osimertinib and Lung-Diseases--Interstitial

Osimertinib, the third generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is the standard treatment for nonsmall cell lung cancer with EGFR mutation. However, osimertinib-induced interstitial lung disease (OsiILD) is considered to be a serious adverse event, so some patients will have to discontinue the use of osimertinib due to OsiILD. Almonertinib is a novel third-generation EGFR-TKI. We herein report a patient who developed OsiILD after the use of osimertinib and then switched to almonertinib for further treatment with success. This is the first report of a successfull rechallenge with low-dose almonertinib after OsiILD. We also reviewed the literature to explore the possible risk factors and the subsequent treatment of OsiILD, suggesting that low-dose almonertinib may be an option for follow-up treatment of OsiILD.

Topics: Adenocarcinoma of Lung; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Mutation; Protein Kinase Inhibitors

The tyrosine kinase activity of epidermal growth factor receptors (EGFRs) plays critical roles in cell proliferation, regeneration, tumorigenesis, and anticancer resistance. Non-small-cell lung cancer patients who responded to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) and obtained survival benefits had somatic EGFR mutations. EGFR-TKI-related adverse events (AEs) are usually tolerable and manageable, although serious AEs, including lung injury (specifically, interstitial lung disease (ILD), causing 58% of EGFR-TKI treatment-related deaths), occur infrequently. The etiopathogenesis of EGFR-TKI-induced ILD remains unknown. Risk factors, such as tobacco exposure, pre-existing lung fibrosis, chronic obstructive pulmonary disease, and poor performance status, indicate that lung inflammatory circumstances may worsen with EGFR-TKI treatment because of impaired epithelial healing of lung injuries. There is limited evidence from preclinical and clinical studies of the mechanisms underlying EGFR-TKI-induced ILD in the available literature. Herein, we evaluated the relationship between EGFR-TKIs and AEs, especially ILD. Recent reports on mechanisms inducing lung injury or resistance in cytokine-rich circumstances were reviewed. We discussed the relevance of cytotoxic agents or immunotherapeutic agents in combination with EGFR-TKIs as a potential mechanism of EGFR-TKI-related lung injury and reviewed recent developments in diagnostics and therapeutics that facilitate recovery from lung injury or overcoming resistance to anti-EGFR treatment.

Topics: Acrylamides; Afatinib; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Gefitinib; Humans; Lung Diseases, Interstitial; Lung Injury; Lung Neoplasms; Mutation; Protein Kinase Inhibitors

In 2015, the FDA approved an unprecedented number of new therapies for non-small cell lung cancer (NSCLC), among them therapies addressing specific genomic tumor subsets in the setting of development of resistance to first-line targeted therapy. Osimertinib (Tagrisso, formerly AZD9291; AstraZeneca) is indicated for patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, who have progressed on or after EGFR tyrosine kinase inhibitor therapy. It received breakthrough therapy designation, priority review status, and accelerated approval from the FDA. Clin Cancer Res; 23(3); 618-22. ©2016 AACR.

Topics: Acrylamides; Adenosine Triphosphate; Aniline Compounds; Antineoplastic Agents; Binding Sites; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Diarrhea; Disease Progression; Drug Eruptions; Drug Resistance, Neoplasm; ErbB Receptors; Genes, erbB-1; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Molecular Targeted Therapy; Mutation, Missense; Neoplasm Proteins; Piperazines; Point Mutation; Protein Kinase Inhibitors; Pyrimidines; Salvage Therapy; Single-Blind Method

