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Ibrutinib plus R-CHOP for non-germinal center DLBCL: Results from a phase III trial

Apr 13, 2019

On 22 March 2019, Anas Younesfrom Memorial Sloan Kettering Cancer Centre, New York, USA and colleagues, published in the Journal of Clinical Oncology results from a phase III clinical trial that investigated the efficacy of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with untreated non-germinal center B-cell (non-GCB) diffuse large B-cell lymphoma (DLBCL).

In this randomized, double-blind, placebo-controlled multicenter study ( NCT01855750), the efficacy and safety of ibrutinib plus R-CHOP was compared to placebo plus R-CHOP in patients with non-GCB DLBCL. The primary endpoint was investigator-assessed event-free survival (EFS) in the intent-to-treat (ITT) population and the activated B-cell (ABC) DLBCL subgroup. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety.

Study design & baseline characteristics

  • N = 838 DLBCL patients with the non-GCB molecular subtype (ITT population)
  • The ABC DLBCL subtype was confirmed in 75.9% (n = 567) of patients across the two cohorts
  • Patients were randomized (1:1 ratio) for six or eight treatment 21-day cycles to either:
    • R-CHOP + placebo (n = 419):
      • R: 375 mg/m 2intravenously
      • C: 750 mg/m 2intravenously
      • H: 50 mg/m 2intravenously
      • O: 1.4 mg/m 2(maximum 2 mg) intravenously
      • P: 100 mg daily orally
    • R-CHOP + ibrutinib (n = 419):
      • Ibrutinib: 560 mg daily orally
      • R-CHOP as above
    • Median patient age: 62.0 years
    • Median time from diagnosis to treatment: 27 days
    • Baseline characteristics were well balanced between the two arms
    • Median follow-up: 34.8 months

Key findings

  • EFS was not significantly increased by the addition of ibrutinib to R-CHOP (HR = 0.934; [95% CI, 0.726−200]; P= 0.5906), neither in the ITT population analysis nor in the ABC population analysis (HR = 0.949; [95% CI, 0.704−1.279]; P= 0.7311)
  • PFS was not significantly increased by the addition of ibrutinib to R-CHOP (HR = 0.917; [95% CI, 0.710−1.183]; P= 0.5027)
  • OS was not significantly increased by the addition of ibrutinib to R-CHOP (HR = 0.991; [95% CI, 0.712−1.380]; P= 0.9593)
  • Overall response rate (ORR; ITT population):
    • R-CHOP + placebo: 93.1%
    • R-CHOP + ibrutinib: 89.3%
    • Comparison: P= 0.0515
  • Complete response (CR; ITT population):
    • R-CHOP + placebo: 68.0%
    • R-CHOP + ibrutinib: 67.3%
    • Comparison: P= 0.8229
  • Central nervous system relapse incidence:
    • R-CHOP + placebo: 3.8%
    • R-CHOP + ibrutinib: 2.4%
  • Proportion of patients receiving at least six treatment cycles of R-CHOP:
    • R-CHOP + placebo: 90.7%
    • R-CHOP + ibrutinib: 80.8%

Subgroup analysis by age:

  • Age and elevated lactate dehydrogenase levels were associated with favourable EFS outcomes
  • Exploratory analysis revealed a robust linear association between age and EFS, PFS, and OS ( P= 0.0365)
  • Multivariate analysis revealed that patients < 65 years old had a more favourable outcome with R-CHOP + ibrutinib than older
  • Among patients < 60 years old:
    • R-CHOP + ibrutinib improved EFS when compared to R-CHOP + placebo (HR = 0.579; [95% CI, 0.380−0.881])
    • R-CHOP + ibrutinib improved PFS when compared to R-CHOP + placebo (HR = 0.556; [95% CI, 0.359−0.860])
    • R-CHOP + ibrutinib improved OS when compared to R-CHOP + placebo (HR = 0.330; [95% CI, 0.162−0.673])
    • ORR was similar between arms in younger patients (R-CHOP + ibrutinib: 93.6% versusR-CHOP + placebo: 94.6%)
    • CR rates were similar between arms in younger patients (R-CHOP + ibrutinib: 71.2% versusR-CHOP + placebo: 69.9%)
    • Durable partial response longer than six months was more frequent in the R-CHOP + ibrutinib arm (57.1%), when compared to the R-CHOP + placebo arm (34.8%)
  • Among patients ≥ 60 years old:
    • R-CHOP + ibrutinib reduced EFS when compared to R-CHOP + placebo (HR = 1.228; [95% CI, 0.887−1.699])
    • R-CHOP + ibrutinib decreased PFS when compared to R-CHOP + placebo (HR = 1.200; [95% CI, 0.866−1.664])
    • R-CHOP + ibrutinib decreased OS when compared to R-CHOP + placebo (HR = 1.440; [95% CI, 0.963−2.152])
    • ORR was similar between arms in younger patients (R-CHOP + ibrutinib: 86.7% versusR-CHOP + placebo: 91.8%)

Safety

  • Any grade treatment-emergent adverse events (TEAEs) occurred in:
    • R-CHOP + placebo: 99%
    • R-CHOP + ibrutinib: 100%
  • Grade ≥ 3 TEAES occurred in:
    • R-CHOP + placebo: 87.1%
    • R-CHOP + ibrutinib: 89.9%
  • Serious AEs occurred in:
    • R-CHOP + placebo: 34.0%%
    • R-CHOP + ibrutinib: 53.1%
  • The most commonly reported SAEs in the ibrutinib + R-CHOP versusthe placebo + R-CHOP arm, were:
    • Febrile neutropenia: 18.8% versus5%
    • Pneumonia: 6.7% versus3%
    • Neutropenia: 4.1% versus1%
    • Diarrhea: 3.6% versus0%
    • Anemia: 3.6% versus2%
    • Lung infection: 3.4% versus7%
  • More patients discontinued all treatment components in the R-CHOP + ibrutinib arm (22.4%) than the R-CHOP + placebo group (13.6%):
    • AEs were the most common reason for this discontinuation (12.2% versus3%)
  • Rate of AEs leading to death:
    • R-CHOP + placebo: 2.9%
    • R-CHOP + ibrutinib: 4.3%
  • SAEs and AEs leading to treatment discontinuation increased with older age in both arms but were more pronounced in the ibrutinib + R-CHOP versusthe placebo + R-CHOP arm

Conclusions

  • In the non-GCB population (ABC subtype) addition of ibrutinib to R-CHOP did not improve efficacy in patients with untreated DLBCL
  • Age seemed to be significantly associated with treatment outcomes after ibrutinib + R-CHOP, with patients younger than 60 years having a prolonged PFS, EFS, and OS, when compared with patients receiving R-CHOP + placebo
  • In older patients (≥ 60 years), ibrutinib + R-CHOP was associated with higher toxicity
  1. Younes A. et al.Randomized Phase III Trial of Ibrutinib and Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Non-Germinal Center B-Cell Diffuse Large B-Cell Lymphoma. J Clin Oncol. 2019 Mar 22:JCO1802403. DOI: 10.1200/JCO.18.02403[Epub ahead of print].