crizotinib and Lung-Diseases--Interstitial

Lung toxicity is a potential fatal effect involving non-small-cell lung cancer (NSCLC) patients exposed to tyrosine kinase inhibitors (TKIs). Moving from our experience regarding a patient who developed lung toxicity while receiving 2 different anaplastic lymphoma kinase (ALK)-TKIs, we performed a systematic review to assess the epidemiologic magnitude and the clinical significance of such toxicity in NSCLC patients treated with ALK-TKIs. Studies were identified using MEDLINE and additional sources (European Society for Medical Oncology, American Society of Clinical Oncology, and World Conference on Lung Cancer abstracts) in agreement with Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Cochrane guidelines. Lung toxicity was reported in 105 of 4943 NSCLC patients (2.1%). Crizotinib was responsible for pulmonary adverse events (AEs) in 1.8% of exposed patients (49 of 2706). With the limit of a lower number of treated patients (n = 359), brigatinib resulted as the most frequently involved in lung toxicity (7%; n = 25). Pulmonary AEs during therapy with ceritinib, alectinib, and lorlatinib occurred in 1.1%, 2.6%, and 1.8% of the patients, respectively. Sixty-five percent of cases accounted for Grade 3 or 4 events, with a mortality rate of 9%. Radiological patterns of pneumonia were reported in 25 patients, whereas imaging evocative of interstitial lung disease in 37. Overall, 26 of 105 patients (25%) permanently discontinued treatment because of lung toxicity. Lung toxicity is a rare albeit potentially severe side effect in NSCLC patients receiving ALK-TKIs, apparently more frequent with brigatinib. Its early recognition and treatment are crucial for the best outcome of this subgroup of patients, whose overall prognosis is being improved by the availability of several targeted agents.

Topics: Adult; Anaplastic Lymphoma Kinase; Betamethasone; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Italy; Lung Diseases, Interstitial; Lung Neoplasms; Organophosphorus Compounds; Pneumonia; Protein Kinase Inhibitors; Pyrimidines; Survival Analysis; Withholding Treatment

Crizotinib is the first-line drug for advanced non-small cell lung cancer with the abnormal expression of anaplastic lymphoma kinase gene. Severe, life-threatening, or fatal interstitial lung disease/pneumonia has been reported in patients treated with crizotinib. The clinical benefit of crizotinib is limited by its pulmonary toxicity, but the underlying mechanisms have not been adequately studied, and protective strategies are relatively scarce. Here, we established an in vivo mouse model in which crizotinib was continuously administered to C57BL/6 at 100 mg/kg/day for 6 weeks and verified that crizotinib induced interstitial lung disease in vivo, which was consistent with the clinical observations. We further treated BEAS-2B and TC-1 cells, the alveolar epithelial cell lines, with crizotinib and found the increased apoptosis rate. We proved that crizotinib-blocked autophagic flux caused apoptosis of the alveolar epithelial cells and then promoted the recruitment of immune cells, suggesting that limited autophagy activity was the key reason for pulmonary injury and inflammation caused by crizotinib. Subsequently, we found that metformin could reduce the macrophage recruitment and pulmonary fibrosis by recovering the autophagy flux, thereby ameliorating impaired lung function caused by crizotinib. In conclusion, our study revealed the mechanism of crizotinib-induced apoptosis of alveolar epithelial cells and activation of inflammation during the onset of pulmonary toxicity and provided a promising therapeutic strategy for the treatment of crizotinib-induced pulmonary toxicity.

Topics: Alveolar Epithelial Cells; Animals; Antineoplastic Agents; Autophagy; Carcinoma, Non-Small-Cell Lung; Crizotinib; Inflammation; Lung Diseases, Interstitial; Lung Neoplasms; Mice; Mice, Inbred C57BL; Protein Kinase Inhibitors

