Malignancy Rates in Brodalumab Clinical Studies for Psoriasis

Psoriasis is a chronic inflammatory disease associated with increased incidence of some cancers [1], a risk that may be related to impaired immune function or predisposing therapies in patients with this disorder [2]. In a population-based study of 67,761 individuals that examined the association between the risk of incident cancers and psoriasis, patients with psoriasis were found to have an increased risk of developing malignancies such as lymphohematopoietic and pancreatic cancers, and the risk of certain cancers was elevated in patients with long-term disease history [1]. Accordingly, patients with psoriasis should be monitored and routinely screened for potential malignancies, particularly skin cancer [3].

There may be an increased risk of malignancy among patients with psoriasis compared with the general population. A systematic review showed increase risk of solid cancers in psoriasis, including respiratory tract cancer (standardized incidence ratio [SIR], 1.52), upper aerodigestive tract cancer (SIR, 3.05), urinary tract cancer (SIR, 1.31), and liver cancer (SIR, 1.90) [2]. Increased incidence of cancer in patients with psoriasis has also been linked to the use of certain immunosuppressive and potentially carcinogenic treatments, such as cyclosporine, methotrexate, and psoralen and ultraviolet A light therapy [3]. For example, in a 5-year cohort study of patients with psoriasis, use of the immunosuppressive therapy cyclosporine was associated with a 2-fold greater incidence of malignancy and a 6-fold greater incidence of nonmelanoma skin cancer (NMSC) compared with incidence in the general population [4]. In a meta-analysis of seven studies, there was a higher risk of squamous cell carcinoma in psoriasis (SIR, 5.3), which was strongly related to the use of 8-methoxypsoralen-ultraviolet-A and, potentially, cyclosporine and methotrexate [2]. This meta-analysis also showed an increased incidence of basal cell carcinoma in patients with psoriasis (SIR, 2.00) [2].

An association between use of anti-tumor necrosis factor α (anti-TNFα) agents and NMSC, especially squamous cell carcinoma, has also been reported in several immune-mediated conditions. A comparison of patients receiving anti-TNFα therapy showed a significantly elevated risk of NMSC in those with psoriasis relative to the risk in those with rheumatoid arthritis (hazard ratio, 6.0 [95% confidence interval 1.6–22.4]) [5]. Expert opinion recommends avoiding the use of TNFα inhibitors in patients who currently have malignancy or those with history of malignancy [6].

Recently developed biologic therapies for psoriasis target immune system messengers such as interleukin-17 (IL-17), and related pathways have also been identified as novel cancer targets. For example, IL-12 plays a role in antitumor immunity through activation of antitumor effectors and blocking the expansion of intratumoral regulatory T cells [7]. IL-12 also contributes to maintaining cancer cells in equilibrium, allowing them to persist in a dormant rather than metastatic state [8]. Consistent with this role of IL-12 in cancer surveillance, inhibition of IL-12/23p40 in a preclinical model enhanced tumor outgrowth [8]. There may be a theoretical risk of compromising cancer surveillance through mechanisms of blocking IL-12, such as with the anti–IL-12/23 p40 antibody ustekinumab. Potential malignancies are considered an event of interest for immunomodulatory biologics, and treatments for psoriasis should be assessed for any possible contribution to risk of malignancy in these patients.

Brodalumab is a fully human anti–IL-17 receptor A monoclonal antibody [9]. Across three large phase III studies of brodalumab for the treatment of moderate-to-severe plaque psoriasis, 75% improvement in psoriasis area severity index (PASI 75) response rates ranged from 83% to 86% in patients receiving brodalumab 210 mg every 2 weeks (Q2W) compared with 3% to 8% in those receiving placebo [10, 11]. Brodalumab is a targeted immunomodulatory agent and is not expected to be broadly immunosuppressive [12, 13]. A network meta-analysis of 109 studies of treatments for chronic plaque psoriasis (which included three studies of brodalumab versus placebo and two studies of brodalumab versus the active comparator ustekinumab and placebo) did not find evidence of increased risk of serious adverse events (AEs) with brodalumab [14]. However, the long-term effect of brodalumab on risk of malignancies remains unknown. The objective of this analysis was to summarize malignancy rates in clinical studies of brodalumab for the treatment of moderate-to-severe plaque psoriasis.

