • FCR: n = 10/175
• Any Grade ≥ 3 treatment-related adverse events (TEAEs) were observed in:
  • IR: 58.5%
  • FCR: 72.1%
  • Comparison: P = 0.004
• Specifically, FCR was more frequently associated with Grade 3, 4 neutropenia (FCR: 44% vs. IR: 23%; P < 0.0001) and infectious complications (FCR: 17.7% vs. IR: 7.1%; P < 0.0001)

Conclusions

• Ibrutinib and rituximab provided superior PFS and OS than FCR in previously-untreated, young, CLL patients
• Ibrutinib and rituximab was well tolerated in young CLL patients