Olumiant ® ▼ (baricitinib)

What is the incidence of malignancy in the Olumiant®▼ (baricitinib) rheumatoid arthritis clinical trials?

For a median of 4.6 and up to 9.3 years, the incidence rates per 100 patient-years at risk were 0.9 and 0.3 for malignancy excluding NMSC and NMSC, respectively, and remained stable over time.

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UK_cFAQ_BAR124A_MALIGNANCY_RA
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Information from the label

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

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

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

Malignancy and Lymphoproliferative Disorders in Rheumatoid Arthritis Clinical Trials

According to standard conventions, the reporting for malignancy was broken into subcategories for NMSC and malignancies excluding NMSC, each with their own set of preferred terms from the standardized Medical Dictionary for Regulatory Activities (MedDRA) query (SMQ) 20000194.2

Analyses were conducted using integrated safety datasets including the

  • 7-study placebo-controlled dataset, which compares the safety of baricitinib 4 mg or 2 mg versus placebo through 24 weeks
  • 4-study extended dataset, which compares the safety of baricitinib 4 mg versus 2 mg including long-term extension data, and
  • All-BARI-RA dataset, the largest dataset including 3770 patients with RA who received any dose of baricitinib from 9 randomized studies and 1 long-term extension study.3,4

Exploratory analyses in a subset of data from the All-BARI-RA dataset were also conducted in patients who had ever taken baricitinib 2 mg or 4 mg.4

More details on each dataset are provided in Integrated Analysis Datasets Used to Evaluate Safety in Rheumatoid Arthritis Clinical Trials.

Data in the

  • 7-study placebo-controlled dataset were censored at rescue
  • 4-study extended dataset were
    • censored at rescue or dose change (as-treated analysis), or
    • not censored at rescue or dose change to account for the long-latency period of most cancers (as-randomized analysis), and
  • All-BARI-RA dataset were not censored for rescue or dose change.3,4

Malignancies Excluding Nonmelanoma Skin Cancers in RA Clinical Trials

7-Study Placebo-Controlled Dataset

Through 24 weeks of treatment, the IR per 100 PY for malignancy excluding NMSC was

  • 0.4 (n=2) in the BARI 4-mg group (N=1142)
  • 0.5 (n=1) in the BARI 2-mg group (N=479), and
  • 0.4 (n=2) in the placebo group (N=1215).3

4-Study Extended Dataset

The IRs per 100 patient-years at risk (PYR) for malignancies excluding NMSC across additional analyses in the 4-study extended dataset were

  • 1.31 in the baricitinib 4-mg group compared with 0.60 in the baricitinib 2-mg group for the “as-treated” analysis, and
  • 1.05 in the baricitinib 4-mg group and 1.04 in the baricitinib 2-mg group for the “as-randomized” analysis.2

All-BARI-RA Dataset

In the All-BARI-RA dataset, 139 patients reported a malignancy excluding NMSC representing an IR of 0.9 per 100 PYR.4

As shown in Malignancies Excluding Nonmelanoma Skin Cancer Over Time in the All-BARI-RA Dataset, the IR for malignancy excluding NMSC was 0.6 during the first 48 weeks and remained stable at approximately 1.0 with prolonged baricitinib treatment.4

Malignancies Excluding Nonmelanoma Skin Cancer Over Time in the All-BARI-RA Dataset4

Abbreviations: BARI = baricitinib; PYE = patient-years of exposure; RA = rheumatoid arthritis.

Incidence by Type of Malignancies

Incidence of Malignancies Excluding Nonmelanoma Skin Cancer by MedDRA High-level Term in the All-BARI-RA Dataset describes the incidence of malignancies excluding NMSC by high-level MedDRA terms in the All-BARI-RA dataset.

The most commonly reported types of malignancies were

  • respiratory and mediastinal
  • breast, and
  • gastrointestinal.4
Incidence of Malignancies Excluding Nonmelanoma Skin Cancer by MedDRA High-level Term in the All-BARI-RA Dataset4

MedDRA High-level (Group) Term

n

EAIR (95% CI)

Respiratory and mediastinal neoplasms malignant and unspecified

26

0.17 (0.11-0.25)

Breast neoplasms malignant and unspecified (including nipple)

23

0.15 (0.10-0.23)

Gastrointestinal neoplasms malignant and unspecified

19

0.13 (0.08-0.20)

Reproductive neoplasms female malignant and unspecified

16

0.11 (0.06-0.17)

Reproductive neoplasms male malignant and unspecified (all reported cases were prostatic neoplasms)

10

0.07 (0.03-0.12)

Skin neoplasms malignant and unspecified (other than NMSC)

10

0.07 (0.03-0.12)

Renal and urinary tract neoplasms malignant and unspecified

9

0.06 (0.03-0.11)

Lymphomas non-Hodgkin’s B cell

6

0.04 (0.01-0.09)

