Does omalizumab increase the risk of malignancy? A retrospective case-control study in a single tertiary hospital

To the editor, Omalizumab, a humanized anti-IgE monoclonal antibody, is a medication for the treatment of IgE-mediated allergic asthma, chronic spontaneous urticaria, and nasal polyps [1,2]. Although omalizumab exhibited a good overall safety, a concern about the risk of malignancy was raised after a pooled clinical trial data showed that the incidence of malignancy was higher in omalizumab-treated patients than in controls (0.5% vs 0.2%) [3]. An epidemiologic study was initiated to assess the 5-year safety of omalizumab. The crude malignancy rates were similar between 5,007 omalizumab-treated patients and 2,829 omalizumab-untreated controls, with a rate ratio of 0.84 (95% confidence interval [CI], 0.62–1.13) for all malignancies [4]. However, a disproportionate analysis (case/noncase study) within VigiBase indicated that omalizumab might be associated with a significantly higher risk of malignancies based on 1,380 individual case safety reports of malignant neoplasms associated with omalizumab [5], with a reporting odds ratio (ROR) of 1.65 (95% CI, 1.56–1.74), which was particularly strong in breast and lung cancers with ROR of 4.12 (95% CI, 3.61–4.69) and 3.04 (95% CI, 2.45–3.76), respectively [5]. However, disproportionate analysis has limitation of selective reporting and asthma is also known to be a risk factor for lung cancer [6]. This study aimed to analyze the frequency of primary malignancy in omalizumab-treated patients in a real-world clinical setting using propensity score obtained for matching baseline patient characteristics such as sex, age, and indication of omalizumab. Patients were selected for retrospective case-control study using the clinical data warehouse of our hospital. Ethical approval for this study (H-2201-063-1290) was provided by the Institutional Review Board of Seoul National University Hospital, Seoul, Republic of Korea (Chairperson Prof Young Tae Kim) on January 20, 2020. First, patients diagnosed with cancer after omalizumab treatment were recruited. As a next step, omalizumab-untreated controls were selected as controls. Each patient's medical records were retrospectively reviewed thoroughly to verify the occurrence of malignancies from the time of diagnosing asthma or chronic urticaria until the end of 2021. Cancer endpoint was the incident of malignancy confirmed by the oncologists 1 year after the start of omalizumab treatment for asthma or urticaria. Patients diagnosed with malignancy prior to their diagnosis of asthma or chronic urticaria were excluded. A total of 2,285 patients (457 patients in the omalizumab-treated group and 1,828 in the omalizumab-untreated group) were included in our study. In the omalizumab-treated group, patients received omalizumab 0.5 ± 5.3 years after they were diagnosed with asthma or chronic urticaria and received omalizumab for a median of 5.8 months (8.0 ± 17.1 doses). While baseline serum total IgE before starting omalizumab treatment was significantly higher in the omalizumab group than in the omalizumab-untreated control group (Supplementary Table S1, https://links.lww.com/PA9/A23), it did not differ between patients diagnosed with and without cancer after their diagnosis of asthma or chronic urticaria (Supplementary Table S2, https://links.lww.com/PA9/A23). Also, when we divided the omalizumab-untreated group using mean IgE value as the cutoff value, the incidence rate of cancer did not show any difference between 2 groups. The morbidity rates of malignancy did not differ between the omalizumab group and the control group (1.3% vs 3.0%, P = 0.99) (Fig. 1). This difference still remained insignificant after dividing the number of patients with malignancy by the observation time to calculate cases per 1,000 person-years (2.1 vs 3.9, P = 0.16). Omalizumab treatment did not show any association with certain type of primary malignancy (Supplementary Figure S1, https://links.lww.com/PA9/A22). In the omalizumab-treated group, patients diagnosed with cancer were older (63.6 ± 13.2 vs 49.2 ± 16.6, P = 0.035) and most patients (83.7%) received omalizumab for the treatment of asthma (P = 0.008) (Supplementary Table S2, https://links.lww.com/PA9/A23). When we calculated the incidence rate of cancer in only patients with asthma, there was no significant difference in omalizumab-treated group and omalizumab-untreated group (4.0% vs 4.6%, P = 0.77). The incidence rate of cancer was not higher in the omalizumab-treated chronic urticaria group as well.Figure 1.: Kaplan-Meier curves for disease-free survival compared using the log-rank test between groups.Our study has strengths as follows: it is the first study to observe the primary malignancy rate in a real-world clinical setting at a mean of 7.32 years per person (6.14 and 7.61 years in each group with and without omalizumab treatment), which is much longer compared to the data from a previous clinical trial [3]. This enabled us to assess slow-growing malignancies with long latency periods. However, limitation of our study is that information on individual risk factors was limited in some patients since many of the study subjects were treated at outpatient clinic without regular laboratory checkup. Also, detailed information on smoking history was not available in many patients. Further studies with larger numbers of patients and longer observation times are required to confirm the results of our study. In conclusion, based on the real-world clinical data from a single tertiary hospital in Korea, omalizumab may not be associated with a higher risk of primary malignancy. Acknowledgements This research was supported by a grant from Ministry of Food and Drug Safety to the regional pharmacovigilance center in 2022. Conflicts of interest The authors declare that they have no relevant conflicts of interest. Author contributions The authors confirm contribution to the paper as follows: study conception and design, data collection, analysis, and interpretation of results: Hyun Jee Kim; draft manuscript preparation: Suh Young Lee, Sang-Heon Cho, Hye-Ryun Kang. All authors reviewed the results and approved the final version of the manuscript. Supplementary material Supplementary Figure S1 and Tables S1 and S2 can be found via https://links.lww.com/PA9/A22 and https://links.lww.com/PA9/A23 Supplementary Figure S1 and Tables S1 and S2 Click here to view