Subgroup Analysis Shows Benefit With Ibrutinib Plus R-CHOP in Younger Patients With DLBCL

January 21, 2019

Article

Anas Younes, MD, discusses findings from a subset analysis from the PHOENIX trial in patients with DLBCL. He also highlights another trial investigating R-CHOP plus a PD-L1 inhibitor in this patient population.

Anas Younes, MD

Although the phase III PHOENIX trial combining ibrutinib (Imbruvica) with R-CHOP (rituximab [Rituxan] with cyclophosphamide, doxorubicin, vincristine, and prednisone) missed its primary endpoint of improvement in event-free survival (EFS), a subset analysis found the regimen did demonstrate a survival benefit in younger patients with diffuse large B-cell lymphoma (DLBCL), explained lead study author Anas Younes, MD.

This randomized trial looked at previously untreated patients with non-germinal center B-cell-like (non-GCB) or activated B-cell (ABC) DLBCL. A total of 838 patients were randomized to receive ibrutinib plus R-CHOP (n = 419) or placebo plus R-CHOP (n = 419). The median patient age was 62 years with 58.5% of patients < 65 years old. The risk of progression was not significantly reduced with the ibrutinib regimen in the non-GCB or ABC groups, with a hazard ratio for EFS of 0.93 (95% CI, 0.73-1.20;P= .5906). However, investigators reported a significant correlation between treatment effect and age, with patients < 65 years treated with the ibrutinib regimen (n = 342) demonstrating a significant risk reduction in EFS, PFS, and OS. These younger patients saw a 12% OS benefit with the addition of ibrutinib (HR, 0.33; 95% CI, 0.16-0.67), which Younes says is the most significant part of these data.

In an interview withTargeted Oncology,Younes, chief of Lymphoma Service at Memorial Sloan Kettering Cancer Center, discussed findings from the subset analysis from the PHOENIX trial in patients with DLBCL. He also highlighted another trial investigating R-CHOP plus a PD-L1 inhibitor in this patient population.

TARGETED ONCOLOGY:Can you provide some background on the PHOENIX trial?

Younes:The PHOENIX trial is a randomized trial comparing standard R-CHOP chemotherapy to an experimental arm, which is R-CHOP with a BTK inhibitor, ibrutinib, in selected patients based on non-GCB phenotype with subset analysis of ABC phenotype.

It’s a randomized trial, double-blinded, placebo controlled with 1:1 randomization. Six to 8 cycles of R-CHOP were compared to 6 to 8 cycles of R-CHOP with ibrutinib. [After that] there is no maintenance; you’re done. There’s just follow-up after that.

TARGETED ONCOLOGY:What were the results from this trial?

Younes:The primary endpoint, which was event-free survival, was not met for the entire group. However, if you look at subset analysis based on prespecified parameters including age, age stood out as a major factor that correlated with treatment outcome. In other words, younger patients benefitted the most from ibrutinib [plus] R-CHOP with a 12% difference, which hasn’t been seen in almost 20 years. It’s true, it’s only a subset analysis, but it’s a substantial difference. Whereas in older patients, the OS was more in favor of the control arm R-CHOP because the addition of ibrutinib to R-CHOP in older patients was more toxic.

TARGETED ONCOLOGY:What is the main takeaway from these data?

Younes:The major message from this trial is that there is hope to break the R-CHOP curse, or taboo, by interrupting B-cell receptor signaling. In this example, a BTK inhibitor, but maybe other B-cell inhibitors may contribute in the future. This would open the field for testing additional targeted therapies that target the B-cell receptor signaling pathway in the ABC or non-GCB subtype.

TARGETED ONCOLOGY:What did you find most interesting about these findings?

Younes:That’s the most interesting part of this data, the 12% OS benefit in younger patients. Yes, this is a subset analysis, but this is a really big subset of almost 350 patients. If you are going to design a new trial from scratch in younger patients and say I want to design it so I can see a 12% difference in OS between the ibrutinib R-CHOP and R-CHOP, all you need is about 500 patients. Here, we are about 350, so we are so close, but not close enough for approval by the FDA or EMA. But it’s a sizeable group of patients.

TARGETED ONCOLOGY:What questions have emerged from this trial?

Younes:There’s a lot of questions that will come out, like with any other large randomized trials. There will be a lot of other things, [such as] biomarkers, genetics, why the elderly patients didn’t benefit, if it’s just toxicity, or if there is different biology between young and old patients. Can we present these toxic side effects in older patients by incorporating antibody or antifungal prophylaxis? There are a lot of other questions that will emerge from this trial.

TARGETED ONCOLOGY:Are there any other studies you are particularly interested in?

Younes:There are quite a few studies I think that are of interest, but I can speak to one that I presented in the poster session, which is atezolizumab (Tecentriq) plus R-CHOP for newly diagnosed patients with DLBCL, unselected patients, so we are not talking about ABC, GCB, or others. It’s unselected patients who will get concurrent atezolizumab, which is the PD-L1 inhibitor, followed by 1-year maintenance of atezolizumab. I think this is an interest because almost every single approval for a checkpoint inhibitor in most cancers and other tumors was actually based on combination with chemotherapy. This is the first frontline regimens combined with checkpoint inhibitors in DLBCL.

TARGETED ONCOLOGY:What were the results of that trial?

Younes:Safety is a part of it, which it looks like there was no added toxicity with this combination. The results in terms of complete response, I wouldn’t say look promising, but it looks okay. Of course, you need a randomized trial in the future, but the early signal in terms of safety and efficacy seems to be encouraging.

TARGETED ONCOLOGY:What are the next steps with that trial?

Younes:More long-term follow-up to see if the data holds. If progression-free survival is holding, one could think about a potential randomized trial in the future.

Reference:

Younes A, Sehn LH, Johnson P, et al. A global randomized placebo-controlled, phase III study of ibrutinib plus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP) in patients with previously untreated non-germinal center B-cell-like (GCB) diffuse large B-cell lymphoma. In: proceedings from the 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 784.