Endocrine neoplasms malignant and unspecified

4

0.03 (0.01-0.07)

Metastases

3

0.02 (0.00-0.06)

Othersa

15

0.10 (0.06-0.16)

Abbreviations: BARI = baricitinib; EAIR = exposure-adjusted incidence rate; MedDRA = Medical Dictionary for Regulatory Activities; NMSC = nonmelanoma skin cancer; RA = rheumatoid arthritis.

aOthers are all high-level group terms with ≤2 cases, including hematopoietic neoplasms (excluding leukemias and lymphomas); hepatobiliary neoplasms malignant and unspecified; leukemias; lymphomas non-Hodgkin’s T cell; lymphomas non-Hodgkin’s unspecified histology; miscellaneous and site-unspecified neoplasms malignant and unspecified; neoplasm-related morbidities; nervous system neoplasms malignant and unspecified not elsewhere classified; not coded; ocular neoplasms; and soft tissue neoplasms malignant and unspecified.

Incidence Rates of Malignancy Excluding Nonmelanoma Skin Cancer by Baricitinib Dose

The exposure-adjusted incidence rate (EAIR) per 100 patient-years exposure (PYE) for malignancy excluding NMSC was similar between patients in the

  • Ever-on-BARI-2-mg group (1.16 [95% CI: 0.79-1.64]), and
  • Ever-on-BARI-4-mg group (0.90 [95% CI: 0.74-1.09]).2

Comparison of Incidence Rates of Malignancy Excluding Nonmelanoma Skin Cancer With the General US Population by Age Category

To account for ageing of the study population, a standardized incidence ratio (SIR) was calculated as the ratio of observed to expected number of malignancies excluding NMSC using age-specific data from the Surveillance, Epidemiology, and End Results 17 (SEER17), 2013–2017 US population cancer rates.4,5

Malignancy events excluding NMSC in each 5-year age category in the All-BARI-RA dataset based on SEER17 data are presented in Malignancies Excluding Nonmelanoma Skin Cancer in 5-Year Age Category in the All-BARI-RA Dataset Based on SEER17 Data.

Overall, the SIR for baricitinib was 1.07 (95% CI: 0.90, 1.26), suggesting that the observed incidence of malignancy with baricitinib in clinical RA studies is similar to the rate in the general US population after controlling for age.4

Malignancies Excluding Nonmelanoma Skin Cancer in 5-Year Age Category in the All-BARI-RA Dataset Based on SEER17 Data4

Figure Description 2: Malignancy excluding nonmelanoma skin cancer observed in the All-BARI-RA dataset and expected based on a US population database (the Surveillance, Epidemiology, and End Results 17 or SEER17) in 5-year age category.

Abbreviations: BARI = baricitinib; NMSC = nonmelanoma skin cancer; RA = rheumatoid arthritis; SEER = Surveillance, Epidemiology, and End Results.

Note: In All-BARI-RA, age group categories were based on the average age at the beginning and end of baricitinib treatment or follow-up.

Additional Comparative Dataset Analyses

The IRs and 95% CIs for malignancies excluding NMSC in each integrated dataset, as well as individual comparator studies, RA-BEAM and RA-BEGIN, are provided in Incidence Rate by Analysis Dataset for Malignancies Excluding Nonmelanoma Skin Cancer in Rheumatoid Arthritis Clinical Trials.

Due to the limited exposure and follow-up period in these comparative studies and the long latency of most malignancies, the data give limited information on the causal relationship with the study treatment.2

Incidence Rate by Analysis Dataset for Malignancies Excluding Nonmelanoma Skin Cancer in Rheumatoid Arthritis Clinical Trials2,3,6

Abbreviations: ADA = adalimumab; BARI = baricitinib; DMARD = disease-modifying antirheumatic drug; IR = inadequate responder; Mono = monotherapy; MTX = methotrexate; PBO = placebo; pts = patients; PYE = patient-years of exposure; RA = rheumatoid arthritis.

Lymphoma in Rheumatoid Arthritis Clinical Trials

7-Study Placebo-Controlled Dataset

There were no cases of lymphoma reported by patients administered with baricitinib in the randomized, controlled periods of the RA clinical program.3

All-BARI-RA Dataset

In the All-BARI-RA dataset, the IR for lymphoma was 0.06 per 100 PYR.4

A total of 9 patients reported lymphoma including

  • 5 patients with diffuse large B-cell lymphoma
  • 1 patient with extranodal marginal zone B-cell lymphoma (MALT type)
  • 1 patient with lymphoproliferative disorder
  • 1 patient with non-Hodgkin’s lymphoma, and
  • 1 patient with T-cell lymphoma.2,4

