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Olumiant ® (baricitinib)
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What is the risk of malignancy in Olumiant® (baricitinib) patients with rheumatoid arthritis?
In all baricitinib treated patients with data up to 9.3 years of treatment and 14.744 patient-years of exposure (PYE), the incidence rates were 0.9 and 0.3 per 100 PYE for malignancy excluding NMSC and NMSC, respectively, and remained stable over time.
Content overview
- Special warnings and precautions regarding baricitinib and malignancy
- Incidence of cancer in placebo-controlled trials and long-term baricitinib exposure
- Incidence of cancer in patients at-risk
- Incidence of cancer with another Janus kinase inhibitor
- Cancer risk in patients with rheumatoid arthritis
- Baricitinib genotoxicity and carcinogenicity
- References
- Appendix: Integrated safety datasets rheumatoid arthritis clinical trials
Special warnings and precautions regarding baricitinib and malignancy
Immunomodulatory medicinal products may increase the risk of malignancies including lymphoma.1
Lymphoma and other malignancies have been reported in patients receiving JAK inhibitors, including baricitinib.1
In a large randomized active‑controlled study of tofacitinib (another JAK inhibitor) in rheumatoid arthritis patients 50 years and older with at least one additional cardiovascular risk factor, a higher rate of malignancies, particularly lung cancer, lymphoma and non-melanoma skin cancer (NMSC) was observed with tofacitinib compared to TNF inhibitors.1
In patients over 65 years of age, patients who are current or past long-time smokers, or with other malignancy risk factors (e.g. current malignancy or history of malignancy) baricitinib should only be used if no suitable treatment alternatives are available.1
Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.1
Incidence of cancer in placebo-controlled trials and long-term baricitinib exposure
Baricitinib was evaluated in up to 14.744 patient-years of exposure and up to 9.3 years. Please find an overview about the datasets used to evaluate safety in the rheumatoid arthritis clinical trials in Appendix: Integrated safety datasets rheumatoid arthritis clinical trials . All incidence rates (IR) were calculated as number of patients with an event per 100 patient years. 2
Placebo-controlled |
All BARI RA |
|||
Event, n (IR per 100 PY) |
Placebo |
BARI 2 mg |
BARI 4 mg |
All doses |
Malignancy excluding NMSC |
2 (0.4) |
1 (0.5) |
2 (0.4) |
139 (0.9) |
NMSC |
3 (0.6) |
0 |
1 (0.2) |
50 (0.3) |
Abbreviations: BARI = baricitinib; IR = incidence rate; NMSC = nonmelanoma skin cancer; PY = patient years; RA = rheumatoid arthritis;
The incidence rates of malignancies exlcuding NMSC and NMSC remained stable over time.2
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.2
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.
In the All-BARI-RA dataset, 50 patients reported cases of NMSC representing an IR of 0.3 per 100 PYs.2 A summary of NMSC in the All-BARI-RA dataset is presented in .
As shown in , the IR for NMSC did not increase over time.2
|
All BARI RA |
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.
Incidence of cancer in patients at-risk
In the All-BARI-RA dataset, 2619 out of 3770 patients were considered at-risk. This was defined as being ≥65 years old or having at least one of the following risk factors: atherosclerotic cardiovascular disease, diabetes mellitus, hypertension, current smoking, high-density lipoprotein cholesterol less than 40 mg/dL, body mass index at least 30, poor mobility on EuroQol-5 Dimension, and history of malignancy ().4
Event, IR per 100 PY |
All-BARI-RA |
Patients at-riska |
Malignancy |
0.9 (excluding NMSC) |
1.23 |
Abbreviations: BARI = baricitinib; IR = incidence rate; NMSC = nonmelanoma skin cancer; PY = patient years; RA = rheumatoid arthritis;
aDefined as being ≥65 years old or having at least one of the following risk factors: atherosclerotic cardiovascular disease, diabetes mellitus, hypertension, current smoking, high-density lipoprotein cholesterol less than 40 mg/dL, body mass index at least 30, poor mobility on EuroQol-5 Dimension, and history of malignancy.
