New evidence suggests that adding the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib to a standard chemotherapy regimen may improve survival among younger people with a specific form of diffuse large B-cell lymphoma (DLBCL). The findings, published by Wyndham Wilson, MD, PhD, in Cancer Cell, come from a new analysis of the previously conducted phase III PHOENIX clinical trial.
Wyndham Wilson, MD, PhD
Initial results from PHOENIX showed that combining ibrutinib with the standard chemotherapy regimen did not help patients with a form of DLBCL called non–germinal center B-cell–like (GCB) DLBCL to live longer overall. However, by analyzing tumor biopsy samples from patients on the trial, researchers have now shown that younger patients with specific genetic subtypes of non-GCB DLBCL, called MCD and N1, had an exceptional response to the treatment combination, with all such patients alive without disease 3 years after diagnosis.
“People thought the trial didn’t work,” said senior study author Louis M. Staudt, MD, PhD, Chief of the Lymphoid Malignancies Branch in the Cancer for Cancer Research at the National Cancer Institute. “But there was something interesting going on—if you just considered younger patients under the age of 60, they had a real benefit from ibrutinib, and we now understand why.”
Louis M. Staudt, MD, PhD
“This new analysis provides a compelling rationale for doctors to consider adding ibrutinib to standard chemotherapy for the initial treatment of younger patients with non-GCB DLBCL,” said Dr. Wilson, senior investigator in the Lymphoid Malignancies Branch.
Trial Background
People with DLBCL are typically treated with the R-CHOP regimen (cyclophosphamide, doxorubicin, vincristine, prednisone, and the monoclonal antibody rituximab), but R-CHOP is not effective for all patients with the disease.
In the 2000s, to better understand individual variation in treatment response, researchers analyzed the patterns of gene activity in DLBCL tumors. They discovered that there are three molecular subgroups of DLBCL: GCB, activated B cell–like (ABC), and unclassified. Researchers later found that these subgroups respond differently to chemotherapy. More recently, researchers showed that the ABC and GCB subgroups can be further divided into seven genetic subtypes that also respond differently to chemotherapy.
Ibrutinib was the first targeted therapy to be evaluated for the treatment of DLBCL. The drug works by blocking the activity of BTK, a protein that is involved in the growth and survival of B cells. In a previous phase II clinical trial involving patients with relapsed DLBCL, researchers found that treatment with ibrutinib alone resulted in tumor shrinkage in 37% of patients with the ABC type but only 5% of those with the GCB type.
Subsequently, researchers launched the PHOENIX trial to evaluate the impact of adding ibrutinib to R-CHOP in patients with newly diagnosed non-GCB DLBCL. Although that trial showed no survival benefit of adding ibrutinib to R-CHOP overall, when the researchers looked specifically at trial participants aged 60 years and younger, the benefits of adding ibrutinib to R-CHOP became evident. Patients older than 60 did not benefit from the addition of ibrutinib to R-CHOP, likely because they frequently did not tolerate this combination well and had to stop treatment early.
PHOENIX Findings
What was unclear from the PHOENIX trial was whether all younger patients with non-GCB DLBCL benefited from ibrutinib or if there was greater benefit for patients with certain genetic subtypes. To gain insights into this question, researchers performed genetic analyses on tumor samples from 773 of the 838 participants and determined their subtypes using an algorithm called LymphGen.
They showed that most of the benefit from ibrutinib was in patients with ABC DLBCL, mirroring the previous study. ABC DLBCL can be divided into four genetic subtypes: MCD, N1, BN2, and A53. The researchers found that patients who were 60 and younger with the MCD subtype had 3-year event-free and overall survival rates of 100% with ibrutinib and R-CHOP, compared with 3-year event-free survival of 48% and 3-year overall survival of 69.6% with R-CHOP alone. Younger patients with the N1 subtype also had 3-year event-free and overall survival rates of 100% with ibrutinib and R-CHOP, compared with 3-year event-free and overall survival of 50% with R-CHOP alone.
Younger patients with the BN2 genetic subtype did not appear to benefit from the addition of ibrutinib. However, patients with that subtype already had an 82% overall survival rate with R-CHOP alone.
In addition to the exceptional response rate in MCD and N1 DLBCL, ibrutinib did provide benefit for some other younger patients with non-GCB DLBCL. More research is needed to determine whether the A53 subtype—which the researchers could not identify in this study because of technical reasons—falls into this category.
Although no tests are commercially available to identify the MCD and N1 subtypes, Dr. Staudt pointed out that the identification of non-GCB DLBCL is done routinely.
“For years we have only had chemotherapy and rituximab to offer these patients,” he said. “Now, we hope that adding ibrutinib to current therapy may give younger patients a better chance of surviving this aggressive cancer.”
Disclosure: This study was supported by the Intramural Research Programs of the National Institutes of Health and National Cancer Institute. Janssen Research and Development, LLC, sponsored the PHOENIX trial. For full disclosures of the study authors, visit cell.com.
