Five-year follow-up data of RESONATE-2 underline the sustained clinical benefit of single-agent ibrutinib as frontline therapy for chronic lymphocytic leukemia

The RESONATE-2 trial established single-agent ibrutinib as a standard first-line therapy for older patients with chronic lymphocytic leukemia (CLL). Updated results of this trial, with a follow-up of 5 years, demonstrate sustained benefit of ibrutinib over chlorambucil in terms of progression-free (PFS) and overall survival (OS). With up to 66 months follow up, more than half of the patients enrolled to ibrutinib were still on therapy clearly indicating the feasibility of a long-term treatment with this agent.

Background

RESONATE-2 is a phase III study comparing the efficacy and safety of first-line ibrutinib with chlorambucil in older patients with CLL or small lymphocytic lymphoma (SLL). Previously, this trial demonstrated superiority of ibrutinib over chlorambucil which formed the basis for the adoption of single-agent ibrutinib as a standard of care for CLL patients who are unfit for more intensive therapy with fludarabine-based chemo-immunotherapy. As single-agent ibrutinib is a continuous therapy, evaluating long-term efficacy and safety is critical to inform clinical practice. To this end, Tedeschi et al. reported long-term data from the RESONATE-2 study with a median follow-up of more than 5 years.

In RESONATE-2, 269 patients with previously untreated CLL/SLL aged 65 years or older were randomly assigned to a treatment with ibrutinib (420 mg once daily until disease progression or unacceptable toxicity) or chlorambucil (0.5 mg/kg to max 0.8 mg/kg on days 1 and 15 of 28-day cycles). In total, 76 patients who progressed in the chlorambucil arm crossed over to ibrutinib in the PCYC-116 extension study. The primary endpoint of the trial was PFS, with OS, overall response rate (ORR) and safety as key secondary objectives. For this long-term follow up, efficacy was assessed by the investigators using a modified version of the 2008 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria.

Results

The baseline characteristics of patients in RESONATE-2 were well balanced between both study arms. The median age was 73 years and approximately 40% of patients had an ECOG performance status of 0. One third of patients had a CIRS score of more than 6 and 45% had a Rai stage III or IV. Just over half of the study cohort had a high prognostic risk, defined as having a TP53 mutation, a del(11q) and/or unmutated IGHV. The median duration of ibrutinib therapy at the time of this analysis was 57.1 months with 65% and 27% of patients being treated with ibrutinib for more than 4 and 5 years, respectively. In total, 58% of patients were still continuing ibrutinib at the time of the analysis. Adverse events (AEs) were the main reason for treatment discontinuation (21%), followed by disease progression and death (both 6%). 

After a median follow-up of 5 years (range: 0.1–66 months), the PFS benefit of ibrutinib over chlorambucil was sustained with a hazard ratio of 0.146. (HR [95% CI]: 0.146 [0.098-0.218]). At the 5-year landmark, 70% of patients in the ibrutinib arm were alive and progression-free as compared to 12% in the chlorambucil arm. Of the 21 patients in the ibrutinib arm who suffered disease progression, 8 did so while being on active ibrutinib therapy. The PFS benefit seen with ibrutinib was maintained in the subgroups of patients with high-risk prognostic features. In fact, ibrutinib improved the PFS compared to chlorambucil in patients with unmutated IGHV (HR [95% CI]: 0.11 [0.06–0.19]) and in patients with a del(11q) (HR [95% CI]: 0.03[0.01–0.11]). As a composite, patients with high-risk genomics (unmutated IGHV, 11q deletion, and/or TP53 mutation) also had a superior PFS outcome with ibrutinib compared with chlorambucil (PFS: HR [95% CI]: 0.08 [0.05–0.15]).

Interestingly, the depth of the responses to ibrutinib improved over time. For example, whereas the rate of complete responses was 10% at 18 months, this increased to 20% at 3 years and 30% at 5 years. The 5-year update of RESONATE-2 also confirmed the superior OS of patients treated with ibrutinib vs chlorambucil. The 5-year estimate for OS was 83% with ibrutinib, which was 15% higher than the 68% estimate calculated in the chlorambucil arm (HR [95%CI]: 0.450 [0.266-0.761]).

The most common grade ≥3 AEs included neutropenia (13%), pneumonia (12%), hypertension (8%), anemia (7%), atrial fibrillation (5%), and cataract (5%). Importantly, the rates of most of these events decreased over time. Also the need for dose reductions due to grade ≥3 AEs decreased over time from 5% in years 0–1 to 1% in years 3–4 and 0 in years 4–5. AEs of any grade leading to ibrutinib discontinuation occurred in 7% of patient in year 0–1, 6% in years 1–2, 5% in years 2–3, 6% in years 3–4, and 1% in years 4–5. Importantly, patients who discontinued ibrutinib still responded to subsequent CLL therapies, including chemo-immunotherapy and idelalisib.

Conclusion

These long-term follow data with a median follow-up of more than 5 years demonstrate a sustained PFS and OS benefit of ibrutinib over chlorambucil as first-line therapy for ‘unfit’ CLL patients. At 5 years, 70% of patients in the ibrutinib arm were still free of progression. The rate of disease progression during ibrutinib therapy was very low, with only 8 patients having disease progression while receiving ibrutinib. No new safety signals emerged and the incidence of nearly all AEs decreased over time. After 5 years of follow up, nearly 6 out of 10 patients randomised to ibrutinib remain on treatment.

Reference

Tedeschi A, Burger J, Barr P, et al. Five-year follow-up of patients receiving ibrutinib for first-line treatment of chronic lymphocytic leukemia. Presented at EHA 2019; Abstract S107.