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are the standard of care for non-small-cell lung cancer (NSCLC) patients harboring EGFR mutations. However, almost all patients develop resistance after approximately 1 y of treatment, with >50% of cases due to the T790M secondary mutation of the EGFR gene. A large global Phase III study (AURA3) demonstrated that osimertinib significantly prolonged progression-free survival (PFS) over platinum-doublet chemotherapy in patients with T790M-positive NSCLC who had progressed on previous EGFR-TKI therapy. However, it is not clear whether efficacy or safety of osimertinib in Japanese patients is similar to the overall population. We report a pre-planned subgroup analysis of pooled Phase II data from the AURA Extension and AURA2 trials to investigate the efficacy and safety of osimertinib in Japanese patients. This study included 81 Japanese patients. Patients were administered 80 mg osimertinib orally once daily until disease progression. The main endpoints were objective response rate (ORR), PFS, and safety. The ORR was 63.6% and median PFS was 13.8 mo. Overall survival rate at 36 mo was 54.0%. The most common all-cause adverse events (AEs) were rash (grouped term; 65.4%), diarrhea (51.9%), paronychia (grouped term; 49.4%), and dry skin (grouped term; 39.5%). Most AEs were grade 1-2. Five patients (6.2%) developed interstitial lung disease, resulting in two deaths (2.5%). Osimertinib demonstrated favorable ORR and PFS in Japanese patients, similar to the overall population. Additionally, osimertinib has good efficacy and a manageable safety profile in Japanese patients with NSCLC who had acquired resistance due to the T790M mutation.

Topics: Acrylamides; Administration, Oral; Adult; Aged; Aged, 80 and over; Aniline Compounds; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Diarrhea; Disease Progression; Drug Resistance, Neoplasm; ErbB Receptors; Exanthema; Humans; Japan; Lung Diseases, Interstitial; Lung Neoplasms; Middle Aged; Paronychia; Progression-Free Survival; Protein Kinase Inhibitors; Survival Analysis; Survival Rate

Osimertinib is associated with a relatively high frequency of drug-induced interstitial lung disease (D-ILD), and transient asymptomatic pulmonary opacities (TAPO) have been reported to occur during osimertinib administration. The frequency of TAPO during first-line treatment and the pros and cons of osimertinib continuation is unknown.. This was a multicenter, retrospective study. The purpose of this study was to research the frequency of TAPO and to evaluate osimertinib continuation in first-line therapy. We also evaluated progression-free survival (PFS) including subgroup analysis.. From August 2018 to December 2020, 133 patients were enrolled into the study. The median observation period was 23.2 months (0.3-48.3 months). Thirty patients (22.6%) experienced D-ILD events, including 16 patients (12.1%) with CTCAE grade 1, five patients (3.8%) with grade 2, and nine patients (6.7%) with grade 3 and above D-ILD. Among the patients with grade 1 D-ILD, 11 cases (8.3%) of TAPO were observed, and all patients succeeded in osimertinib continuation. The TAPO images were characterized by localized patchy opacities (73%). The median PFS was 22.6 months (95% confidence interval [CI]: 17.8-28.7 months). Patients with TAPO had a significantly longer PFS than patients with non-TAPO D-ILD in the multivariate analysis.. This study showed that grade 1 D-ILD might include TAPO and that patients with TAPO might have good PFS. We need to consider the possibility of osimertinib continuation when lung opacities appear.

Topics: Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Retrospective Studies

Osimertinib (OSI), a third-generation tyrosine kinase inhibitor (TKI), efficiently benefits lung adenocarcinoma (LUAD) patients with epidermal growth factor receptor (EGFR) mutations. However, combined OSI and immune checkpoint inhibitor in EGFR-mutant patients increases the incidence of interstitial lung disease (ILD), although the mechanism is unknown. Here, we investigated the interaction between dendritic cells (DCs), a potential critical player in ILD, and OSI. Seventeen LUAD patients received TKI therapy, and only the OSI therapy group (N = 10) showed a significant increase in CD40 and CD83 on immature DCs (iDCs), and an elevated trend for both markers on mature DCs (mDCs) during short- and long-term OSI therapy. Our results indicated that OSI therapy may potentially activate DC functions, which might increase the potential immune toxicity when combined with onco-immunotherapy.

