To the editor:
Biologicals indicated for the treatment of severe asthma and other
allergic/eosinophilic conditions include monoclonal antibodies which
target interleukin (IL)-5 or IL-5R (mepolizumab, reslizumab and
benralizumab), IL4-Rα (dupilumab) and IgE (omalizumab). Previously we
have shown that omalizumab may be associated with an increased risk of
cancer 1.
Recent studies have suggested a role for eosinophils in cancer
pathogenesis. Although still controversial, most studies point out an
anti-tumorigenic role of eosinophils mediated by α‐defensins, TNF‐α,
granzyme A and IL‐18, while in a few others they are innocent bystanders
or their presence in the tumor microenvironment have been linked to poor
prognosis 2,3. Therefore, biological agents which
antagonize IL-5/IL-5R may lead to a reduction in peripheral eosinophil
counts. Concerning the inhibition of the IL-4/IL-13 pathways no evidence
of potential safety signals related to malignancy exists. Moreover,
studies evaluating the safety of these drugs have not demonstrated an
increased risk for malignancies4,5. However, neither
the clinical trials’ design nor included participants are broadly
representative of patients found in everyday practice. Thus, we aimed to
assess cancer risk associated with the use of these drugs in a
real-world life dataset.
A disproportionality analysis (case/non-case study) was performed within
the World Health Organization global database of individual case safety
reports (VigiBase) developed and maintained by Uppsala Monitoring
Centre, to identify a signal of cancer, expressed as the reporting odds
ratio (ROR) and its 95% confidence interval (CI) for each biological
(i.e., mepolizumab, reslizumab, benralizumab and dupilumab). Cases were
defined as adverse drug reactions (ADR) coded as Neoplasms according to
the Medical Dictionary for Regulatory Activities terminology reported
between 2008 and 2020. Non-cases were defined as all other ADRs reported
during the same period. No data about the age or gender of cases were
provided.
A total of 19983350 ADR reports were included, from which 478278 cases
referred to these biologicals (Figure 1). Most data were reported
between 2018 and 2020. Among biologicals, dupilumab had the most
reported cases with a total of 363, followed by mepolizumab with 233 and
benralizumab with 62. Only 8 cases were linked to reslizumab. The most
frequently reported malignancies for each biologic drug included breast
cancer and lung cancer. ROR for neoplasms was neither positive nor
significant for any biological (Table 1).
Overall, no signal of cancer was detected for any biological drug, as
ROR was less than 1 for the total number of neoplasms (i.e., when
compared to other drugs, there were no more reports of cancer related to
these biologicals). Considering specific cancers, there may be some
associations but the number of cases is too small to be considered as a
strong signal. Cutaneous T-cell lymphoma cases associated with dupilumab
showed the most significant positive signal (ROR=11.11) and this
connection has been reported before and is under investigation6.
The strengths of our study result from the analysis of real-world life
data, from an uncontrolled population of patients. However, our
observations are limited as the information present in VigiBase comes
from a variety of sources, and the probability that the suspected
adverse effect is drug-related is not the same in all cases. Some
important data such as the demographic profile of patients or the
duration of therapy with these biologicals were not available, which
would have allowed the analysis of other factors that could impact the
risk of cancer. Another limitation of our study may be related to
competition biases, since some of these biologicals have been strongly
associated with other adverse drug reactions (i.e., dupilumab and ocular
disorders) and this may have led to an underestimation of ROR.
In conclusion, real-world life data does not support any association
between anti-IL-5 and anti-IL-4Ra biologicals and cancer. Since these
biologicals have only been available for a short period, the effect may
be underestimated, and a larger period may be needed to better assess
cancer incidence.
References
1. Mota D, Rama TA, Severo M, Moreira A. Potential cancer risk with
omalizumab? A disproportionality analysis of the WHO’s VigiBase
pharmacovigilance database. Allergy Eur J Allergy Clin Immunol .
2021;76(10):3209-3211. doi:10.1111/all.15008
2. Varricchi G, Galdiero MR, Loffredo S, et al. Eosinophils: The unsung
heroes in cancer? Oncoimmunology . 2018;7(2):1-14.
doi:10.1080/2162402X.2017.1393134
3. Di Gioacchino M, Della Valle L, Allegra A, Pioggia G, Gangemi S.
AllergoOncology: Role of immune cells and immune proteins. Clin
Transl Allergy . 2022;12(3). doi:10.1002/clt2.12133
4. Jackson DJ, Korn S, Mathur SK, et al. Safety of Eosinophil-Depleting
Therapy for Severe, Eosinophilic Asthma: Focus on Benralizumab.Drug Saf . 2020;43(5):409-425. doi:10.1007/s40264-020-00926-3
5. Deleuran M, Thaçi D, Beck LA, et al. Dupilumab shows long-term safety
and efficacy in patients with moderate to severe atopic dermatitis
enrolled in phase 3 open-label extension study. J Am Acad
Dermatol . 2020;82(2):377-388. doi:10.1016/j.jaad.2019.07.074
6. Elston DM. Dupilumab and cutaneous T-cell lymphoma. J Am Acad
Dermatol . 2020;83(1):33-34. doi:10.1016/j.jaad.2020.03.051