In clinical studies of brodalumab, rates of malignancy were generally low. In the long-term analysis of 4464 patients receiving brodalumab over 8655 total PY of exposure, the event rate for all malignancies was 0.9 per 100 PY, and the event rate for NMSC was 0.6 per 100 PY. Through 52 weeks, the event rate for all malignancies was 2.6 per 100 PY for the active comparator ustekinumab. Three NMSCs were reported in patients with malignancy history receiving constant brodalumab 210 mg Q2W through 52 weeks.

The risk of malignancy among patients receiving treatment for psoriasis has been previously assessed in numerous studies of commonly used treatments, including the anti-TNFα antibodies infliximab and adalimumab, the anti–IL-12/23 p40 antibody ustekinumab, and the anti–IL-17A antibodies secukinumab and ixekizumab. Comparison of event rates between studies must be made with caution because there are differences in study setting, inclusion and exclusion criteria (including definition of psoriasis and psoriatic arthritis), design, treatment type and regimen, and methods of defining, determining, and reporting AEs. However, malignancy findings from studies of other psoriasis agents provide context for the current analysis of brodalumab safety.

Malignancy risk with use of anti–IL-12/23 or anti–IL-17 treatment for psoriasis has been investigated in long-term analyses of clinical study data. After 5 years of follow-up of ustekinumab treatment for psoriasis, an analysis of 8998 total PY of follow-up found event rates of 0.64 per 100 PY (45 mg) and 0.44 per 100 PY (90 mg) for NMSC and 0.59 per 100 PY (45 mg) and 0.61 per 100 PY (90 mg) for other malignancies [18]. In an analysis of 2725 total PY of secukinumab exposure over 52 weeks, the event rate was 0.48 per 100 PY for NMSC and also 0.48 per 100 PY for other malignant or unspecified tumors [19]. Over 6480 total PY of ixekizumab exposure over 60 weeks, the incidence rate was 0.4 per 100 PY for NMSC and 0.5 per 100 PY for malignancies excluding NMSC [20]. Finally, over 1373 total PY of ixekizumab exposure in psoriatic arthritis, the incidence rate of malignancy was 0.7 per 100 PY [21]. As stated previously, comparisons between different studies must be made with caution, but rates of malignancy in the current study of brodalumab (0.9 events per 100 PY for all malignancies and 0.6 events per 100 PY for NMSC) appear consistent with rates reported for other psoriasis treatments. Three NMSCs were reported over 52 weeks in patients with malignancy history who were treated with brodalumab 210 mg Q2W. Furthermore, 1-year post-marketing pharmacovigilance monitoring showed three cases of malignancy (hepatic, lung, and ovarian), all considered unrelated to brodalumab [22]. Overall, there is limited clinical evidence that use of biologic treatments for psoriasis increases malignancy risk. The complex role of inflammatory cytokines such as IL-17 in mediating tumor growth, development, and immunity is an active area of clinical and preclinical investigation [23]. Real-world studies are needed to understand any potential long-term malignancy risk with anti–IL-17 biologic treatments for psoriasis.

Several studies have assessed malignancy risk with anti-TNFα therapy. In one registry study among patients with psoriasis, an analysis including 23,660 total PY of adalimumab use found a rate of 1.0 events of malignancy per 100 PY of exposure [24]. In a retrospective cohort study, incidence rates per 100 PY of observation for malignancies excluding NMSC were higher for infliximab (2.30) and lower for adalimumab (0.78) compared with the rate in the overall psoriasis population (1.42). However, for NMSC, incidence rates per 100 PY were lower for infliximab (1.68) and higher for adalimumab (2.41) compared with the psoriasis population (1.80) [25]. A systematic review of adalimumab safety in psoriasis registries found event rates of 0.9 per 100 PY for malignancy, < 0.6 per 100 PY for malignancies excluding NMSC, and a range of < 0.5–0.6 per 100 PY for NMSC [26]. Another systematic review found an increased risk of NMSC, but not other malignancies, among patients with psoriasis treated with anti-TNFα therapy, compared with the general population and with patients with rheumatoid arthritis treated with anti-TNF therapy [27].

