Immune checkpoint inhibitors (ICIs) have been revolutionary in the treatment of various cancer types, demonstrating favorable outcomes and having been generally well-tolerated by patients with cancer compared to cytotoxic therapy (Front Oncol 2021; doi: 10.3389/fonc.2021.625872). ICIs enhance and promote anti-tumor immunity, leading to immune-related adverse events, which are characterized by excessive immunity response.
Recently, there are reports suggesting that the occurrence of active pulmonary or extrapulmonary tuberculosis (TB) is becoming increasingly frequent in patients during or after ICI therapy (Eur J Cancer 2020; https://doi.org/10.1016/j.ejca.2020.03.015). According to the World Health Organization, TB remains a major cause of morbidity and mortality worldwide. In advanced cancers, development of active TB implies significant risk, including delayed antineoplastic therapy and death. Furthermore, the risk of developing active TB is 2-3 times greater in patients with solid cancer than in the general population (Eur Clin Respir J 2017; doi: 10.1183/13993003.00157-2017). In particular, the incidence of TB in patients with lung cancer was reported to be up to 9 times greater than that of the general population (Clin Infect Dis 2017; https://doi.org/10.1093/cid/ciw838).
Although the prevalence of TB is much higher among immunosuppressed patients, limited data exist on the development of TB in cancer patients receiving ICIs. Therefore, a better understanding of the association between ICI exposure and the ensuing development of active TB in a cancer-patient cohort is warranted.
To address this unmet need, a recent study, published in the Journal for ImmunoTherapy of Cancer, evaluated the risk of TB in patients with cancer exposed to ICIs using the National Health Insurance claims data in South Korea (2021; doi: 10.1136/jitc-2021-002960).
In this nationwide, population-based, observational cohort study, 141,550 patients with non-small cell lung cancer (NSCLC), urothelial carcinoma, or melanoma between August 2017 and June 2019 were identified using ICD-10 codes. Of these cases, 916 new TB cases were detected.
Clinical characteristics of study patients, use of ICIs, confirmed diagnosis, treatment modality, and outcomes of pulmonary TB were collected retrospectively. The majority of the patients with cancer were male, elderly, and had lung cancer. Patients who received nivolumab, pembrolizumab, and atezolizumab within the study period were classified as the ICI group (n=5,037; 3.6%). The remaining patients were classified as the ICI non-exposure group (n=136,513; 96.4%).
Among the 5,037 patients exposed to ICIs, 20 were diagnosed with TB at a median of 2.2 months (range: 04-16.5) after the ICI was initiated, and 80 percent of the cases were pulmonary infections. The crude incidence rate of TB per 100,000 person-years was 675.8 (95% CI 412.8-1,043.8) for the ICI exposure group and 599.1 (95% CI: 560.5-639.6) for the ICI non-exposure group. The incidence of TB in the patients exposed to ICIs was approximately 8-fold higher relative to the general population: the standardized incidence ratio for TB was 8.1 (95% CI: 8.0-8.2) in the ICI exposure group, 6.0 (95% CI: 5.9-6.1), and 10.9 (95% CI: 10.7-11.1) for the total, male, and female participants, respectively.
After adjusting for potential confounding factors, ICI treatment was shown not to be significant risk factor associated with an increased risk of TB in the univariable analysis (HR=0.85; 95% CI: 0.55-1.33) and in the multivariable Cox regression analysis (HR=0.73; 95% CI: 0.47-1.14). Subgroup and sensitivity analysis revealed no significant difference in incidence for TB between ICI exposure and ICI non-exposure groups regardless of sex, age, and type of cancer (all P values for interaction >0.05).
Oncology Times reached out to senior author, Sang-Oh Lee, MD, PhD, for his perspectives on the incidence of TB in patients with cancer treated with ICIs. Lee is Professor of Medicine in the Department of Infectious Diseases at the Asan Medical Center of the University of Ulsan College of Medicine, Seoul, South Korea.
Oncology Times: What are some challenges in terms of estimating the incidence of active TB in patients with lung cancer?
Lee: "First, it is difficult to estimate the incidence of TB due to the rarity of TB. Generally, the TB incidence in a low TB burden country is fewer than 30 cases per 100,000 person-years. Therefore, it is not possible to estimate the TB burden in patients with lung cancer from a limited number of patients, and large-scale data at the national level are required."
Oncology Times: What are the clinical implications of the findings of this study?
Lee: "Use of ICI has been widely [shown] to be effective in treating patients with advanced solid cancers. Recently, several studies have reported the development of TB in patients during or after ICI therapy. Therefore, epidemiological evidence was needed to determine whether the risk of TB was high in the patients exposed to ICI. Estimating the TB risk and burden in the ICI group can contribute to establishing a strategy for screening and treating latent tuberculosis as in patients receiving anti-TNF treatment.
"Using claim data from South Korea, which is an intermediate TB burden country, we analyzed the incidence of tuberculosis in about 140,000 patients with cancer, including more than 5,000 ICI users during the same period. Our findings reaffirm the higher risk of TB in cancer patients, while suggesting there is no evidence to support additional measures to prevent active TB in the use of ICI."
Oncology Times: What are some independent risk factors for active TB in patients with cancer?
Lee: "In the analysis controlled for various confounding variables, increasing age, male sex, type of insurance (medical aids comparable to U.S. Medicaid), lung malignancy, chronic lung disease, and active chemotherapy were observed as independent risk factors for the development of TB.
Oncology Times: Considering the high risk for TB in patients with cancer irrespective of ICI exposure, what types of studies still need to be conducted?
Lee: "First, the risk of TB in patients with other types of cancers, as well as in those receiving other types of ICIs, such as CTLA-4 inhibitors, needs to be evaluated, since only a limited number of ICIs (nivolumab, atezolizumab, and pembrolizumab) and types of cancer (lung cancer, urothelial carcinoma, and skin cancer) were assessed in this study.
"Second, studies investigating cost-effectiveness for latent TB infection (LTBI) screening and treatment in cancer patients are needed. Although the use of ICI is not significantly associated with the active TB, the risk of developing TB in patients with cancer is significantly higher than the general population. However, no societal guidelines recommend for screening or treatment of LTBI in patients with cancer.
"The relatively short life expectancy of patients with cancer may lead to conclusions similar to those reported in previous studies that LTBI screening is not cost-effective in patients with end-stage renal disease (JAMA Intern Med 2017; doi:10.1001/jamainternmed.2017.3941); however, further studies are still needed to clarify this issue."
Dibash Kumar Das is a contributing writer.