Olumiant ® (baricitinib)

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What was the incidence of malignancy with baricitinib for the treatment of atopic dermatitis in adults?

In the atopic dermatitis clinical trials, there were 14 events of malignancies excluding nonmelanoma skin cancer (NMSC) and 11 events of NMSC in 2636 baricitinib-treated adult patients with up to 3.9 years.

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UK_cFAQ_BAR124B_MALIGNANCY_AD
en-GB

Warnings and Precautions Related to Malignancy

The risk of malignancies including lymphoma is increased in patients with rheumatoid arthritis. Immunomodulatory medicinal products may increase the risk of malignancies including lymphoma. The clinical data are insufficient to assess the potential incidence of malignancies following exposure to baricitinib. Long-term safety evaluations are ongoing.1

Baricitinib Genotoxicity and Carcinogenicity

Non-clinical data reveal no special hazard for humans based on conventional studies of

  • safety pharmacology,
  • genotoxicity and
  • carcinogenic potential.1

Baricitinib was not genotoxic in the

  • bacterial mutagenicity assay (Ames assay)
  • in vitro chromosomal aberration assay using cultured human lymphocytes, or
  • in vivo micronucleus assay in the rat.2,3

Baricitinib did not produce neoplastic changes in 2-year rat and 6-month transgenic mouse carcinogenicity studies.2,3

Risk of Malignancies in Patients With Atopic Dermatitis

Published literature regarding risk of various malignancies in patients with AD is inconclusive.4 Based on the literature, patients with AD may have

  • no increased risks for malignancies overall5,6
  • increased risk for skin cancers, including melanoma and nonmelanoma skin cancers5,6, and
  • a slight increased risk of lymphoma, with severity of AD as a significant risk factor.6,7

According to published literature the background rate in patients with atopic dermatitis is

  • 0.12 to 0.85 per 100 patient-years of exposure (PYE) for malignancy excluding NMSC, and
  • 0.04 to 1.12 per 100 PYE for NMSC.8-10

Atopic Dermatitis Clinical Trial Criteria Related to Malignancies

Patients were excluded from enrollment in the AD clinical trials if they had

  • a history of lymphoproliferative disease
  • signs or symptoms suggestive of possible lymphoproliferative disease, including lymphadenopathy or splenomegaly
  • active primary or recurrent malignant disease, or
  • remission from clinically significant malignancy for <5 years.2

Patients were allowed to participate in the AD clinical trials if they had

  • cervical carcinoma in situ that has been appropriately treated with no evidence of recurrence or metastatic disease for ≥3 years, or
  • basal cell or squamous epithelial skin cancers that have been appropriately treated with no evidence of recurrence for ≥3 years.2

Patients were discontinued from study drug if a treatment-emergent malignancy occurred during the clinical trials. However, patients with successfully treated basal or squamous cell skin carcinoma could continue on study drug.2

Incidence of Malignancies in Baricitinib Atopic Dermatitis Clinical Trials

The integrated safety datasets used to evaluate treatment-emergent malignancies are described in Integrated Analysis Datasets Used to Evaluate Safety in Atopic Dermatitis Clinical Trials.

According to standard conventions, the reporting for malignancy was broken into subcategories for nonmelanoma skin cancer (NMSC) and malignancies excluding NMSC, each with their own set of preferred terms from the standardized Medical Dictionary for Regulatory Activities (MedDRA) query (SMQ).11

Malignancy excluding NMSC and NMSC events across all safety datasets are presented in Malignancy and Nonmelanoma Skin Cancers in Atopic Dermatitis Clinical Trials.

Malignancy and Nonmelanoma Skin Cancers in Atopic Dermatitis Clinical Trials11,12

 

16-Week Placebo-Controlleda
n (adj %) [adj IR]b

BARI 2 mg and 4 mg Extended
(up to 3.9 years)
n [adj IR]b

All BARI AD
(up to 3.9 years)
n [IR]


Placebo
n=743
PYE=211.8

BARI 2 mg
n=576
PYE=169.1

BARI 4 mg
n=489
PYE=147.1

BARI 2 mg
n=584
PYE=727.1

BARI 4 mg
n=497
PYE=800.1

All doses
N=2636
PYE=4628.4

Malignancy excluding NMSC

2c (0.2) [0.66]

0

0

2 [0.28]

0

14 [0.30]

NMSCd

1e (0.2) [0.68]

0

0

1 [0.10]

1 [0.12]

11 [0.23]

