ADHERENCE AND DOSE INTENSITY FOLLOWING ADMINISTRATION OF THE IBRUTINIB 420 MG DOSE IN PATIENTS WITH PREVIOUSLY TREATED CLL
(Abstract release date: 05/21/15)
EHA Library. Jäger U. 06/13/15; 103137; S435
Disclosure(s): Medical University of Vienna
Prof. Dr. Ulrich Jäger
Contributions
Contributions
Abstract
Abstract: S435
Type: Oral Presentation
Presentation during EHA20: From 13.06.2015 12:30 to 13.06.2015 12:45
Location: Room A7
Background
Ibrutinib is a first-in-class, once-daily, oral, covalent inhibitor of Bruton’s tyrosine kinase (BTK). Pharmacokinetic analyses have shown that ibrutinib is rapidly absorbed, extensively distributed, and rapidly eliminated from systemic circulation after oral administration (Advani, JCO 2013, Poggesi, AACR 2014). In a study of BTK occupancy in peripheral blood, ibrutinib achieved complete or near complete occupancy of the BTK active site (median >90%) at 4 hours which was maintained at 24 hours following administration of the 420 mg once-daily dose (O’Brien, Lancet Oncology 2013). PK/PD analysis of BTK engagement at different dose levels predicted that at the lower doses of 140 or 280 mg fewer patients would attain complete BTK occupancy (Poggesi, AACR 2014).
Aims
To evaluate the effect of the ibrutinib 420 mg once-daily dose adherence on independent review committee-assessed progression-free survival (PFS) in patients with previously treated CLL from the phase 3 RESONATE trial.
Methods
Dose intensity was defined as the proportion of actually administered vs planned doses of ibrutinib 420 mg. Dose intensity was also defined in the 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. Mean duration of missed doses was based on the sum of all consecutive days of missed dose for each patient.
Results
Patients treated with ibrutinib (n=195) had a mean dose intensity of 95% (median 100%) with 8.3 months of treatment. Of all patients with dose reductions (4.1%), 3.6% had 1 dose reduction and 0.5% had 2 dose reductions due to adverse events. Only diarrhea led to dose reduction in >1 patient in the ibrutinib arm (n=3). The majority of dose interruptions were restarted at 420 mg as per protocol. There were fewer PFS events in patients not missing ibrutinib doses (n=136) vs those missing (n=59) ibrutinib doses for ≥8 consecutive days (13% vs 31%, respectively), with median PFS of NR vs 11 months, respectively. The mean duration of missed doses was 26 days for patients missing ≥8 days. For patients missing ≥2 – 7 days consecutively (n=33), the mean duration of missed doses was 6 days; 103/195 patients did not miss >1 day. Patients with higher dose intensity experienced longer PFS compared to those with lower dose intensity (median NR vs 11 months). This trend was confirmed (HR=0.4 [P=0.0127]) using an adjusted mean dose intensity of 96% in the first 8 weeks and post week-8 PFS. In patients with del17p CLL (n=63), p53 mutation (n=61), or del11q CLL (n=63), those with higher dose intensity also had a lower rate of progression or death events compared to those with lower dose intensity (18% vs 42%, 9% vs 29%, 14% vs 16%, respectively). Dose reduction due to diarrhea, infection, and arthralgia occurred in patients with del17p (n=2), p53 mutation (n=3), but not del11q CLL. No difference was seen in median PFS with lower vs higher ibrutinib exposure (AUC or Cmax) in the 179 patients receiving ibrutinib 420 mg with PK assessment at weeks 1 and 4. Patients receiving ibrutinib without concomitant CYP3A inhibitors had similar outcomes.
Summary
Improvement in PFS is associated with a higher mean dose intensity of ibrutinib, with patients missing more than 1 week of treatment experiencing more PFS events. This improvement in PFS is seen regardless of del17p, del11q, or p53 mutation status. These results support sustained adherence to the once-daily ibrutinib 420 mg dose in patients with previously treated CLL.
Keyword(s): Chronic lymphocytic leukemia, Dose intensity
Session topic: CLL: Novel agents
Type: Oral Presentation
Presentation during EHA20: From 13.06.2015 12:30 to 13.06.2015 12:45
Location: Room A7
Background
Ibrutinib is a first-in-class, once-daily, oral, covalent inhibitor of Bruton’s tyrosine kinase (BTK). Pharmacokinetic analyses have shown that ibrutinib is rapidly absorbed, extensively distributed, and rapidly eliminated from systemic circulation after oral administration (Advani, JCO 2013, Poggesi, AACR 2014). In a study of BTK occupancy in peripheral blood, ibrutinib achieved complete or near complete occupancy of the BTK active site (median >90%) at 4 hours which was maintained at 24 hours following administration of the 420 mg once-daily dose (O’Brien, Lancet Oncology 2013). PK/PD analysis of BTK engagement at different dose levels predicted that at the lower doses of 140 or 280 mg fewer patients would attain complete BTK occupancy (Poggesi, AACR 2014).
