Olumiant ® (baricitinib)

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Olumiant® (baricitinib): were malignancies reported in patients treated for alopecia areata?

In the alopecia areata clinical trials, 4 malignancies and 2 nonmelanoma skin cancers have been reported among the 1303 patients treated with baricitinib for a median of 1.6 years and up to 3.6 years.

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Incidence of malignancies in the baricitinib alopecia areata clinical trials

The baricitinib alopecia areata (AA) clinical trial program includes

The incidence of malignancies in the BRAVE-AA trials were reported in 3 integrated safety datasets including the

  • 36-week placebo-controlled BARI AA dataset with patients exposed to placebo, baricitinib 2 mg, and baricitinib 4 mg from randomization to week 36
  • extended BARI AA dataset with patients exposed to baricitinib 2 mg or 4 mg from randomization to dose or treatment change, or data cut-off, and
  • All-BARI-AA dataset with all patients exposed to any baricitinib dose (1-mg, 2-mg, or 4-mg) at any time during the studies.4

Safety data were integrated from the BRAVE-AA1 Phase 2 and 3 cohorts (data cut-off May 24, 2022) and from BRAVE-AA2 (data cut-off May 10, 2022).5

More details on patient exposure and censoring rules in each dataset are provided in Integrated Analysis Datasets Used to Evaluate Safety in Alopecia Areata Clinical Trials.

According to standard conventions, the reporting for malignancy was broken into subcategories for malignancies excluding NMSC and NMSC, each with their own set of preferred terms from the standardized Medical Dictionary for Regulatory Activities (MedDRA) query (SMQ).5

The incidence of malignancies excluding NMSC and NMSC across the 3 integrated safety datasets is presented in Incidence of Malignancies From the 36-Week Placebo-Controlled Period, Extended, and All BARI Integrated Datasets, and types and case details are presented in Details of Malignancies in the Alopecia Areata Clinical Trials.

Incidence of Malignancies From the 36-Week Placebo-Controlled Period, Extended, and All BARI Integrated Datasets4,5

Event

36-Week Placebo-Controlled BARI AA
n (%) [IR]

Extended BARI AA
n (%) [IR]

All BARI AA
n (%) [IR]

Placebo
(n=371)

BARI 2 mg
(n=365)

BARI 4 mg
(n=540)

BARI 2 mg
(n=383)

BARI 4 mg
(n=565)

All Doses
(N=1303)

Malignancies excluding NMSCa

1 (0.3) [0.4]

0

1 (0.2) [0.3]

0

2 (0.4) [0.2]

4 (0.3) [0.2]

NMSCb

0

0

0

1 (0.3) [0.2]

0

2 (0.2) [0.1]

Abbreviations: AA = alopecia areata; BARI = baricitinib; IR = incidence rate; NMSC = nonmelanoma skin cancer.

Data cut-off: May 24, 2022, for BRAVE-AA1 and May 10, 2022, for BRAVE-AA2.

aEvents of prostate cancer in the placebo arm and B-cell lymphoma and breast cancer in the baricitinib 4-mg arm.

bEvent of squamous cell carcinoma of the skin.

Details of Malignancies in the Alopecia Areata Clinical Trials5

Event

Age (years)

Sex

Treatment

Duration of treatment

Relevant history

Malignancies excluding NMSCa

B-cell lymphoma

40

male

baricitinib 4 mg

4 months

current user of alcohol and tobacco

Breast cancer

56

female

baricitinib 4 mg

10 months

history of ovarian cyst and hysterectomy; former tobacco user and current user of alcohol

Chronic lymphocytic leukemia

55

male

placebo to baricitinib 2 mg

18 months on baricitinib

no relevant history

Malignant melanoma in situ

58

female

placebo to baricitinib 2 mg

16 months on baricitinib

family history of melanoma, history of sunburns

Prostate cancer

58

male

placebo

6 months

none

NMSCb

Basal cell carcinoma

41

female

baricitinib 2 mg

16 months

pre-existing AD

Squamous cell carcinoma

67

female

baricitinib 2 mg

16 months

history of AD

Abbreviations: AD = atopic dermatitis; NMSC = non melanoma skin cancer.

Data cut-off: May 24, 2022, for BRAVE-AA1 and May 10, 2022, for BRAVE-AA2.

aAfter diagnosis, all patients were discontinued from the study drug and study.

bBoth patients were successfully treated by surgery and no action was taken with the study drug.

Risk of malignancies in patients with alopecia areata

The association between AA and cancer has not been extensively studied and appears to vary based on the type of malignancy.

Published literature reported that AA was associated with an increased risk for thyroid cancer.6-9

Conversely, a minimal or rather negative association was found between AA and other malignancies.6-11

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.12

Baricitinib genotoxicity and carcinogenicity

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

  • safety pharmacology,
  • genotoxicity and
  • carcinogenic potential.12

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.5,13

Baricitinib did not produce neoplastic changes in 2-year rat and 6-month transgenic mouse carcinogenicity studies.5,13

Alopecia areata clinical trial criteria related to malignancies

Patients were excluded from enrollment in the BRAVE-AA1 and BRAVE-AA2 studies if they had

  • a history of lymphoproliferative disease
  • signs or symptoms suggestive of possible lymphoproliferative disease, including lymphadenopathy or splenomegaly
  • an active primary or recurrent malignant disease, or
  • been in remission from clinically significant malignancy for <5 years.1

Patients were allowed to participate in the BRAVE-AA1 and BRAVE-AA2 studies if they had

  • cervical carcinoma in situ that has been successfully treated with no evidence of recurrence or metastatic disease for ≥3 years, or
  • basal cell or squamous cell skin cancers that have been successfully treated with no evidence of recurrence for ≥3 years.1

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.5

Description integrated safety datasets

Integrated Analysis Datasets Used to Evaluate Safety in Alopecia Areata Clinical Trials5,14

Analysis Set

Description

36-Week placebo-controlled BARI AA

Assesses BARI 4 mg, BARI 2 mg, and placebo.

