Do Biologics Cause Cancer?

Medscape | Determining risk for cancer associated with biologic therapy in patients with autoimmune rheumatic diseases is problematic. Patients often have a history of cancer before starting biologic therapy,^[1,2] treatment may be carcinogenic, and the disease may predispose the patient to cancer.^[3] For example, patients with rheumatoid arthritis (RA) may have a rate of lymphoma 2- to 4-fold higher than that of the general population.^[3]

Although new biologics are in use and more are being developed, the long-term risks for cancer have yet to be fully elucidated. Research and systematic reviews have studied the risk for cancer associated with tumor necrosis factor (TNF) blockers, and despite no clear association, patients receiving these agents must be warned of the potential risk. (Reviews of anti-TNF therapy and risk for cancer can be found elsewhere.^[4,5]) This article discusses the incidence for cancer with biologic agents used for rheumatologic diseases other than TNF blockers.

Tocilizumab

Tocilizumab, approved for rheumatoid arthritis (RA), is a humanized monoclonal antibody that binds interleukin (IL)-6 receptors. Clinical trials 6 months in duration found 15 cases of cancer in the tocilizumab group compared with 8 in the control group. Tocilizumab had an exposure-adjusted incidence for cancer of 1.32 events per 100 patient-years; the placebo plus disease-modifying antirheumatic drug (DMARD) group had 1.37 events per 100 patient-years.^[6] A meta-analysis of 6 randomized, controlled trials of tocilizumab (combination and monotherapy) until September 2009 found no increased incidence of cancer.^[7]

Ustekinumab

Ustekinumab, indicated for plaque psoriasis, is a human immunoglobulin (Ig) G1 antibody that neutralizes IL-12- and IL-23-mediated immune responses. Animal studies and trial safety evaluations suggest that this mechanism of action may increase risk for cancer.^[6] In clinical trials, patients receiving ustekinumab had a cancer occurrence (excluding nonmelanoma skin cancer [NMSC]) of 0.36 per 100 patient-years and an occurrence of NMSC in 0.8 per 100 patient-years.^[8]

Recently, data regarding ustekinumab use for up to 4 years were presented. Pooled analysis of clinical trials found an occurrence of NMSC (0.7; 0.53 per 100 patient-years), and other cancers (0.63; 0.61 per 100 patient-years). Rates (excluding NMSC) were consistent with that expected in the general US population.^[9]

Alefacept

Alefacept, a fusion protein of the CD2-binding region of leukocyte function-associated antigen-3 and the CH2 and CH3 domains of Ig G1, inhibits T-cell activation and induces apoptosis of memory T cells. Clinical trial data suggest that alefacept, indicated for plaque psoriasis, may increase the risk for cancer. The incidence of cancer was 1.3% for alefacept-treated patients compared with 0.5% for placebo-treated patients in the first 24-week timeframe of placebo-controlled studies. Of 1869 patients, 43 were diagnosed with 63 new malignancies, primarily NMSC (46 cases in 27 patients).^[10]

An integrated analysis of 13 alefacept trials with patients who had received up to 9 courses of therapy found that the incidence of NMSC in treated patients seemed consistent with the rate expected in patients with moderate to severe psoriasis. In addition, the incidences of solid-organ cancer and malignant melanoma were consistent with rates in the general US population.^[11]

Abatacept

Abatacept, indicated for RA and juvenile idiopathic arthritis (JIA), selectively modulates the CD80/CD86: CD28 costimulatory signal needed for activation of T cells. In clinical trials with a median 12 months of treatment, the abatacept group had an overall cancer frequency of 1.3% compared with the placebo-controlled group, which had a frequency of 1.1%. The abatacept group had more cases of lung cancer (n = 4, 0.2%) than did the placebo group (n = 0).^[12] An analysis of 4134 patients treated with abatacept found a total of 51 malignancies (excluding NMSC). Site-specific malignancies included breast (n = 7), lung (n = 13), and colorectal (n = 2) cancer and lymphoma (n = 5). The incidence ratios of total malignancies (excluding NMSC) and site-specific malignancies in abatacept patients were consistent with a comparable population of RA patients.^[13]

Anakinra

Anakinra, indicated for RA, competitively inhibits IL-1 binding to the IL-1 type I receptor. Clinical trials evaluating anakinra therapy in 5300 patients for a mean 15 months found a rate of 0.12 cases of lymphoma per 100 patient-years. Although this rate is 3.6-fold higher than that of the general population, patients with RA may already be at higher risk for lymphoma. Thirty-seven other cases of cancer were noted, including that of the breast, respiratory tract, and digestive system.^[14] An analysis of a registry of 5120 RA patients with 122 patients having a prior malignancy found a crude recurrence rate per 1000 patient-years of 32.3 for patients exposed to anakinra and 31.4 for patients exposed to DMARDs only. There was no significant difference in the overall incidence of cancer in patients exposed or unexposed to anakinra.^[15]

Rituximab

This CD20-directed cytolytic antibody has many indications, including RA, Wegener granulomatosis, and microscopic polyangiitis. The product information states that rates (none provided) of cancer in RA studies were higher in older patients.^[16] A recent analysis of safety data from a cohort of RA patients (n = 186) who had received at least 1 course of rituximab was published. The overall cancer rate was 1.45 per 100 patient-years; new malignancies were diagnosed in 4 patients, and 1 patient had a cancer recurrence.^[17] Rituximab is indicated for non-Hodgkin lymphoma and chronic lymphocytic leukemia and may attenuate development of certain types of cancer.^[3]

Belimumab

This new B-lymphocyte stimulator-specific inhibitor is indicated for systemic lupus erythematosus. Clinical trials found similar rates of cancer (including NMSC) between belimumab and placebo. However, the mechanism of action of belimumab, like that of all immunomodulating agents, could theoretically increase the risk for cancer.^[18] A 52-week, phase-3 trial of belimumab reported no cases of cancer.^[19]

Conclusion

A recent Cochrane review^[20] sought to identify risk estimates of adverse effects associated with biologics, including anti-TNF therapies, anakinra, tocilizumab, abatacept, and rituximab. Limiting the data for lymphoma, the authors found no statistically significant difference between biologics and controls. However, more studies are urgently needed. As most of these agents are new, postmarketing data are extremely important. Clinicians should report any case of cancer associated with biologic use to the US Food and Drug Association MedWatch Adverse Event Reporting program. This information will help establish whether an association exists between biologic therapies and development of cancer.