Abbreviations: AD = atopic dermatitis; adj = adjusted; BARI = baricitinib; IR = incidence rate; MedDRA SMQ = Medical Dictionary for Regulatory Activities query; NMSC = nonmelanoma skin cancer; PYE = patient-years of exposure.

aData through 16-week placebo-controlled period.

bFor the integrated controlled analysis sets where the randomized ratio of patients receiving BARI to placebo or BARI to active control is not the same across all the integrated studies (example 2:1:1:1 vs 1:1:1:1), the study-size adjusted percentages were calculated for the adverse events to provide appropriate direct comparisons between treatment groups.

cbreast cancer n=1; papillary thyroid cancer n=1.

dAll the cases identified by the malignant tumors MedDRA SMQ were assessed through medical review to determine confirmed NMSC cases. Cases of NMSC were defined by 12 terms that included squamous cell carcinoma of skin, Bowen’s disease, basal cell carcinoma, basosquamous carcinoma, basosquamous carcinoma of skin, squamous cell carcinoma, skin squamous cell carcinoma metastatic, skin cancer, carcinoma in situ of skin, keratoacanthoma, vulvar squamous cell hyperplasia, and skin squamous cell carcinoma recurrent.

eBowen's disease n=1.

Malignancy Excluding Nonmelanoma Skin Cancer

All Baricitinib-Treated Patients With Extended Data

Of the 2636 adult patients treated with baricitinib in the atopic dermatitis (AD) clinical trials, 14 (IR=0.30) had a reported malignancy excluding NMSC. Case details are described in Malignancies Excluding Nonmelanoma Skin Cancer in Baricitinib-Treated Patients.

Malignancies Excluding Nonmelanoma Skin Cancer in Baricitinib-Treated Patients2

Malignancy Preferred Term

Age (years)

Sex

Baricitinib dose

Baricitinib duration of treatment (days)

Uterine Cancer

56

Female

2 mg

120

Testis Cancer

48

Male

1 mg

993

Prostate cancer

50

Male

4 mg

248

Prostate cancer

74

Male

2 mg

69

Prostate cancer

54

Male

2 mg

629

Prostate cancer

67

Male

2 mg

899

Rectal cancer

54

Female

2 mg

150

Small cell lung cancer metastatic

67

Male

2 mg

588

Lung adenocarcinoma

72

Male

2 mg

91

Diffuse large B-cell lymphoma

36

Female

2 mg

246

Anaplastic large cell lymphoma T and null cell types

45

Female

4 mg

174

Peripheral T-cell lymphoma unspecified

48

Male

4 mg

679

Follicular lymphoma

44

Male

2 mg

420

Hodgkin's disease

29

Male

4 mg

873

Nonmelanoma Skin Cancer

All Baricitinib-Treated Patients With Extended Data

Of the 2636 patients treated with all baricitinib doses in the AD clinical trials, 11 (IR=0.23) had a reported NMSC that included 12 TEAEs.2,12 The 12 TEAEs of NMSC included

  • 6 events of basal cell carcinoma
  • 3 events of Bowen's disease
  • 2 events of squamous cell carcinoma, and
  • 1 event of keratoacanthoma.2,12

Integrated Safety Datasets Table

Integrated Analysis Datasets Used to Evaluate Safety in Atopic Dermatitis Clinical Trials2,11

Analysis Set

Description

BARI 2 mg Placebo-Controlled

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE- AD4, BREEZE- AD5, and BREEZE-AD7

Compares BARI 2 mg vs placebo

Includes patients with AD from 1 phase 2 and 5 phase 3 studies who were randomized to

  • BARI 2 mg (n=721, PYE=210.6), or
  • placebo (n=889, PYE=252.7).

Treatment period was 0 to 16 weeks.

BARI 4 mg Placebo-Controlled

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE- AD4, and BREEZE-AD7

Compares BARI 4 mg vs placebo

Includes patients with AD from 1 phase 2 and 4 phase 3 studies who were randomized to

  • BARI 4 mg (n=489, PYE=147.1), or
  • placebo (n=743, PYE=211.8).

Treatment period was 0 to 16 weeks.

BARI 2 mg vs 4 mg

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, and BREEZE-AD7

Compares BARI 2 mg vs BARI 4 mg through 16 weeks

Includes patients with AD from 1 phase 2 and 4 phase 3 studies who were randomized to

  • BARI 2 mg (n=576, PYE=169.1), or
  • BARI 4 mg (n=489, PYE=147.1).

Treated for 0 to 16 weeks during the placebo-controlled period.

