Results from the AUGMENT phase III trial: Lenalidomide + rituximab for R/R MZL and FL

On 21 March 2019, John Leonard from Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY, USA, and colleagues, published in the Journal of Clinical Oncology results from the phase III clinical trial AUGMENT. This study investigated the efficacy of lenalidomide plus rituximab in patients with relapsed or refractory (R/R) indolent non-Hodgkin lymphoma (NHL).

In this multicenter analysis of the AUGMENT phase III trial (NCT01938001), placebo with rituximab was compared against lenalidomide and rituximab combination in patients with R/R marginal zone lymphoma (MZL) or follicular lymphoma (FL). The primary endpoint of this study was progression-free survival (PFS) as assessed by independent radiology review. Secondary endpoints included safety, overall response rate (ORR), overall survival (OS), event-free survival (EFS), complete response (CR) rate, duration of response (DoR), and time-to-next anti-lymphoma treatment (TTNL).

Study design & baseline characteristics

• N = 358 patients with R/R FL (Grade 1−3a; n = 295) or MZL (n = 63)
• Median age (range): 63 (26−88) years
• Males: 48%
• Eastern Cooperative Oncology Group (ECOG) performance status (total cohort):
  • ECOG 0: 68% of patients
  • ECOG 1: 31% of patients
  • ECOG 2: 1% of patients
• Ann Arbor disease stage (total cohort):
  • I or II: 27% of patients
  • III or IV: 73% of patients
• Histology (total cohort):
  • FL any grade: 82%
    • FL Grade 1−2: 69%
    • FL Grade 3a: 13%
  • MZL: 18%
    • Extranodal of mucosa-associated lymphoid tissue:8%
    • Nodal: 5%
    • Splenic: 4%
  • High tumor burden (total cohort): 51% of patients
  • Median number of prior lines (range): 1 (1−12)
• Patients who had relapsed or progressed in ≤ 2 years of initial diagnosis (total cohort): 33%
• Dosing:
  • 1:1 randomisation to either (for 12 cycles or relapse, progressive disease [PD] or unacceptable toxicity):
    • Lenalidomide + rituximab (n = 178):
      • Lenalidomide: 20 mg orally, daily on Days 1−21
      • Rituximab: 375 mg/m² intravenously on Days 1, 8, 15, and 22 of cycle 1 and Day 1 of cycles 2−5, every 28 days
    • Placebo + rituximab (n = 180) was administered similarly to the above
  • Dose adjustments of lenalidomide were planned to manage toxicity
• Baseline characteristics were not statistically different between the two groups

Key findings

• The full treatment course was completed in 71% of patients with lenalidomide + rituximab and 61% with placebo + rituximab
• Median follow-up of 28.3 months
• Median PFS (assessed by an Independent Review Committee [IRC]):
  • Lenalidomide + rituximab: 39.4 months (95% CI, 22.9−not reached [NR])
  • Placebo + rituximab: 14.1 months (95% CI, 11.4−16.7)
  • Comparison: HR = 0.46 (95% CI, 0.34−0.62); P < 0.001
• Two-year PFS estimate (IRC):
  • Lenalidomide + rituximab: 58% (95% CI, 49−65)
  • Placebo + rituximab: 36% (95% CI, 29−44)
• ORR(IRC):
  • Lenalidomide + rituximab: 78% (95% CI, 71−83)
  • Placebo + rituximab: 53% (95% CI, 46−61)
  • Comparison: P < 0.001
• CR rate (IRC):
  • Lenalidomide + rituximab: 34% (95% CI, 27−41)
  • Placebo + rituximab: 18% (95% CI, 13−25)
  • Comparison: P = 0.0010
• Partial response (PR; IRC):
  • Lenalidomide + rituximab: 44%
  • Placebo + rituximab: 35%
• Stable disease (SD; IRC):
  • Lenalidomide + rituximab: 11%
  • Placebo + rituximab: 31%
• PD or death (IRC):
  • Lenalidomide + rituximab: 4%
  • Placebo + rituximab: 13%
• Median DoR (IRC):
  • Lenalidomide + rituximab: 36.6 months (95% CI, 22.9−NR)
  • Placebo + rituximab: 21.7 months (95% CI, 12.8−27.6)
  • Comparison: P = 0.0015
• Median EFS (IRC):
  • Lenalidomide + rituximab: 27.6 months (95% CI, 22.1−NR)
  • Placebo + rituximab: 13.9 months (95% CI, 11.4−16.7)
  • Comparison: P < 0.001
• Median TTNLT:
  • Lenalidomide + rituximab: NR (95% CI, NR−NR)
  • Placebo + rituximab:32.2 months (95% CI, 23.2−NR)
  • Comparison: P = 0.007

Safety

• Any grade adverse events (AEs) within 28 days after last treatment dose:
  • Lenalidomide + rituximab (n = 176): 99% of patients
  • Placebo + rituximab (n = 180): 96% of patients
• AEs of any grade that were most frequently (≥ 10% difference) observed in the lenalidomide + rituximab versus the placebo + rituximab group:
  • Neutropenia: 58% versus 22%
  • Constipation: 26% versus 14%
  • Leukopenia: 20% versus 9%
  • Anemia: 16% versus 4%
  • Thrombocytopenia: 15% versus 4%
  • Tumor flare: 11% versus 1%
• AEs leading to dose interruptions (results presented as lenalidomide + rituximab vs placebo + rituximab): 64% vs 26%
  • Dose reductions: 26% vs 3%
  • Discontinuations: 9% vs 5%
• More patients who received lenalidomide + rituximab (69%) had at least one Grade 3 or 4 AE compared to placebo + rituximab (32%)
• Neutropenia led to lenalidomide discontinuation in five patients
• All Grade 3 or 4 neutropenia AEs in the lenalidomide + rituximab group recovered to Grade ≤ 1 with a median time of 9 days
• Grade 5 AEs occurred in 1% of patients in the total cohort:
  • Lenalidomide + rituximab: n = 2 patients (arrhythmia, cardiopulmonary failure)
  • Placebo + rituximab: n = 2 patients (general physical health deterioration, pneumonia)
• At least one serious AE occurred in:
  • Lenalidomide + rituximab: 26% (n = 45) of patients
  • Placebo + rituximab: 14% (n = 25) of patients
• The most common serious AEs across the cohort were:
  • Pneumonia
  • Deep vein thrombosis
  • Secondary primary cancers

Conclusions

• Lenalidomide + rituximab was clinically superior to placebo + rituximab in patients with R/R MZL or FL
• In this study, lenalidomide improved the efficacy of rituximab and led to statistically longer PFS in patients with R/R FL or MZL, along with an acceptable safety profile