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

Abstract

IntroductionIbrutinib (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.MethodsA 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.ResultsOur 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.ConclusionOur 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.FundingJanssen-Cilag Ltd.Electronic supplementary materialThe online version of this article (doi:10.1007/s12325-017-0564-1) contains supplementary material, which is available to authorized users.

A cross-trial comparison of single-agent ibrutinib versus chlorambucil-obinutuzumab in previously untreated patients with chronic lymphocytic leukemia or small lymphocytic lymphoma

“…9 Our results confirm prior observations that ibrutinib appears to diminish the negative prognostic impact of del(11q) and unmutated IGHV observed with chemoimmunotherapy regimens. 10,11 Additionally, these results, which used patient-level data, are consistent with a recent cross-trial study that reported favorable PFS with single-agent ibrutinib (from REShaematologica 2020; 105:e166 ONATE-2) compared with published data from studies on first-line chemoimmunotherapy in CLL, 12,13 particularly for patients with del(11q) or unmutated IGHV. The median time to next treatment was not reached in either group (HR 0.115; 95% CI: 0.055-0.242; P<0.0001).…”

“…Alessandra Tedeschi, 1 Richard Greil, 2 Fatih Demirkan, 3 Tadeusz Robak, 4 Carol Moreno, 5 Paul M. Barr, 6 Bertrand Anz, 7 David Simpson, 8 Gianluca Gaidano, 9 Osnat Bairey, 10 Don Stevens, 11 Devinder Gill, 12 Ian W. Flinn, 13 Thomas J. Kipps, 14 Jan A. Burger, 15 Jennifer Lin, 16 Thomas Webb, 17 Viktor Fedorov, 16…”

Front-line treatment of patients with chronic lymphocytic leukemia: a systematic review and network meta-analysis

“…These include patient age [6], fitness/comorbidities [7] and molecular cytogenetics [6,8]. Generally, for fit patients with advanced, symptomatic disease, the so-called 'full-dose fludarabine-based' regimen of fludarabine + cyclophosphamide + rituximab (FCR) is recommended [1].…”

A matching-adjusted indirect comparison of combination nivolumab plus ipilimumab with BRAF plus MEK inhibitors for the treatment of BRAF-mutant advanced melanoma☆

“…The MAIC methodology has been applied extensively in oncology to assess the effects of treatments for various tumor types. 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 …”

“…The MAIC methodology has been applied extensively in oncology to assess the effects of treatments for various tumor types. [11][12][13][14][15][16][17][18] The objective of this analysis was to evaluate the relative efficacy and safety of NIVOþIPI (index therapy) versus DABþTRAM, ENCOþBINI, and VEMþCOBI (comparators) in patients with BRAF-mutant advanced melanoma using MAICs. This analysis expands on a previously reported MAIC analysis that compared NIVOþIPI with DABþTRAM and VEMþCOBI in this patient population.…”