Rituximab/Lenalidomide Regimen Misses Endpoint in Phase III Follicular Lymphoma Study

Gilles A. Salles, MD, PhD

The combination of rituximab (Rituxan) and lenalidomide (Revlimid) followed by maintenance therapy with the same regimen did not improve response nor progression-free survival (PFS) compared with rituximab and chemotherapy with rituximab maintenance for patients with previously untreated follicular lymphoma.

The lack of superior efficacy with the rituximab/lenalidomide (R2) combination was seen in the open-label phase III RELEVANCE study, which had a co-primary endpoint of PFS and complete response or unconfirmed complete response (CR/CRu) at 120 weeks. In the comparator arm, rituximab combinations include R-CHOP, R-CVP, and rituximab plus bendamustine. Lenalidomide was administered at 20 mg for 6 cycles followed by 10 mg, if there was a CR.

"This is the first phase III trial to evaluate a chemotherapy-free regimen to the established standard of care in patients with previously untreated follicular lymphoma and represents a landmark study in this disease setting," Gilles Salles, MD, PhD, president of the Lymphoma Study Association, which help conduct the study, said in a statement. "We look forward to further analyzing and presenting these important data at a future medical congress."

Findings from the RELEVANCE trial have not yet been released. The study was conducted by Celgene, the manufacturer of lenalidomide, and the Lymphoma Study Association. The companies noted that AEs in the RELEVANCE trial were similar to prior reports for the R2 combination. Additional analyses remain ongoing.

“Follicular lymphoma patients frequently choose less effective treatments—like rituximab alone versus rituximab/chemo—based on perceived quality of life advantage,” lymphoma expert John P. Leonard, MD, medical oncology, at Weill Cornell Medicine and NewYorkPresbyterian Hospital, commented on Twitter. “R2 might be a choice made by some patients, even if less effective. The details of efficacy, toxicity, and qualify of life are key here.”

Prior to results from the RELEVANCE study, the MAGNIFY trial had also explored R2 for patients with relapsed/refractory indolent non-Hodgkin's lymphoma. Results from the MAGNIFY trial, which were presented at the 2017 International Conference on Malignant Lymphoma (ICML) in Lugano, Switzerland, did not have a comparator arm.

The MAGNIFY trial enrolled patients with follicular lymphoma (n = 160) and marginal zone lymphoma (MZL; n = 38) to receive induction therapy with R2 for 12 cycles followed by randomization to continued maintenance therapy for 18 cycles with lenalidomide plus rituximab or rituximab alone. The median age of patients across groups was 65 years and all had an ECOG performance status of 0 or 1.

In the follicular lymphoma group, patients had received a median of 2 prior therapies (range, 0-9) and in the MZL group patients had received 1 prior therapy (range, 1-4). In the follicular lymphoma group, 52 patients had early relapse (within 2 years of diagnosis) and 50 patients were double-refractory (refractory to rituximab and an alkylating agent). In the MZL group, patients had nodal MZL (n = 18), splenic MZL (n = 10), and mucosa-associated lymphoid tissue (MALT) lymphoma (n = 10).

The objective response rate (ORR) for patients with follicular lymphoma was 66%, which included a 38% rate of CR or CRu. In those with MZL, the ORR with the chemotherapy-free combination was 66% and the CR/CRu was 44%. The 1-year progression-free survival (PFS) rate across all patients was 70% with R2. In the double refractory and early relapse groups of patients with follicular lymphoma, the 1-year PFS rates were 65% and 49%, respectively.

In those with double-refractory and early relapsing follicular lymphoma, respectively, the most common grade 3/4 treatment-emergent adverse events (AEs) were neutropenia (42% vs 37%), leukopenia (8% vs 10%), thrombocytopenia (8% vs 4%), and lymphopenia (6% vs 4%). Other grade 3/4 AEs in the double refractory and early relapse arms, respectively, included febrile neutropenia (4% vs 4%) and thrombosis (2% vs 0%).

The phase III AUGMENT trial is currently assessing R2 versus placebo plus rituximab in patients with relapsed/refractory indolent non-Hodgkin lymphoma. The trial is including those with grade 1, 2, or 3a follicular lymphoma or MZL. The primary endpoint of the study, which has enrolled 357 patients, is PFS. Results from the study are anticipated soon (NCT01938001).

Coleman M, Andorsky DJ, Yacoub A, et al. Phase IIIB study of lenalidomide plus rituximab followed by maintenance in relapsed or refractory NHL: analysis of marginal zone lymphoma. Presented at: 14th International Conference on Malignant Lymphoma; June 14-17, 2017; Lugano, Switzerland. Abstract 139. DOI: 10.1002/hon.2437_138.