Flinn Analyzes Data from 5-Year Follow-Up of Phase III BRIGHT Trial in Frontline MCL

Ian W. Flinn, MD, PhD

Ian W. Flinn, MD, PhD

Five-year results from the phase III BRIGHT trial support the use of bendamustine plus rituximab (Rituxan; BR) as a frontline treatment option for patients with indolent non-Hodgkin lymphoma (iNHL) and mantle cell lymphoma (MCL), according to a report published in theJournal of Clinical Oncology.

In this study, 447 patients with treatment-naive iNHL or MCL were randomized to receive either a BR regimen (n = 224) or the standard of care, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; n = 104) or rituximab plus cyclophosphamide, vincristine, and prednisone (R-CVP; n= 119). The trial was designed as a noninferiority trial.

After completion of 6 cycles of treatment, all patients were observed for a minimum of 5 years. The median time to progression was not reached in either arm of the trial, and the progression-free survival (PFS) rates were 65.5% in the BR arm and 55.8% in the R-CHOP/R-CVP arm. Overall survival (OS) was similar between both arms, and investigators concluded BR was noninferior to R-CHOP/R-CVP in the population including both patients with iNHL and MCL.

According to lead study investigator, Ian W. Flinn, MD, PhD, BR had better complete remission (CR) and PFS rates compared to R-CHOP/R-CVP in the patients with MCL versus iNHL. In addition, BR had a more tolerable side effect profile in the patients with MCL compared to the R-CHOP/R-CVP regimen.

“For patients with MCL who are not candidates for a stem cell transplant, the combination of bendamustine plus rituximab is an effective therapeutic option,” Flinn said.

In an interview withTargeted Oncology, Flinn, director of lymphoma research at Sarah Cannon Research Institute, discussed the findings from the phase III BRIGHT trial for patients with MCL. He also highlighted the impact of BR in this patient population and other combinations under active investigation.

TARGETED ONCOLOGY:What did the frontline treatment landscape for MCL look like prior to the BRIGHT trial?

Flinn:It’s interesting because the frontline therapies for MCL have evolved over recent years, and this study goes back 6 to 8 years when the first patients were enrolled on the trial. Previously, the most common standard therapy for patients with MCL was R-CHOP. Alternative therapies included more aggressive regimens like hyper-CVAD(cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride (Adriamycin), and dexamethasone)and cytarabine-containing regimens. At the time this study was initially conducted, the majority of patients would have received RCHOP, especially if they were not planning on a transplant.

TARGETED ONCOLOGY:What was the rationale for looking at the BR combination in patients with MCL?

Flinn:There were earlier phase II data to suggest that this combination was effective in patients with MCL. The StiL trial, which was another large, randomized phase III trial also indicated superiority of BR compared to RCHOP.

TARGETED ONCOLOGY:What were the findings from the phase III BRIGHT trial?

Flinn:The study was initially set up to be a noninferiority trial designed to look at CR rates. In the initial report in 2014, data showed that this combination was not inferior to R-CHOP or R-CVP in the entire population, but it certainly looked like the MCL patients had a higher CR rate. If we now look at the study data recently published in theJournal of Clinical Oncology, we see that the magnitude of improvement of PFS was even better in the MCL patients than it was in the low-grade lymphoma patient populations. There is a significant difference in PFS seen between the patients with MCL compared to those who were in the control arm of R-CHOP or R-CVP. This supports other data sets that show we should not be using R-CHOP or R-CVP in patients with MCL. BR is a more effective treatment in terms of response rate and PFS.

Additionally, the AEs in BR compared to R-CHOP appear to be different; one is not necessarily better than the other, but many would say it’s more tolerable compared to R-CHOP or R-CVP. It’s not without side effects - with R-CHOP, 100% of patients get alopecia, while with BR, that’s a rare event. We still have to pay attention to things like nausea and vomiting, but there are not the same toxicities that you see with a vinca, such as neuropathy, with BR.

There certainly are AEs with BR, but many patients would choose BR over R-CHOP or R-CVP because of the outcomes.

TARGETED ONCOLOGY:What else should we know about the safety profile?

Flinn:If we look at the entire population of patients treated on this study and not just the patients with MCL, one of the unexpected findings is an increased risk of second malignancies. The second malignancies were primarily skin cancers, such as basal cell carcinoma and squamous cell carcinoma, which could be addressed under the care of a dermatologist. We are still exploring why that is. It was not seen in the other large randomized trial, the StiLtrial, although the granularity of the follow-up was closer on this study. 

The original paper published in 2014 detailed the AEs associated with BR, R-CHOP or R-CVP including nausea and vomiting in both arms. The common perception of BR was that it has less nausea. That perception may have contributed to investigators using less aggressive anti-emetic prophylaxis with BR than with R-CHOP or R-CVP. Unfortunately, this perception is not correct. BR requires equally as aggressive anti-emetic prophylaxis as R-CHOP.  

Additionally, there was a substantial proportion of patients that developed rash. We did not see a significant occurrence of peripheral neuropathy which is typically associated with the vincristine in R-CHOP or R-CVP. We also did not see issues with constipation that would have been expected with these medications. There was less grade 3 or 4 neutropenia or febrile neutropenia with BR compared to R-CHOP or R-CVP.

TARGETED ONCOLOGY:Were there any concerns with giving patients 6 cycles of the BR combination?

Flinn:There’s a perception that it’s difficult to keep all people on the full course, 6 cycles of BR. However, when we look at the dose intensity and the number of cycles, more than 90% of the patients received all 6 cycles of BR, indicating there was no difference in R-CHOP/R-CVP in the number of cycles delivered and the dose intensity (96%).

TARGETED ONCOLOGY:How do you see this fitting into the treatment landscape for MCL?

Flinn:BR is an effective treatment option for patients with MCL who will not be receiving a stem cell transplant, which is likely the majority of patients based on various factors. BR may be a treatment approach before SCT, once further research is conducted.

In my opinion, at this point, I think BR has become the treatment of choice. There is ongoing work looking into how to build upon this approach, including adding other therapies to the BR backbone. We know that for many patients, rituximab maintenance after chemotherapy and SCT with MCL improves PFS and also OS, indicating this may be another area to be explored further. Other studies are looking at adding Bruton’s tyrosine kinase (BTK) inhibitors, such as ibrutinib (Imbruvica) or acalabrutinib (Calquence). 

TARGETED ONCOLOGY:Is there any research already looking at the addition of BTK inhibitors to this regimen?

Flinn:Randomized phase III trials are in the process of being conducted, and some have already concluded comparing BR plus/minus a BTK inhibitor. We will be interested to see the data.

We know that BTK inhibitors are effective in the relapsed setting in MCL, so finding ways to move these earlier in the course of the disease treatment could be effective. Incorporating BTK inhibitors with BR is likely an important step.

TARGETED ONCOLOGY:Are there any other agents or combinations under investigation for MCL that you would like to highlight?

Flinn: