The Bruton Tyrosine Kinase (BTK) Inhibitor Ibrutinib Promotes a High Frequency of Durable Response in Relapsed/ Refractory and Older Treatment-Naïve CLL Patients: Final Results of a Phase Ib/II Study Susan O’Brien, MD 1 , Steven Coutre, MD 3 , Ian W. Flinn, MD, PhD 4 , Jan Burger, MD, PhD 1 , Kristie Blum, MD 5 , Jeff Sharman, MD 6 , Barbara Grant, MD 7 , Jeff Jones MD 5 , William Wierda MD, PhD 1 , Weiqiang Zhao, MD, PhD 5 , Nyla A. Heerema, PhD 5 , Amy Johnson, PhD 5 , Anh Tran, BS 8 Fong Clow, SCD 8 , Lori A. Kunkel, MD 8 , Danelle F. James, MD, MAS 8 , John C. Byrd, MD 5 1 Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, 3 Division of Hematology and Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA, 4 Sarah Cannon Research Institute, Nashville, TN, 5 Division of Hematology and The Department of Pathology, The Ohio State University, Columbus, OH, 6 US Oncology, Springfield, OR, 7 Department of Medicine, Vermont Cancer Center, University of Vermont, Burlington, VT, 8 Pharmacyclics, Inc., Sunnyvale, CA
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The Bruton Tyrosine Kinase (BTK) Inhibitor Ibrutinib Promotes a High Frequency of Durable Response in Relapsed/ Refractory and Older Treatment-Naïve CLL.
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The Bruton Tyrosine Kinase (BTK) Inhibitor Ibrutinib Promotes a High Frequency of Durable Response in
Relapsed/ Refractory and Older Treatment-Naïve CLL Patients: Final Results of a Phase Ib/II Study
Susan O’Brien, MD1 , Steven Coutre, MD3, Ian W. Flinn, MD, PhD4, Jan Burger, MD, PhD1, Kristie Blum, MD5, Jeff Sharman, MD6, Barbara Grant, MD7, Jeff Jones MD5, William Wierda MD, PhD1, Weiqiang Zhao, MD, PhD5, Nyla A. Heerema, PhD5, Amy Johnson, PhD5, Anh Tran, BS8 Fong Clow, SCD8, Lori A. Kunkel, MD8, Danelle F.
James, MD, MAS8, John C. Byrd, MD5
1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, 3Division of Hematology and Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA, 4Sarah
Cannon Research Institute, Nashville, TN, 5Division of Hematology and The Department of Pathology, The Ohio State University, Columbus, OH, 6US Oncology, Springfield, OR, 7Department of Medicine, Vermont
Cancer Center, University of Vermont, Burlington, VT, 8Pharmacyclics, Inc., Sunnyvale, CA
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Disclosure
• Dr. O’Brien has received research support and is a Consultant for Pharmacylics, Inc.
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• BTK is an essential mediator of B-cell receptor signaling in normal and malignant B cells
Bruton’s Tyrosine Kinase (BTK)
Honigberg et al. Proc Natl Acad Sci U S A. 2010;107:13075-13080; Ponader et al. Blood. 2012;119:1182-1189.
Ibrutinib (PCI-32765)A Selective Inhibitor of BTK
• Forms a specific bond with cysteine-481 in BTK
• Highly potent BTK inhibition at IC50 = 0.5 nM
• Orally administered with once daily dosing resulting in 24-hr target inhibition
• No cytotoxic effect on T-cells or natural killer (NK)-cells
• In chronic lymphocytic leukemia (CLL) cells promotes apoptosis and inhibits CLL cell migration and adhesion
N
N N
N
N
O
NH2
O
Advani, R. et al, J Clin Oncol. 2012;42:7906.Honigberg LA et al, Proc Natl Acad Sci U S A.2010;107:13075.Herman SEM et al, Blood.2011;117: 6287-6296.Ponader, et al, ASH Meeting Abstracts. 2010; 116:45.
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PCYC 1102Study Design
Relapsed/Refractory (R/R)a
420 mg/d (n= 51) 840 mg/d (n= 34)
Median follow-up 22.1 months
n = 85
Treatment Naïve (TN) > 65 yrs
420 mg/d (n= 27) 840 mg/d (n= 4)
Median follow-up 22.1 months
n = 31
aR/R includes high-risk (n=24) patients with CLL/SLL defined as progression of disease < 24 months after initiation of a chemoimmunotherapy regimen or failure to respond
Error bars are 95% distribution-free confidence limits of median
50% increase in ALC: 55% 50% increase in ALC: 78%
Absolute Lymphocyte Count and Lymph Node Size
TN R/R
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• Among those patients whose initial response was PR-L, the majority achieved classic response by iwCLL criteria:
TN: 9/13 (69%) R/R: 38/49 (78%)
• Combined ORR + (PR-L) in TN (84%) and R/R (88%)
PCYC 1102Best Overall Response
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Risk featureTN
ORR, n (%)R/R
ORR, n (%)
All patients 31 (71.0) 85 (75.3)
Age, ≥ 70 years 23 (65.2) 30 (80.0)
ECOG at baseline ≥ 1 8 (75.0) 50 (76.6)
Rai stage at baseline III-IV 17 (70.6) 52 (75.0)
Disease ≥ 5 cm 6 (66.7) 43 (79.1)
Del 17p Positive
2 (100) 29 (58.6)
Del 11q Positive
1 (100) 29 (82.8)
Unmutated 15 (86.7) 65 (80.0)
Beta Microglobulin≥ 3 mg/mL 8 (62.5) 39 (71.1)
PCYC 1102Best Overall Response by Risk Features
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PCYC 1102Platelet Counts and Hemoglobin Levels
Error bars are 95% distribution-free confidence limits of median
Platelet Counts and Hemoglobin Levels
TN R/R
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PCYC 1102Change in Median Serum Immunoglobulin
Levels
*
**
**
*
*P < 0.05 for change from baseline by Wilcoxon Signed Rank Test
Error bars are 95% distribution-free confidence limits of median
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PCYC 1102Progression-Free Survival
(R/R)
TN Est. PFS at 26 mo is 96.3% ---- R/R Est. PFS at 26 mo is 73.6%
No del17p or del11q Est. PFS at 26 mo is 92.2%del11q Est. PFS at 26 mo is 72.9%del17p Est. PFS at 26 mo is 53.1%
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PCYC 1102Overall Survival
(R/R)
TN Est. OS at 26 mo is 96.6% ---- R/R Est. OS at 26 mo is 77.5%
No del17p or del11q Est. OS at 26 mo is 92.6%del11q Est. OS at 26 mo is 81.3%del17p Est. OS at 26 mo is 59.6%
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• Ibrutinib in CLL is:‒ highly active‒ produces durable responses*‒ well tolerated‒ effective in high risk groups‒ non-myelosuppresive and improves cytopenias
Conclusions – PCYC 1102
*median DOR not reached at 22.1 month median follow-up; 95% and 88% of responders were progression free and alive (and therefore censored) in the TN and R/R groups, respectively
• Phase 3 randomized trials: ‒ Ibrutinib Versus Ofatumumab in Patients With R/R CLL
(RESONATE [NCT01578707])‒ Ibrutinib Versus Chlorambucil in Patients 65 Years or
Older With TN CLL or SLL (RESONATE-2 [NCT01722487])
‒ Bendamustine and Rituximab (BR) +/- Ibrutinib Patients With R/R CLL or SLL (HELIOS [NCT01611090])
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All the patients who participated in the study and their supportive families
Investigators and clinical research staff from all the clinical centers