A 54-year-old, non-smoking woman was diagnosed as stage ⅣB adenocarcinoma with widespread bone metastasis (cT4N2M1c) in the First Affiliated Hospital, Zhejiang University School of Medicine. Immunohistochemistry result showed the presence of anaplastic lymphoma kinase (ALK) gene rearrangement; next-generation sequencing (NGS) indicated. 一例54岁不吸烟的女性患者因背部疼痛就诊，影像学检查提示右下肺肿块。肺部穿刺活检提示腺癌，正电子发射计算机断层显像（PET）/计算机断层扫描（CT）提示肿瘤全身骨转移，确诊为ⅣB期右下肺腺癌（cT4N2M1c）伴骨转移。免疫组织化学检测显示间变性淋巴瘤激酶（ALK）基因重排，二代测序结果提示

Topics: Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Middle Aged

Both crizotinib and osimertinib have been reported to have an adverse effect of interstitial pneumonitis in the treatment of non-small cell lung cancer (NSCLC). Here, we report the case of a 60-year-old male patient with advanced NSCLC resistant to osimertinib. Crizotinib was administered in combination with osimertinib due to elevated mesenchymal epithelial transition (MET) copy number amplification. However, early-onset interstitial pneumonitis occurred within two days.

Topics: Acrylamides; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Male; Middle Aged

The study objective was to determine the incidence and characteristics of drug-induced interstitial lung disease (ILD) associated with an orally available small-molecule tyrosine kinase inhibitor, crizotinib, in a real-world clinical setting.. Post-marketing surveillance was performed in Japan to obtain information on the safety and efficacy of crizotinib. Target patients included all patients with anaplastic lymphoma kinase-positive NSCLC who received crizotinib during the enrollment period between May 2012 and December 2014. The observation period was 52 weeks. Expert analysis of the ILD incidence was performed by an ILD independent review committee composed of five medical specialists.. The safety analysis set included 2028 patients, and more than half of the patients (56.4%) were nonsmokers. The incidence of ILD associated with crizotinib therapy was 5.77%; and 3.45% patients showed grade 3 or greater. Pulmonary edema-like shadows with or without diffuse alveolar damage pattern were observed in crizotinib-associated ILD (incidence: 0.39%), but a causal relationship with the prognosis could not be identified. ILD developed within 4 weeks from initiation of crizotinib administration in 41.9% and within 8 weeks in 69.2% of the patients. Age 55 years or older, Eastern Cooperative Oncology Group performance status 2-4, smoking history, previous or concomitant ILD, and comorbid pleural effusion were statistically determined as significant risk factors for crizotinib-induced ILD.. Crizotinib therapy should be applied to the NSCLC patients with any of above risk factors under a cautious monitoring for ILD occurrence, and clinicians should pay attention to the risks of severe ILD.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Child; Child, Preschool; Crizotinib; Female; Humans; Japan; Lung Diseases, Interstitial; Lung Neoplasms; Male; Middle Aged; Risk Factors; Young Adult

Topics: Crizotinib; Humans; Japan; Lung Diseases, Interstitial; Lung Neoplasms; Molecular Targeted Therapy; Receptor Protein-Tyrosine Kinases; Risk Factors

The treatment of advanced non-small-cell lung cancer shifted with the development of molecular-targeted therapies, like the tyrosine kinase inhibitors. One example of tyrosine kinase inhibitors is crizotinib, an anaplastic lymphoma tyrosine kinase inhibitor, which targets an echinoderm microtubule-associated protein-like-4-anaplastic lymphoma kinase gene fusion. This mutation is found in only 2% to 7% of non-small-cell lung cancer cases. Although these new therapies have shown promising results, the occurrence of interstitial lung disease as a side effect could be problematic. As the diagnosis of drug-related-interstitial lung disease is difficult to make, computed tomography is an important diagnostic tool. The recognition of computed tomography manifestations of tyrosine kinase inhibitors -induced interstitial lung disease is the key for an early recognition and management of this pulmonary toxicity. We aim to raise awareness of tyrosine kinase inhibitors-induced interstitial lung disease, by reporting the first case of a Portuguese patient treated with crizotinib for non-small-cell lung cancer who developed drug-induced interstitial lung disease.. O tratamento do carcinoma do pulmão de não pequenas células avançado mudou com o desenvolvimento de novas terapêuticas moleculares, tais como os inibidores da tirosina quinase. Um destes exemplos é o crizotinib que tem como alvo inibir a translocação do gene da quinase do linfoma, que se encontra presente em 2% a 7% dos casos de carcinoma do pulmão de não pequenas células. Apesar destes novos tratamentos mostrarem resultados promissores, a ocorrência de doença pulmonar intersticial como efeito secundário pode ser problemática. O diagnóstico de doença pulmonar intersticial associada ao tratamento é de difícil confirmação, o que tornou a tomografia computorizada uma importante ferramenta no diagnóstico. Pretendemos alertar para a doença pulmonar intersticial relacionada com os inibidores da tirosina quinase através da apresentação do primeiro caso de uma doente portuguesa tratada com crizotinib para carcinoma do pulmão de não pequenas células que desenvolveu doença pulmonar intersticial.

