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CORRESPONDENCE
Year : 2018  |  Volume : 14  |  Issue : 12  |  Page : 1227-1229

Fatal interstitial lung disease associated with AZD9291


1 Department of Nuclear Medicine, The First Affiliated Hospital of Soochow University, Suzhou 215000, China
2 Department of Respiratory Medicine, The First Affiliated Hospital of Soochow University, Suzhou 215000, China

Date of Web Publication11-Dec-2018

Correspondence Address:
Yan-bin Chen
Department of Respiratory Medicine, The First Affiliated Hospital of Soochow University, 899#, Pinghai Road, Suzhou 215000
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.199380

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 > Abstract 


AZD9291 is one of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) for non-small cell lung cancer (NSCLC). Interstitial lung disease (ILD) induced by AZD9291 is very seldom. We provide a case of NSCLC treated with AZD9291 who developed ILD and died in order to improve the knowledge on AZD9291.

Keywords: AZD9291, drug-induced lung injury, epidermal growth factor receptor-tyrosine kinase inhibitor, interstitial lung disease, nonsmall cell lung cancer


How to cite this article:
Deng Sm, Huang Ja, Chen Yb. Fatal interstitial lung disease associated with AZD9291. J Can Res Ther 2018;14, Suppl S5:1227-9

How to cite this URL:
Deng Sm, Huang Ja, Chen Yb. Fatal interstitial lung disease associated with AZD9291. J Can Res Ther [serial online] 2018 [cited 2019 Sep 20];14:1227-9. Available from: http://www.cancerjournal.net/text.asp?2018/14/12/1227/199380




 > Introduction Top


AZD9291 is one of the third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). It has shown outstanding activity in targeting both sensitizing and resistant T790M mutations.[1] The most common adverse events of AZD9291 are diarrhea, rash, nausea, and decreased appetite. Interstitial lung disease (ILD) induced by AZD9291 is approximately 2.7% according to the AstraZeneca announcement on April 17, 2015 (https://www.astrazeneca.com/our- company/media-centre/press- releases/2015/astrazeneca- non-small- cell-lung- cancer- medicine- data-european-lung- cancer-congress- 17042015.html). Herein, we report a female lung adenocarcinoma patient treated with AZD9291 for 1 week then developed ILD and died.


 > Case Report Top


A 65-year-old female patient with a complaint of dyspnea for about 3 days was admitted to our hospital on February 8, 2015. She had a history of lung adenocarcinoma (T4N0M1b, Stage IV) for about 27 months. Twenty-seven months ago, lesions on both sides of her lung were found by routine examination accidently, positron emission tomography-computed tomography (CT) detection revealed signs of malignant tumor. The lesion of the left upper lobe measured 2.3 cm × 1.5 cm in size while the lesion in the right upper lobe measured 1.5 cm × 1.0 cm in maximum diameter. The maximum of standard uptake value, i.e. SUVmax, was 8.9 and 1.4 for the two lesions, respectively [Figure 1]a, [Figure 1]b, [Figure 1]c, [Figure 1]d. Pathological diagnosis was confirmed by video-assisted thoracic surgery on the right upper lobe, and the result was lung adenocarcinoma. She received cisplatin (75 mg/m2) and pemetrexed (500 mg/m2) every 3 weeks for four cycles 1 month after operation as an initial anticancer treatment. Then, she began to take erlotinib (Tarceva) 150 mg once daily for 22 months because of harboring EGFR-activating mutation (exon 19 deletion) with excellent tolerance and clinical benefit.
Figure 1: (a-d) Positron emission tomography-computed tomography showing nodules in the right and left upper lobe, with standard uptake value increased, maximum of standard uptake value are 8.9 and 1.54 in left and right nodules, respectively

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On her admission, physical examination revealed diminished breath sounds on the left side. Ultrasound and CT scan showed pleural effusion in the left hemithorax [Figure 2]a and [Figure 2]b. The pleural effusion was drained, and the pleural fluid cytology was positive for adenocarcinoma. A cell block samples made from pleural fluid showed that the tumor harbored EGFR exon 20 T790M mutation. The patient was not eligible for chemotherapy due to her poor performance status, and she received AZD9291 (80 mg/day). Rapid aggravation with symptoms of cough and dyspnea was observed 1 week after the initiation of AZD9291; high-resolution chest CT (HRCT) scan revealed multiple patchy ground-glass opacities in both lungs, especially in the right side [Figure 2]c, [Figure 2]d, [Figure 2]e, [Figure 2]f.
Figure 2: (a and b) Computed tomography scan showing massive pleural effusion in the left pleural cavity. (c-f) High-resolution chest computed tomography scan reveals multiple patchy ground-glass opacities in both lungs, especially in the right side 1 week after AZD9291 therapy

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Because it appeared that the patient could not tolerate bronchoscopy and transbronchial lung biopsy, AZD9291-induced ILD was impressed on clinical and radiological diagnosis without pathological support. Immediate withdrawal of AZD9291 and administration of methylprednisolone 2 mg/kg/day was prescribed, along with supplemental oxygen, antibiotics, and best supportive care. General conditions of the patient were deteriorated in the following days; progressive dyspnea and respiratory failure developed. The patient died 1 week later (2 weeks after commencing AZD9291). No autopsy was obtained due to her family's request.


