Comparative Efficacy of Ibrutinib Versus Obinutuzumab + Chlorambucil in First-Line Treatment of Chronic Lymphocytic Leukemia: A Matching-Adjusted Indirect Comparison

Abstract

Introduction

Ibrutinib (ibr) monotherapy and the combination of obinutuzumab plus chlorambucil (obi) are approved for previously untreated chronic lymphocytic leukemia (CLL). No trials directly comparing their efficacy are available. Therefore a matching-adjusted indirect comparison (MAIC) was performed to provide insight into their relative efficacy in terms of progression-free survival (PFS) and overall survival (OS). MAIC attempts to adjust for between-trial differences in factors known or suspected to influence treatment effects, to minimize bias.

Methods

A MAIC within a Bayesian framework was conducted using individual patient data from the RESONATE-2 study of ibr versus chlorambucil and published data from the CLL11 study of obi versus chlorambucil. Both studies were conducted in patients ineligible for full-dose fludarabine-based therapy. After matching, the reweighted adjusted relative efficacy measure of ibr versus chlorambucil from RESONATE-2 [hazard ratio (HR), 95% credible interval (CrI)] was compared with that of obi versus chlorambucil from CLL11 for each endpoint, using a Bayesian indirect comparison.

Results

Our results suggest that in a population with similar average baseline characteristics to CLL11, ibr would improve PFS and OS outcomes compared to obi. Before matching, the HRs for ibr versus obi were 0.48 [CrI = 0.22–1.02, p(HR <1) = 97%], 0.85 [CrI = 0.44–1.63, p(HR <1) = 69%], and 0.40 [CrI = 0.10–1.54, p(HR <1) = 91%] for PFS by investigator assessment, PFS by independent review committee, and OS, respectively. After matching on all available characteristics the HRs decreased to 0.12 [CrI = 0.02–0.97, p(HR <1) = 98%], 0.24 [CrI = 0.04–1.35, p(HR <1) = 95%], and 0.21 [CrI = <0.01–8.89, p(HR <1) = 79%], respectively. There was a large variance around the treatment effect for OS due to the low number of deaths.

Conclusion

Our analysis suggests that ibrutinib is highly likely to provide greater PFS benefit than obinutuzumab plus chlorambucil in older or less fit patients with previously untreated CLL. There is also an indication of improvement in OS, albeit with a higher uncertainty due to the low number of events.

Funding

Janssen-Cilag Ltd.

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