Multiple studies in disease states other than psoriasis have investigated risk of malignancy, particularly lymphoma, associated with use of anti-TNFα agents [28‐31]. These studies found no increase in risk of malignancy compared with patients with the same disease treated with other classes of agents [28‐31]. One study of self-reported data among patients with rheumatoid arthritis found a small (hazard ratio, 1.24) but not statistically significant increase in the rate of NMSC with use of anti-TNFα therapy [32]. A systematic review found no evidence of increased risk of overall cancer, lymphoma, or melanoma with use of anti-TNFα therapy across disease states, but findings for NMSC were inconsistent [33]. A prospective cohort study in Sweden showed that patients with rheumatoid arthritis treated with TNF inhibitors had an increased risk of invasive melanoma relative to patients not treated with biologics (hazard ratio, 1.5) [34]. An examination of electronic medical records from an academic medical center identified 35 cases of melanoma among 6045 patients exposed to a TNFα inhibitor [35]. There were also 972 reports of melanoma associated with TNFα inhibitors in the US Food and Drug Administration Adverse Events Reporting System database (from the date of approval for each drug through August 2012) [35]. However, a systematic review found no sufficient evidence to conclude that anti-TNFα agents increase malignancy risk [36].

Among studies that reported findings across multiple drug classes in patients with psoriasis, a network meta-analysis including clinical trials of anti-TNFα, anti–IL-12/23, and anti–IL-17 therapies found that malignancies were reported in both the intervention and placebo groups across all of these classes; however, event rates were not reported [14]. In the Psoriasis Longitudinal Assessment Registry, treatment with ustekinumab was not associated with increased malignancy risk compared with no ustekinumab treatment, but treatment for >12 months with a TNFα inhibitor (infliximab, adalimumab, or etanercept) was associated with a 1.5-fold increase in malignancy risk compared with no TNFα inhibitor treatment [37]. In a Psoriasis Longitudinal Assessment and Registry (PSOLAR) analysis of 12,095 patients treated with biologics who were followed up for 31,818 PY, the rate of malignancies excluding NMSC was 0.68 per 100 PY in the overall group; this rate was lower for patients in the infliximab (0.58 per 100 PY) or ustekinumab (0.53 per 100 PY) groups [38]. In a later PSOLAR analysis over a total of 40,388 PY of exposure to biologics, the rate of malignancies excluding NMSC remained 0.68 per 100 PY in the overall group; this rate was 0.79 per 100 PY in the infliximab group and 0.48 per 100 PY in the ustekinumab group, possibly indicating increasing incidence of malignancy over time for the anti-TNFα agent infliximab [39]. Further investigations are needed to characterize long-term malignancy risk across these biologic classes.

This study had some limitations. Fewer patients received ustekinumab than those receiving brodalumab, resulting in less exposure to ustekinumab. Patients in the clinical studies received varying doses of brodalumab on varying schedules, which limits the ability to generalize to patients receiving the recommended dose of 210 mg Q2W [9]. Longer follow-up time is needed to understand the potential clinical implications of the ratio of basal cell carcinoma to squamous cell carcinoma (3.8:1 through 52 weeks) in patients who received any dose of brodalumab, and observations such as the occurrence of eight cases of prostate cancer over a total of 9174 PY of follow-up. Follow-up in this analysis continued for only 266 weeks at most, and the mean exposure was <2 years in the long-term pool. Increased rates of malignancy beyond this time period could not be assessed.

In conclusion, on the basis of an analysis of >8000 PY of exposure, brodalumab appears to have a low carcinogenic risk. Rates of malignancy among brodalumab-treated patients with psoriasis were low in clinical studies. Few events of malignancy occurred in patients with a history of malignancy through 52 weeks. Longer follow-up and real-world evidence are needed to characterize the long-term risk of malignancy with brodalumab.