 > Discussion Top


EGFR-mutant lung cancer is a subtype of nonsmall cell lung cancer (NSCLC). EGFR-TKIs, such as erlotinib and gefitinib, are the standard of care in EGFR-mutant NSCLC because of their superior efficacy over chemotherapy. Unfortunately, despite a striking initial response to treatment, disease progression generally occurs within 1–2 years after treatment initiation due to acquired resistance. The substitution of threonine with methionine at amino acid position 790 (T790M), as the second-site EGFR point mutation, is the most common resistance mechanism and is detected in tumor cells from more than 50–60% of patients after disease progression.[1],[2],[3],[4]

AZD9291, as a mono-aniline-pyrimidine compound, is a novel selective third-generation irreversible EGFR-TKI by targeting the cysteine-797 residue in the ATP binding site via covalent binding. AZD9291 has been shown to be effective against both EGFR-TKI-sensitizing and T790M-resistant mutations.[2] AZD9291 is associated with a higher objective response rate and longer progression-free survival in patients with T790M-mediated drug resistance than in those with non-T790M-mediated resistance. Among patients with confirmed EGFR T790M who could be evaluated for response, the response rate is 61%. The median progression-free survival is 9.6 months in EGFR T790M-positive patients.[5],[6] The patient in our report harbored EGFR mutation (exon 19 deletion), and she received erlotinib after four cycles of pemetrexed/platinum doublets therapy for about 22 months with good response until disease progression. T790M was detected from her tumor cell block of pleural effusion. Hence, we think of the existence of erlotinib resistant that AZD9291 is the best choice for her. Unfortunately, ILD occurred just 1 week later. Because the patient did not have signs of infection, such as fever and purulent sputum. Furthermore, empirical usage of broad spectrum antibiotics could not improve her condition. We do not think the existence of pneumonia. As to pleural effusion, it could cause dyspnea to some extent; however, after drainage, the patient still had the same chief complaint of dyspnea, so we think pleural effusion plays little role in her dyspnea. Acute pulmonary embolism, especially tumor embolism, can induce dyspnea too. However, this kind of dyspnea often accompanied by acute pulmonary hypertension, right heart failure, plasma D-dimer elevated, and so on. For this patient, we did not find any hint of acute pulmonary embolism. According to changes in HRCT, we think ILD induced by AZD9291 is the real reason of dyspnea. Unfortunately, her condition deteriorated continuously and died 1 week later (2 weeks after her commencing AZD9291).

The first-generation EGFR-TKIs (especially gefitinib and erlotinib) are nonselective, which can also affect wild-type EGFR in skin and gastrointestinal tissue, so their most common adverse effects, such as skin rash and diarrhea, are unavoidable and unacceptable. ILD is emerging as a major concern during EGFR-TKIs treatment, and several fatal events have been reported since their approval.[7] AZD9291 has the high selectivity of mutant EGFR. The most common adverse events of AZD9291 are diarrhea, rash, nausea, and decreased appetite. The patient in our report received erlotinib for nearly 22 months with good response before disease progression. She should benefit from AZD9291 according to her T790M-positive result, but the fatal complication of ILD destroyed “her dream.”

The incidence of all-grade ILD associated with the first-generation EGFR-TKIs is 1.6%, with a mortality of 13.0%.[8] While ILD induced by AZD9291 is approximately 2.7% according to the AstraZeneca announcement, ILD is not associated with treatment duration of EGFR-TKIs.[9]

The mechanism of EGFR-TKIs-induced ILD has not been fully elucidated. Previous findings demonstrate that EGFR and its family members are usually upregulated earlier in the response to acute lung injury and implicated in the repair of pulmonary damage. Thus, inhibition of EGFR signal could impair the rehabilitation of lung injury and then exacerbate pulmonary injury.[8] It is well known that EGFR-TKIs can induce ILD in human lung cancer patients with ethnic differences. According to the US Food and Drug Administration, the incidence of ILD is higher in Japanese patients (1.7%) compared to patients from the US (0.3%) who received gefitinib. There is also a significant difference in the median time to onset (TTO) of ILD between Japanese and US patients. The TTO is about 24 days in the former but around 42 days in the latter.[10] The epidermal growth factor (EGF) 61A/G polymorphism may be associated with sporadic ILD.[3] It is a pity for us that we do not detect whether the EGF 61A/G polymorphism exist or not for our patient.

