Download - Tofacitinib, an oral janus kinase inhibitor, analysis of malignancies across the ra clinical program
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Tofacitinib, an Oral Janus Kinase Inhibitor: Analysis of Malignancies Across the
Rheumatoid Arthritis Clinical Program
JR Curtis
Presentation Number: 802
JR Curtis,1 X Mariette,2 EB Lee,3 B Benda,4 I Kaplan,5 K Soma,5 D Gruben,5
J Geier,6 L Wang,5 R Riese5 1University of Alabama at Birmingham, Birmingham, AL, USA; 2Paris-Sud University, Paris, France; 3Seoul National University,
Seoul, Republic of Korea; 4Pfizer Inc, Collegeville, PA, USA; 5Pfizer Inc, Groton, CT, USA; 6Pfizer Inc, New York, NY, USA
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Disclosure
X Mariette and JR Curtis have received grant/research support from Pfizer Inc, and have acted as consultants for Pfizer Inc
EB Lee has acted as a consultant for Pfizer Inc
B Benda, I Kaplan, K Soma, D Gruben, J Geier, L Wang and R Riese are all employees and shareholders of Pfizer Inc
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Introduction
Tofacitinib is a novel oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA)
Tofacitinib 5 mg and 10 mg twice daily demonstrated efficacy and a manageable safety profile in patients with RA in randomized Phase 21–6 and Phase 37–12 studies
Certain types of malignancies may occur in higher frequency in patients with RA
Additionally, malignancies are a concern with therapeutic agents that treat RA by modulation of the immune system
Presented here is an analysis of malignancy data from the clinical development program of tofacitinib in patients with moderate to severe active RA. Data cut-off date: April 2013
1. Fleischmann R et al. Arthritis Rheum 2012; 64: 617–629. 2. Kremer JM et al. Arthritis Rheum 2009; 60: 1895–1905. 3. Kremer JM et al. Arthritis Rheum 2012; 64: 970–981. 4. Tanaka Y et al. Arthritis Care Res 2011; 63: 1150–1158. 5. Tanaka Y et al. Arthritis and Rheumatism 2011; 63: S854. 6. McInnes IB et al. Ann Rheum Dis 2013; 2013 Mar 12. [Epub ahead of print] 7. van Vollenhoven RF et al. N Engl J Med 2012; 367: 508–519. 8. van der Heijde D et al. Arthritis Rheum 2013; 65: 559–570. 9. Kremer J et al. Ann Intern Med 2013; 159: 253–261. 10. Fleischmann R et al. N Engl J Med 2012; 367: 495–507. 11. Burmester G et al. Lancet 2013; 381: 451–460. 12. Lee EB et al. Arthritis Rheum 2012; 64(10 Suppl): S1049, Abst 2486.
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Methods
Data were pooled from 6 randomized Phase 21–6, 6 randomized Phase 37–12 and 213-14 open-label long-term extension (LTE) studies
Tofacitinib was dosed as either monotherapy or with nonbiologic disease-modifying antirheumatic drugs
● Phase 2 studies were of 6 weeks’ to 6 months’ duration and Phase 3 studies were of ≥6 months’ duration
● Two ongoing open-label LTE studies enrolled patients who participated in the prior Phase 2 and 3 studies.
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1. Fleischmann R et al. Arthritis Rheum 2012; 64: 617–629. 2. Kremer JM et al. Arthritis Rheum 2009; 60: 1895–1905. 3. Kremer JM et al. Arthritis Rheum 2012; 64: 970–981. 4. Tanaka Y et al. Arthritis Care Res 2011; 63: 1150–1158. 5. Tanaka Y et al. Arthritis and Rheumatism 2011; 63: S854. 6. McInnes IB et al. Ann Rheum Dis 2013; 2013 Mar 12. [Epub ahead of print] 7. van Vollenhoven RF et al. N Engl J Med 2012; 367: 508–519. 8. van der Heijde D et al. Arthritis Rheum 2013; 65: 559–570. 9. Kremer J et al. Ann Intern Med 2013; 159: 253–261. 10. Fleischmann R et al. N Engl J Med 2012; 367: 495–507. 11. Burmester G et al. Lancet 2013; 381: 451–460. 12. Lee EB et al. Arthritis Rheum 2012; 64(10 Suppl): S1049, Abst 2486. 13. W ollenhaupt J et al. Arthritis Rheum 2012; 64: S548. 14. Yamanaka et al. Arthritis Rheum 2011; 63: S473.