Topics: Adenocarcinoma of Lung; Carcinoma, Non-Small-Cell Lung; Dendritic Cells; ErbB Receptors; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Mutation; Protein Kinase Inhibitors

Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) approved as first-line therapy for advanced. In this multicentric study, we retrospectively analyzed 92 patients with. TAPO were found in 18/92 patients (19.6%), with a median follow-up of 114 weeks. Median onset time was 16 weeks (range 6-80) and median duration time 14 weeks (range 8-37). The most common radiologic pattern was focal ground-glass opacity (54.5%). We did not find any individual clinical variable significantly associated with the onset of TAPO or significant difference in clinical outcomes between TAPO-positive and TAPO-negative groups.. TAPO are benign pulmonary findings observed in patients treated with osimertinib. TAPO variability in terms of CT features can hinder the differential diagnosis with either osimertinib-related mild ILD or tumor progression. However, because TAPO are asymptomatic, it could be reasonable to continue therapy and verify the resolution of the CT findings at follow-up in selected cases.

Topics: Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Protein Kinase Inhibitors; Retrospective Studies

Osimertinib-induced interstitial lung disease (ILD) is an uncommon, but fatal pulmonary toxicity in some patients. We report a case of a 64-year-old male with stage IV adeno-non-small cell lung cancer (NSCLC) harboring an exon 19 deletion in the epidermal growth factor receptor (EGFR) treated with osimertinib 80 mg/d for first-line targeted therapy. On day 60 after initiating treatment of osimertinib, the patient developed ILD. Osimertinib was discontinued immediately and oral prednisone 60 mg/d was initiated, ILD improved within 13 d. After balancing the risk and benefit, osimertinib was restarted concurrently with prednisone. The patient showed neither disease progression nor a recurrence of ILD for more than 16 months. Based on our case and literature review, retreatment with osimertinib under steroid coverage could be considered as an effective treatment option after careful risk-benefit assessment for patients with EGFR-mutant NSCLC.
.. 【中文题目：EGFR突变非小细胞肺癌患者奥希替尼诱导间质性肺疾病后奥希替尼再挑战：病例报道】 【中文摘要：奥希替尼诱导的间质性肺疾病（interstitial lung disease, ILD）是一种罕见的、致命的肺毒性疾病。我们报道1例64岁男性IV期肺腺癌患者，伴有表皮生长因子受体（epidermal growth factor receptor, EGFR）外显子19缺失，使用奥希替尼80 mg/d作为一线靶向治疗。奥希替尼开始治疗后第60天患者出现ILD。立即停用奥希替尼，并开始口服泼尼松60 mg/d，ILD在13 d内得到改善。权衡风险和获益后，再次开始奥希替尼与泼尼松治疗。奥希替尼治疗16个月以上，患者既没有疾病进展，也没有ILD复发。根据我们的病例和既往文献，在仔细评估EGFR突变非小细胞肺癌（non-small cell lung cancer, NSCLC）患者的风险及获益后，在类固醇激素辅助下再次使用奥希替尼可被视为一种有效的治疗选择。
】 【中文关键词：表皮生长因子受体；间质性肺疾病；肺肿瘤；奥希替尼】.

Topics: Acrylamides; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Male; Middle Aged; Prednisone; Protein Kinase Inhibitors

Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has exhibited efficacy in patients with EGFR-mutant non-small cell lung cancer (NSCLC). Interstitial lung disease (ILD) is a fatal adverse event of osimertinib treatment, and it requires treatment discontinuation. There are few reports regarding the safety and efficacy of osimertinib re-challenge in patients who experienced osimertinib-induced ILD. This retrospective study assessed this treatment option. We retrospectively collected data for patients treated with osimertinib who developed ILD at Shizuoka Cancer Center from April 2016 to March 2020. ILD was diagnosed by two doctors based on imaging tests and blood tests to exclude other causes. Among 215 patients treated with osimertinib, 28 developed ILD. The median age of patients with ILD was 69.5 years (range, 39.0-80.0). In addition, 29% of patients were men, and 46% had a history of smoking. Eleven patients were re-administered EGFR TKIs, including eight patients treated with osimertinib and three patients treated with alternative EGFR TKIs. Among patients re-challenged with osimertinib, none who previously experienced grade 1 ILD exhibited ILD relapse, even with the same osimertinib dose and without the concurrent administration of systemic steroids. Meanwhile, one of the four patients who previously exhibited grade 2 ILD experienced despite a dose reduction for osimertinib and systemic steroid administration. For patients with EGFR-mutant NSCLC who experience grade 1 ILD during osimertinib therapy, osimertinib re-challenge may be suitable when no other treatments are available.

