Lenalidomide/Rituximab Data Published as FDA Weighs Non-Hodgkin Lymphoma Approval

John P. Leonard, MD

The R² regimen of lenalidomide (Revlimid) plus rituximab (Rituxan) significantly reduced the risk of disease progression or death compared with rituximab alone in patients with relapsed/refractory indolent non-Hodgkin lymphoma, according to results from the pivotal phase III AUGMENT trial, now published in the Journal of Clinical Oncology.

The study findings showed that 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, translating to a 54% reduction in the risk of disease progression or death (HR, 0.46; 95% CI, 0.34-0.62; P <.001).

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 <.001). 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 <.001). The 78% ORR rate in the R² arm comprised a 34% complete response rate and a 44% partial response rate.

Based on these data, the FDA granted a priority review designation in February 2019 to a supplemental new drug application for use of R² in this setting. Under the Prescription Drug User Fee Act, the FDA is scheduled to make a decision on the application by June 27, 2019.

“The magnitude of efficacy differences between the two treatments is clinically meaningful and suggests that lenalidomide plus rituximab should replace rituximab monotherapy as a standard of care for patients with relapsed or refractory indolent [non-Hodgkin lymphoma],” lead author John P. Leonard, MD, of Weill Cornell Medicine and New York Presbyterian Hospital, and coauthors wrote.

The double-blind, phase III AUGMENT trial included 358 patients with relapsed/refractory follicular lymphoma or marginal zone lymphoma (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).

“No difference in PFS was observed between treatment groups in the MZL subgroup. Although this could relate to lack of effect in this subset, the small number of patients and imbalance in prognostic factors between arms limit interpretation for this histology,” wrote Leonard et al.

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.

Treatment with R² resulted in higher rates of grade 3/4 neutropenia (50% vs 13%) and leukopenia (7% vs 2%); however, no other grade 3/4 AEs varied by more than 5% between the 2 arms. All-grade febrile neutropenia occurred in 3% and 1% of the R² and control arms, respectively.

“Dose modifications successfully addressed neutropenia, with only five patients (3%) discontinuing lenalidomide because of neutropenia,” wrote Leonard et al.

Leonard JP, Trneny M, Izutsu K, et al. AUGMENT: A phase III study of lenalidomide plus rituximab versus placebo plus rituximab in relapsed or refractory indolent lymphoma [published online March 21, 2019]. J Clin Oncol. doi: 10.1200/JCO.19.00010.