The R<sup>2</sup> regimen of lenalidomide (Revlimid) with rituximab (Rituxan) significantly improved progression-free survival compared with rituximab monotherapy in the treatment of patients with relapsed/refractory indolent lymphoma, meeting the primary endpoint of the phase III AUGMENT trial, Celegene, the manufacturer of lenalidomide, has announced.
The R2regimen of lenalidomide (Revlimid) with rituximab (Rituxan) significantly improved progression-free survival (PFS) compared with rituximab monotherapy in the treatment of patients with relapsed/refractory indolent lymphoma, meeting the primary endpoint of the phase III AUGMENT trial, Celegene, the manufacturer of lenalidomide, has announced.
The company plans to present findings from the randomized, double-blind, international trial at an upcoming oncology conference and is targeting the beginning of 2019 for regulatory filings.
"Indolent non-Hodgkin lymphomas, such as follicular lymphoma and marginal zone lymphoma (MZL), are diseases of underlying immune dysfunction with a need for new options beyond currently available therapies," Jay Backstrom, MD, chief medical officer for Celgene, said in a statement.
"We are encouraged by the highly significant improvement in progression-free survival observed in this study and look forward to engaging with regulatory authorities as soon as possible. The R2regimen represents a potentially new chemotherapy-free option for these patients,” added Backstrom.
In results presented at the 2018 ASCO Annual Meeting, the R2combination showed similar efficacy compared with rituximab plus chemotherapy, which failed to satisfy the primary endpoint for the phase III RELEVANCE trial for patients with untreated follicular lymphoma; however, the chemotherapy-free regimen had a more favorable safety profile, making it a potential first-line option.
After 120 weeks, R2showed a complete remission (CR) or unconfirmed CR (CRu) rate of 48% compared with 53% for rituximab/chemotherapy (P= .13).1The objective response rate (ORR) with the R2regimen was 84% compared with 89% for rituximab/chemotherapy. The 3-year duration of response was 77% with R2compared with 74% for rituximab/chemotherapy.
The RELEVANCE trial randomized 1030 patients to receive R2(n = 513) or rituximab/chemotherapy (n = 517), which consisted of R-CHOP (72%), rituximab/bendamustine (23%), and R-CVP (5%). The chemotherapy regimens were given at standard doses. In the R2arm, lenalidomide was administered at 20 mg/day on days 2 through 22 of a 28-day cycle until CR/CRu then at 10 mg/day. Rituximab was given at 375 mg/m2weekly in cycle 1 and then on day 1 of cycle 2 through 6. It was continued in responders every 8 weeks for 12 cycles.
Baseline characteristics were well-balanced across groups. The median age in both arms was 59 years and two-thirds of patients were ECOG performance status 0. Bulky disease (>7 cm) was found in 42% of those in the R2group and for 38% in the rituximab/chemotherapy group. FLIPI score was low (15%), intermediate (36% to 37%), and high (48% to 49%). B symptoms were presented for approximately one-quarter of patients.
At a median follow-up of 37.9 months, PFS was similar in both arms. By independent review, 3-year PFS rate was 77% with R2compared with 78% for rituximab/chemotherapy (HR, 1.10; 95% CI, 0.85-1.43;P= .048). By investigator assessment, the 3-year PFS rate was 77% with R2and 78% with rituximab/chemotherapy (HR, 0.94; 95% CI, 0.73-1.22;P= 0.63).
Outcomes were similar across prespecified subgroups for PFS. There were some outliers, although the overall patient numbers were small and these findings were not statistically significant. For those with stage I/II disease, the HR was 2.23 (95% CI, 0.66-7.55) and for those with FLIPI score 0 to 1, the HR was 2.06 (95% CI, 0.88-4.80).
Overall survival remained immature at the time of the analysis, which had a data cutoff of May 2017. The 3-year OS rate was 94% (95% CI, 91%-96%) with R2compared with 94% (95% CI, 91%-96%) for rituximab/chemotherapy (HR, 1.16; 95% CI, 0.72-1.86).
The rate of grade 3/4 neutropenia was 32% for patients treated with R2compared with 50% for rituximab/chemotherapy. The grade 4 rates were 8% and 31%, respectively. Just 1% of patients in the R2arm had an absolute neutrophil count nadir of <100/μL compared with 6% for rituximab/chemotherapy. Moreover, the time to grade 3/4 neutropenia was significantly longer with the chemotherapy-free regimen (3.7 vs 0.6 months).
All patients in each group experienced treatment-emergent adverse events (TEAEs). The rage of grade ≥3 TEAEs was higher in the chemotherapy arm (approximately 60% vs 70%). Grade 3/4 infections were twice as likely in the chemotherapy arm (2% vs 4%) and more patients experienced febrile neutropenia in the chemotherapy group (2% vs 7%). Febrile neutropenia requiring hospitalization was more than double in the chemotherapy arm (2% vs 5%) and nearly 3-times as many patients received growth factor agents in the chemotherapy group compared with R2(23% vs 68%).
Although most TEAEs were more common the in the chemotherapy arm, there was a higher rate of rash in the R2group. Grade ≥3 rash was experienced by 7% of those in the R2group compared with 1% for the rituximab/chemotherapy arm.
The development of secondary primary malignancies (SPM) was similar in each arm. In the R2group, 7% of patients developed an SPM compared with 10% in the rituximab/chemotherapy arm. Invasive SPMs occurred in 5% of patients in each group.
Prior to results from the RELEVANCE study, the MAGNIFY trial had also explored R2for patients with relapsed/refractory indolent non-Hodgkin lymphoma. Results from the MAGNIFY trial, which were presented at the 2017 International Conference on Malignant Lymphoma in Lugano, Switzerland, did not have a comparator arm.2
The MAGNIFY trial enrolled patients with follicular lymphoma (n = 160) and MZL (n = 38) to receive induction therapy with R2for 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 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 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 TEAEs 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 AUGMENT trial (NCT01938001) randomized 358 patients with relapsed/refractory follicular lymphoma or MZL to rituximab plus either lenalidomide or placebo. Beyond the primary PFS endpoint, secondary outcome measures included response, overall survival (OS), and safety. Celgene reported that there were no new safety signals with the combination, and toxicities were consistent with findings from previous studies of single-agent use of the therapies.