Topics: Acrylamides; Adult; Aged; Aged, 80 and over; Aniline Compounds; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Female; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Recurrence; Retrospective Studies

Osimertinib is the standard treatment for epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer. However, drug-induced interstitial lung disease (ILD) is recognized as a serious adverse event associated with EGFR-tyrosine kinase inhibitors (TKIs). We herein report a 78-year-old woman with stage IV lung adenocarcinoma harboring an EGFR L858R mutation on exon 21 who received rechallenge treatment with afatinib after osimertinib-induced ILD with an organizing pneumonia pattern. This is the first report of successful rechallenge with afatinib after osimertinib-induced ILD. Treatment with other EGFR-TKIs after osimertinib-induced ILD may be an option for subsequent therapy.

Topics: Acrylamides; Afatinib; Aged; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Female; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Mutation; Protein Kinase Inhibitors

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

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have elicited favorable anti-tumor activity in non-small cell lung cancer especially the lung adenocarcinoma. Interstitial lung disease (ILD) is 1 of the fatal side effects of EGFR-TKIs. However, such type of side effect has not been observed in the follow-up during the treatment of the third-generation EGFR-TKI Almonertinib (also called HS-10296). Here, we first report an Almonertinib-induced ILD in an elderly female patient.. A 70-year-old female diagnosed with " lung adenocarcinoma with intracranial metastasis" harboring a mutation of EGFR 19DEL was administrated with Almonertinib 110 mg orally as the first-line treatment. However, she presented with chest tightness, and shortness of breath, accompanying with paroxysmal dry cough 3 months after the initiation of Almonertinib.. Extensive relevant examinations did not provide conclusive results and the chest computed tomography showed a diffuse ILD in bilateral pulmonary.. The patient was diagnosed with Almonertinib-induced ILD in the absence of no other potential causes. She discontinued Almonertinib and was treated with oxygen uptaken and methylprednisolone.. The whole symptoms were eliminated and the chest computed tomography showed ILD got remission after the prescription of methylprednisolone.. Almonertinib has potential to cause the rare but severe interstitial lung disease. Clinicians should keep cautious of this when prescribing Almonertinib.

Topics: Acrylamides; Aged; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Female; Humans; Lung Diseases, Interstitial

Osimertinib is the standard therapy for epidermal-growth-factor-receptor (EGFR)-mutant lung cancers. We herein report a case of osimertinib-induced interstitial lung disease (OsiILD) with an organizing pneumonia (OP) pattern and provide a literature-based review. Six months after osimertinib administration, a 75-year-old woman with right pleural carcinomatosis developed ILD with an OP pattern. After salvage chemotherapy, osimertinib with corticosteroid was successfully re-administered. A literature review suggested that 1) OsiILD with an OP pattern was rare but should be recognized, and 2) re-administration of osimertinib in OsiILD was successful in select patients. A criterion that determines whether a patient would benefit from re-administration is warranted.

Topics: Acrylamides; Adenocarcinoma; Aged; Aniline Compounds; Antineoplastic Agents; ErbB Receptors; Female; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Pneumonia; Protein Kinase Inhibitors; Salvage Therapy

Topics: Acrylamides; Aniline Compounds; Humans; Indoles; Lung Diseases, Interstitial; Lung Neoplasms

Background Osimertinib is one of the first-line treatments for advanced non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. However, the occurrence rate of osimertinib-induced interstitial lung disease (ILD) is particularly high in Japanese patients and little information on subsequent cancer treatment options after recovery from osimertinib-induced ILD is currently available. Thus, this study aims to determine the safety and efficacy of afatinib for the treatment of NSCLC following osimertinib-induced ILD. Methods We retrospectively investigated the clinical courses of all NSCLC patients with EGFR mutations at our facility between August 2018 and September 2019, who received osimertinib as first-line treatment and were subsequently treated with afatinib after developing osimertinib-induced ILD. Results Forty-two patients received osimertinib treatment at our facility during the study period, and four patients received afatinib after developing osimertinib-induced ILD. All events of ILD improved either spontaneously or with steroid therapy before the initiation of afatinib. For the four patients who were retrospectively reviewed, the overall response rate to afatinib therapy was 75%, and the disease control rate was 100%. During the study period, no ILD recurrence was observed in any of the four patients. Conclusions According to our study findings, afatinib treatment after osimertinib-induced ILD is considered safe and effective and it can be used as one of the treatment options for NSCLC following osimertinib-induced ILD.