Of patients with lymphoma,

  • the mean age was 60.6 years
  • the average time to onset was 2 years
  • all patients received baricitinib 4 mg
  • all except 1 patient had treatment with methotrexate (MTX)
  • 1 patient received tacrolimus that started before the treatment with baricitinib and continued up to the event, and
  • 1 other patient received sulfasalazine during the year before the event.2

In all cases, relationship with baricitinib was not established, as the contribution of advancing age, autoimmune disease, and in particular the use of MTX or tacrolimus is implicated. Four out of the 9 cases were from Japan.2

There were no deaths due to any type of lymphoma.2

Incidence Rates of Lymphoma by Baricitinib Dose

The EAIR per 100 PYE for lymphoma was 0.08 for patients in the Ever-on-BARI-4-mg group. There were no patients with lymphoma in the Ever-on-BARI-2-mg group.2

Lymphoproliferative Disorders in Rheumatoid Arthritis Clinical Trials

In the All-BARI-RA dataset, the EAIR of lymphoproliferative disorder was 0.05 per 100 PYE.2

Of the 7 patients who reported cases of lymphoproliferative disorders,

  • all received MTX for their RA at least 1 year before the start of baricitinib and during the entire treatment period with baricitinib up to the event, and
  • three also received adalimumab before the start of baricitinib.2

Six of the 7 cases of lymphoproliferative disorders were from Japan.2

Nonmelanoma Skin Cancers in Rheumatoid Arthritis Clinical Trials

7-Study Placebo-Controlled Dataset

Through 24 weeks of assigned treatment, the IR per 100 PY for NMSC was

  • 0.6 (n=3) in the baricitinib 4-mg group (N=1142)
  • 0.0 in the baricitinib 2-mg group (N=479), and
  • 0.2 (n=1) in the placebo group (N=1215).3

4-Study Extended Dataset

The IRs per 100 PYR for NMSC were 1.22 for BARI 4 mg compared with 0.24 for BARI 2 mg for the “as-treated” analysis.2

All-BARI-RA Dataset

In the All-BARI-RA dataset, 50 patients reported cases of NMSC representing an IR of 0.3 per 100 PYs.4 A summary of NMSC in the All-BARI-RA dataset is presented in Summary of Nonmelanoma Skin Cancer in the All-BARI-RA Dataset.

As shown in Nonmelanoma Skin Cancer Over Time in the All-BARI-RA Dataset, the IR for NMSC did not increase over time.4

Summary of Nonmelanoma Skin Cancer in the All-BARI-RA Dataset2

 

All BARI RA
(N=3770)

NMSC, n (%) [IR] [CI]

50 (1.3) [0.33] [0.25-0.44]

Squamous cell carcinoma, n (%) [EAIR]

16 (0.4) [0.11]

Bowen’s disease, n (%) [EAIR]

8 (0.2) [0.05]

Basal cell carcinoma, n (%) [EAIR]

28 (0.7) [0.19]

Abbreviations: BARI = baricitinib; EAIR = exposure-adjusted incidence rate; IR = incidence rate; NMSC = nonmelanoma skin cancer; PY = patient-years; RA = rheumatoid arthritis.

Nonmelanoma Skin Cancer Over Time in the All-BARI-RA Dataset4

Figure description 3: Cumulative incidence rate of nonmelanoma skin cancer by 48-week interval beyond 336 weeks of baricitinib treatment in the All-BARI-RA dataset. The incidence rate for nonmelanoma skin cancer did not increase over time.

Abbreviations: BARI = baricitinib; PYE = patient-years of exposure; RA = rheumatoid arthritis.

In the All-BARI-RA dataset, there were no deaths due to NMSC. Nine patients had NMSC cases that met serious adverse event criteria.2

Incidence Rates of NMSC by Baricitinib Dose

The EAIR per 100 PY for NMSC was similar between patients in the

  • Ever-on-BARI-2-mg group (0.41 [95% CI: 0.21-0.73]), and
  • Ever-on-BARI-4 mg group (0.35 [95% CI: 0.25-0.47]).2

Additional Comparative Dataset Analyses

The IRs and 95% CIs for NMSC in each integrated dataset as well as individual comparator studies, RA-BEAM and RA-BEGIN, are provided in Incidence Rate by Analysis Dataset for Nonmelanoma Skin Cancer in Rheumatoid Arthritis Clinical Trials.

Incidence Rate by Analysis Dataset for Nonmelanoma Skin Cancer in Rheumatoid Arthritis Clinical Trials2,3,6

Abbreviations: ADA = adalimumab; BARI = baricitinib; DMARD = disease-modifying antirheumatic drug; IR = inadequate responder; Mono = monotherapy; MTX = methotrexate; PBO = placebo; pts = patients; PYE = patient-years of exposure; RA = rheumatoid arthritis.

