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.
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.