Topics: Adult; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Protein Kinase Inhibitors; Tomography, X-Ray Computed

We present the case of an old woman with ALK-rearranged stage IV lung adenocarcinoma who received crizotinib. She presented with severe dyspnea on the 34th day, and diffuse ground-glass opacifications in her chest. A diagnosis of crizotinib-induced ILD was confirmed. Corticosteroids were administered. However, the disease was still progressing rapidly. Therefore, as a monoclonal antibody against vascular endothelial growth factor, bevacizumab was administered in low doses (200 mg on days one and three). Her symptoms began to improve. Our clinical experience indicates that bevacizumab combined with corticosteroids might be a promising treatment in crizotinib-induced ILD patients.

Topics: Adenocarcinoma of Lung; Adrenal Cortex Hormones; Bevacizumab; Crizotinib; Female; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Middle Aged

　The aim of this study was to investigate the time-to-onset of drug-induced interstitial lung disease (DILD) following the administration of small molecule molecularly-targeted drugs via the use of the spontaneous adverse reaction reporting system of the Japanese Adverse Drug Event Report database. DILD datasets for afatinib, alectinib, bortezomib, crizotinib, dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, osimertinib, sorafenib, sunitinib, temsirolimus, and tofacitinib were used to calculate the median onset times of DILD and the Weibull distribution parameters, and to perform the hierarchical cluster analysis. The median onset times of DILD for afatinib, bortezomib, crizotinib, erlotinib, gefitinib, and nilotinib were within one month. The median onset times of DILD for dasatinib, everolimus, lapatinib, osimertinib, and temsirolimus ranged from 1 to 2 months. The median onset times of the DILD for alectinib, imatinib, and tofacitinib ranged from 2 to 3 months. The median onset times of the DILD for sunitinib and sorafenib ranged from 8 to 9 months. Weibull distributions for these drugs when using the cluster analysis showed that there were 4 clusters. Cluster 1 described a subgroup with early to later onset DILD and early failure type profiles or a random failure type profile. Cluster 2 exhibited early failure type profiles or a random failure type profile with early onset DILD. Cluster 3 exhibited a random failure type profile or wear out failure type profiles with later onset DILD. Cluster 4 exhibited an early failure type profile or a random failure type profile with the latest onset DILD.

Topics: Adverse Drug Reaction Reporting Systems; Afatinib; Bortezomib; Carbazoles; Cluster Analysis; Crizotinib; Dasatinib; Databases as Topic; Datasets as Topic; Drug-Related Side Effects and Adverse Reactions; Humans; Japan; Lung Diseases, Interstitial; Molecular Targeted Therapy; Particle Size; Piperidines; Pyrazoles; Pyridines; Quinazolines; Time Factors

We present a 45-year-old patient diagnosed with anaplastic lymphoma kinase (ALK)-rearranged metastatic lung cancer who developed grade 4 interstitial lung disease (ILD) while on crizotinib treatment and was lately treated with brigatinib with no reappearance of ILD. To our knowledge, this is the first case report of successful treatment with brigatinib after crizotinib-induced ILD. Even though ILD secondary to brigatinib has been reported in clinical trials, no pulmonary toxicity has been seen in our patient, suggesting no crosslink lung toxicity between crizotinib and brigatinib.

