Bortezomib Leads to More Complete Remissions in Patients With High-Risk Follicular Lymphoma
Andrew M . Evens , DO , MSc
With few monotherapy treatment options available for patients with high-risk follicular lymphoma ( FL ), investigators are evaluating combinations with agents approved for other indications to improve outcomes for these patients . At the 2016 American Society of Clinical Oncology ( ASCO ) Annual Meeting , Andrew M . Evens , DO , MSc , presented results of the Eastern Cooperative Oncology Group−American College of Radiology Imaging Network Cancer Research Group ( ECOG-ACRIN ) E2408 trial , which demonstrated that adding bortezomib to bendamustine plus rituximab ( BR ) led to higher remissions than BR alone in patients with previously untreated FL .
Dr . Evens spoke with ASH Clinical News at the 2016 ASCO Annual Meeting about the trial results and the need for new therapeutic options for patients with this disease .
Bortezomib is the standard of care in myeloma – what made you think it would work in FL ? When my colleagues and I were designing this randomized study in 2008 , preliminary data showed that bortezomib had some clinical activity in relapsed / refractory FL . So , we assessed the landscape of untreated patients with FL and high tumor burden – that ’ s a big differentiator . We did not look at patients who were asymptomatic , but focused instead on patients who needed treatment . We know that the first phase of standard treatment consists of some type of induction therapy with rituximab and chemotherapy , followed by a second phase of maintenance or consolidation therapy .
Originally , we had rituximab-CHOP ( R-CHOP ) as a standard therapy arm but , as we were going through the approval process , data about BR was released and showed that it was at least as effective as R-CHOP – and probably less toxic .
At that point , we went back to the National Cancer Institute ( the study ’ s sponsor ) and changed our standard arm to include BR plus two years of maintenance therapy with rituximab .
What were you hoping to find with the trial ? Our first question was , ‘ How can we make the induction better ?’ Given the preliminary data with bortezomib , we added it to standard induction therapy . We included 236 patients who were treated on one of the following regiments : BR for six cycles followed by maintenance rituximab for two years ; BR plus bortezomib for six cycles then maintenance rituximab for two years ; or BR for six cycles then maintenance rituximab for two years plus lenalidomide for one year .
We chose lenalidomide as continuing therapy partly because it ’ s an oral agent , and we thought that might make sense for extended therapy .
The primary endpoint of this study was the rate of complete remission ( CR ). We know that the most important endpoints in indolent lymphomas – which we know to be treatable but not curable – is changing the natural history of the disease . In other words , ‘ Can we improve overall survival ( OS )?’ However , this takes a long time to follow , so we looked at CR as a surrogate for OS .
How did bortezomib plus standard therapy compare with standard therapy alone ? We set a mark of 16 percent absolute improvement in rates of CR , and the short answer is that bortezomib hit the mark . When we compared BR with and without bortezomib , we found that the bortezomib-treated patients had 18 percent higher rates of CRs . Also , in a subgroup of patients with the highest-risk FL , bortezomib treatment led to a 23 percent higher rate of CRs .
How safe was the bortezomib combination ? Earlier studies showed that there were potentially some safety concerns , but we found that bortezomib was really well tolerated . We were very cautious about mandating antiviral treatment for these patients , which partly mitigated the risk of viral infections .
Surprisingly , we did not see an increase in peripheral neuropathy , which has been associated with bortezomib . We also started the study with bortezomib administered intravenously , but , once we switched to subcutaneous administration , the rate of grade 3 neuropathy decreased from 16 percent to 2 to 3 percent . It ’ s not completely eradicated , but it was substantially reduced . Another important point is that there was no difference in response rates when we switched from intravenous to subcutaneous administration .
What are the next steps for this research ? We ’ re hoping that future analyses of this data will show that improvements in CR translate to improvements in progression-free and OS . We are optimistic about the results we presented here , but the ultimate question we want to answer is whether or not CR rate , the surrogate endpoint for OS , confer a survival advantage in terms of OS and progression-free survival ?’ Hopefully , we ’ ll have some of those initial data in time for this year ’ s ASH Annual Meeting .
Andrew M . Evens , DO , MSc , is director of the Tufts Cancer Center ; chief of the Division of Hematology / Oncology ; director of the Lymphoma Program ; and professor at Tufts University School of Medicine in Boston , Massachusetts .
Reference
Evens AM , Hong F , Habermann TM , et al . Effect of bortezomib on complete remission ( CR ) rate when added to bendamustine-rituximab ( BR ) in previously untreated high-risk ( HR ) follicular lymphoma ( FL ): A randomized phase II trial of the ECOG-ACRIN Cancer Research Group ( E2408 ). Abstract # 7507 . Presented at the 2016 American Society of Clinical Oncology Annual Meeting , June 6 , 2016 ; Chicago , IL .
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