Five-Year Results and Overall Survival Update from the Phase 3 Randomized Study Augment: Lenalidomide Plus Rituximab (R²) Vs Rituximab Plus Placebo in Patients with Relapsed/Refractory Indolent Non-Hodgkin Lymphoma

Background: The combination of lenalidomide + rituximab (R²) showed superior efficacy vs rituximab + placebo (R-placebo) in patients (pts) with relapsed refractory (R/R) indolent non-Hodgkin lymphoma (iNHL) (Leonard et al. J Clin Oncol 2019). Based on these AUGMENT study results, R² was approved for the treatment of adult pts with previously treated follicular lymphoma (FL) or marginal zone lymphoma (MZL) in the US, Japan, and Brazil, and for FL in Europe. Reported here are updated long-term follow-up results from AUGMENT.

Methods: AUGMENT (NCT01938001) is a multicenter, double-blind, randomized phase 3 study of R² vs R-placebo (control) in pts with FL grade 1-3a or MZL who were previously treated with ≥ 1 prior systemic therapy with documented relapsed or refractory disease but not refractory to rituximab (refractory was defined as < partial response to rituximab or rituximab-chemotherapy OR disease progression < 6 mo after last rituximab dose). Pts were stratified by prior rituximab treatment (yes vs no), time since last antilymphoma therapy (≤ 2 vs > 2 y), and histology (FL vs MZL), and then randomized 1:1 to R² or control for up to 1 y. R² pts received oral lenalidomide 20 mg/d, d1-21/28 for 12 cycles plus rituximab IV 375 mg/m² weekly in cycle 1 and d1 of cycles 2-5. Control pts received rituximab and placebo on the same schedule. Dose modifications were prespecified in the protocol to manage toxicities. The primary endpoint was progression-free survival (PFS) per 2007 IWG criteria without PET as assessed by Independent Review Committee (IRC; central review). During the follow-up period, pts were followed every 6 mo to assess endpoints, including overall survival (OS), time-to-next antilymphoma treatment (TTNLT), progression, second primary malignancies (SPMs), and histological transformation.

Results: A total of 358 pts were randomized (n = 178 R²; n = 180 control); baseline characteristics were similar in both groups. As of January 26, 2022 at a median follow-up of 65.9 mo, median PFS per 2007 IWG criteria as assessed by Investigator was 27.6 mo for R² vs 14.3 mo for control, with HR = 0.50 (95% CI, 0.38-0.66; P < 0.0001). Although median OS was not reached for either group, there was an improvement in OS for R² (HR = 0.59, 95% CI, 0.37-0.95, P = 0.0285; Figure). 5-y OS rates for the R² vs control groups were 83.2% (95% CI, 76.3-88.3) vs 77.3% (95% CI, 70.1-83.1). Median TTNLT (after 12 cycles of time-limited therapy) was 73.1 mo for R² vs 31.8 mo for control with HR = 0.53 (95% CI, 0.39-0.71; P < 0.0001). In the R² group, 73 pts (41%) received ≥ 1 subsequent antilymphoma treatment compared with 109 (61%) in the control group, most commonly rituximab in both groups (25% and 34%). 3 (2%) and 5 (3%) pts received lenalidomide as part of any subsequent anti-lymphoma treatment in the R² and control groups, respectively. The updated overall safety profile of both groups was consistent with the 1st analysis. SPMs occurred in 13 (7%) R²-treated and 21 (12%) control pts, an increase from 6 (3%) and 10 (6%), respectively, in the previous analysis. 9 pts died of SPM (n = 3 R², n = 6 R-placebo), an increase from 2 pts (both R-placebo) in the previous analysis. The incidence rate of SPMs per 100 y was 1.62 (95% CI, 0.94-2.78) in the R² group vs 2.66 (95% CI, 1.73-4.07) in the control group. Fewer histological transformations occurred in the R² arm than in the control group (n = 10 vs n = 15, respectively). The updated incidence rate of histological transformation in the overall population was 1.24% (95% CI, 0.66-2.3) in the R² arm and 1.85% (95% CI, 1.12-3.07) in the control arm.

Conclusions: R² continues to demonstrate superior efficacy over rituximab monotherapy (plus placebo) as measured by the primary endpoint of PFS (as assessed by Investigator in long-term follow up). The updated results for OS are consistent with the improvement observed in PFS. The OS KM curve separation after 5 y continues to favor R², providing evidence for a survival benefit. The updated TTNLT KM curves continue to demonstrate that fewer R²-treated patients needed subsequent antilymphoma treatment to date, well beyond the 1-y treatment period. The safety profile of R² and R-placebo remain consistent with the primary analysis, with continued lower rates of SPM and rates of histologic transformation comparable to historical experience. These updated results, including OS data, provide further support for the use of the R² regimen as a standard of care for pts with R/R iNHL.

Leonard:Constellation: Consultancy; Calithera: Consultancy; Novartis: Consultancy; Mustang Bio: Consultancy; Merck: Consultancy; MEI Pharma: Consultancy; Lilly: Consultancy; Karyopharm: Consultancy; Janssen: Consultancy; Incyte: Consultancy; Sutro: Consultancy; Second Genome: Consultancy; Seattle Genetics: Consultancy; Pfizer: Consultancy; Grail: Consultancy; Gilead/Kite: Consultancy; Genmab: Consultancy; Roche/Genentech: Consultancy; Epizyme: Consultancy; Eisai: Consultancy; ADC Therapeutics: Consultancy; BMS/Celgene: Consultancy; Bristol-Myers Squibb: Consultancy; Beigene: Consultancy; Bayer: Consultancy; AstraZeneca: Consultancy; Astellas: Consultancy; AbbVie: Consultancy; Regeneron: Consultancy; Miltenyi: Consultancy. Trneny:Takeda: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; MorphoSys: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Zentiva: Consultancy, Honoraria. Mayer:Sierra Oncology: Research Funding; Celgene: Research Funding. Nowakowski:Bantam Pharmaceutical: Consultancy; Blueprint Medicines Corporation: Consultancy; Celgene Corporation/Bristol Myers Squibb: Consultancy, Research Funding; Curis, Inc.: Consultancy; Daiichi Sankyo Inc: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Genentech, Inc: Consultancy, Research Funding; Incyte: Consultancy; Karyopharm: Consultancy; Kite Pharma Inc.: Consultancy; Kymera Therapeutics: Consultancy; MorphoSys US Inc: Consultancy; NanoString: Research Funding; Ryvu Therapeutics: Consultancy; Selvita: Consultancy; TG Therapeutics: Consultancy; Zai Lab: Consultancy. Scheinberg:Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BioCryst: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy. Gkasiamis:Bristol Myers Squibb: Current Employment. Mikita-Geoffroy:Bristol Myers Squibb: Current Employment, Other: RSU. Rowe:BMS: Current Employment; many including BMS in my 401k.: Current equity holder in publicly-traded company. Gribben:Gilead Sciences: Consultancy, Honoraria; Morphosys AG: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; European Hematological Association: Membership on an entity's Board of Directors or advisory committees.