Five-Year Experience With Single-Agent Ibrutinib in
Patients With Previously Untreated and
Relapsed/Refractory Chronic Lymphocytic
Leukemia/Small Lymphocytic Leukemia
Susan O’Brien, MD1,2, Richard R. Furman, MD3, Steven Coutre, MD4,
Ian W. Flinn, MD, PhD5, Jan Burger, MD, PhD1, Kristie Blum, MD6,
Jeff Sharman, MD7, William Wierda MD, PhD1, Jeffrey Jones MD, MPH6,
Weiqiang Zhao, MD, PhD6, Nyla A. Heerema, PhD6, Amy J. Johnson, PhD6,
Ying Luan, PhD8, Danelle F. James, MD, MAS8, Alvina D. Chu, MD8,
John C. Byrd, MD6
1Department
of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX;
2University of California, Irvine, CA;
3Department of Medicine, Weill Cornell Medical College, New York, NY;
4Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA;
5Sarah Cannon Research Institute, Nashville, TN;
6The Ohio State University, Columbus, OH;
7Willamette Valley Cancer Institute and Research Center, Springfield, OR;
8Pharmacyclics, LLC, an AbbVie Company, Sunnyvale, CA.
Background

Ibrutinib is a first-in-class, once-daily Bruton’s tyrosine kinase
inhibitor
– Approved by the US FDA for treatment of patients with CLL/SLL both as
firstline treatment and for relapsed/refractory (R/R) disease

– Allows for treatment without chemotherapy
Earlier results reported from the phase 1b/2 study (PCYC-1102)
and extension study (PCYC-1103)1,2,3
– Demonstrated single-agent efficacy and tolerability in treatment-naïve (TN)
and R/R CLL/SLL