Topics: Adenocarcinoma; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Crizotinib; Drug Substitution; Female; Gene Rearrangement; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Middle Aged; Neoplasm Metastasis; Oncogene Proteins, Fusion; Organophosphorus Compounds; Pyrimidines; Treatment Outcome

Crizotinib is a multi-target inhibitor approved for the treatment of advanced non-small-cell lung cancer patients with a ROS1 rearrangement. However, interstitial lung disease is a rare but severe and fatal side effect of crizotinib that should lead to immediate discontinuation of the drug. Unfortunately, the pathophysiology, molecular mechanism and risk factors for crizotinib-induced interstitial lung disease remain poorly understood.. We first identified and reported interstitial lung disease induced de novo by crizotinib in a 47-year-old female patient who was diagnosed with advanced lung adenocarcinoma with a ROS1 rearrangement in a malignant pleural effusion. Subsequent next-generation sequencing analysis revealed both ROS1 rearrangement and an EGFR exon 19 deletion mutation in lung biopsy specimens, which were histologically confirmed to be interstitial lung disease. Although crizotinib treatment was ceased immediately and a shock treatment with high-dose methylprednisolone as well as other necessary treatment procedures was applied to reverse the interstitial lung disease process, the patient died.. The present case indicates that while treating non-small-cell lung cancer patients with crizotinib, it is important to constantly monitor any newly emerging respiratory symptoms and unexplained imaging changes, which may suggest an adverse effect related to drug-induced interstitial lung disease or even lethality. Histopathology and molecular pathological examination of lung biopsy specimens may help clinicians understand the development mechanism and exclude other causes.

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Crizotinib; ErbB Receptors; Fatal Outcome; Female; Humans; Lung; Lung Diseases, Interstitial; Lung Neoplasms; Middle Aged; Mutation; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Tomography, X-Ray Computed

Interstitial lung disease (ILD) is a rare, but potentially serious, side effect associated with crizotinib, a tyrosine kinase inhibitor for anaplastic lymphoma kinase-positive (ALK. Grade ≥ 3 respiratory adverse events (AEs) and serious AEs (SAEs) and any grade AEs/SAEs reported as pneumonitis, ILD, or radiation pneumonitis in trials PROFILE 1001, PROFILE 1005, PROFILE 1007, and PROFILE 1014 were evaluated by an expert independent review committee that included a pulmonologist, medical oncologist, and radiologist. Events were designated as disease progression, de novo ILD possibly or probably related to crizotinib, exacerbation or recurrence of pre-existing ILD, concurrent illness, other toxicity not thought to be related to ILD, or inconclusive.. The independent review committee evaluated 446 events (in 368 of 1669 patients who had received crizotinib therapy). They classified these events as follows: progressive disease, 77; de novo ILD, 20; pre-existing ILD, 3; concurrent illness, 9; other toxicities, 310; and inconclusive, 27. The incidence of de novo ILD was 1.2% overall, 1.3% in whites, and 1.2% overall in Asians, but greater at 3.7% in Japanese patients. The median onset of ILD from the initiation of crizotinib therapy was 23 days (range, 3-763 days). The mortality rate due to ILD was 50%. Survival was improved if crizotinib was discontinued on presentation of ILD (9 of 14 patients) compared with discontinued later or continued (1 of 6 patients).. ILD associated with crizotinib, although rare, can occur at any time and requires close monitoring.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Asian People; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Humans; Incidence; Japan; Lung Diseases, Interstitial; Lung Neoplasms; Male; Middle Aged; Pyrazoles; Pyridines; Randomized Controlled Trials as Topic; Retrospective Studies; White People; Young Adult

