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

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

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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)

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 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


0.19 0.21 0.20 0.07 0.13 0.27

0.56

0.00


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‡

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


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


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Incidence rate for lymphoma

13

0.0

Tofacitinib

All†

Rate/100

patient

years

of

observation

(95% CI)


5677

10

1609

3

681

0

204

0

1452

3

3375

2

1587

0

4827

5

N

n


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


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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)


5671

66

1609

8

681

2

204

2

1587

6

N

n


1.13 0.99

0.53 0.35

0.41 0.53

0.84 0.62

8

0

6

4

2



802

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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IR


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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IR


Tofacitinib

N=4791

SIR

(95% CI) Tofacitinib

N=4791

IR


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

References 1. Simon TA, Smitten AL, Franklin J, et al. Ann Rheum Dis 2009;68:1819-26.

2. Wolfe F, Michaud K. Arthritis Rheum 2007;56:2886-95.

3. Pallavicini FB, Caporali R, Sarzi-Puttini P, et al. Autoimmun Rev 2010;9:175-80.

4. Carmona L, Abasolo L, Descalzo MA, et al. Semin Arthritis Rheum 2011;41:71-80.

5. Howlader N, Noone A, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2008. Available

at: http://seer.cancer.gov. Accessed April 27, 2012.

6. Smitten AL, Simon TA, Hochberg MC, et al. Arthritis Res Ther 2008;10:R45.

7. Thomas E, Brewster DH, Black RJ, et al. Int J Cancer 2000;88:497-502.

8. Mellemkjaer L, Linet MS, Gridley G, et al. Eur J Cancer 1996;32A:1753-7.

9. Ekstrom K, Hjalgrim H, Brandt L, et al. Arthritis Rheum 2003;48:963-70.

10. Gridley G, McLaughlin JK, Ekbom A, et al. J Natl Cancer Inst 1993;85:307-11.

11. Kauppi M, Pukkala E, Isomaki H. Cancer Causes Control 1997;8:201-4.

12. Kinlen LJ. J Autoimmun 1992;5 Suppl A:363-71.

13. Mariette X, Cazals-Hatem D, Warszawki J, et al. Blood 2002;99:3909-15.

14. Parikh-Patel A, White RH, Allen M, et al. Cancer Causes Control 2009;20:1001-10.

15. Mariette X, Matucci-Cerinic M, Pavelka K, et al. Ann Rheum Dis 2011;70(11):1895-904.

16. Wolfe F, Michaud K. Arthritis Rheum 2007;56(9):2886-95.

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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

http://seer.cancer.gov/

tofacitinib, an oral janus kinase inhibitor, analysis of malignancies across the ra clinical program

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