EGFR, ALK, ROS1, MET and BRAF are the most
common driver mutations investigating in adenocarcinomas.
Patients who had this rearrengements have
been showed improved response rates and progression-
free survival compared with chemotherapy.[
ALK mutation has seen approximately in %3-5 of
the patients especially young age, nonsmoker female.[
Alectinib - an highly selective, oral second generation
ALK-TKI has been currently preferred first-line
therapy in ALK positive NSCLC based on ALEX, JALEX
and ALESIA study.[
At the updated ALEX study, median treatment duration
of 28.1 months, among 152 patients, any-grade AEs were seen in 147 patients (97%), grade 3-5 AEs of
79 (52%). Furthermore, alectinib discontinuation, dose
reduction and interruption were done due to AEs, 22
(15%), 31(20%), 40 (26%), respectively.[
Herein we presented a patient with lung adenocarcinoma
receieved Alectinib 1200 mg po for 90 days
with a complete radiological response presented with
skin rash which was consistent with SJS/TEN and controlled
with high dose of steroid. With maintenance
dose of steroid Alectinib desentitation was performed
and after 2 weeks full dosage of alectinib could be
achieved. In the literature, there were no reports that
demonstrate the relation between toxicity and response.
While the efficacy of targeted therapy has been
well-established, the relationship between the severity
of treatment-related toxicities and clinical response remains
a subject of debate.
Our case is noteworth because after desensitization
with increasing dosage, response achieved maximally
without any complication. We also highlight
the response-toxicity relation by analyzing 6 cases in
terms of approach, treatment and response in which
alectinib-induced toxicity is occurred.
Case: A 67 year-old never-smoking female, presented
with dry cough and shortness of breath for 3
month symptoms increased progressively. PET/CT
revealed primary lung cancer with bone, surrenal and pleural metastases, supraclavicular and mediastinal
lymphadenopathies. Cranial MRI was compatible
also with metastases. Supraclavicular lymph node
biopsy confirmed lung adenocancarcinoma metastases.
Alectinib 600 mg twice a day was commenced
following the genetic test which revealed EM4-ALK
fusion. After 45 days of treatment, maculopapular
rashes started in abdominal region. The patient was
followed up with a dermatologist for macular eruptions.
Although antihistaminic therapy, itchy white
skin that tends to coalesce widely on an erythematous
base all over the body after 3 months of Alectinib.
Punch biopsy taken from the right leg reported with
no eosinophils and the findings were interpreted as a
Drug Reaction because of MPO (Myeloperoxidase)
positive - PMNLs (Polymorphonuclear neutrophils).
Stevens-Johnson Syndrome was conceded and Alectinib
was stopped with commencement of 1 mg/kg
steroid threapy. There was no mucosal involvement
in the patient whose skin involvement was 10-30% of
the body surface area and was followed up with the
diagnosis of SJS/TEN (Fig.
After 3 months of Alectinib, PET/CT was consistent
with metabolic complete radiological response.
Furthermore, Cranial MRI demonstrated complete
radiological response. Skin involvement was 10-30%
and the patient followed up with the diagnosis of SJS/
TEN evaluated as Grade 4 cutaneous toxicity. The rash
of the patient,who was followed up without Alectinib
for 2 week, regressed and the prednisolone dose was reduced
by 8 mg. Desentinization was started with a daily
dose of 150 mg of alectiniB for 3 days than increased
to 300 mg for 5 days, 600 mg for 7 days finally reached
to therapeutic dose which is 1200 mg /day (Table
SJS/TEN: Stevens-Johnson Syndrome/Toxic Epidermal
Necrolysis.
Rash is one of the most common alectinib- induced
hypersensitivity reaction. In ALEX trial in 2019, 21
(13,8%) of 152 patients had experienced rash in which
3 (%2) of them were grade 3-5.[
In our unique case we discussed SJS/TEN 3 months
from Alectinib therapy and represented successful desentisitation
therapy with radiologically complete responsive
disease.
SJS/TEN is a potentially life-threatening disease
which is a type-IVc immune reaction and present with
mucocutaneous blistering reactions with epidermal
detachment and extensive necrosis.[
The diagnosis of SJS/TEN may be rendered
clinically or histopathologically. In skin biopsy,
scattered keratinoosytes in the basal epidermis and
full thickness epidermal necrosis or subepidermal
bullae may be seen, accompanied by perivascular
lymphohistiocytic infiltrate with eosinophils in the
supeficial dermis.[
We classified dermatological toxicity according to
CTCAE (Common terminology criteria for adverse
events) as grade 4 because of maculopapular rash
covering >10-30% body surface area with severe and
life-theratening symptoms.[
According to literature there were 6 more reported
cases mentioned alectinib-induced skin toxicity
in the treatment of NSCLC. (Table
Various skin toxicities were seen in 7 cases, including,
Erythema Multiforme, Type-4 Hypersensitivity
Reaction, Grade - 3 MP Skin Rash, DRESS
and SJS/TEN - in our case.[
On the other hand, in 5 cases, including our case,
desentization was performed.[
According to our review, 3 cases, including our
case had full clinical response to the Alectinib therapy,
in which grade-3 and more skin toxicity following
treatment and desentization protocole had done. In
Seegobin et al.'s[
The notion that more severe adverse events indicate
a stronger therapeutic effect of targeted agents is
not universally applicable. While it is true that certain
adverse events, such as immune-related toxisities
observed with immune checkpoint inhibitors,
may be associated with improved clinical response,
this relationship cannot be generalized across all targeted
therapies.
More researches have to be done to demonstrate the
relation between the toxicity and the effectiveness in
targeted therapies.
Alectinib-an oral TKI agent- which is currently the
approved first-line treatment of NSCLC, has a low toxicity
profile however, such as in our case grade-3 and
more sever adverse events can be occur. Considering
the possible positive correlation between the severity
of the adverse events and the clinical response to
treatment, we recommend desentization with a close
follow-up. This case report will provide brief summary
in the management of skin toxicities due to Alectinib
use and also present different successful desentization
protocoles in the recent literature.
