Dose adherence and baseline exposure analysis of the ibrutinib 420 mg dose administered to patients with previously treated chronic lymphocytic leukemia (CLL).

7012 Background: Ibrutinib (ibr), a first-in-class, once-daily, oral, covalent inhibitor of Bruton’s tyrosine kinase (BTK), is rapidly eliminated from plasma after oral administration (Advani, JCO 2013). Complete or near complete BTK active site occupancy (median > 90%) is achieved at 4 hours and maintained at 24 hours with ibr 420 mg once-daily (O’Brien, Lancet Oncology 2013). At 140 or 280 mg doses, fewer patients (pts) attained complete BTK occupancy (Poggesi, AACR 2014). This analysis evaluated the effect of the ibr 420 mg once-daily dose on IRC-assessed progression-free survival (PFS) in pts with previously treated CLLfrom thephase 3 RESONATE trial. Methods: Dose intensity (DI) was defined as the proportion of actually administered vs planned doses of 420 mg. DI was also defined in first 8 weeks to compare statistically with post-week 8 PFS. Steady-state AUC/Cmax was estimated per NONMEM modeling using 2 timepoint samples (weeks 1 and 4). Missed doses had to be consecutive. Results: Ibr-treated pts (n = 195) had a mean DI of 95% (median 100%) with 8.3 months of treatment. The majority of dose interruptions restarted at 420 mg; 3.6% of pts had 1 and 0.5% had 2 dose reductions due to AEs. Pts with higher DI experienced longer PFS (median NR) compared to lower DI (11 months). Using an adjusted mean DI of 96% in first 8 weeks and post week-8 PFS, this trend was confirmed with HR = 0.4 (P= 0.0127). Pts with higher DI had a lower rate of progression regardless of del17p, p53 mutation, or del11q CLL. In 179 pts receiving ibr 420 mg with PK assessment at weeks 1 and 4, no difference was seen in median PFS with lower vs higher ibr exposure (AUC or Cmax). There were fewer PFS events in pts not missing (n = 136) vs those missing (n = 59) ibr doses for ≥ 8 consecutive days (13% vs 31%, respectively), with median PFS of NR vs 11 months, respectively. The mean duration of these missed doses was 26 days. Conclusions: A higher mean dose intensity of ibr is associated with improved PFS, with patients missing more than 1 week of treatment experiencing more PFS events. These results, and the established clinical profile, support the clinical utility of sustained adherence to the once-daily 420 mg dose of ibr in patients with previously treated CLL. Clinical trial information: NCT01578707.