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Analysis
Malignancies were identified by review of investigator-reported adverse events (AEs), serious AE reports, and output from the central laboratory histology review
A malignancy over-read process involved a centralized, external, blinded review of each biopsy case performed by at least two independent, board-certified pathologists
● Discordance in opinion was resolved by using the most conservative interpretation from either the local or central pathology review
● Patients with no pathology report were classified according to the type of malignancy reported by the study investigator
Standard incidence ratios (SIRs) compared with the Surveillance Epidemiology and End Result (SEER) database (United States) were also calculated for select malignancies
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Patient demography in Phase 3 studiesa
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aTofacitinib monotherapy or tofacitinib + methotrexate (MTX) or other nonbiologic disease-modifying antirheumatic drugs (DMARDs); bPatients
randomized to placebo were advanced to tofacitinib at Month 3 or Month 6; cActive control arm of adalimumab (ADA) or ADA + MTX. ADA was
dosed 40 mg subcutaneously every 2 weeks
Tofacitinib
5 mg BID
Tofacitinib
10 mg BID
Placebo to
tofacitinib
5 mg BIDb
Placebo to
tofacitinib
10 mg BIDb
ADAc
n=1216 n=1214 n=343 n=338 n=204
Mean age (range),
years
53.2
(18-86)
52.5
(18-85)
52.8
(18-82)
52.2
(18-80)
52.5
(23-77)
Gender, % Female 84.5 84.9 81.0 81.4 79.4
Race, %
White 60.6 61.0 66.8 62.1 72.5
Black 3.7 2.9 2.3 4.7 1.5
Asian 26.9 25.9 23.6 25.1 14.2
Other 8.8 10.2 7.3 8.0 11.8
Disease duration, years 8.7 9.1 8.9 9.7 8.1
Phase 2 and LTE baseline characteristics were similar
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Exposure to tofacitinib
Number of patients receiving tofacitinib in Phase 2, Phase 3 and LTE studies (all doses combined):
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Duration of exposure (LTE studies only):
● Tofacitinib 5 mg BID up to 72 months; mean 554.0 days, maximum 2187 days
● Tofacitinib 10 mg BID up to 66 months; mean 997.2 days, maximum 1996 days
No. of
patients
Tofacitinib treatment
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4748
3873
3080
1910
556
0
1000
2000
3000
4000
5000
> 6 months > 1 year > 2 years > 3 years > 4 years
Common types of malignancies
107 out of 5671 patients treated with tofacitinib were observed with malignancies (excluding NMSC)
● 66 patients were observed with NMSC
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Placebo treated patients (≤6 month duration):
● No malignancies (excluding NMSC)
● 2 out of 681 patients receiving placebo were observed with NMSC
Adalimumab treated patients:
● 1 renal cell carcinoma and 1 non-small-cell lung cancer
66
2419
10
0
10
20
30
40
50
60
70
NMSC Lung Breast Lymphoma
No. of
patients
†
802
†all female patients; NMSC, non-melanoma skin cancer
Incidence rates for all malignancies (excluding NMSC)
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Rate/100
patient
years
of
observation
(95% CI)
†Phase 2, Phase 3 and LTE studies, all doses
ADA, adalimumab; CI, confidence interval; LTE; long-term extension; N, total number of patients; n, number of patients with an event; NMSC, non-melanoma skin cancer; PBO, placebo; pyo, patient years of observation
0
4
3
2
1
5671
107 12664
1609
13 1501
681
0 203
204
1 179
1452
41 4005
3375
42 5191
1587
8 1464
4827
83 9196
N
n pyo
Phase 3 LTE (all tofacitinib)
Tofacitinib
All†
10 mg PBO ADA 5 mg 10 mg 5 mg LTE All
0.85 0.90
0.55
0.87 1.02 0.81
0.00
0.56
802 Incidence rates over time for all malignancies (excluding NMSC)
10
2.00
0.80
0.60
0.40
0.20
0.00
0-6
Rate/100
patient
years of
observation
(95% CI)
