Ibrutinib, the first Bruton’s tyrosine kinase (BTK) inhibitor approved for several B-cell malignancies, was shown to inhibit BTK enzymatic activity in B-cell proliferation.^1,2 Several studies showed promising results for ibrutinib’s activity in diffuse large B-cell lymphoma (DLBCL), mainly non-germinal center B-cell-like (GCB) lymphoma, but the PHOENIX trial demonstrated no survival benefits with its addition to R-CHOP.^1,3,4 However, recent findings from a new analysis of the PHOENIX trial published in Cancer Cell highlighted the benefits of ibrutinib and R-CHOP in younger patients with non-GCB DLBCL and certain genetic subtypes.⁵

Diffuse large B-cell lymphoma (DLBCL), the most common form of non-Hodgkin lymphoma (NHL), is an aggressive lymphoma categorized into primary mediastinal B-cell lymphoma, primary central nervous system (CNS) lymphoma, or DLBCL not otherwise specified (DLBCL-NOS).⁶ The DLBCL-NOS category is further classified based on the marker present on the cancer cell surface into genetic subtypes that are named according to the cancer cell's origin and include germinal center B-cell-like (GCB), activated B-cell-like (ABC), and unclassified.¹ The chemotherapy regimen R-CHOP is most widely used for DLBCL, but its outcomes remain poor in patients with incomplete remission or disease relapse.² Approved for several B-cell malignancies, ibrutinib inhibits BTK enzymatic activity, which signals molecules of the B-cell antigen receptor and cytokine receptor pathways.²

A phase 1 study evaluating the safety and efficacy of ibrutinib and R-CHOP in treatment-naïve CD-20 positive B-cell NHL patients demonstrated an overall response in all DLBCL patients with a complete response in all patients with non-GCB subtype.³

Another phase 2 study examining ibrutinib in patients with relapsed or refractory ABC DLBCL showed a response rate of 37% with ABC DLBCL and 5% with GCB DLBCL (p=0.0106). ABC DLBCL tumors with CD79B alone or with MYD88 mutations were more likely to respond to ibrutinib.⁴

In the PHOENIX study, patients aged 18 years or older with previously untreated non-GCB DLBCL were administered R-CHOP with either ibrutinib 560mg daily or placebo in a 21-day cycle for six or eight cycles to determine if the addition of ibrutinib would show improved efficacy.¹ The primary endpoint was the event-free survival (EFS) in the intent to treat (ITT) and ABC populations.¹ The median age among the 838 patients was 62 years with 75% of ABC subtypes detected in evaluable patients and a median follow-up of 34.8 months.¹ Results showed no improvement in the EFS, PFS, OS, or ORR in patients receiving ibrutinib plus R-CHOP compared to R-CHOP alone.¹ The subgroup analysis by age of both the ITT and ABC population demonstrated that patients younger than 65 years receiving ibrutinib experienced significantly favorable outcomes compared to the control group while patients aged 60 years or older with non-GCB or ABC DLBCL had worse outcomes.¹ Adverse events were similar in both treatment arms, but more serious adverse events occurred in the ibrutinib plus R-CHOP arm leading to a higher discontinuation rate.¹

However, a new analysis of the PHOENIX trial, published in Cancer Cell, was conducted to examine whether the benefit of ibrutinib is present in all non-GCB patients aged ≤60 years or in those with certain genetic subtypes, such as the MCD, N1, BN2, and A53, identified in the PHOENIX trial biopsy analysis.⁵ Using LymphGen, subtype determination was analyzed in 773 tumor samples from 838 patients.⁵ Similar to the previous study, patients with ABC DLBC had the most benefit, and the 3-year EFS and OS were both 100% in patients with the MCD subtype on ibrutinib and R-CHOP compared with an EFS of 48% and OS of 69.6% with R-CHOP alone.⁵ Additionally, the presence of the N1 subtype led to an EFS and OS of 100% with ibrutinib plus R-CHOP and 50% with R-CHOP alone.⁵ This benefit was also evident in patients with non-GCB DLBCL, but patients with the BN2 subtype were not likely to have additional benefits.⁶ Since the A53 subtype was not identified in this study, further research is needed to better understand the response of ibrutinib in this subtype.⁵

Dr. Louis Staudt, the senior study author, believes that these promising results may provide a better chance of surviving to younger patients with non-GCB DLBCL with the addition of ibrutinib.