NICE Recommends Lenalidomide/Rituximab for Follicular Lymphoma

Meindert Boysen, PharmD

The United Kingdom’s National Institute for Health and Care Excellence (NICE) has recommended the combination of lenalidomide (Revlimid) and rituximab (Rituxan; R²) as a treatment option for adult patients with grade 1 to 3A previously treated follicular lymphoma.^1,2

The recommendation was supported by findings from the double-blind, 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.³

“Lenalidomide is a new type of targeted cancer therapy for people with previously treated follicular lymphoma,” Meindert Boysen, director of the Centre for Health Technology Evaluation at NICE, stated in a press release. “It not only offers patients a chemotherapy-free treatment option, but it also benefits those whose disease has become resistant to chemotherapy or rituximab. Lenalidomide fights cancer cells in a different way to current treatments which should help reduce resistance and improve disease outcomes.”

The combination is only recommended if Celgene, the manufacturer of lenalidomide, provides the immunomodulatory drug at a discounted price according to the commercial arrangement, NICE stated in its appraisal consultation document.

Moreover, while R² does cost more than rituximab combined with chemotherapy, its cost-effectiveness estimate is within a range in which NICE considers to be an acceptable use of National Health Service resources, the agency added. For a 21-capsule pack, lenalidomide costs £4,168.50 ($5373.82); details of the discount will be made available to relevant NHS organizations. Rituximab’s list price is £349.25 ($450.24) for two 100-mg vials and £873.15 ($1125.62) for one 500-mg vial.

The recommended starting dose of oral lenalidomide is 20 mg, given once daily on days 1 to 21 of 28-day cycles for up to 12 cycles of therapy. Rituximab is recommended at 375 mg/m² intravenously in a weekly schedule in cycle 1—on days 1, 8, 15, and 22—and day 1 of every 28-day cycle for cycles 2 to 5.

In the phase III AUGMENT trial, 358 patients total with relapsed/refractory follicular lymphoma (n = 295) or marginal zone lymphoma (MZL; n = 63). Patient had to have received ≥1 prior chemotherapy, immunotherapy, or chemoimmunotherapy regimen, and could not be rituximab refractory.

Patients were randomized to receive 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).

Baseline characteristics were well balanced between the 2 arms. About 60% of patients were aged ≥60 years, over 70% of patients had advanced-stage disease at study entry, and approximately 50% of patients had high tumor burden per 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 prior regimens. 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 on placebo had progressed within 2 years of their last regimen.

Results 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 (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).

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.

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).

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.

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.

Regarding safety, the most common all-grade adverse events (AEs) occurring in patients with MZL/follicular lymphoma were neutropenia (58%), diarrhea (31%), constipation (26%), cough (24%), fatigue (22%), rash (22%), pyrexia (21%), leukopenia (20%), pruritus (20%), upper respiratory tract infections (18%), abdominal pain (18%), anemia (16%), headache (15%), and thrombocytopenia (15%).

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 ≥1 AE-related dose interruption.

Findings of a subgroup analysis of AUGMENT were presented during the 2019 ASH Annual Meeting. Results showed that R² led to a 34% reduction in the risk of disease progression or death versus rituximab/placebo in patients ≥70 years old with indolent non-Hodgkin lymphoma, although it was not found to be statistically significant.⁴ However, the PFS benefit was more pronounced in patients with follicular lymphoma and were ≥70 years old (HR, 0.49; 95% CI, 0.25-0.99; P = .043).

“This new drug offers cancer patients treatment which is free from the gruelling side effects of chemotherapy, as well as giving fresh hope to those who have built resistance to existing medicines,” Jo Churchill, Health Minister, stated in the press release. “Revolutionary treatments such as this demonstrate how our NHS continues to push boundaries to ensure patients receive the best possible care as research develops.”

In May 2019, the FDA approved the R² regimen for use in patients with previously treated follicular lymphoma and marginal zone lymphoma, also based on the AUGMENT findings.

References

1. Appraisal consultation document: Lenalidomide with rituximab for previously treated follicular lymphoma. National Institute for Health and Care Excellence. Published February 2020. bit.ly/3a99DF7. Accessed February 27, 2020.
2. NICE recommends new ‘chemotherapy-free’ treatment for lymphoma [news release]. National Institute for Health and Care Excellence. Published February 27, 2020. https://bit.ly/2T4aAbU. Accessed February 27, 2020.
3. Leonard JP, Trneny 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. J Clin Oncol. 2019;37(14):1188-1199. doi: 10.1200/JCO.19.00010.
4. Trneny M, Leonard JP, Zhang H, et al. Subgroup analyses of elderly patients aged ≥ 70 years in AUGMENT: a phase III randomized study of lenalidomide plus rituximab (R²) vs rituximab plus placebo (r-placebo) in patients with relapsed/refractory (r/r) indolent non-Hodgkin lymphoma (iNHL). Blood. 2019;134(suppl_1):347. doi: 10.1182/blood-2019-122461.