All malignancies (excluding NMSC)
6-12 12-18 18-24 24-30 30-36 36-42 >42
1.80
1.60
1.40
1.20
1.00
Time period (months)
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CI, confidence interval; NMSC, non-melanoma skin cancer
Incidence rates for lung cancer
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4
0
Tofacitinib
All†
Rate/100
patient
years
of
observation
(95% CI)
10 mg PBO ADA 5 mg 10 mg
3
2
1
5 mg LTE All
5671
24
1609
1
681
0
204
1
1452
5
3375
14
1587
3
4827
19
N
n
Phase 3 LTE (all tofacitinib)
0.19 0.21 0.20 0.07 0.13 0.27
0.56
0.00
†Phase 2, Phase 3 and LTE studies, all doses
ADA, adalimumab; CI, confidence interval; LTE, long-term extension; N, total number of patients; n, number of patients with an event; PBO, placebo
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Incidence rates for breast cancer‡
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0.8
0.0
Tofacitinib
All†
Rate/100
patient
years
of
observation
(95% CI)
10 mg PBO ADA 5 mg 10 mg
0.6
0.4
0.2
5 mg LTE All
4712
19
1355
3
553
0
162
0
1452
7
3375
8
1310
1
4827
15
N
n
Phase 3 LTE (all tofacitinib)
0.00 0.00
0.18 0.16
0.08
0.24
0.18 0.15
‡all female patients; †Phase 2, Phase 3 and LTE studies, all doses
ADA, adalimumab; CI, confidence interval; LTE, long-term extension; N, total number of patients; n, number of patients with an event; PBO, placebo
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Incidence rate for lymphoma
13
0.0
Tofacitinib
All†
Rate/100
patient
years
of
observation
(95% CI)
10 mg PBO ADA 5 mg 10 mg 5 mg LTE All
5677
10
1609
3
681
0
204
0
1452
3
3375
2
1587
0
4827
5
N
n
Phase 3 LTE (all tofacitinib)
0.05
0.00
0.20
0.08
0.04 0.00 0.00
†Phase 2, Phase 3 and LTE studies, all doses; for completeness 2 additional cases were included from an ongoing blinded Phase 3 study
ADA, adalimumab; CI, confidence interval; LTE, long-term extension; N, total number of patients; n, number of patients with an event; PBO, placebo
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0.08
0.8
0.6
0.4
0.2
Incidence rates for non-melanoma skin cancer (NMSC)
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Tofacitinib
All†
Rate/100
patient
years
of
observation
(95% CI)
10 mg PBO ADA 5 mg 10 mg 5 mg LTE All
5671
66
1609
8
681
2
204
2
1587
6
N
n
Phase 3 LTE (all tofacitinib)
1.13 0.99
0.53 0.35
0.41 0.53
0.84 0.62
8
0
6
4
2
†Phase 2, Phase 3 and LTE studies, all doses
ADA, adalimumab; CI, confidence interval; LTE, long-term extension; N, total number of patients; n, number of patients with an event; PBO, placebo
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1452
14
3375
43
4827
57
Incidence* rates for tofacitinib-treated patients
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*IRs from randomized clinical trial data; †SIRs from published observation date; $United States National Data Bank for Rheumatic Diseases; #United States National Data Bank for Rheumatic Diseases and cohorts of RA patients treated with DMARDs; @SEER database (US General Population), which excludes NMSC; ‡female patients
CI, confidence interval; bDMARDs, biologic disease modifying antirheumatic drugs; IR, incidence rate; N/A, not available; NMSC, non-melanoma skin cancer; pyo, patient years of observation; RA, rheumatoid arthritis; SEER, Surveillance Epidemiology and End Result database; SIR, standardized incidence ratio (as compared with the SEER); TNF, tumor necrosis factor
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IR
Events/100 pyo (95% CI)
Tofacitinib
N=4791
All malignancies
(excluding NMSC)
0.85
(0.70, 1.02)
Lung 0.190
(0.127, 0.283)
Breast‡ 0.18
(0.12, 0.28)
Lymphoma 0.08
(0.04, 0.14)
NMSC 0.53
(0.41, 0.67)
Incidence* and standardized† incidence rates for tofacitinib-treated patients