Aims
To evaluate the effect of the ibrutinib 420 mg once-daily dose adherence on independent review committee-assessed progression-free survival (PFS) in patients with previously treated CLL from the phase 3 RESONATE trial.
Methods
Dose intensity was defined as the proportion of actually administered vs planned doses of ibrutinib 420 mg. Dose intensity was also defined in the 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. Mean duration of missed doses was based on the sum of all consecutive days of missed dose for each patient.
Results
Patients treated with ibrutinib (n=195) had a mean dose intensity of 95% (median 100%) with 8.3 months of treatment. Of all patients with dose reductions (4.1%), 3.6% had 1 dose reduction and 0.5% had 2 dose reductions due to adverse events. Only diarrhea led to dose reduction in >1 patient in the ibrutinib arm (n=3). The majority of dose interruptions were restarted at 420 mg as per protocol. There were fewer PFS events in patients not missing ibrutinib doses (n=136) vs those missing (n=59) ibrutinib doses for ≥8 consecutive days (13% vs 31%, respectively), with median PFS of NR vs 11 months, respectively. The mean duration of missed doses was 26 days for patients missing ≥8 days. For patients missing ≥2 – 7 days consecutively (n=33), the mean duration of missed doses was 6 days; 103/195 patients did not miss >1 day. Patients with higher dose intensity experienced longer PFS compared to those with lower dose intensity (median NR vs 11 months). This trend was confirmed (HR=0.4 [P=0.0127]) using an adjusted mean dose intensity of 96% in the first 8 weeks and post week-8 PFS. In patients with del17p CLL (n=63), p53 mutation (n=61), or del11q CLL (n=63), those with higher dose intensity also had a lower rate of progression or death events compared to those with lower dose intensity (18% vs 42%, 9% vs 29%, 14% vs 16%, respectively). Dose reduction due to diarrhea, infection, and arthralgia occurred in patients with del17p (n=2), p53 mutation (n=3), but not del11q CLL. No difference was seen in median PFS with lower vs higher ibrutinib exposure (AUC or Cmax) in the 179 patients receiving ibrutinib 420 mg with PK assessment at weeks 1 and 4. Patients receiving ibrutinib without concomitant CYP3A inhibitors had similar outcomes.
Summary
Improvement in PFS is associated with a higher mean dose intensity of ibrutinib, with patients missing more than 1 week of treatment experiencing more PFS events. This improvement in PFS is seen regardless of del17p, del11q, or p53 mutation status. These results support sustained adherence to the once-daily ibrutinib 420 mg dose in patients with previously treated CLL.
Keyword(s): Chronic lymphocytic leukemia, Dose intensity
Session topic: CLL: Novel agents
Abstract: S435
Type: Oral Presentation
Presentation during EHA20: From 13.06.2015 12:30 to 13.06.2015 12:45
Location: Room A7
Background
Ibrutinib is a first-in-class, once-daily, oral, covalent inhibitor of Bruton’s tyrosine kinase (BTK). Pharmacokinetic analyses have shown that ibrutinib is rapidly absorbed, extensively distributed, and rapidly eliminated from systemic circulation after oral administration (Advani, JCO 2013, Poggesi, AACR 2014). In a study of BTK occupancy in peripheral blood, ibrutinib achieved complete or near complete occupancy of the BTK active site (median >90%) at 4 hours which was maintained at 24 hours following administration of the 420 mg once-daily dose (O’Brien, Lancet Oncology 2013). PK/PD analysis of BTK engagement at different dose levels predicted that at the lower doses of 140 or 280 mg fewer patients would attain complete BTK occupancy (Poggesi, AACR 2014).
Aims
To evaluate the effect of the ibrutinib 420 mg once-daily dose adherence on independent review committee-assessed progression-free survival (PFS) in patients with previously treated CLL from the phase 3 RESONATE trial.
Methods
Dose intensity was defined as the proportion of actually administered vs planned doses of ibrutinib 420 mg. Dose intensity was also defined in the 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. Mean duration of missed doses was based on the sum of all consecutive days of missed dose for each patient.