We present outcomes after 5 years of follow-up, the longest
experience to date for ibrutinib-treated patients
1. O’Brien S, et al. Lancet Oncol. 2014; 5:48-58; 2. Byrd JC, et al. N Engl J Med. 2013;369:32-42; 3. Byrd JC, et al. Blood 2015; 125:2497-2506.
ASH 2016, 1102-03 5-year Update; O’Brien et al.
PCYC-1102/1103 Phase 2 Study Design
Phase 2 (PCYC-1102)
N=132
Patients with CLL/SLL
treated with
oral, once-daily ibrutinib
(420 or 840 mg/day)
Extension Study
(PCYC-1103)
Treatment Naïve (TN)
≥65 years
n=31
≥SD
Long-Term
Follow-Up
Relapsed/Refractory*
(R/R)
n=101
*R/R
includes patients with high-risk CLL/SLL,
defined as progression of disease <24 months
after initiation of a chemoimmunotherapy
regimen or failure to respond
ASH 2016, 1102-03 5-year Update; O’Brien et al.
Baseline Characteristics
TN
(n=31)
R/R
(n=101)
Median age, years (range)
≥70 years
71 (65–84)
74%
64 (37–82)
34%
ECOG performance status
0
1
2
74%
26%
0
43%
53%
4%
Rai stage
0–II
III–IV
Unknown
42%
55%
3%
38%
57%
5%
Bulky disease
≥5 cm
≥10 cm
19%
0
54%
15%
β2 microglobulin level >3.0 mg/L
26%
49%
Characteristic
ASH 2016, 1102-03 5-year Update; O’Brien et al.
Baseline Characteristics
TN
(n=31)
R/R
(n=101)
Cytogenetic abnormalities
Del17p
Del11q
Trisomy 12
Del13q
Complex karyotype
6%
3%
26%
55%
13%
34%
35%
12%
47%
37%
Unmutated IGHV
48%
78%
—
—
—
4 (1–12)
27%
14%
59%
Characteristic
Median lines of prior therapies, n (range)
1–2
3
≥4
ASH 2016, 1102-03 5-year Update; O’Brien et al.
Ibrutinib Treatment Continued in 65% of TN
and 30% of R/R Patients
TN
(n=31)
R/R
(n=101)
62
(1–67)
49
(1–67)
Duration of study treatment, n (%)
≤1 year
>1–2 years
>2–3 years
>3–4 years
≥4 years
5 (16%)
0
1 (3%)
1 (3%)
24 (77%)
24 (24%)
14 (14%)
9 (9%)
19 (19%)
35 (35%)
Patients remaining on ibrutinib therapy, n (%)
20 (65%)
30 (30%)
Primary reason for discontinuation, n (%)
Progressive disease
Adverse event
Consent withdrawal
Investigator decision
Lost to follow-up
1 (3%)
6 (19%)
3 (10%)
0
1 (3%)
33 (33%)
21 (21%)
5 (5%)
11 (11%)
1 (1%)
Disposition
Median time on study, months (range)
• After ~5 years of follow-up, 65% of TN and 30% of R/R patients continue treatment on study.
ASH 2016, 1102-03 5-year Update; O’Brien et al.
Best Response
100%
TN (n=31)
R/R (n=101)
Total (N=132)
87%
89%
89%
10%
14%
80%
29%
CR
PR
PR-L
60%
76%
71%
3%
3%
3%
NR (0.0+ to 65.5+)
56.8 (0.0+ to 65.5+)
NR (0.0+ to 65.5+)
62 (1 – 67)
49 (1+ – 67)
56 (1+ – 67)
40%
55%
20%
0%
Median DOR,
months (range)
Median follow-up,
months (range)
NR, not reached.
7
ASH 2016, 1102-03 5-year Update; O’Brien et al.
Best Response in Patients With High-Risk
Abnormalities
R/R del11q
(n=35)
100%
97%
R/R Unmutated
IGHV
(n=79)
R/R Complex
Karyotype
(n=41)
9%
90%
90%
9%
7%
80%
R/R del17p
(n=34)
79%
6%
CR
PR
PR-L
60%
40%
86%
77%
76%
3%
4%
7%
9%
38.7 (0.0+ to 65.3+)
53.2 (0.0+ to 65.5+)
38.7 (0.0+ to 65.5+)
30.6 (0.0+ to 65.3+)
55 (1+ – 67)
49 (1+ – 67)
55 (1 – 67)
47 (1 – 67)
65%
20%
0%
Median DOR,
months (range)
Median follow-up,
months (range)
NR, not reached.
ASH 2016, 1102-03 5-year Update; O’Brien et al.
Survival Outcomes: Overall Population
Progression-Free Survival
TN (n=31)
R/R (n=101)
Median PFS
5-year PFS
NR
52 mo
92%
43%
Overall Survival
TN (n=31)
R/R (n=101)
Median OS
5-year OS
NR
NR
92%
57%
NR, not reached.
ASH 2016, 1102-03 5-year Update; O’Brien et al.
Survival by IGHV Mutational Status in R/R
Patients*
Progression-Free Survival
Overall Survival
Median PFS 5-year PFS
Median OS 5-year OS
Mutated IGHV (n=16)
63 mo
53%
Mutated IGHV (n=16)
Unmutated IGHV (n=79)
43 mo
38%
Unmutated IGHV (n=79)
63 mo
66%
NR
55%
*Only 2 patients in the TN group showed disease progression or death. Subgroup analyses, therefore, focused on the R/R population.
NR, not reached.
ASH 2016, 1102-03 5-year Update; O’Brien et al.
Survival Outcomes by Chromosomal Abnormalities
Detected by FISH in R/R Patients*
Progression-Free Survival
Overall Survival
Median PFS 5-year PFS
Median OS
5-year OS
Del17p (n=34)
26 mo
19%
Del17p (n=34)
57 mo
32%
Del11q (n=28)
55 mo
33%
Del11q (n=28)
NR
61%
Trisomy 12 (n=5)
NR
80%
Trisomy 12 (n=5)
NR
80%
Del13q (n=13)
No abnormality** (n=16)
NR
NR
91%
66%
Del13q (n=13)
No abnormality** (n=16)
NR
NR
91%
83%
*Only 2 patients in the TN group showed PD or death. Subgroup analyses, therefore, focused on the R/R population.
**No del17p, del11q, del13q, or trisomy 12; in hierarchical order for del17p, and then del11q
ASH 2016, 1102-03 5-year Update; O’Brien et al.
NR, not reached.
Survival by Complex Karyotype
Progression-Free Survival
Complex karyotype (n=41)
No complex karyotype (n=71)
Overall Survival
Median
PFS
5-year
PFS
33 mo
36%
Complex karyotype (n=41)
NR
69%
No complex karyotype (n=71)
Median
OS
5-year
OS
57 mo
46%
NR
84%
• The majority (90%) of patients with complex karyotype had R/R disease (median 4
prior therapies).
NR, not reached.
ASH 2016, 1102-03 5-year Update; O’Brien et al.
Survival by Number of Lines of Prior Therapies
Progression-Free Survival
Median
PFS
0 prior therapies (n=31)
NR
1-2 prior therapies* (n=27) 63 mo
3 prior therapies (n=14)
59 mo
≥4 prior therapies (n=60)
39 mo
*Only 2 patients had received 1 prior therapy.
NR, not reached.
5-year
PFS
92%
60%
41%
38%
Overall Survival
Median 5-year
OS
OS
0 prior therapies (n=31)
NR
92%
1-2 prior therapies* (n=27) 63 mo
60%
3 prior therapies (n=14)
NR
85%
≥4 prior therapies (n=60)
57 mo
47%
ASH 2016, 1102-03 5-year Update; O’Brien et al.
Multivariate Analysis* for PFS and OS
Factors considered
 Del17p
 Del11q
 Trisomy 12
 Del13q
 Lines of prior therapy (1-2,




