To the Editor: A 32-year-old Chinese male patient with 1 week cough and dyspnea on
exertion was presented to hospital. He was a metastatic lung adenocarcinoma patient
with 3 years treatment history. In October 2012, the patient complained cough, short
of breath, and thoracic computerized axial tomography scan (CAT-scan) revealed left
lung hilum mass with the right lung multismall patches or opacities. Core needle biopsy
on supraclavicular lymph nodes was performed and diagnosis of Stage IV (T3N3M1a) lung
adenocarcinoma was made by radiologist, pathologist, and oncologist. Chemotherapy
with cisplatin and pemetrexed was initiated and a partial response (PR) was reached.
After 6 cycles of double-bullet chemotherapy, maintenance therapy with pemetrexed
was used. In January 2014, positron emission tomography-computed tomography scan showed
the right lung disease progression and bone metastasis. Fine needle aspiration (FNA)
was performed on right lung node and genetic sequencing study showed epidermal growth
factor receptor (EGFR) 19 del erlotinib (Tarceva, Roche, Switzerland) was administrated
orally and both lung lesions became shrunk and a good PR was achieved after 1 month
of erlotinib treatment. This result maintained 9.5 months until patient's lung disease
progression and liver metastasis which were confirmed by CAT-scan and FNA. The 3rd
line treatment with docetaxel (Qilu Pharmaceutical Co., China) and bevacizumab (Avastin,
Roche, Switzerland) was administered, PR was reached. Patient's symptoms got severe
and CAT-scan showed disease progression on both lungs after 4 months of above treatment.
FNA was performed on the right lung lesion and gene panels were tested, it showed
EGFR T790M, 19 del, and TP53 mutation. AZD9291 (Tagrisso, Osimertinib, AstraZeneca,
UK) was used at a dose of 80 mg oral daily. The patient performed well and CAT-scan
showed PR at 1 month follow-up, and the lesions continued remission on the last follow-up
at 5.5 months therapy. The patient complained light cough and short of breath on exertion
at 4.5 months of AZD9291 therapy. Physical examination was unremarkable; there were
no rales or wheezes on chest auscultation. Oxygen saturation was 98%, blood works
results were all within normal range. CAT-scan revealed interstitial lung fibrosis
change on both lungs and obvious ground-glass opacities on the right upper lung [Figure
1a]. After carefully reviewed patient's history and series CAT-scans, drug-induced
acute interstitial lung disease (ILD) was confirmed by pathologist, radiologist, and
oncologist.
Figure 1
CAT-scan revealed interstitial lung fibrosis change on both lungs. (a) 4.5 months
after AZD9291 treatment, right upper lung interstitial fibrosis. (b) One month after
AZD9291 dose reduction and dexamethasone treatment.
Because AZD9291 was the 4th line therapy of this patient, stop taking it to avoid
worsening ILD was quite dangerous for him. The aggressive treatment plan was immediately
initiated with dose reduction to 80 mg every other day, low-dose continued oxygen
inhalation, and high-dose corticosteroid (10 mg dexamethasone infusion once a day
for 10 days). Patient's symptoms got improved, ground-glass opacities on the right
lung were remarkable attenuated, and both lung fields got clearer on CAT-scan at 1
month follow-up [Figure 1b].
AZD9291 is an oral, potent, irreversible 3rd generation EGFR tyrosine kinase inhibitor
(TKI), inhibits kinase activity. In vitro and in vivo studies, it showed strong inhibition
lung cancer cells with EGFR sensitizing mutation or with T790M resistance mutation,
but less activity on wild-type compare to the 1st generation gefitinib or erlotinib.[1]
In patients with relapsed or metastasized disease after 1st generation TKI, its overall
response rate (ORR) was around 50%; and patients with EGFR T790M mutation positive
or negative had a 60% ORR and PFS 9.6 months or 21% ORR and PFS 2.8, respectively.[2]
ILD is a rare complication during EGFR-TKI therapy, about 1–3% patients will acquire
it. The mechanism of TKI-induced ILD is not very clear, TKI interrupting type II pneumocytes
and alveolar wall repair may play an important role.[3]
There is no standard guideline for the treatment of TKI-induced ILD; current management
includes oxygen inhalation, drug discontinuation, and high-dose and prolongs corticosteroids
or immunosuppressive. High-dose N-acetylcysteine alleviates pulmonary fibrosis in
rats but needs further study in human.[4] The patient had been treated with multiline
therapies, maintenance 3rd generation EGFR-TKI is the most reliable method to sustain
patient's survival. We reduced 50% dosage of the drug administration according to
the half-life and metabolic characters of it,[1] to maintain effective blood drug
concentration and maximally reduce its side effects.
Drug-induced ILD is a severe and a fatal complication if not intervened promptly.
This case showed that early diagnosis and early intervention of this complication
is critical important during TKI treatment of advanced nonsmall cell lung cancer.
AZD9291 dose reduction and aggressive corticosteroid treatment could be a promising
treatment option for patient who required 3rd generation TKI to maintain disease remission.
Clinical physicians must cautiously weigh the benefits and risks of targeted therapies
causing ILD in order to provide optimal treatments and favorable outcomes.
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Conflicts of interest
There are no conflicts of interest.