Can tumor uptake of [18F]afatinib in NSCLC patients be quantified, and does [18F]afatinib uptake identify patients who will benefit from afatinib therapy ?

Non-small cell lung cancer (NSCLC) patients that harbour an activating
epithelial growth factor receptor (EGFR) mutation are best treated with EGFR
tyrosine kinase inhibitors (TKI). First, second and third generation EGFR TKI
have shown efficacy in the common EGFR mutations, i..e. the exon 19 deletion
and exon 21 point mutation L858R. Afatinib, a second generation EGFR TKI, has
also shown efficacy in the *uncommon* EGFR mutations L861Q, G719X and S768I.
Moreover, for these indications the FDA approved the use of afatinib.
However, identifying EGFR mutation positive patients can be challenging because
obtaining representative tumor biopsies for DNA analysis may be difficult or
even impossible in some patients due to difficult to reach tumor sites.
Positron emission tomography (PET) using radiolabelled afatinib, i.e.
[18F]afatinib, as a tracer, may overcome the limitations associated with
obtaining representative biopsies.
The aim of our study is to evaluate whether [18F]afatinib and PET could
identify patient groups that are sensitive to afatinib. We hypothesized that
tumour [18F]afatinib uptake would be higher in the sensitive groups, i.e.
higher in the TKI-naïve EGFR (common and uncommon) mutation positive group as
compared to the wild type group.

1. To define the optimal pharmacokinetic tracer model for [18F]afatinib.
2. To determine the optimal simplified measure for quantifying tumor
[18F]afatinib uptake
3. To assess [18F]afatinib uptake differences between patients (1) with wild
type EGFR, (2) EGFR mut+, TKI-resistant EGFR mut+ (3) with and (4) without
T790M mutations.
4. To assess whether [18F]afatinib uptake is predictive for tumor response to
afatinib in patients with wild type EGFR and EGFR mut+, prior to TKI therapy
and after resistance occurs to a 1st generation TKI.

Prospective observational study with invasive intervention

Intervention:
There will be 2 subsequent steps involving 4 and 11 patients, respectively, in
order to find the optimal PET scanning conditions.

Step 0: Dosimetric measures for safety are legally required in new PET tracers,
therefore the first patient will be used for dosimetry. The data obtained is
not intended for the purpose of this study.

Step 1: The first 4 patients will undergo a low dose CT scan, followed by a
dynamic [15O]H2O PET scan and thereafter a prolonged (90 + 30 minutes) dynamic
[18F]afatinib PET scan. Arterial sampling will be performed.

After step 1, kinetic analysis of the prolonged dynamic PET data will be
performed to determine the best scanning interval for a whole body static PET
scan.

Step 2: The subsequent 8 patients (regardless of the groups they are in) will
undergo 2 scanning procedures on subsequent days for determining test-retest
repeatability. A low dose CT scan, followed by a dynamic [15O]H2O PET scan and
thereafter a 60-min dynamic [18F]afatinib PET scan will be done, followed by a
break (duration will be determined by step 1). After this, a low dose CT and a
40-min static [18F]afatinib whole body PET scan will be made. Arterial sampling
will be performed.

Patients in step 1 will be lying for a total of approximately 2.5 hours on the
scanner, a pause of 30 minutes is scheduled to break up this period. A venous
cannula will be inserted in an arm vein to inject the tracers. After local
anaesthesia, a cannula will be inserted the radial artery to drawn blood, both
continuously and at seven time point manually. Per patient no more than 115cc
blood will be drawn. There will be a total radiation burden of 5.7 mSv.

Patients in step 2 will undergo two scanning procedures on subsequent days.
Patients will be lying for approximately 2 hours on the scanner, a break is
scheduled to make the procedure easier. A cannula will be inserted in an arm
vein (tracer injection) and in the radial artery to drawn blood, both
continuously and at 7 time point manually. Per patient no more than 230cc blood
will be drawn over the whole of day 1 and 2 together. There will be a total
radiation burden of 16.8 mSv for both days together.

During follow up visits all assessments using CT-thorax and laboratory analyses
will be similar to routine care during regular chemotherapy, and will therefore
not be an extra burden.