Based on preclinical evidence, it was hypothesized that the combination of the Bruton’s tyrosine kinase inhibitor ibrutinib plus the immunomodulator lenalidomide and the anti-CD20 antibody rituximab may have synergistic activity in relapsed/refractory (R/R) non–germinal center B-cell-like (GCB) diffuse large B-cell lymphoma (DLBCL). A multicenter, open-label phase 1b/2 study (PCYC-1123, NCT02077166) is evaluating the ibrutinib, lenalidomide, and rituximab (iR2) regimen in R/R DLBCL.
Eligible patients were ≥18 years of age with R/R non-GCB DLBCL who were ineligible for stem-cell transplantation (SCT). Patients received 2 doses of lenalidomide (20 mg or 25 mg orally on days 1-21 of each 28-day cycle) plus ibrutinib (560 mg orally once daily) and (rituximab 375 mg/m2 intravenously on day 1 of cycles 1-6) until progressive disease (PD) or unacceptable toxicity. The primary end point was overall response rate (ORR); secondary end points were complete response (CR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.
A total of 89 patients were enrolled and treated (lenalidomide 20 mg, 55; lenalidomide 25 mg, 34). The median patient age was 64 years; 58% were male. At study entry, 53% of patients were refractory to their last therapy and 16% were primary refractory, 47% had relapsed, and 63% had stage IV disease. The median number of prior DLBCL therapies was 2 (range, 1-5); 20 patients had prior SCT.
The median time on study was 20 months (range, <1-31). Twenty-four patients (27%) received iR2 treatment for ≥1 years and 8 patients (9%) for ≥2 years. At the time of the present analysis, 24 patients (27%) were actively receiving iR2 treatment.
All 89 patients were evaluable for response. The ORR was 47% (95% confidence interval [CI], 36-58), including 31% with CR and 16% with partial response; 16% had stable disease. The median time to response was 3 months. The median DOR (n = 40) was not reached (range, <1-27) overall. Estimated 18-month PFS was 32% (95% CI, 22-42), and median PFS was 5 months (95% CI, 3-6). Estimated 18-month OS was 45% (95% CI, 34-56), and median OS was 14 months (95% CI, 10 months-not estimable).
The most common adverse events (AEs; >30%) were diarrhea (53%), fatigue (43%), and neutropenia (44%). The most common grade 3/4 AEs were neutropenia (39%), maculopapular rash (18%), and anemia (13%). Grade 5 treatment-emergent AEs occurred in 12 patients; of these, 7 were due to worsening of DLBCL, and 5 were not related to PD (pneumonia [n = 3], sepsis [n = 1], and cardiac arrest [n = 1]). Study discontinuation due to AEs was reported in 18% of patients (n = 16).
Based on these results, the study investigators concluded that the iR2 combination of ibrutinib, lenalidomide, and rituximab was active and produced durable CRs with a manageable safety profile in patients with R/R non-GCB DLBCL ineligible for SCT.
Ramchandren R, et al. ASH Abstract 761. Session 626.