Topics: Acrylamides; Adult; Afatinib; Aged; Aged, 80 and over; Aniline Compounds; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Male; Protein Kinase Inhibitors; Retrospective Studies

Using real-world Japanese postmarketing data, we characterized interstitial lung disease (ILD) development during the second- or later-line osimertinib treatment for EGFR mutation-positive NSCLC. Retrospective radiologic image evaluation of patients developing ILD was also performed.. Patients who had ILD events reported as an adverse drug reaction by their physicians and who were assessed as having developed ILD as assessed by an ILD expert committee in Japan were included.. Among 3578 patients, 252 ILD events were reported in 245 patients (6.8%) by their attending physicians. The median (range) time to the first onset of ILD after osimertinib treatment initiation was 63.0 (5-410) days, and 29 patients with a fatal outcome were reported. The ILD expert committee assessed 231 of 3578 patients (6.5%) as having ILD. A previous history of nivolumab therapy (adjusted OR: 2.84; 95% confidence interval: 1.98-4.07) and a history or concurrence of ILD (3.51; 2.10-5.87) were identified as factors potentially associated with ILD onset during osimertinib treatment. In patients who had received a previous nivolumab treatment, the number and proportion of patients developing ILD were highest for patients who discontinued nivolumab treatment within the first month before initiating osimertinib; trends for decreasing incidence and proportion were observed, with an increasing duration between the end of nivolumab treatment and the initiation of osimertinib treatment.. The frequency of ILD was consistent with the known osimertinib safety profile in the Japanese population. A history or concurrence of ILD and history of previous nivolumab therapy are factors potentially associated with ILD onset during osimertinib treatment.

Topics: Acrylamides; Aniline Compounds; ErbB Receptors; Humans; Incidence; Japan; Lung Diseases, Interstitial; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Retrospective Studies

The aim of our study was to retrospectively assess the incidence of interstitial lung disease (ILD) related to EGFR-tyrosine kinase inhibitor (TKI) treatment immediately before and/or after the administration of a PD-1 antibody.. We analyzed the data of 26 patients who underwent treatment with EGFR-TKIs immediately before and/or after the administration of an anti-PD-1 antibody.. Four out of the 26 patients developed ILD during EGFR-TKI treatment: three patients during the administration of osimertinib immediately after, and one during afatinib immediately before treatment with an anti-PD-1 antibody. Three of 12 patients who underwent EGFR-TKI therapy immediately after anti-PD-1 antibody treatment experienced osimertinib-induced ILD. ILD was not observed in the five patients administered an anti-PD-1 antibody followed by first or second-generation EGFR-TKIs.. ILD was observed in the treatment sequence of an anti-PD-1 antibody followed by osimertinib, but not with first or second-generation EGFR-TKIs.

Topics: Acrylamides; Adult; Afatinib; Aged; Aged, 80 and over; Aniline Compounds; Antineoplastic Agents, Immunological; Female; Humans; Incidence; Lung Diseases, Interstitial; Lung Neoplasms; Male; Middle Aged; Nivolumab; Protein Kinase Inhibitors; Retrospective Studies; Treatment Outcome

Lung cancer is globally one of the leading causes of malignant tumor-related mortality and ranks as having the highest incidence found in men and second in women. Osimertinib is a drug used to target lung cancer but its toxicity is not fully understood. Here we present a case of lung adenocarcinoma in a 78-year-old man that was treated and responded favorably with Osimertinib after the failure of other therapies. Unfortunately, the patient developed severe interstitial lung disease during the treatment procedure.