Crizotinib, an oral tyrosine kinase inhibitor that targets anaplastic lymphoma kinase, has proven to offer sustained progression-free survival in anaplastic lymphoma kinase-rearranged non-small-cell lung cancers. Occurrence of severe interstitial lung disease (ILD) was one of the crucial adverse events reported in randomized clinical trials and case reports.. In September 2011, we observed a crizotinib-associated ILD case. Following this index case, we reviewed the clinical and computed tomographic scan features of all patients treated with crizotinib in our department, between October 2010 and July 2013, comparing patients with and without ILD. A systematic literature review was performed.. During this period, 29 patients were treated with crizotinib, five of whom developed ILD, in addition to the index case. Two types of adverse lung reactions may be observed in patients undergoing crizotinib therapy. The first is a severe, usually fatal, ILD that occurs during the first month of treatment (n = 1). The second is a less severe ILD, occurring later in time (n = 5). It occurs gradually with only few clinical symptoms, but predominant ground-glass opacities on computed tomography, along with an intensive lymphocytic alveolitis in bronchoalveolar lavage fluid. These cases had a longer response with a median progression-free survival duration at 19.9 months (17.9-23.5) compared with 6.2 months (1.2-13.6) for controls (p = 0.04).. Forty-nine cases of crizotinib-associated ILD have been identified by the systematic review of the literature, including our six cases. Two types of adverse lung reactions may be observed with different presentation, prognosis, and treatment. Their potential mechanisms should be clarified. Nine patients with the less severe form of ILD were safely retreated.

Topics: Adult; Aged; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Crizotinib; Disease-Free Survival; Female; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Retrospective Studies; Severity of Illness Index; Survival Rate; Tomography, X-Ray Computed

We herein report a case of a 46-year-old woman with anaplastic lymphoma kinase (ALK)-rearranged stage IV lung adenocarcinoma who received the ALK inhibitor crizotinib as second-line therapy. On the 47th day following crizotinib initiation, a chest computed tomography scan revealed ground-glass opacities with a clinical manifestation of desaturation, although a partial response to treatment was detected. The diagnosis of crizotinib-induced interstitial lung disease (ILD) was confirmed, and crizotinib was discontinued, followed by the initiation of corticosteroid therapy. After improvement of ILD with corticosteroid therapy, alectinib was administered as salvage therapy, resulting in tumor shrinkage without any recurrence of ILD. To the best of our knowledge, this is the first report of successful alectinib treatment following crizotinib-induced ILD. Our results indicate that alectinib could be a promising alternative treatment option in patients with crizotinib-induced ILD.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Antineoplastic Agents; Carbazoles; Crizotinib; Female; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Radiography, Thoracic; Tomography, X-Ray Computed; Treatment Outcome

Topics: Acute Disease; Aged; Carcinoma, Non-Small-Cell Lung; Chronic Disease; Crizotinib; Fatal Outcome; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Male; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Pyrazoles; Pyridines

Topics: Aged; Carcinoma, Non-Small-Cell Lung; Crizotinib; ErbB Receptors; Female; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Treatment Outcome

Topics: Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lung Diseases, Interstitial; Male; Middle Aged; Protein Kinase Inhibitors; Pyrazoles; Pyridines

We report the case of a 70-year-old Japanese male diagnosed with advanced lung adenocarcinoma harboring the echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion gene. As soon as crizotinib was administered, tumor shrank immediately. On Day 25, he developed interstitial lung disease. Bronchoalveolar lavage fluid analysis demonstrated elevated lymphocytes fractionation. A drug lymphocyte stimulating test for crizotinib with the bronchoalveolar lavage lymphocytes was negative. Crizotinib administration was discontinued, but a life-threatening flare of tumor growth occurred. Since there was no alternative treatment for the lung cancer, we restarted crizotinib in combination with prednisolone. The patient experienced neither disease progression nor recurrence of interstitial lung disease at 6 months. In cases in which no alternate treatment is known, crizotinib retreatment combined with steroid therapy after crizotinib-induced interstitial lung disease could be considered after a careful consideration of the potential risks and benefits.

Topics: Aged; Antineoplastic Agents, Hormonal; Bronchoalveolar Lavage Fluid; Bronchoscopy; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Therapy, Combination; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Lymphocytes; Male; Prednisolone; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Tomography, X-Ray Computed; Treatment Outcome

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Crizotinib; Female; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Middle Aged; Mutation; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Retreatment

Topics: Acute Disease; Adenocarcinoma; Adult; Carcinoma, Non-Small-Cell Lung; Crizotinib; Fatal Outcome; Gene Rearrangement; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Male; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Tomography, X-Ray Computed