Single-agent ibrutinib in RESONATE-2™ and RESONATE™ versus treatments in the real-world PHEDRA databases for patients with chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults [1, 2]. CLL primarily affects the elderly, with median age of onset of approximately 70 years [3]. Therapy for CLL has evolved from monotherapy with alkylating agents to chemoimmunotherapy [4, 5], often including an anti-CD20 antibody (e.g., rituximab, ofatumumab, or obinutuzumab) and combinations of fludarabine, cyclophosphamide, bendamustine, or chlorambucil [1, 6‐9]. However, conventional CLL therapies, such as fludarabine + cyclophosphamide + rituximab (FCR), may have toxic side effects and are poorly tolerated in frail patients [1, 7]. Therefore, the trade-off between efficacy and toxicity requires consideration of patient fitness, particularly in the elderly [1, 3, 10].

Ibrutinib is a first-in-class, oral, once-daily covalent Bruton’s tyrosine kinase inhibitor approved in the USA [11], Europe [12], and other countries worldwide for patients with treatment-naïve (TN) and relapsed/refractory (R/R) CLL. In randomized registration trials of patients with CLL, ibrutinib significantly improved progression-free survival (PFS) and overall survival (OS) versus chlorambucil in TN patients (RESONATE-2™; NCT01722487) [13] and versus ofatumumab in R/R patients (RESONATE™; NCT01578707) [14]. Additional head-to-head clinical trial comparisons of ibrutinib-based regimens versus other widely used treatments (including current standard-of-care chemoimmunotherapy regimens and other novel regimens incorporated into CLL guidelines [15‐17]) are ongoing [18, 19], and recent results from multiple phase 3 trials have been positive [data available as abstracts] [20‐22].

Real-world (RW) evidence, derived from the analysis of RW data, is becoming increasingly important in understanding the impact of different diseases and treatments [23, 24]. The Platform for Hematology in Europe, Middle East, Africa (EMEA): Data for Real-life Analyses (PHEDRA) is a unique, noninterventional project based on secondary data collection from RW patient-level databases, and was developed to gain a better insight into the treatment of CLL (and other hematological malignancies) in clinical practice [25]. PHEDRA has three main objectives: (1) to describe treatment patterns; (2) to compare outcomes, PFS and OS, between patients treated with ibrutinib in randomized clinical trials (RCTs) and patients treated with commonly used treatment regimens in clinical practice; (3) to confirm that ibrutinib outcomes in the RCT setting are comparable with outcomes in clinical practice. Methods and findings relating to these objectives in CLL are reported here.

Table 1 shows baseline and disease characteristics for the RCTs and pooled RW cohort by setting (reported by database in Online Resource Tables 1 [TN] and 2 [R/R]). Figure 1 shows the numbers of patients and treatment lines included in the analysis for the RW cohort.

Registrational phase 3 RCTs demonstrated the significant clinical benefits of ibrutinib in TN and R/R CLL versus chlorambucil (RESONATE-2™) and ofatumumab (RESONATE™), respectively [13, 14, 29, 30]. However, CLL treatment has advanced over the past few years, with an increase in available options for patients with TN or R/R disease. It is therefore informative to consider the comparative effectiveness of ibrutinib with other PC regimens being used in clinical practice.

In the current retrospective analyses, an adjusted comparison was performed using PLD on ibrutinib outcomes from RCTs versus outcomes for PC regimens from two existing RW databases in France and the Czech Republic. In the TN setting, the adjusted HRs for PFS and OS comparing ibrutinib from the RESONATE-2™ study and the RW PC cohort suggest a 4.3-fold improvement in PFS (i.e., the inverse of the reported HR of 0.23) and 2.5-fold (HR = 0.40) improvement in OS with ibrutinib. Comparative results for ibrutinib versus chlorambucil are in line with and confirm available RCT evidence in TN patients with CLL [13]. The adjusted comparison yielded similar findings in the R/R setting, with an estimated 4.8-fold (HR = 0.21) improvement in PFS and 3.4-fold (HR = 0.29) improvement in OS with ibrutinib versus PC regimens from the RW databases; results specific to anti-CD20 therapy are in line with those of the RESONATE™ trial, which had ofatumumab as a comparator [14]. These data show that ibrutinib is consistently associated with improved survival outcomes compared with other PC treatments across lines of therapy.

Sensitivity analyses excluding treatments received prior to 2005 did not impact the results in the TN or R/R setting and illustrate that ibrutinib therapy maintains its benefits compared with newer therapies and novel treatments, including anti-CD20 agents.

Other published analyses support the current findings, showing the clinical benefits of ibrutinib outside of RCTs [31]. Using similar methodology to the current study, PLD were collected from an observational cohort of R/R patients (n = 144) diagnosed with CLL between 2002 and 2013 in Sweden, and the ibrutinib arm of RESONATE™. Comparing survival outcomes for ibrutinib versus previous standard-of-care regimens used in second or later lines, the HRs (adjusted for age, sex, disease stage, performance status, and line of therapy) were 0.15 (p < 0.0001) for PFS and 0.36 (p < 0.0001) for OS, consistent with the results reported in this manuscript. HRs in line with these results have also been reported in studies using a similar modeling approach to compare PLD for single-agent ibrutinib from RESONATE™ with BR from the HELIOS trial (0.13 for PFS and 0.45 for OS) [data available as an abstract] [32].