Includes patients from the phase 2/3 BRAVE-AA1 and phase 3 BRAVE-AA2 studies who were randomized to

  • BARI 4 mg (n=540, PYE=363.4)
  • BARI 2 mg (n=365, PYE=240.6), or
  • placebo (n=371, PYE=243.2).

Evaluation time period included randomization to week 36.

Extended BARI AA

Assesses BARI 4 mg and BARI 2 mg including extended evaluations.

Includes patients from the phase 2/3 BRAVE-AA1 and phase 3 BRAVE-AA2 studies who were randomized to

  • BARI 4 mg (n=565, PYE=912.9), or
  • BARI 2 mg (n=383, PYE=470.2).

Evaluation time period included randomization up to data cutoff, May 10, 2022 for BRAVE-AA2 and May 24, 2022 for BRAVE-AA1. Data were censored after a patient was switched to another dose or treatment.

All BARI AA

No between-group assessments.

Includes 1303 (total PYE=2217.9) patients from the phase 2/3 BRAVE-AA1 and phase 3 BRAVE-AA2 studies who were exposed to any BARI dose, including

  • BARI 4 mg (n=996, PYE=1478.7)
  • BARI 2 mg (n=595, PYE=734.4), or
  • BARI 1 mg (n=28, PYE=14.6).

Evaluation time period included any time points during the studies either from randomization or from switch or rescue from placebo.

Abbreviations: AA = alopecia areata; BARI = baricitinib; PYE = patient-years of exposure.

Note: BARI 1 mg was studied in pivotal trials, however it is not approved. Please refer to section 4.2 of the Olumiant Summary of Product Characteristics for approved dosage.

References

1King B, Ohyama M, Kwon O, et al; BRAVE-AA investigators. Two phase 3 trials of baricitinib for alopecia areata. N Engl J Med. 2022;386(18):1687-1699. https://doi.org/10.1056/nejmoa2110343

2A study of baricitinib (LY3009104) in adults with severe or very severe alopecia areata (BRAVE-AA2). ClinicalTrials.gov identifier: NCT03899259. Updated January 26, 2022. Accessed March 4, 2022. https://clinicaltrials.gov/ct2/show/NCT03899259

3A study of baricitinib (LY3009104) in participants with severe or very severe alopecia areata (BRAVE-AA1). ClinicalTrials.gov identifier: NCT03570749. Updated February 3, 2022. Accessed March 4, 2022. https://clinicaltrials.gov/ct2/show/study/NCT03570749

4King B, Mostaghimi A, Shimomura Y, et al. Integrated safety analysis of baricitinib in adults with severe alopecia areata from two randomized clinical trials. Poster presented at: Annual Meeting of the American Academy of Dermatology Association (AAD); March 25-29, 2022; Boston, MA. Accessed April 29, 2022. https://aad-eposters.s3.amazonaws.com/AM2022/poster/33966/Integrated+safety+analysis+of+baricitinib+in+adults+with+severe+alopecia+areata+from+two+randomized+clinical+trials.pdf

5Data on file, Eli Lilly and Company and/or one of its subsidiaries.

6Lee JH, Song Y, Do Han K, et al. Cancer risk by the subtype of alopecia. Sci Rep. 2018;8(1):9748. https://doi.org/10.1038/s41598-018-28142-1

7Lee S, Lee H, Lee CH, Lee WS. Comorbidities in alopecia areata: a systematic review and meta-analysis. J Am Acad Dermatol. 2019;80(2):466-477.e16. https://doi.org/10.1016/j.jaad.2018.07.013

8Seo HM, Han SS, Kim JS. Cancer risks among patients with alopecia areata: a population-based case-control study in Korea. J Am Acad Dermatol. 2018;78(1):209-211. https://doi.org/10.1016/j.jaad.2017.08.011

9Phan K, Smith SD. Alopecia areata and risk of cancer varies based on type of malignancy. J Am Acad Dermatol. 2021;85(suppl 3):AB25. https://dx.doi.org/10.1016/j.jaad.2021.06.126

10Conic RZ, Rambhia P, Atanaskova-Mesinkovska N, et al. Lack of an association between alopecia areata and visceral or hematopoietic cancers. J Am Acad Dermatol. 2017;77(5):981-982. https://doi.org/10.1016/j.jaad.2017.06.045

11Chen CC, Chang YT, Liu HN, Chen YJ. Cancer risk in patients with alopecia areata: a nationwide population-based matched cohort study. Cancer Med. 2018;7(5):2153-2159. https://doi.org/10.1002/cam4.1448

12Olumiant [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

13Carfagna 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

14King B, Mostaghimi A, Shimomura Y, et al. Integrated safety analysis of baricitinib in adults with severe alopecia areata from two randomized clinical trials. Br J Dermatol. Published online November 11, 2022. https://doi.org/10.1093/bjd/ljac059

Date of Last Review: 20 October 2022


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