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\begin{document}

\title{Potential cancer risk with omalizumab: a disproportionality analysis of
the WHO's VigiBase pharmacovigilance database}



\author[1]{Diogo Mota}%
\author[2]{Tiago Rama}%
\author[3]{Milton Severo}%
\author[1]{André Moreira}%
\affil[1]{Faculty of Medicine}%
\affil[2]{Faculdade de Medicina da Universidade do Porto, Porto, Portugal \& Centro Hospitalar São João}%
\affil[3]{Faculty of Medicine, University of Porto}%


\vspace{-1em}



  
  \date{May 19, 2024}


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\textbf{Potential cancer risk with omalizumab: a disproportionality
analysis}

\textbf{of the WHO's VigiBase pharmacovigilance database}

\textbf{To the editor,}

An increasing body of evidence strongly suggests that immunoglobulin E
(IgE) plays a key role in cancer immune surveillance. Moreover, a
possible link between absent or very low serum IgE levels and malignancy
risk has also been suggested \textsuperscript{1}. Still, two studies on
omalizumab, a widely used anti-IgE drug, failed to suggest any influence
on the development or progression of malignancy \textsuperscript{2,3}.
However, they were based on the analysis of data from efficacy clinical
trials, including carefully selected participants, enrolled for a
limited time, and neither powered nor designed to assess long-term
complications such as incident cancer. Therefore, we aimed to examine
the incidence of malignancy using comprehensive data from real-life
omalizumab-treated patients.

We performed a disproportionality analysis (case/non-case
study)\textsuperscript{4} within VigiBase, the World Health
Organization's global database of individual case safety reports, to
identify a signal of cancer, expressed as the reporting odds-ratio
{[}ROR{]} and its 95\% confidence interval {[}CI{]} for
omalizumab.\textsuperscript{5} Cases were defined as Adverse Drug
Reactions (ADR) coded as Neoplasms according to the Medical Dictionary
for Regulatory Activities (MedDRA) terminology reported between 2000 and
2020. Non-cases were defined as all other ADRs during the same period.
The main analysis estimated the risk of reporting ``Neoplasms''
associated with Omalizumab compared with all other ADRs for Omalizumab
to the remaining reported drugs. Analysis for other selected cancers
according to MedDRA terminology was also performed.

A total of 1380 reports mentioned neoplasms associated with omalizumab.
The disproportionality signal was significant and positive: ROR
{[}95\%CI{]} = 1.65 {[}1.56 to 1.74{]}. (Table 1). The association was
particularly strong in breast and lung cancer, with 232 cases and ROR
{[}95\%CI{]} = 4.12 {[}3.61-4.69{]} and, 85 cases and ROR {[}95\%CI{]} =
3.04 {[}2.45-3.76{]} respectively (Table 1).

The finding that omalizumab increases by two-thirds the risk of incident
cancer is of major relevance but should be interpreted with caution.
Disproportionality analysis is exploratory in the context of signal
detection, not allowing quantification of the true risk. These studies
have been shown to detect early signals that later are confirmed by
controlled studies.\textsuperscript{4} As such, a confirmatory study is
needed to ascertain our findings. 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. Additionally,
under-reporting may have occurred. However, when referring to serious
events, like cancer, this is less prone to happen and, if it did, would
increase the strength of the signal. Similarly, the notoriety effect
cannot apply as former studies failed to show any association between
omalizumab and cancer.

Our study has important strengths. Our analysis was based on the most
global and comprehensive pharmacovigilance database. Moreover, the
safety of omalizumab was evaluated using post-marketing surveillance
data overcoming the limitations of clinical trials inclusion criteria
and limited follow-up.

In conclusion, using real-world data mining, we reported a signal that
omalizumab may be associated with a significantly higher risk of
malignancies. Until further studies confirm the long-term safety of
omalizumab, this observation should be reflected on the benefit-risk
assessment when considering anti-IgE for the treatment of allergic
conditions.

