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 suggested1. Still, two studies on
omalizumab, a widely used anti-IgE drug, failed to suggest any influence
on the development or progression of
malignancy2,3.
However, one of them was based on the analysis of data from efficacy
clinical trials, including carefully selected participants, enrolled for
a limited period, and neither powered nor designed to assess long-term
complications such as incident cancer while the other one was performed
for a shorter period when compared to the latency period some solid
tumors need to develop. Therefore,
we aimed to examine the incidence of malignancy using comprehensive data
from no selected omalizumab-treated patients recorded in a
pharmacovigilance database, through assessment of a signal of
cancer4.
We performed a disproportionality analysis (case/non-case
study)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.5 All Adverse Drug Reaction (ADR) reports
related to omalizumab and the total number of neoplasms recorded in
VigiBase were provided by the Uppsala Monitoring Centre (UMC). 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).
Some of the most reported and with
more statistical significance malignancies are presented in 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).
Other neoplasms with strong
association included prostate cancer, colon cancer, malignant melanoma,
thyroid cancer and leukemia (Table 1). At the time data from VigiBase
were provided, a total of more than 21 million reports were recorded in
VigiBase (Figure 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. This method has been previously used with several
drugs, namely, pioglitazone, which has shown the ability to detect an
early signal for cancer, later confirmed by retrospective and
prospective cohorts.6. 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. Also, VigiBase does not
provide demographic data, other than gender on only some of the cases,
which would allow a more accurate analysis of the risk. Duration of
therapy with Omalizumab before the report of cancer is not recorded in
the database. 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, and it could lead to an overestimation of ROR.
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 drugs targeting IgE for the
treatment of allergic conditions.