Single-agent ibrutinib versus chemoimmunotherapy regimens for treatment-naïve patients with chronic lymphocytic leukemia: A cross-trial comparison of phase 3 studies

Abstract

Chemoimmunotherapy (CIT) and targeted therapy with single-agent ibrutinib are both recommended first-line treatments for chronic lymphocytic leukemia (CLL), although their outcomes have not been directly compared. Using ibrutinib data from the RESONATE-2 (PCYC-1115/1116) study conducted in patients ≥65 years without del(17p), we performed a cross-trial comparison with CIT data from published phase 3 studies in first-line treatment of CLL. Progression-free survival (PFS), overall survival (OS), and safety data for ibrutinib (median follow-up 35.7 months) were evaluated alongside available CIT data. CIT regimens included: fludarabine + cyclophosphamide + rituximab (CLL8, CLL10), bendamustine + rituximab (CLL10), obinutuzumab + chlorambucil and rituximab + chlorambucil (CLL11), and ofatumumab + chlorambucil (COMPLEMENT-1). Median age across studies was 61-74 years, with older populations receiving ibrutinib, obinutuzumab + chlorambucil, or rituximab + chlorambucil. Median follow-up varied across studies/regimens (range 14.5-37.4 months). Among all patients, PFS appeared longer with ibrutinib relative to CIT and OS appeared comparable. Relative to CIT studies that similarly excluded patients with del(17p) (CLL10) or enrolled older/less-fit patients (CLL11), PFS appeared favorable for ibrutinib in high-risk subgroups, including advanced disease, bulky lymph nodes, unmutated IGHV status, and presence of del(11q). Grade ≥ 3 infections ranged from 9% (ofatumumab + chlorambucil) to 40% (fludarabine + cyclophosphamide + rituximab), and was 25% with ibrutinib. Grade ≥ 3 neutropenia was 12% for ibrutinib and 26%-84% for CIT. Although definitive conclusions cannot be made due to inherent limitations of cross-trial comparisons, this report suggests that ibrutinib has a favorable benefit/risk profile and may potentially eliminate the need for chemotherapy in some patients. Randomized, comparative studies are needed to support these findings.

Figure 1

Progression‐free survival and overall survival for ibrutinib and comparator studies. Progression‐free survival (A) and overall survival (C) for ibrutinib from RESONATE‐2/PCYC‐1116 (ongoing extension study) and studies in older patients or patients with comorbidities (CLL11, COMPLEMENT‐110, 11) and progression‐free survival (B) and overall survival (D) for ibrutinib and studies in younger patients (CLL8, CLL104, 6). Shaded area represents 95% confidence band with ibrutinib. BR, bendamustine plus rituximab; Clb, chlorambucil; FCR, fludarabine, cyclophosphamide, and rituximab; G, obinutuzumab; Ofa, ofatumumab; R, rituximab.

Figure 2

Forest plot of hazard ratios for PFS with ibrutinib from RESONATE‐2 (PCYC‐1115)16 and obinutuzumab plus chlorambucil, and rituximab plus chlorambucil from CLL11.10 The display of HRs shows that the magnitude of PFS benefit of ibrutinib vs chlorambucil was generally greater than that seen with the anti‐CD20 monoclonal antibodies plus chlorambucil vs chlorambucil, particularly in high‐risk patient subgroups. Dosing for chlorambucil in RESONATE‐2: 0.5 mg/kg (max 0.8 mg/kg) days 1 and 15 of each 28‐day cycle (total 12). Dosing for chlorambucil in CLL11: 0.5 mg/kg on days 1 and 15 of each 28‐day cycle (total 6). CI, confidence interval; CIT, chemoimmunotherapy; Clb, chlorambucil; FISH, fluorescence in situ hybridization; G, obinutuzumab; PFS, progression‐free survival; R, rituximab.