Results
Patients treated with ibrutinib (n=195) had a mean dose intensity of 95% (median 100%) with 8.3 months of treatment. Of all patients with dose reductions (4.1%), 3.6% had 1 dose reduction and 0.5% had 2 dose reductions due to adverse events. Only diarrhea led to dose reduction in >1 patient in the ibrutinib arm (n=3). The majority of dose interruptions were restarted at 420 mg as per protocol. There were fewer PFS events in patients not missing ibrutinib doses (n=136) vs those missing (n=59) ibrutinib doses for ≥8 consecutive days (13% vs 31%, respectively), with median PFS of NR vs 11 months, respectively. The mean duration of missed doses was 26 days for patients missing ≥8 days. For patients missing ≥2 – 7 days consecutively (n=33), the mean duration of missed doses was 6 days; 103/195 patients did not miss >1 day. Patients with higher dose intensity experienced longer PFS compared to those with lower dose intensity (median NR vs 11 months). This trend was confirmed (HR=0.4 [P=0.0127]) using an adjusted mean dose intensity of 96% in the first 8 weeks and post week-8 PFS. In patients with del17p CLL (n=63), p53 mutation (n=61), or del11q CLL (n=63), those with higher dose intensity also had a lower rate of progression or death events compared to those with lower dose intensity (18% vs 42%, 9% vs 29%, 14% vs 16%, respectively). Dose reduction due to diarrhea, infection, and arthralgia occurred in patients with del17p (n=2), p53 mutation (n=3), but not del11q CLL. No difference was seen in median PFS with lower vs higher ibrutinib exposure (AUC or Cmax) in the 179 patients receiving ibrutinib 420 mg with PK assessment at weeks 1 and 4. Patients receiving ibrutinib without concomitant CYP3A inhibitors had similar outcomes.
Summary
Improvement in PFS is associated with a higher mean dose intensity of ibrutinib, with patients missing more than 1 week of treatment experiencing more PFS events. This improvement in PFS is seen regardless of del17p, del11q, or p53 mutation status. These results support sustained adherence to the once-daily ibrutinib 420 mg dose in patients with previously treated CLL.
Keyword(s): Chronic lymphocytic leukemia, Dose intensity
Session topic: CLL: Novel agents
Type: Oral Presentation
Presentation during EHA20: From 13.06.2015 12:30 to 13.06.2015 12:45
Location: Room A7
Background
Ibrutinib is a first-in-class, once-daily, oral, covalent inhibitor of Bruton’s tyrosine kinase (BTK). Pharmacokinetic analyses have shown that ibrutinib is rapidly absorbed, extensively distributed, and rapidly eliminated from systemic circulation after oral administration (Advani, JCO 2013, Poggesi, AACR 2014). In a study of BTK occupancy in peripheral blood, ibrutinib achieved complete or near complete occupancy of the BTK active site (median >90%) at 4 hours which was maintained at 24 hours following administration of the 420 mg once-daily dose (O’Brien, Lancet Oncology 2013). PK/PD analysis of BTK engagement at different dose levels predicted that at the lower doses of 140 or 280 mg fewer patients would attain complete BTK occupancy (Poggesi, AACR 2014).
Aims
To evaluate the effect of the ibrutinib 420 mg once-daily dose adherence on independent review committee-assessed progression-free survival (PFS) in patients with previously treated CLL from the phase 3 RESONATE trial.
Methods
Dose intensity was defined as the proportion of actually administered vs planned doses of ibrutinib 420 mg. Dose intensity was also defined in the 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. Mean duration of missed doses was based on the sum of all consecutive days of missed dose for each patient.
Results
Patients treated with ibrutinib (n=195) had a mean dose intensity of 95% (median 100%) with 8.3 months of treatment. Of all patients with dose reductions (4.1%), 3.6% had 1 dose reduction and 0.5% had 2 dose reductions due to adverse events. Only diarrhea led to dose reduction in >1 patient in the ibrutinib arm (n=3). The majority of dose interruptions were restarted at 420 mg as per protocol. There were fewer PFS events in patients not missing ibrutinib doses (n=136) vs those missing (n=59) ibrutinib doses for ≥8 consecutive days (13% vs 31%, respectively), with median PFS of NR vs 11 months, respectively. The mean duration of missed doses was 26 days for patients missing ≥8 days. For patients missing ≥2 – 7 days consecutively (n=33), the mean duration of missed doses was 6 days; 103/195 patients did not miss >1 day. Patients with higher dose intensity experienced longer PFS compared to those with lower dose intensity (median NR vs 11 months). This trend was confirmed (HR=0.4 [P=0.0127]) using an adjusted mean dose intensity of 96% in the first 8 weeks and post week-8 PFS. In patients with del17p CLL (n=63), p53 mutation (n=61), or del11q CLL (n=63), those with higher dose intensity also had a lower rate of progression or death events compared to those with lower dose intensity (18% vs 42%, 9% vs 29%, 14% vs 16%, respectively). Dose reduction due to diarrhea, infection, and arthralgia occurred in patients with del17p (n=2), p53 mutation (n=3), but not del11q CLL. No difference was seen in median PFS with lower vs higher ibrutinib exposure (AUC or Cmax) in the 179 patients receiving ibrutinib 420 mg with PK assessment at weeks 1 and 4. Patients receiving ibrutinib without concomitant CYP3A inhibitors had similar outcomes.
Summary
Improvement in PFS is associated with a higher mean dose intensity of ibrutinib, with patients missing more than 1 week of treatment experiencing more PFS events. This improvement in PFS is seen regardless of del17p, del11q, or p53 mutation status. These results support sustained adherence to the once-daily ibrutinib 420 mg dose in patients with previously treated CLL.
Keyword(s): Chronic lymphocytic leukemia, Dose intensity
Session topic: CLL: Novel agents
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