ASH 2018 | Phase III results from R-CHOP and ibrutinib in untreated non-GCB DLBCL patients

On Monday 3 December 2018, Oral Session 626 took place at the 60^th American Society of Hematology (ASH) Annual Meeting, San Diego, CA. During that session, Abstract #784 was presented by Anas Younes from Memorial Sloan Kettering Cancer Center, New York, NY, USA.

A global, randomized, double-blind, placebo-controlled phase III trial took place, investigating the efficacy of ibrutinib plus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in previously-untreated patients with non-germinal center B-cell-like (non-GCB) diffuse large B-cell lymphoma (DLBCL). The primary endpoint of the study was event-free survival (EFS) in the intention-to-treat (ITT) non-GCB population and the ABC subgroup. Secondary endpoints, included progression-free survival (PFS), complete response (CR) rate, overall survival (OS), and safety.

Study design & baseline characteristics

• N = 838 previously untreated non-GCB DLBCL patients with stage II−IV disease, Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2, and revised International Prognostic Index (R-IPI) ≥ 1
• Median age = 62 years; 58.5% of patients were < 65 years old
• Patients were randomized 1:1 to either of the following regimens:
  • R-CHOP (6-8 cycles) and placebo (n = 419) [R-CHOP + pl]
  • R-CHOP (6-8 cycles) and ibrutinib (n = 419) [R-CHOP + ibr]
• Dosing:
  • R-CHOP: pre-specified by site
  • Ibrutinib: 560 mg
• Similar number of patients with ABC subtype in both arms (77.0% vs8% for R-CHOP + ibr vs R-CHOP + pl)
• Slightly more patients ≥ 65 years in the ibrutinib + R-CHOP arm
• Median follow-up = 34.8 months
• Median time from diagnosis to treatment = 27 days

Results

• R-CHOP + ibr did not improve EFS in patients with non-GCB DLBCL (HR = 0.934; 95% CI, 0.726−200; P = 0.5906)
• R-CHOP + ibr did not improve EFS in patients with ABC DLBCL (HR = 0.949; 95% CI, 0.704−279; P = 0.7311)
• Overall response rate (ITT population):
  • R-CHOP + ibr: 89.3%
  • R-CHOP + pl: 93.1%
  • No statistical difference in overall response rate between the two arms
• CR rates (ITT population):
  • R-CHOP + ibr: 67.3%
  • R-CHOP + pl: 68%
  • No statistical difference in overall response rate between the two arms
• Central nervous system progression was observed in 2.4% (n = 10) of patients in the R-CHOP + ibr group and in 3.8% (n = 16) in the R-CHOP + pl group
• Patient age demonstrated significant interaction with treatment for all efficacy outcomes (EFS, PFS, and OS):
  • Significant risk reduction in EFS (30%), PFS (33%), and OS (43%) was observed for patients in the R-CHOP + ibr arm, who were younger than 60 years
  • A similar trend was also observed for the ABC subtype patients (HR = 0.532; 95% CI, 0.307−922 for EFS; HR = 0.345; 95% CI, 0.138−0.862 for OS)
• More patients in the R-CHOP + pl group received subsequent anti-lymphoma therapy (25.2% vs5%)

Safety

• Grade ≥ 3 adverse events (AEs) occurred in:
  • R-CHOP + ibr: 89.9%
  • R-CHOP + pl: 87.1%
• AEs were similar across arms for both age groups
• Serious AEs were greater in the R-CHOP + ibr group (53.1%), when compared to the R-CHOP + pl group (34.0%), with febrile neutropenia and pneumonia being the two most common AEs for R-CHOP discontinuation
• Treatment-related AEs (TEAEs) were consistent with those expected for R-CHOP and ibrutinib
• Higher rates of serious AEs and AEs leading to treatment discontinuation occurred in older patients (≥ 60 years) with R-CHOP + ibr
• Prophylactic granulocyte-colony stimulating factor (G-CSF) was used in 66.1% of patient in the R-CHOP + ibr arm vs9% in the R-CHOP + pl arm:
  • In patients < 60 years: 56.5% (R-CHOP + ibr) vs2% (R-CHOP + pl)
  • In patients ≥ 60 years: 71.8% (R-CHOP + ibr) vs0% (R-CHOP + pl)
• In the safety population, treatment exposure was reduced in the R-CHOP + ibr arm, when compared to the R-CHOP + pl group
• This reduced treatment exposure in the R-CHOP + ibr arm was primarily observed in older patients (≥ 60 years)

Conclusions

• In the ITT population, R-CHOP + ibr did not improve efficacy in patients with untreated non-GCB DLBCL patients
• The benefit-risk profile of R-CHOP + ibr is age-dependent:
  • In patients ≥ 60 years, R-CHOP + ibr increased serious AEs and AEs leading to treatment discontinuation
  • In patients < 60 years, R-CHOP + ibr was associated with prolonged EFS, PFS, and OS
• In older patients (≥ 60 years) the addition of ibrutinib to R-CHOP outweighs the benefits