Del17p was identified as a
significant predictor of PFS
and OS
3, and ≥4 lines vs 0 lines)
Bulky disease (≥5cm vs <5
cm)
IGHV mutation status
Complex karyotype
*Multivariate regression analysis using Cox Proportional Hazard model and stepwise selection. There might be confounding effects
between covariates considered.
ASH 2016, 1102-03 5-year Update; O’Brien et al.
Cumulative Frequency of Grade ≥3 Adverse
Events Over 5-Year Follow-Up
Non-hematologic ≥5%
R/R
Hematologic
TN
R/R
Grade 3
Grade 4
Infectious
TN
R/R
TN
Grade 5
ASH 2016, 1102-03 5-year Update; O’Brien et al.
Onset of Most Grade ≥3 Adverse Events
Decreased Over Time
≤1 year
•
>1–2 years
>2–3 years
>3–4 years
>4 years
Dose reductions and dose discontinuations due to AEs occurred more frequently in R/R patients
than in TN patients, and during the first year after treatment compared with subsequent time
periods.
*Listed adverse events include those that occurred in ≥5% of patients in all-treated population; denominator for each term and time period
can vary based on those at risk
ASH 2016, 1102-03 5-year Update; O’Brien et al.
Conclusions

At 5-years of follow-up, durable responses with ibrutinib in TN and R/R CLL/SLL
–





For RR patients with 4 prior lines of therapy, median PFS is 52 mo, median
OS has not been reached
– For TN patients 92% are progression free at 5 years
CR rates have increased over time to 29% in TN and 10% in R/R patients
Survival outcomes for patients with complex karyotype or del17p were less
robust compared to those in lower risk genetic groups
In a multivariate analysis, del17p was identified as a significant predictor of PFS
and OS
Ibrutinib was well tolerated with onset of most new grade ≥3 AEs decreasing
over time
Manageable safety profile allows for extended dosing; 65% of older TN patients
and 30% of R/R patients continue treatment with 5 years of follow-up
ASH 2016, 1102-03 5-year Update; O’Brien et al.
Acknowledgements
We thank the patients who participated in the study and their supportive families
as well as the investigators and clinical research staff from the study centers.
This study was sponsored by Pharmacyclics, LLC, an AbbVie Company.
Editorial support was provided by Supriya Srinivasan, PhD, and funded by
Pharmacyclics, LLC, an AbbVie Company.
ASH 2016, 1102-03 5-year Update; O’Brien et al.
BACK-UP SLIDES
Best Response to Ibrutinib Improves Over
Time
ASH 2016, 1102-03 5-year Update; O’Brien et al.
AEs Leading to Discontinuation
≤1 Year
>1–2 years
>2–3 years
>3–4 years
>4 years*
(N=132)
(n=103)
(n=89)
(n=79)
(n=59)
n=0
n=2
n=7
Patients with any AE leading to discontinuation
n=12
n=5
• Infections** (n=6) • Infections (n=4)
• Subdural
hematoma (n=2)
• None
• Diarrhea (n=1)
• Pruritic rash (n=1)
• Gastrointestinal
hemorrhage (n=1)
• Arteriosclerosis of • Diarrhea (n=1)
the coronary
• Arthralgia (n=1)
artery (n=1)
• Recurrent lung
• Atrial fibrillation
adenocarcinoma
(n=1)
(n=1)
• Fatigue (n=1)
• Dementia (n=1)
• Decreased weight
(n=1)
• Malignant
neoplasm (n=1)
• Peripheral T-cell
lymphoma (n=1)
• Skin lesion (n=1)
• Hypertension
(n=1)
*>4 years includes all AEs that occurred up to 70 months of follow-up.
**Not a preferred term.
ASH 2016, 1102-03 5-year Update; O’Brien et al.