The benefit of ibrutinib in the RW has also been shown to be comparable with that observed in clinical trials when analyzing data from patient access programs. Analysis of a series of 372 efficacy-evaluable patients with poor prognosis, R/R CLL from the French Temporary Authorization for Use database (December 2013 to November 2014) reported a best overall response rate of 88.5% with ibrutinib treatment after a median follow-up of 3 months [33] (similar to the 90% response rate reported in RESONATE™ at 12 months [14]). Results for 95 poor prognosis patients with CLL who were treated with ibrutinib in a Swedish compassionate use program (from May 2014 to May 2015) found in patients with R/R disease, with median follow-up of 10.2 months, the overall response rate was 84%, and 77% of patients were progression free (vs 88% at 6 months in RESONATE™) [14, 34]. A study of 216 R/R patients with CLL included in the named patient program for ibrutinib in Italy (from April 2014 to January 2015) reported an 80% response rate and PFS rate of 65% at 24 months [data available as an abstract] [35]. In addition, an observational retrospective study of data from 2908 patients with R/R CLL enrolled in the international named patient program for ibrutinib (from March 2014 to March 2015) found that estimated time on treatment (which broadly reflects PFS) in the RW was also similar to that observed in RESONATE™. Multivariate analysis showed that younger age (< 50 years) and achievement of complete or partial response to prior therapy were independent factors significantly associated with longer time on treatment [36].

It is important to note that, since our comparative analyses were conducted, additional data have become available from multiple phase 3 RCTs investigating ibrutinib in comparison with more modern and aggressive chemoimmunotherapy regimens for TN CLL than utilized in RESONATE-2™. These recent trial results support the benefit of ibrutinib-based regimens compared with modern standard therapeutic options. In the E1912 trial of young (≤ 70 years of age), fit patients with TN CLL, ibrutinib combined with rituximab led to superior PFS and OS compared with FCR [20], whereas in the ALLIANCE A014202 trial of fit, older patients (≥ 65 years of age), first-line treatment with single-agent ibrutinib or ibrutinib + rituximab significantly prolonged PFS compared with BR [21]. Further, in the iLLUMINATE study of patients with CLL and ≥ 65 years of age (or younger but with comorbidities), a chemotherapy-free regimen of ibrutinib + obinutuzumab improved PFS, response rates, and depth of remission compared with chlorambucil + obinutuzumab chemoimmunotherapy, irrespective of the presence of high-risk genomic features [22]. These RCT findings are likely to be practice changing in the TN setting. A recent cross-comparison of RCT data for ibrutinib from RESONATE-2™ and chemoimmunotherapy regimens from CLL8 (FCR), CLL10 (FCR and BR), CLL11 (obinutuzumab + chlorambucil and rituximab + chlorambucil), and COMPLEMENT-1 (ofatumumab + chlorambucil) found that PFS appeared longer with ibrutinib and OS was similar; in trials excluding patients with del17p (CLL10), or including older or less fit patients (CLL11), ibrutinib prolonged PFS in high-risk subgroups [37]. Although firm conclusions cannot be drawn from this analysis, the results are generally supportive of the favorable outcomes provided by ibrutinib in TN CLL populations compared with alternative standard regimens.

In the R/R setting, the current PHEDRA study is the first to compare outcomes for ibrutinib with other PC treatments in CLL patients from RW databases. HRs for PFS and OS confirmed the results of the ibrutinib RCT and RW database PC treatment comparison, suggesting that ibrutinib is more effective than several other frequently used regimens. However, results suggest the relative benefit (expressed as an HR) to be less in favor of ibrutinib than the RCT-based ibrutinib versus PC treatment comparison. As ibrutinib was first evaluated and approved for a more difficult to treat CLL population (i.e., in R/R disease/later lines of treatment, patients with del17p [14]), physicians might tend to reserve its use in patients with more advanced disease, or high-risk cytogenetic abnormalities, in clinical practice. Such channeling bias could then have led to a conservative estimate of the clinical benefit of ibrutinib versus PC treatment. There is also some uncertainty around the findings of the comparison of RW data owing to the small sample size for RW ibrutinib (n = 53), as reflected in the wide CIs. Further comparisons of outcomes with RW ibrutinib data versus PC treatment in both the TN and R/R CLL settings will be conducted as further data become available.

Our results should be interpreted in light of the following potential limitations. Firstly, estimates on OS benefit when comparing ibrutinib with specific regimens often had large CIs, due to the low number of events and small patient numbers. Pooling data from both RW databases helped to increase sample sizes and statistical power. Secondly, despite all attempts to adjust for differences between both compared patient populations, residual confounding cannot be excluded, as is the case for any nonrandomized comparison.

Finally, the use of time to next treatment as proxy for missing progression dates (in the RW cohort only) may have biased results for PFS against ibrutinib, as time to next treatment is expected to be longer than PFS.

In conclusion, as therapeutic options continue to expand in CLL and there is no single standard-of-care regimen for all patients in the TN or R/R settings, it is worthwhile to compare the outcomes of different treatments in clinical practice as well as in RCTs. Our comparisons of outcomes for ibrutinib and PC treatments from two large high-quality data sources in CLL confirm RCT results, showing improved PFS and OS for ibrutinib over alternative regimens in both the TN and R/R settings. Outcomes for ibrutinib treatment based on RW data were also favorable. These findings extend available evidence on the benefit of ibrutinib versus a range of regimens, including those not yet evaluated in RCTs. Additionally, the results provide information on patient characteristics and treatment patterns, which is important given the absence of a pan-European registry of patients with CLL. Overall, the results from the PHEDRA project can help inform the choice of regimen for CLL across different lines of treatment.