AbstractBackgroundFollicular lymphoma (FL) and marginal zone lymphoma (MZL) are indolent non‐Hodgkin lymphomas (iNHL). Median survival for iNHL is approximately 20 years. Because standard treatments are not curative, patients often receive multiple lines of therapy with associated toxicity—rationally designed, combination therapies with curative potential are needed. The immunomodulatory drug lenalidomide was evaluated in combination with rituximab for the frontline treatment of FL in the phase 3 RELEVANCE study. Ibrutinib, an oral Bruton tyrosine kinase inhibitor, is active in NHL and was evaluated in combination with lenalidomide, rituximab, and ibrutinib (IRR) in a phase 1 study.MethodsThe authors conducted an open‐label, phase 2 clinical trial of IRR for previously untreated FL and MZL. The primary end point was progression‐free survival (PFS) at 24 months.ResultsThis study included 48 participants with previously untreated FL grade 1–3a (N = 38), or MZL (N = 10). Participants received 12, 28‐day cycles of lenalidomide (15 mg, days 1–21 cycle 1; 20 mg, cycles 2–12), rituximab (375 mg/m² weekly in cycle 1; day 1 cycles 2‐12), and ibrutinib 560 mg daily. With a median follow‐up of 65.3 months, the estimated PFS at 24 months was 78.8% (95% confidence interval [CI], 68.0%–91.4%) and 60‐month PFS was 59.7% (95% CI, 46.6%–76.4%). One death occurred unrelated to disease progression. Grade 3–4 adverse events were observed in 64.6%, including 50% with grade 3–4 rash.ConclusionsIRR is highly active as frontline therapy for FL and MZL. Compared to historical results with lenalidomide and rituximab, PFS is similar with higher grade 3–4 toxicity, particularly rash. The study was registered with ClinicalTrials.gov (NCT02532257).