MONOPOLY: predicting clinical benefit of dupilumab in adult patients with chronic rhinosinusitis with nasal polyps (CRSwNP)

Chronic rhinosinusitis (CRS) is a global commonly prevalent disease negatively
effecting the quality of life of patients and with a significant burden on
society in terms of healthcare consumption and productivity loss. Traditionally
CRS is dichotomously classified by phenotype, either with or without nasal
polyps (respectively CRSwNP and CRSsNP). The last decades gave rise to a
paradigm-shift, with a focus on the underlying endotype driven
immunopathophysiology. Besides dominating the current basic research on this
topic, the endotype perspective increasingly seeps into clinical practice, with
new current and future treatment possibilities coming to light. In Western
countries, CRSwNP is a mainly type-2 inflammatory driven morbidity, involving
IL-4, -5, -9 and -13. Human monoclonal antibodies (hMABs, also called
biologicals) directed against the cytokines involved have proven effective in
other, often related, type-2 driven pathologies, such as asthma, atopic
dermatitis and eosinophilic esophagitis. Dupilumab is one of such hMABs,
directed against IL*4Rα, a component shared by the IL-4 and IL-13 receptors. By
inhibiting IL*4R signaling of both IL*4 and IL*13 it effectively downregulates
the molecular pathways that drive the type-2 inflammation. As of 2019,
dupilumab has been approved in Europe and the US for the treatment of CRSwNP
with type-2 inflammation. The prefacing phase 2 and 3 trials showed dupilumab
to be safe and mostly clinically effective, although 10% of patients appeared
non-responding to the treatment. It is yet unknown if this number corresponds
with the regular care setting. Importantly, these studies did not investigate
phenotypical or endotypical biomarkers to predict clinical response to this new
and expensive treatment option. This is paramount for improving future
indication assessment and clinical monitoring of dupilumab in the treatment of
patients with CRSwNP, enabling precision medicine and optimizing health-care
efficiency. By defining such biomarkers, more insight will also be gained into
the underlying immunopathophysiologic mechanisms of CRSwNP and the involved
endotypes.

Additional for amendment 1:
a) less patients are non-responsive to dupilumab in our real-world
observational cohort than calculated and expected from the preceding clinical
trials. This is probably due to the stricter indication criterion applied as
towards dupilumab*s underlying pharmacological mechanism, being proven Type-2
endotype, in our cohort; we hereby adhere to the currently ruling European
guideline, EPOS2020. As such, research specimens can be obtained by biopsy on
baseline, but hardly after six months of treatment, impeding comparison between
the clinically distinguishable groups of (very) fast responders and (very) slow
/ non-responders. An additional nasal cyto-brush, with only mild discomfort and
no additional risk for the patient, at baseline and six months after treatment
initiation can amend this issue.

b) dupilumab is known to cause (temporary) rise of serum eosinophils. Per
interim analysis of provisional study data we found patients with initial serum
eosinophilia of >= 1.0 x 109/L to be of increased risk of serum eosinophil
levels of >= 1.5 x 109/L, necessitating intensified blood checks every two
weeks, and adapted dosing frequency when eosinophil levels of >= 3.0 x 109/L are
met due to cautiousness for hypereosinophilic syndrome (HES), complicating
treatment and possibly necessitating treatment cessation in case of persisting
(hyper)eosinophilia (as for now +/- 1% of total treatment cohort). We want to
gain insight into these dynamics, evaluate the proportionality of
active/inactive eosinophils to assess the chance of developing HES, and
evaluate possible biomarkers for (persisting) (hyper)eosinophilia. This can be
obtained by performing the regular phlebotomy in patients with initial
eosinophilia of >= 1.0 x 109/L at week 4 and 12 by our research nurses instead
of by the clinical laboratory and taking 1 x 10mL blood extra per person per
moment (thus total extra 2 x 10 mL); the total amount of phlebotomies is
unchanged and it saves the patients time otherwise spent visiting the clinical
laboratory.

Additional for amendment 2:
in daily practice the dupilumab treatment is tapered from 24 weeks onward.
Every >=24 weeks the interdose interval of dupilumab is prolonged with 2 weeks,
conditional to adequate treatment response and CRS-control, as defined by
EPOS2020. This reduces the patients* treatment burden and reduces the direct
costs related to dupilumab purchase. Intermediate evaluation demonstrates
general feasibility up to interdose intervals of 6 - 8 weeks. Advanced tapering
hereafter demonstrates heterogeneous results. We want to evaluate (predictive)
biomarkers for the maximal interdose interval. This will eventually benefit
patient centered care and gain further insight into underlying pheno- and
endotypes.

Primary objective: to identify predicting phenotypical and endotypical
biomarkers for the response to dupilumab in adult patients with CRSwNP, by
comparing the type 2 inflammation in the peripheral blood and nasal polyp
tissue at baseline and after 6 months of treatment with dupilumab between
responders and non-responders, and between clusters of maximally tapered
interdose interval.
Secondary objective: defining phenotypical differences in the peripheral blood
and nasal polyp ILC2s, eosinophils, basophils, and mast cells between
responders and non-responders to dupilumab, and between clusters of maximally
tapered interdose interval.

Open prospective observational study with consecutive patient inclusion

On the visits at baseline and six months, extra blood (100 instead of 10mL)
will be drawn during the standard phlebotomy and an endoscopic nasal polyp
biopsy will be taken on one side and a nasal cyto-brush on the other side.

In patients with initial serum eosinophilia of >= 1.0 x 109/L, extra blood will
also be drawn during the standard check-ups 4 and 12 weeks after treatment
initiation (total 2 x 10 mL extra).

From 6 months on every 24 weeks up until and including 36 months: if during the
standard check-up it is decided to prolong the interdose interval (conform
daily practice), extra blood will be drawn during the standard phlebotomy
(100mL instead of 10mL) and a nasendoscopic polyp tissue biopsy (if polyps are
present) and cyto-brush is performed.

Risks of trial participation include:
- phlebotomy: possible increased discomfort
- biopsy: discomfort, minor bleeding
- cyto-brush: mild discomfort