BARI 2 mg vs 4 mg Extended

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, BREEZE-AD7, and extension study BREEZE-AD3

Compares BARI 2 mg vs BARI 4 mg including extended evaluations

Includes patients with AD from 1 phase 2 and 4 phase 3 studies and any further exposure for those patients in the phase 3 extension study, BREEZE-AD3, who were randomized to

  • BARI 2 mg (n=576, PYE=425.5), or
  • BARI 4 mg (n=489, PYE=459.3).

Data censored at dose or treatment change (rescue, dose switch, or re-randomization to a different BARI dose or placebo) for BREEZE-AD4 and BREEZE-AD3.

All BARI AD

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, BREEZE-AD5, BREEZE-AD7, and extension studies BREEZE-AD3, BREEZE-AD6

No between-group comparisons

Includes 2531 (total PYE=2247.4) patients with AD from 1 phase 2, 5 phase 3, and 2 phase 3 extension studies who received BARI at a variety of doses, including

  • BARI 1 mg (n=538, PYE=245.9)
  • BARI 2 mg (n=1580, PYE=1129.5), and
  • BARI 4 mg (n=914, PYE=872.8).

Includes all patients who were exposed to any BARI dose at any time during the studies, either from randomization or from switch or rescue from placebo.

 No censoring of data at dose change.

Abbreviations: AD = atopic dermatitis; BARI = baricitinib; PYE = patient-years of exposure.

Note: BARI 1 mg was studied in pivotal trials, however it is not approved. Please refer to Olumiant Summary of Product Characteristics for recommended dose.

References

1Olumiant [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

2Data on file, Eli Lilly and Company and/or one of its subsidiaries.

3Carfagna M, Cannady E, Ryan T, et al. Carcinogenicity assessment of baricitinib in Tg.rasH2 mice and Sprague-Dawley (Crl:CD) rats. Regul Toxicol Pharmacol. 2018;92:458-471. https://www.ncbi.nlm.nih.gov/pubmed/29203403

4Bieber T, Feist E, Irvine AD, et al. A review of safety outcomes from clinical trials of baricitinib in rheumatology, dermatology and COVID-19. Adv Ther. 2022;39(11):4910-4960. https://dx.doi.org/10.1007/s12325-022-02281-4

5Andersen YMF, Egeberg A, Skov L, Thyssen JP. Comorbidities of atopic dermatitis: beyond rhinitis and asthma. Curr Dermatol Rep. 2017;6(1):35-41. http://dx.doi.org/10.1007/s13671-017-0168-7

6Paller A, Jaworski JC, Simpson EL, et al. Major comorbidities of atopic dermatitis: beyond allergic disorders. Am J Clin Dermatol. 2018;19(6):821-838. http://dx.doi.org/10.1007/s40257-018-0383-4

7Legendre L, Barnetche T, Mazereeuw-Hautier J, et al. Risk of lymphoma in patients with atopic dermatitis and the role of topical treatment: a systemic review and meta-analysis. J Am Acad Dermatol. 2015;72(6):992-1002. http://dx.doi.org/10.1016/j.jaad.2015.02.1116

8Arana A, Wentworth CE, Fernández-Vidaurre C, et al. Incidence of cancer in the general population and in patients with or without atopic dermatitis in the U.K. Br J Dermatol. 2010;163(5):1036-1043. https://dx.doi.org/10.1111/j.1365-2133.2010.09887.x

9Mansfield KE, Schmidt SAJ, Darvalics B, et al. Association between atopic eczema and cancer in England and Denmark. JAMA Dermatol. 2020;156(10):1086-1097. https://dx.doi.org/10.1001/jamadermatol.2020.1948

10Asgari MM, Tsai AL, Avalos L, et al. Association between topical calcineurin inhibitor use and keratinocyte carcinoma risk among adults with atopic dermatitis. JAMA Dermatol. 2020;156(10):1066-1073. https://dx.doi.org/10.1001/jamadermatol.2020.2240

11Bieber T, Thyssen JP, Reich K, et al. Pooled safety analysis of baricitinib in adult patients with atopic dermatitis from 8 randomized clinical trials. J Eur Acad Dermatol Venereol. 2021;35(2):476-485. https://doi.org/10.1111/jdv.16948

12Bieber T, Katoh N, Simpson EL, et al. Safety of baricitinib for the treatment of atopic dermatitis over a median of 1.6 and up to 3.9 years treatment: an updated integrated analysis of 8 clinical trials. Poster presented at: 31st Annual European Academy of Dermatology and Venereology Congress; September 7-10, 2022; Milan, Italy.

Date of Last Review: 17 August 2022


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