FDA Grants Lenalidomide/Rituximab Priority Review for Non-Hogkin Lymphoma Subtype

The FDA has granted a priority review designation to a supplemental new drug application (sNDA) for the R² regimen of lenalidomide (Revlimid) plus rituximab (Rituxan) for use in patients with previously treated follicular lymphoma and marginal zone lymphoma (MZL).

The sNDA is based on the phase III AUGMENT trial, in which the R² regimen reduced the risk of disease progression or death by 54% versus rituximab alone in patients with relapsed/refractory indolent non-Hodgkin lymphoma. At a median follow-up of 28.3 months, the median progression-free survival (PFS) per independent review was 39.4 months (95% CI, 22.9—not evaluable) with R² versus 14.1 months (95% CI, 11.4-16.7) with rituximab alone (HR, 0.46; 95% CI, 0.34-0.62; P <.0001).

By investigator assessment, the median PFS was 25.3 months (95% CI, 21.2—not evaluable) versus 14.3 months (95% CI, 12.4-17.7), respectively (HR, 0.51; 95% CI, 0.38-0.69; P <.0001). Overall response rate (ORR) was also significantly improved with the combination. The ORR per independent review was 78% with R² versus 53% with rituximab alone (P <.0001). The 78% ORR rate in the R² arm comprised a 44% complete response rate and a 34% partial response rate.

Under the Prescription Drug User Fee Act, the FDA is scheduled to make a decision on the sNDA by June 27, 2019.

“R² has the potential to offer patients with previously treated follicular lymphoma and marginal zone lymphoma a chemotherapy-free option” Jay Backstrom, MD, chief medical officer and head of Global Regulatory Affairs for Celgene, the manufacturer of lenalidomide, said in a statement . “We look forward to working with the FDA to bring the R² regimen to patients as quickly as possible.”

The double-blind, phase III AUGMENT trial included 358 patients with relapsed/refractory follicular lymphoma or MZL in need of treatment. Across the study, 295 patients had follicular lymphoma and 63 patients had MZL. Patient had to have received at least 1 prior chemotherapy, immunotherapy, or chemoimmunotherapy regimen, and could not be rituximab refractory.

Patients were randomized to rituximab at 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1, and day 1 of cycles 2 through 5, plus either 20 mg of lenalidomide/daily on days 1 through 21 every 28 days for up to 12 cycles (n = 178) or placebo (n = 180).

Patient characteristics at baseline were well balanced overall between the 2 arms. About 60% of patients were aged ≥60 years. Over 70% of patients had advanced-stage disease at study entry. About 50% of patients had high tumor burden per the GELF criteria. Around 83% of patients in each arm had follicular lymphoma, with the remaining 17% having MZL.

The FLIPI scores in the R² arm were low at 29%, intermediate at 31%, and high at 39%. The respective rates were 37%, 32%, and 30% in the placebo arm.

In the R² arm, 57% of patients had received 1 prior systemic regimen, 17% had received 2, and 25% had received ≥3. In the control arm, the corresponding rates were 54%, 23%, and 23%, respectively. Eighty-five percent of patients in the R² arm and 83% of patients in the placebo arm had prior rituximab. About 75% of patients in each arm had received a prior rituximab-containing chemotherapy regimen. Thirty-seven percent of patients in the R² arm and 42% of patients in the placebo arm had progressed within 2 years of their last regimen.

The PFS benefit with R² was sustained across almost all prespecified subgroups, regardless of age, disease histology, whether or not they had prior rituximab, number of prior regimens, time since last antilymphoma therapy, geographic region where treatment was received, chemoresistance status, or tumor burden status.

The one exception in which the PFS advantage in a subgroup was not consistent with the overall population was the subgroup of patients with MZL. In this group, the HR for PFS was 1.00 (95% CI, 0.47-2.13). “This relates to the fact that there were roughly 30 patients in each arm with MZL, which limits these comparisons,” lead study author John Leonard, MD, associate dean for Clinical Research and Richard T. Silver Distinguished Professor of Hematology and Medical Oncology at Weill Cornell Medicine and New York-Presbyterian Hospital, said when presenting the data at the 2018 ASH Annual Meeting.

Overall survival (OS) data across the entire population showed that at a median follow-up of 28.3 months, the HR for OS was 0.61 (95% CI, 0.33-1.13). The 2-year OS rate was 93% (95% CI, 87-96) for R² and 87% (95% CI, 81-92) for rituximab alone.

In a prespecified subgroup analysis of patients with follicular lymphoma, at a median follow-up of 28.3 months, the HR for OS was 0.45 (95% CI, 0.22-0.91; P = .02). The 2-year OS rate was 95% (95% CI, 90-98) for R² and 86% (95% CI, 79-91) for rituximab alone.

Thirty percent of patients in the R² arm discontinued treatment early compared with 39% of patients in the placebo arm. The primary cause of discontinuation was disease progression, at 12% in the R² arm versus 30% in the control arm. Adverse events (AEs) led to discontinuation in 8% of the R2 group versus 4% of the placebo group. Among patients receiving lenalidomide, 66% had at least 1 AE-related dose interruption.

“The main grade 3/4 AE difference [between the 2 arms] in adverse events [was] in neutropenia.” However, the neutropenia generally did not result in febrile neutropenia, with only 3% of patients in the R² arm having febrile neutropenia.

Also of note, 6 patients in the R² arm and 10 patients in the placebo arm had secondary malignancies. “Venous and arterial thromboembolic AEs were relatively low and similar in both arms,” said Leonard.

In a discussion after his presentation, Leonard was asked where he sees the R² regimen fitting into the treatment landscape for relapsed/recurrent follicular lymphoma, given that there are several agents already approved in this setting.

“Obviously, there are other agents approved for relapsed/recurrent follicular lymphoma in different settings. There is a meaningful percentage of patients that are currently treated with single-agent rituximab. These data suggest that many of those patients, instead, could benefit from the combination of R²,” said Leonard.

“How this compares with chemotherapy, as well as other approaches, such as PI3-kinase inhibitors, really depends on the individual situation of the patient,” added Leonard.

This article originally appeared on OncLive as, “FDA Grants Lenalidomide/Rituximab Priority Review for Indolent Non-Hodgkin Lymphoma.”

Leonard JP, Trn&#283;ný M, Izutsu K, et al. AUGMENT: a phase III randomized study of lenalidomide plus rituximab (R²) vs rituximab/placebo in patients with relapsed/refractory Indolent non-Hodgkin lymphoma. Presented at: ASH Annual Meeting and Exposition; December 4-8, 2018; San Diego, California. Abstract 445.