1) An analysis was conducted of malignancy data from clinical trials of tofacitinib, an oral Janus kinase inhibitor for rheumatoid arthritis (RA). Over 5,600 patients were treated with tofacitinib across phase 2, 3, and long-term extension studies. 2) 107 patients treated with tofacitinib developed malignancies excluding non-melanoma skin cancer (NMSC), with rates similar to those expected in RA patients and the general population. The most common malignancies were lung cancer, breast cancer, and lymphoma. 3) The incidence of malignancies was stable over time with tofacitinib exposure and was not higher than placebo or the active control ad

1. 1
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
802
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
2
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3
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.
4
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. BurmesterG 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
5
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Patient demography in Phase 3 studiesa
6
aTofacitinib monotherapyor tofacitinib+ methotrexate (MTX) or other nonbiologic disease-modifying antirheumaticdrugs (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 subcutaneouslyevery 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
802

2. 2
Exposure to tofacitinib
 Number of patients receiving tofacitinib in Phase 2, Phase 3 and LTE studies
(all doses combined):
7
 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
802
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
8
 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
24
19
10
0
10
20
30
40
50
60
70
NMSC Lung Breast Lymphoma
No. of
patients
†
802
†all female patients; NMSC, non-melanomaskin cancer
Incidence rates for all malignancies
(excluding NMSC)
9
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 numberof 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 mg5 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)
802
CI, confidence interval; NMSC, non-melanomaskin cancer
Incidence rates for lung cancer
11
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 0.210.20 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 numberof patients; n, number of patients with an event; PBO, placebo
802
Incidence rates for breast cancer‡
12
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)
0.000.00
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 numberof patients; n, number of patients with an event; PBO, placebo
802

3. 3
Incidence rate for lymphoma
13
0.0
Tofacitinib
All†
Rate/100
patient
years
of
observation
(95% CI)
10 mg PBO ADA 5 mg 10 mg5 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
0.000.00
†Phase 2, Phase 3 and LTE studies, all doses; for completeness2 additionalcases were included from an ongoing blinded Phase 3 study
ADA, adalimumab;CI, confidence interval; LTE, long-term extension; N, total numberof patients; n, number of patients with an event; PBO, placebo
802
0.08
0.8
0.6
0.4
0.2
Incidence rates for non-melanoma
skin cancer (NMSC)
14
Tofacitinib
All†
Rate/100
patient
years
of
observation
(95% CI)
10 mg PBO ADA 5 mg 10 mg5 mg LTE All
5671
66
1609
8
681
2
204
2
1587
6
N
n
Phase 3 LTE (all tofacitinib)
1.130.99
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 numberof patients; n, number of patients with an event; PBO, placebo
802
1452
14
3375
43
4827
57
Incidence* rates
for tofacitinib-treated patients
15
*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
802
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
16
*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
802
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
17
*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
802
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
18
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
802

4. 4
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
20
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Questions