Case presentation
In this case presentation we report on a 63 year old man treated for
BRAF-mutated metastatic melanoma spread to lymph nodes, pleural cavity,
lungs, liver as well as a suspected asymptomatic brain metastasis.
Initially, the patient received dabrafenib in combination with
trametinib resulting in excellent clinical and radiological response.
Due to grade 2 pyrexia and chills the patient’s treatment was
discontinued and he was switched to ipilimumab in combination with
nivolumab. After 2 courses he developed grade 3 colitis treated first
with prednison and subsequently with infliximab. Unfortunately he showed
progressive disease with new peritoneal metastases. In addition, he was
in clinical distress caused by pleural effusion and ascites. He was
re-challenged with dabrafenib plus trametinib, which again resulted in
significant clinical and radiological response. However chills grade 2
also reoccurred and he was switched to encorafenib in combination with
binimetinib, a regime known with low prevalence of pyrexia or chills as
adverse events (5, 6). At that moment medication used by the patient was
paracetamol 1000 mg QID p.r.n., omeprazole 40 mg BID, metoclopramide 10
mg TID p.r.n; cotrimoxazol 480 mg QD, fluconazole 100 mg QD; salbutamol
QID p.r.n; gastilox chewable tablet TID. Prednisolone dose was 10 mg QD
for 1 week, followed by 5 mg or 10 mg every other day, for the next
week, followed by 5mg QD for a week, after which prednisolone intake
stopped. For encorafenib the dose prescribed was 450 mg QD (08.00h),
consisting of 6 capsules of 75 mg and 45 mg BID (08.00h and 18.00h),
consisting of 3 tablets of 15 mg for binimetinib.
Sixteen days after having started the new oral oncolytic therapy the
patient came to the hospital mentioning an upset stomach, bloating,
occasional vomiting, and muscle pain probably caused by him working in
and around the house. After an in depth anamneses of the patient it
seemed that he had taken a double dose (900 mg QD instead of 450 mg QD)
encorafenib in combination with the prescribed dose of binimetinib (45
mg BID) for 16 days. After inquiring about the reason for taking this
double dose, the patient confirmed that the nurse practitioner had
discussed the medication prescription correctly with him, but he himself
had not read the prescription with enough detail (flyer was too full
with confusing pictograms). Additionally, due to the covid-19 pandemic,
his medication was delivered at home, so he missed the additional
information normally given at the first dispensing by the pharmacy. To
treat the patient’s chronic intoxication it was decided to opt for an
observational approach, sustained by the fact that the product label did
not mention any specific treatment in case of an overdose encorafenib
and the patient did not mention suffering from any serious conditions
besides the above-mentioned. Based on the most occurring adverse events
of encorafenib, liver values, kidney function parameters and QTc
interval were measured (Table 1). It can be concluded that kidney
function was not affected by this chronic intoxication, whereas liver
values (mainly LD, GGT) were slightly increased. The ECG showed a
slightly prolonged QTc interval of 447 ms (reference value
<420 ms).
Based on the pharmacokinetic profile of encorafenib such as short
half-life =6.32 hours (1) which is independent of the dose and
non-saturable absorption of encorafenib, no signs of accumulation and no
delayed intoxication related symptoms were to be expected. However,
because of lacking literature on encorafenib pharmacokinetics in case of
a chronic intoxication it was decided to monitor plasma levels 3 hours
after the last dose. Levels were measured at the Department of Pharmacy
& Pharmacology, Netherlands Cancer Institute, Amsterdam, the
Netherlands, using a liquid chromatography-tandem mass spectrometric
assay (7). This level turned out to be 2110 ng/mL
It was decided to re-start the treatment with encorafenib in combination
with binimetinib. As the patient had ingested a double dose of
encorafenib for 16 days, he no longer had any encorafenib tablets
available at home. As a new supply would be available after the weekend,
it was decided to re-start encorafenib as well as binimetinib after 3
days after the last dose.