Rates of malignancy among patients with rheumatoid arthritis being treated with the oral Janus kinase inhibitor tofacitinib (Xeljanz) were within the rates expected of patients with moderate-to-severe disease, pooled data from the drug's clinical development program showed.
Compared with expected rates, the age- and sex-adjusted standardized incidence ratio for all malignancies (excluding nonmelanoma skin cancer) among tofacitinib-treated patients was 1.17 (95% CI 0.96-1.41), according to Jeffrey R. Curtis, MD, of the University of Alabama at Birmingham, and colleagues.
Action Points
- Note that this surveillance study found that treatment with tofacitinib was not associated with an increased incidence of malignancies.
- Be aware that follow-up time was short. Given the time it takes for malignancies to develop, ongoing surveillance is warranted.
And for the most common malignancy, lung cancer, the standardized incidence ratio was 2.19 (95% CI 1.39-3.29), but 20 of the 24 cases were in current or former smokers, the researchers reported online in Annals of the Rheumatic Diseases.
"In the development of immunomodulatory agents with new mechanisms of action such as tofacitinib, there is a particular need for close monitoring of safety events of special interest, including malignancies, to uncover potential adverse drug reactions," Curtis and colleagues observed.
Accordingly, they analyzed malignancy data from six phase II, six phase III, and two long-term extension studies that evaluated tofacitinib in patients with moderate-to-severe rheumatoid arthritis.
The analysis focused in particular on all malignancies as well as lung and breast cancer, lymphoma, and nonmelanoma skin cancers because of frequency, and also on lymphoma because of its underlying association with rheumatoid arthritis.
A total of 5,671 patients were included. Exposure to the drug was longer than 1 year in 4,204, more than 2 years in 3,084, and more than 3 years in 1,948.
By April 2013, with median exposure time of 2.35 years, there had been 107 malignancies other than nonmelanoma skin cancer, including 24 cases of lung cancer, 19 breast cancers, 10 lymphomas, and six gastric cancers.
More than one malignancy occurred in eight patients receiving tofacitinib in dosages of 5 mg twice per day and in 13 receiving 10 mg twice per day.
The incidence rate of all malignancies was 0.85 (95% CI 0.70-1.02) per 100 patient-years. In the phase III studies, the incidence rate was 0.32 (95% CI 0.10-0.99) per 100 for patients given tofacitinib as monotherapy and 0.83 (95% CI 0.53-1.28) per 100 for those on combination therapy.
For patients receiving the 5-mg twice daily dosage, the incidence rate for all malignancies was 0.55 (95% CI 0.27-1.09) per 100, while the rate was 0.87 (95% CI 0.50-1.49) per 100 for the 10-mg twice daily dose.
No association was seen for overall malignancy rate and duration of treatment with tofacitinib, the researchers reported.
For breast cancer, the incidence rate was 0.18 (95% CI 0.12-0.28) per 100 patient-years, and the standardized incidence ratio was 0.78 (95% CI 0.47-1.22) compared to the expected rate.
A total of 82 nonmelanoma skin cancers were reported by 66 patients, and the incidence rate was 0.53 (95% CI 0.41-0.67) per 100. Rates were higher among patients in the 10-mg dose group.
For lymphoma, the incidence rate was 0.08 (95% CI 0.04-0.14) per 100 patient-years, and the age- and sex-adjusted standardized incidence ratio was 2.64 (95% CI 1.27-4.86).
"Lymphoma is a risk associated with rheumatoid arthritis and with agents used for rheumatoid arthritis treatment that affect the immune system," Curtis and colleagues noted.
The types of lymphomas that developed among patients receiving tofacitinib were similar to those that have been reported in rheumatoid arthritis patients in general, as well as in the wider population.
The lymphomas were "histopathologically heterogeneous," with one being positive and two equivocal for Epstein-Barr virus. "Increased risk of EBV-associated lymphoma has been associated with high tofacitinib blood concentrations in renal transplantation studies," in which tofacitinib has been given in combination with immunosuppressives such as mycophenolate mofetil.
"Ongoing analysis of long-term extension studies and postmarketing vigilance will be important to understand whether a relationship exists between tofacitinib and EBV-associated lymphomas in patients with rheumatoid arthritis," the researchers cautioned.
Eighteen patients died of malignancies during follow-up. Ten were from lung cancer, with seven being in the higher-dose group. One patient receiving 10 mg twice per day died of synovial sarcoma, and one each in the 5-mg group died from colon, gastric, gallbladder, hepatic, ovarian, breast, and rectosigmoid cancers.
Limitations of the study included the exclusion from the randomized trials of patients with a history of cancer and the short exposure time.
Disclosures
The study was funded by Pfizer.
Curtis has disclosed financial relationships with Pfizer, Genentech, UCB, Janssen, Amgen, BMS, Crescendo, and AbbVie. His co-authors are consultants and/or employees of Pfizer.
Primary Source
Annals of the Rheumatic Diseases
Source Reference: Curtis J, et al "Tofacitinib, an oral Janus kinase inhibitor: analysis of malignancies across the rheumatoid arthritis clinical development program" Ann Rheum Dis 2015; DOI: 10.1136/annrheumdis-2014-205847.