CT scan, especially HRCT, is helpful for the diagnosis of ILD induced by EGFR-TKIs.[11] In our report, the patient's ILD was confirmed by her HRCT features and clinical symptoms 1 week after she received AZD9291.

There have been no randomized controlled or prospective trials to guide the management of ILD induced by EGFR-TKIs, especially by AZD9291. The choices of treatment include supplemental oxygen, mechanical ventilation, immediate discontinuation of AZD9291, and systemic corticosteroid. Nie et al. reported a 32-year-old Chinese male patient who suffered from Stage IV lung adenocarcinoma. The patient developed short of breath on exertion after 4.5 months of AZD9291 therapy and was diagnosed as AZD9291-induced acute ILD. Fortunately for him, after the therapy of AZD9291 dose reduction, low-dose continued oxygen inhalation, and high-dose corticosteroid, his symptoms improved and ground-glass opacities on the right lung were remarkably attenuated.[12] As to the patient in our report, corticosteroids were ineffective, and she died of progressive respiratory failure. The two patients are both Stage IV lung adenocarcinoma, all developed ILD induced by AZD9291, and received nearly same treatment protocol, but their prognosis is quite different. Whether the occurrence and prognosis of ILD induced by AZD9291 are associated with age, gender, acute or relatively chronic onset, even genetic background or not, still needs further research.


 > Conclusion Top


The incidence of ILD induced by AZD9291 seems to be low but may cause death; clinicians should be alert to the potential fatal complication of AZD9291.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Planchard D, Loriot Y, André F, Gobert A, Auger N, Lacroix L, et al. EGFR-independent mechanisms of acquired resistance to AZD9291 in EGFR T790M-positive NSCLC patients. Ann Oncol 2015;26:2073-8.  Back to cited text no. 1
    
2.
Jänne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med 2015;372:1689-99.  Back to cited text no. 2
    
3.
Li C, Wei R, Jones-Hall YL, Vittal R, Zhang M, Liu W. Epidermal growth factor receptor (EGFR) pathway genes and interstitial lung disease: An association study. Sci Rep 2014;4:4893.  Back to cited text no. 3
    
4.
Gil-Bazo I, Rolfo C. AZD9291 in TKI EGFR resistance in non-small cell lung cancer and the new concept of phase I trials. Transl Lung Cancer Res 2016;5:85-8.  Back to cited text no. 4
    
5.
Cross DA, Ashton SE, Ghiorghiu S, Eberlein C, Nebhan CA, Spitzler PJ, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov 2014;4:1046-61.  Back to cited text no. 5
    
6.
Stinchcombe TE. AZD9291 in epidermal growth factor receptor inhibitor-resistant non-small-cell lung cancer. Transl Lung Cancer Res 2016;5:92-4.  Back to cited text no. 6
    
7.
Johkoh T, Sakai F, Kusumoto M, Arakawa H, Harada R, Ueda M, et al. Association between baseline pulmonary status and interstitial lung disease in patients with non-small-cell lung cancer treated with erlotinib – a cohort study. Clin Lung Cancer 2014;15:448-54.  Back to cited text no. 7
    
8.
Qi WX, Sun YJ, Shen Z, Yao Y. Risk of interstitial lung disease associated with EGFR-TKIs in advanced non-small-cell lung cancer: A meta-analysis of 24 phase III clinical trials. J Chemother 2015;27:40-51.  Back to cited text no. 8
    
9.
Shi L, Tang J, Tong L, Liu Z. Risk of interstitial lung disease with gefitinib and erlotinib in advanced non-small cell lung cancer: A systematic review and meta-analysis of clinical trials. Lung Cancer 2014;83:231-9.  Back to cited text no. 9
    
10.
Yoneda KY, Shelton DK, Beckett LA, Gandara DR. Independent review of interstitial lung disease associated with death in TRIBUTE (paclitaxel and carboplatin with or without concurrent erlotinib) in advanced non-small cell lung cancer. J Thorac Oncol 2007;2:537-43.  Back to cited text no. 10
    
11.
Guo LC, Wang XM, Deng SM, Chen YB. Fatal interstitial lung disease associated with erlotinib: A case report and review of literature. J Cancer Res Ther Oncol 2015;1:1-4.  Back to cited text no. 11
    
12.
Nie KK, Zou X, Geng CX, Zhang L, Liu SC, Zhang CL, et al. AZD9291-induced acute interstitial lung disease. Chin Med J (Engl) 2016;129:1507-8.  Back to cited text no. 12
    


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