The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended the combination of lenalidomide and rituximab for the treatment of adult patients with grade 1 to 3a previously treated follicular lymphoma.
John Gribben, MD, DSc, FRCP, FRCPath, FMed Sci.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended the combination of lenalidomide (Revlimid) and rituximab (Rituxan; R2) for the treatment of adult patients with grade 1 to 3a previously treated follicular lymphoma.1
The positive opinion is primarily based on results from the phase III AUGMENT study, which showed that the combination reduced the risk of disease progression or death by 54% versus rituximab alone in patients with relapsed/refractory indolent non-Hodgkin lymphoma.2 Moreover, the median progression-free survival (PFS) per independent review was 39.4 months (95% CI, 22.9—not evaluable [NE]) with R2 versus 14.1 months (95% CI, 11.4-16.7) with rituximab alone at a median follow-up of 28.3 months (HR, 0.46; 95% CI, 0.34-0.62; P <.0001).
Findings from the MAGNIFY study were also included to support the safety and the efficacy of lenalidomide combined with rituximab in patients with relapsed or refractory FL, which also included those were refractory to rituximab. In this trial, the investigator-assessed overall response rate (ORR) was 74% in the follicular lymphoma group and 65% in a cohort of patients with marginal zone lymphoma (MZL).3
The European Commission, which generally follows the recommendation of the CHMP, is expected to make a decision on the approval in approximately 2 months.
“Chemotherapy is a standard of care for indolent forms of NHL, but most patients will relapse or become refractory to their current treatment,” John Gribben, MD, DSc, FRCP, FRCPath, FMed Sci., president of the European Hematology Association and Centre for Haemato-Oncology, Barts Cancer Institute, stated in a press release. “The combination of Revlimid and rituximab could represent a new, chemotherapy-free treatment option for patients with previously treated follicular lymphoma.”
In the multicenter, double-blind, phase III AUGMENT study, investigators evaluated 358 patients total with relapsed/refractory follicular lymphoma (n = 295) or MZL (n = 63). Patient had to have received ≥1 prior chemotherapy, immunotherapy, or chemoimmunotherapy regimen, and could not be refractory to rituximab. Patients also had to have grade 1, 2 or 3a follicular lymphoma.
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).
The 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, and about 50% of patients had high tumor burden per the Groupe d'Etude des Lymphomes Folliculaires criteria. The Follicular Lymphoma International Prognostic Index (FLIPI) scores in the R2 arm were low at 29%, intermediate at 31%, and high at 39% of patients. The respective rates were 37%, 32%, and 30% in the placebo arm.
In the R2 arm, 57% of patients 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 primary endpoint was PFS; secondary and exploratory endpoints included ORR, durable complete response rate, complete response rate, duration of response, duration of complete response, overall survival (OS), event-free survival, and time to next anti-lymphoma therapy.
Additional results of AUGMENT showed that the investigator-assessed 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). The overall response rate (ORR) was also significantly improved with the combination. By independent review, the ORR was 78% with R2 versus 53% with rituximab alone (P <.0001). The 78% ORR in the R2 arm comprised a 34% complete response rate.
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 anti-lymphoma therapy, geographic region where treatment was received, chemoresistance status, or tumor burden status. However, the PFS advantage in a subgroup was not consistent with the overall population was in the subgroup of patients with MZL (HR, 1.00; 95% CI, 0.47-2.13).
At a median follow-up of 28.3 months, 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 estimated 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, the HR for OS was 0.45 (95% CI, 0.22-0.92; P = .02). The 2-year OS rate was 95% (95% CI, 90-98) for R2 and 86% (95% CI, 79-91) for rituximab alone.
Regarding safety, all-grade adverse events (AEs) occurring in ≥10% of patients with lenalidomide/rituximab versus placebo/rituximab were neutropenia (58% vs 22%), constipation (26% vs 14%), leukopenia (20% vs 9%), anemia (16% vs 4%), thrombocytopenia (15% vs 4%), and tumor flare (11% vs 1%).
“Since its initial approval in 2007, Revlimid has continued to demonstrate its benefits across a range of serious blood disorders in Europe and a CHMP positive opinion for this combination with rituximab is very good news for patients with follicular lymphoma. We look forward to the European Commission decision,” Tuomo Pätsi, president of Hematology/Oncology for Celgene Worldwide Markets, stated in the press release.
In May 2019, the FDA approved the R2 regimen of lenalidomide plus rituximab for use in patients with previously treated follicular lymphoma and marginal zone lymphoma, also primarily based on the AUGMENT data and supported by the findings in the MAGNIFY trial.