• Incidence of malignancies in the baricitinib alopecia areata clinical trials
• Risk of malignancies in patients with alopecia areata
• Warnings and precautions related to malignancy
• Baricitinib genotoxicity and carcinogenicity
• Alopecia areata clinical trial criteria related to malignancies
• Description integrated safety datasets
• References

The baricitinib alopecia areata (AA) clinical trial program includes

• BRAVE-AA1, an adaptive phase 2/3 study (NCT03570749), and
• BRAVE-AA2, a phase 3 study (NCT03899259).1-3

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.

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

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

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

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

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.