\textbf{References}

1. Ferastraoaru D, Bax HJ, Bergmann C, et al. AllergoOncology: Ultra-low
IgE, a potential novel biomarker in cancer - A Position Paper of the
European Academy of Allergy and Clinical Immunology (EAACI). \emph{Clin
Transl Allergy} . 2020;10(1):1-16. doi:10.1186/s13601-020-00335-w

2. Busse W, Buhl R, Fernandez Vidaurre C, et al. Omalizumab and the risk
of malignancy: results from a pooled analysis. \emph{J Allergy Clin
Immunol} . 2012;129(4):983-989.e6. doi:10.1016/j.jaci.2012.01.033

3. Long A, Rahmaoui A, Rothman KJ, et al. Incidence of malignancy in
patients with moderate-to-severe asthma treated with or without
omalizumab. \emph{J Allergy Clin Immunol} . 2014;134(3).
doi:10.1016/j.jaci.2014.02.007

4. Faillie JL. Case--non-case studies: Principle, methods, bias and
interpretation. \emph{Therapie} . 2019;74(2):225-232.
doi:10.1016/j.therap.2019.01.006

5. Montastruc JL, Sommet A, Bagheri H, Lapeyre-Mestre M. Benefits and
strengths of the disproportionality analysis for identification of
adverse drug reactions in a pharmacovigilance database. \emph{Br J Clin
Pharmacol} . 2011;72(6):905-908. doi:10.1111/j.1365-2125.2011.04037.x

Authors:

Diogo Mota\textsuperscript{1}

Tiago Azenha Rama\textsuperscript{1,2}

Milton Severo\textsuperscript{3}

Andr\selectlanguage{ngerman}é Moreira\textsuperscript{1,2,3}

\textsuperscript{1} Serviço de Imunoalergologia, Centro Hospitalar
Universitário de São João, Porto, Portugal;

\textsuperscript{2} Serviço de Imunologia Básica e Clínica, Faculdade de
Medicina da Universidade do Porto, Portugal;

\textsuperscript{3} EPIUnit, Instituto de Saúde Pública, Universidade do
Porto, e Laboratório para a Investigação Integrativa e Translacional em
Saúde Populacional (ITR), Porto, Portugal

\textbf{Corresponding author:}

André Moreira

andremoreira@med.up.pt

EPIUnit, Instituto de Saúde Pública, Universidade do Porto, e
Laboratório para a Investigação Integrativa e Translacional em Saúde
Populacional (ITR), Porto, Portugal

\textbf{Acknowledgments}

The information does not represent the opinion of the Uppsala Monitoring
Centre (UMC) or the World Health Organization.

\textbf{Declaration of Competing Interest}

All authors disclose no financial and personal relationships with other
people or organizations that could inappropriately influence their work.

\textbf{Contributors}

DM drafted the manuscript. AM conceived, and coordinated subsequent
edits and revisions. MS and TR participated in drafting the manuscript
and its finalization. All authors have read and approved the final
manuscript.

\textbf{Table 1} Disproportionality analysis (reporting odds ratio
{[}ROR{]} and its 95\% confidence interval {[}CI{]}) of selected cancers
and total neoplasms for omalizumab in VigiBase for the period between
2000 and 2020.\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
Neoplasm & Cases associated with Omalizumab (No.) & Total cases, (No.) &
ROR & 95\% CI\tabularnewline
\midrule
\endhead
Breast cancer & 232 & 34449 & 4.12 & 3.61 -- 4.69\tabularnewline
Lung cancer & 85 & 17012 & 3.04 & 2.45 -- 3.76\tabularnewline
Prostate cancer & 57 & 13625 & 2.54 & 1.96 -- 3.30\tabularnewline
Colon cancer & 46 & 7595 & 3.68 & 2.76 -- 4.92\tabularnewline
Malignant melanoma & 45 & 8258 & 3.31 & 2.47 -- 4.44\tabularnewline
Thyroid cancer & 22 & 3841 & 3.48 & 2.29 -- 5.30\tabularnewline
Leukemia & 21 & 4604 & 2.77 & 1.80 -- 4.25\tabularnewline
Neoplasms (total) & 1380 & 515120 & 1.65 & 1.56 -- 1.74\tabularnewline
\bottomrule
\end{longtable}

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