Incidence of cancer with another Janus kinase inhibitor
A large randomized active-controlled study of another Janus kinase (JAK) inhibitor (tofacitinib), found a higher rate of cancer when compared with tumor necrosis factor (TNF) inhibitors in rheumatoid arthritis (RA) patients 50 years and older with at least one CV risk factor ().3,6
A total 4362 patients were randomized and
- 1455 received tofacitinib 5 mg twice daily
- 1456 received tofacitinib 10 mg twice daily, and
- 1451 received a TNFi.6
During a median follow-up of 4 years, the incidence of cancer was higher with the combined tofacitinib doses than with a TNFi. The incidence for cancer was 4.2% (122 patients) for combined tofacitinib doses vs 2.9% (42 patients) for TNFi (HR=1.48; [95% CI, 1.04 to 2.09]).
Noninferiority of tofacitinib was not shown.6
Event, IR per 100 PY (95% CI) |
Tofacitinib 5 mg twice daily |
Tofacitinib 10 mg twice daily |
TNF inhibitor |
Cancer |
1.13 (0.87-1.45) |
1.13 (0.86-1.45) |
0.77 (0.55-1.04) |
Abbreviations: CI = confidence interval; IR = incidence rate; TNF = tumour necrosis factor
Cancer risk in patients with rheumatoid arthritis
Evidence suggests that chronic inflammation may increase the risk of cancer. Rheumatoid arthritis is one source of chronic inflammation and may have a role in increasing the risk of cancer.7-9
Several studies suggest that RA can increase the risk of certain malignancies, including
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.2,12
Malignancy events excluding NMSC in each 5-year age category in the All-BARI-RA dataset based on SEER17 data are presented in .
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.2
Baricitinib genotoxicity and carcinogenicity
Baricitinib was not genotoxic in the
Baricitinib did not produce neoplastic changes in 2-year rat and 6-month transgenic mouse carcinogenicity studies.3,13
Non-clinical data reveal no special hazard for humans based on conventional studies of
- safety pharmacology,
- genotoxicity and
- carcinogenic potential.1
References
1Olumiant [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.
2Taylor 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. 2022;81(3):335-343. https://doi.org/10.1136/annrheumdis-2021-221276
3Data on file, Eli Lilly and Company and/or one of its subsidiaries.
4Taylor, P.C., Bieber, T., Alten, R. et al. Baricitinib Safety for Events of Special Interest in Populations at Risk: Analysis from Randomised Trial Data Across Rheumatologic and Dermatologic Indications. Adv Ther (2023). https://doi.org/10.1007/s12325-023-02445-w
5Taylor PC, Bieber T, Alten R, et al. Baricitinib safety for events of special interest in populations at risk: analysis from randomised trial data across rheumatologic and dermatologic indications. Adv Ther. 2023;40:1867-1883. https://doi.org/10.1007/s12325-023-02445-w
6Ytterberg SR, Bhatt DL, Mikuls TR, et al; ORAL Surveillance Investigators. Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis. N Engl J Med. 2022;386(4):316-326. http://dx.doi.org/10.1056/NEJMoa2109927
7Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140(6):883-899. http://dx.doi.org/10.1016/j.cell.2010.01.025
8Sansone P, Bromberg J. Environment, inflammation, and cancer. Curr Opin Genet Dev. 2011;21(1):80-85. http://dx.doi.org/10.1016/j.gde.2010.11.001
9Franks AL, Slansky JE. Multiple associations between a broad spectrum of autoimmune diseases, chronic inflammatory diseases and cancer. Anticancer Res. 2012;32(4):1119-1136. http://ar.iiarjournals.org/content/32/4/1119.long
10Ekström K, Hjalgrim H, Brandt L, et al. Risk of malignant lymphomas in patients with rheumatoid arthritis and in their first-degree relatives. Arthritis Rheumatol. 2003;48(4):963-970. http://dx.doi.org/10.1002/art.10939
11Chen YJ, Chang YT, Wang CB, Wu CY. The risk of cancer in patients with rheumatoid arthritis: a nationwide cohort study in Taiwan. Arthritis Rheumatol. 2011;63(2):352-358. http://dx.doi.org/10.1002/art.30134
12Howlader 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/
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
14Genovese 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):642-643. European League Against Rheumatism abstract FRI0123. https://ard.bmj.com/content/79/Suppl_1/642.1
15Genovese 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
Appendix: Integrated safety datasets rheumatoid arthritis clinical trials
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
Patients in the placebo group could have been taking
Evaluation time periods included
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
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
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.
Date of Last Review: 05 June 2023