Up to 8-year follow-up from RESONATE-2: first-line ibrutinib treatment for patients with chronic lymphocytic leukemia

Abstract

We report long-term follow-up from the RESONATE-2 phase 3 study of the once-daily Bruton's tyrosine kinase inhibitor ibrutinib, which is the only targeted therapy with significant progression-free survival (PFS) and overall survival (OS) benefit in multiple randomized chronic lymphocytic leukemia (CLL) studies. Patients (≥65 years) with previously untreated CLL, without del(17p), were randomly assigned 1:1 to once-daily ibrutinib 420 mg until disease progression/unacceptable toxicity (n = 136) or chlorambucil 0.5-0.8 mg/kg ≤12 cycles (n = 133). With up to 8 years of follow-up (range, 0.1-96.6 months; median, 82.7 months), significant PFS benefit was sustained for ibrutinib vs chlorambucil (hazard ratio [HR], 0.154; 95% confidence interval [CI], 0.108-0.220). At 7 years, PFS was 59% for ibrutinib vs 9% for chlorambucil. PFS benefit was also observed for ibrutinib- vs chlorambucil-randomized patients with high-risk genomic features: del(11q) (HR, 0.033; 95% CI, 0.010-0.107) or unmutated immunoglobulin heavy chain variable region (HR, 0.112; 95% CI, 0.065-0.192). OS at 7 years was 78% with ibrutinib. Prevalence of adverse events (AEs) was consistent with previous 5-year follow-up. Ibrutinib dosing was held (≥7 days) for 79 patients and reduced for 31 patients because of AEs; these AEs resolved or improved in 85% (67 of 79) and 90% (28 of 31) of patients, respectively. With up to 8 years of follow-up, 42% of patients remain on ibrutinib. Long-term RESONATE-2 data demonstrate sustained benefit with first-line ibrutinib treatment for CLL, including for patients with high-risk genomic features. These trials were registered at www.clinicaltrials.gov as #NCT01722487 and #NCT01724346.

Graphical abstract

Figure 1.

Investigator-assessed PFS. (A) PFS with single-agent ibrutinib vs chlorambucil in first-line CLL/SLL in the intent-to-treat population. PFS by (B) del(11q) status and (C) IGHV mutational status. Survival analyses are from randomization until event or censoring at last evidence of non-PD; vertical tick marks indicate censored patients. NE, not estimable; NR, not reached.

Figure 2.

Subgroup analysis of PFS. Forest plot of PFS in baseline factor subgroups of interest. ECOG, Eastern Cooperative Oncology Group.

Figure 3.

Long-term OS. OS with single-agent ibrutinib vs chlorambucil in first-line CLL/SLL for intent-to-treat population. Brackets indicate that OS was not captured for chlorambucil arm of patients with PD after the median 5 years of complete follow-up. Survival analyses are from randomization until event or censoring at last follow-up; vertical tick marks indicate censored patients. NR, not reached.

Figure 4.

Investigator-assessed ORR. Cumulative best response over time in all ibrutinib-randomized patients. Percentages of patients in each category of response may not add up to the overall proportion with a response because of rounding. nPR, nodular partial response; PR-L, partial response with lymphocytosis; SD, stable disease.

Figure 5.

Summary of AEs for ibrutinib-treated patients. The most common any-grade (A) and grade ≥ 3 AEs (B) are shown by yearly interval. Prevalence was determined by the proportion of patients with a given AE (existing event or new onset of an event) during each yearly interval. Multiple onsets of the same AE term within a specific yearly interval were counted once, and the same AE term continuing across several yearly intervals was counted in each of the intervals. Atrial fibrillation and hypertension are shown in Figure 6. URTI, upper respiratory tract infection; UTI, urinary tract infection.

Figure 5.

Summary of AEs for ibrutinib-treated patients. The most common any-grade (A) and grade ≥ 3 AEs (B) are shown by yearly interval. Prevalence was determined by the proportion of patients with a given AE (existing event or new onset of an event) during each yearly interval. Multiple onsets of the same AE term within a specific yearly interval were counted once, and the same AE term continuing across several yearly intervals was counted in each of the intervals. Atrial fibrillation and hypertension are shown in Figure 6. URTI, upper respiratory tract infection; UTI, urinary tract infection.

Figure 6.

AEs of clinical interest for ibrutinib-treated patients. Any-grade AEs of clinical interest are shown by yearly interval. Prevalence was determined by the proportion of patients with a given AE (existing event or new onset of an event) during each yearly interval. Multiple onsets of the same AE term within a specific yearly interval were counted once, and the same AE term continuing across several yearly intervals was counted in each of the intervals. ^aCombined terms.