Description of Integrated Safety Datasets

Integrated Analysis Datasets Used to Evaluate Safety in Rheumatoid Arthritis Clinical Trials2-4,7

Analysis Set

Descriptiona

7-Study Placebo-Controlled Dataset

Studies: JADC, JADA, JADN, RA-BEAM, RA-BUILD, RA-BEACON, RA-BALANCE

Compares BARI 4 mg vs placebo

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

  • BARI 4 mg (N=1142, [exposure through 24 weeks: PYE=471.8, median exposure=169 days, maximum exposure=211 days]), or
  • placebo (N=1215, [exposure through 24 weeks: PYE=450.8, median exposure=166 days, maximum exposure=235 days]).

Patients in the placebo group could have been taking

  • background MTX, or
  • in some studies, other conventional DMARD therapy.

Evaluation time periods included

  • through the 12-week placebo-controlled period in phase 2 studies
  • through 16 weeks of assigned treatment before any opportunity for rescue therapy in phase 3 studies, and
  • through 24 weeks of assigned treatment or until rescue in phase 3 studies.

BARI 2 mg Analysis Set

BARI 2 mg data is derived from 4 studies in which both BARI 2 mg (N=479, [exposure through 24 weeks: PYE=185.8, median exposure=168 days, maximum exposure=197 days]) and BARI 4 mg were options during randomization (JADA, JADN, RA-BUILD, RA-BEACON).

4-Study Extended Dataset

Studies: JADA, JADN, RA-BUILD, RA-BEACON, RA-BEYOND (extension)

Compares BARI 4 mg vs BARI 2 mg including extended evaluations

Includes patients with RA from 2 phase 2 and 2 phase 3 studies and any further exposure for those patients in the phase 3 extension study, RA-BEYOND, who were randomized to

  • BARI 4 mg (N=479, PYE=781.1, median exposure=342 days, maximum exposure=3085 days), or
  • BARI 2 mg (N=479, PYE=774.9, median exposure=257 days, maximum exposure=2370 days).

Evaluation time period included randomization through last available observation incorporating extension data through 01 September 2019 unless otherwise specified.

All BARI RA Dataset

Studies: JADB, JADC, JADA, JADN, RA-BEGIN, RA-BEAM, RA-BUILD, RA-BEACON, RA-BALANCE, RA-BEYOND (extension)

No between-group comparisons

Includes patients with RA (N=3770, PYE=14,744 PY exposure to BARI and 15,114 PY overall observation including time on BARI and follow up, median exposure=4.6 yrs, maximum exposure=9.3 yrs) from 1 phase 1b, 3 phase 2, 5 phase 3 studies, and 1 phase 3 extension study who received BARI at a variety of doses, including

  • BARI 4 mg (n=3401, PYE=11,872)
  • BARI 2 mg (n=1077, PYE=2678), and
  • BARI 1 mg, 7 mg, 8 mg, and 10 mg QD doses not evaluated in confirmatory studies.

Patients had to have received at least 1 dose of BARI and could have received different doses throughout the trials.

Evaluation time period is all exposure time points including after rescue or changes in study drug unless otherwise specified.

Abbreviations: BARI = baricitinib; DMARD = disease-modifying antirheumatic drug; MTX = methotrexate; PY = patient-years; PYE = patient-years of exposure; QD = once daily; RA = rheumatoid arthritis.

aPatients with renal function impairment who were randomized to BARI 4 mg, but treated with the 2-mg dose were analyzed in the BARI 4-mg group.

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.

3Genovese MC, Smolen JS, Takeuchi T, et al. Safety profile of baricitinib for the treatment of rheumatoid arthritis over a median of 3 years of treatment: an updated integrated safety analysis. Lancet Rheumatol. 2020;2(6):E347-E357. https://doi.org/10.1016/S2665-9913(20)30032-1

4Taylor PC, Takeuchi T, Burmester GR, et al. Safety of baricitinib for the treatment of rheumatoid arthritis over a median of 4.6 and up to 9.3 years of treatment: final results from long-term extension study and integrated database. Ann Rheum Dis. Published online October 27, 2021. https://doi.org/10.1136/annrheumdis-2021-221276

5Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2018. National Cancer Institute, Bethesda, MD. April 2021. https://seer.cancer.gov/csr/1975_2018/

6Genovese MC, Smolen JS, Takeuchi T, et al. Safety profile of baricitinib for the treatment of rheumatoid arthritis up to 8.4 years: an updated integrated safety analysis. Poster presented at: European League Against Rheumatism Virtual Congress; June 3-6, 2020.

7Genovese MC, Smolen JS, Takeuchi T, et al. Safety profile of baricitinib for the treatment of rheumatoid arthritis up to 8.4 years: an updated integrated safety analysis. Ann Rheum Dis. 2020;79(suppl 1):638. European League Against Rheumatism abstract FRI0123. https://ard.bmj.com/content/79/Suppl_1/642.1

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

Date of Last Review: October 08, 2021


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