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*IRs from randomized clinical trial data; †SIRs from published observation date; $United States National Data Bank for Rheumatic Diseases; #United States National Data Bank for Rheumatic Diseases and cohorts of RA patients treated with DMARDs; @SEER database (US General Population), which excludes NMSC; ‡female patients
CI, confidence interval; bDMARDs, biologic disease modifying antirheumatic drugs; IR, incidence rate; N/A, not available; NMSC, non-melanoma skin cancer; pyo, patient years of observation; RA, rheumatoid arthritis; SEER, Surveillance Epidemiology and End Result database; SIR, standardized incidence ratio (as compared with the SEER); TNF, tumor necrosis factor
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IR
Events/100 pyo (95% CI)
Tofacitinib
N=4791
SIR
(95% CI) Tofacitinib
N=4791
All malignancies
(excluding NMSC)
0.85
(0.70, 1.02)
SEER: -1.08
(0.89, 1.31)
Lung 0.190
(0.127, 0.283)
SEER: 1.91
(1.22, 2.84)
Breast‡ 0.18
(0.12, 0.28)
SEER: 0.77
(0.46, 1.20)
Lymphoma 0.08
(0.04, 0.14)
SEER: 2.58
(1.24, 4.74)
NMSC 0.53
(0.41, 0.67)
N/A
Incidence* and standardized† incidence rates for tofacitinib- and bDMARD-treated patients
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*IRs from randomized clinical trial data; †SIRs from published observation date; $United States National Data Bank for Rheumatic Diseases; #United States National Data Bank for Rheumatic Diseases and cohorts of RA patients treated with DMARDs; @SEER database (US General Population), which excludes NMSC; ‡female patients
CI, confidence interval; bDMARDs, biologic disease modifying antirheumatic drugs; IR, incidence rate; N/A, not available; NMSC, non-melanoma skin cancer; pyo, patient years of observation; RA, rheumatoid arthritis; SEER, Surveillance Epidemiology and End Result database; SIR, standardized incidence ratio (as compared with the SEER); TNF, tumor necrosis factor
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IR
Events/100 pyo (95% CI)
Tofacitinib
N=4791
SIR
(95% CI) Tofacitinib
N=4791
IR
Events/100 pyo (95% CI)
TNF inhibitors/
bDMARDs
N=4791
SIR
(95% CI) TNF inhibitors/
bDMARDs
N=4791
All malignancies
(excluding NMSC)
0.85
(0.70, 1.02)
SEER: -1.08
(0.89, 1.31)
0.3-1.771-4 0.9-1.1@5
Lung 0.190
(0.127, 0.283)
SEER: 1.91
(1.22, 2.84)
0.23-0.26# 1.08-3.56
Breast‡ 0.18
(0.12, 0.28)
SEER: 0.77
(0.46, 1.20)
0.11-0.34# 0.4-1.686
Lymphoma 0.08
(0.04, 0.14)
SEER: 2.58
(1.24, 4.74)
0.06-0.14$1,2 1.1-9.72,7-14
NMSC 0.53
(0.41, 0.67)
N/A 0.23-1.3415,16 N/A
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Conclusions
Overall, the malignancies that occurred in the tofacitinib
development program in RA are consistent with the type and
distribution of malignancies expected for this population of patients
with moderate to severe active RA
The IRs for all malignancies (excluding NMSC), lung cancer, breast
cancer, lymphoma and NMSC are consistent with published
estimates in RA patients treated with biologic and nonbiologic
DMARDS and do not show an increase over time
Longer-term follow-up is necessary to further evaluate the potential
risk of malignancies in the tofacitinib RA program
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Incidence* and standardized† incidence rates for tofacitinib treated patients
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Acknowledgments
The authors would like to thank the patients, investigators and study team who were involved in the studies (NCT00413660, NCT00603512, NCT01059864, NCT00147498, NCT00550446, NCT00687193, NCT00814307, NCT00847613, NCT00960440, NCT00856544, NCT00853385, NCT00413699, NCT00661661)
This study was sponsored by Pfizer Inc
Editorial support was provided by Martin Goulding, PhD, of Complete Medical Communications and was funded by Pfizer Inc
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Questions