Topics: Acrylamides; Aged; Aniline Compounds; Antineoplastic Agents; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Male; Tomography, X-Ray Computed; Treatment Outcome

A 62-year-old male with lung adenocarcinoma harboring an exon 19 deletion in the Epidermal growth factor receptor (EGFR) was treated with EGFR-tyrosine kinase inhibitors (TKIs) and several cytotoxic agents. After administering a fifth-line chemotherapy regimen, a liver biopsy revealed a diagnosis of recurrence with a T790M mutation. After an 82-day course of osimertinib therapy, the patient developed osimertinib-induced interstitial lung disease (ILD). Osimertinib was discontinued, and oral prednisolone was started. The ILD quickly improved, but liver metastases progressed and osimertinib was restarted concurrently with prednisolone. The patient showed neither disease progression nor a recurrence of ILD at 5 months. In situations in which no alternative treatment is available, osimertinib rechallenge should thus be considered as an alternative treatment.

Topics: Acrylamides; Aged; Aniline Compounds; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Male; Middle Aged; Piperazines; Prednisolone; Treatment Outcome

Osimertinib demonstrated promising efficacy for refractory leptomeningeal metastases (LM) in preclinical data and a clinical study at 160 mg, but there is limited data for the standard 80 mg dose.. T790M-positive patients with suspected LM after classical epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) failure were enroled.. We investigated 13 patients (5 definitive and 8 possible LM cases). In two of the five definitive cases with T790M in and outside the central nervous system (CNS), osimertinib was effective for both lesions, with cerebrospinal fluid (CSF) clearance of cancer cells and sensitive/T790M mutations. In three definitive cases with extra-CNS T790M without CSF T790M, cancer cells and sensitive mutations in the CSF persisted after osimertinib initiation. The median progression-free survival of all 13 patients was 7.2 months. Osimertinib was generally well-tolerated despite poor performance status, but interstitial lung disease (grade 2) was confirmed in one patient. Based on 25 samples from 13 patients, the osimertinib CSF penetration rate was 2.5±0.3%.. Osimertinib 80 mg is a useful therapeutic option for refractory LM after classical EGFR-TKI failure. It appears more effective in CSF T790M-positive cases.

Topics: Acrylamides; Aged; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Meningeal Neoplasms; Middle Aged; Mutation; Pilot Projects; Piperazines; Progression-Free Survival; Prospective Studies; Protein Kinase Inhibitors; Treatment Outcome

Nivolumab and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are now the standard-of-care therapies in non-small cell lung cancer (NSCLC). Although EGFR-TKIs are well understood and have well-defined safety profiles, our experience with immune checkpoint inhibitors is still growing, particularly regarding the use of combinations of different classes of antitumor agents, including both the concomitant and sequential use of such agents.. To determine whether nivolumab increases EGFR-TKI-associated interstitial pneumonitis (IP).. A database study of 20 516 participants with NSCLC in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database, performed between April 2015 and March 2017.. We compared the incidence of EGFR-TKI-associated IP in patients receiving and not receiving nivolumab treatment.. The mean (SD) age of participants treated with EGFR-TKI, with and without nivolumab, was 64.4 (15.5) and 68.9 (11.8) years, respectively, and the proportion of men was 40.0% and 53.8%, respectively. Of the 20 516 participants with NSCLC, 985 cases (4.80%; 95% CI, 4.51-5.10) developed IP. Of 5777 patients treated with EGFR-TKI, 265 developed IP (4.59%; 95% CI, 4.06-5.16). Of 70 patients treated with both EGFR-TKI and nivolumab, 18 developed IP (25.7%; 95% CI, 16.0-37.6). The adjusted odds ratio for an interaction between EGFR-TKI and nivolumab was 4.31 (95% CI, 2.37-7.86; P < .001), suggesting the existence of an interaction. When we further stratified the patients by treatment with and without nivolumab, the odds ratio of EGFR-TKI-associated IP in cases with and without nivolumab treatment was 5.09 (95% CI, 2.87-9.03) and 1.22 (95% CI, 1.00-1.47), respectively.. We found a higher proportion of reports of IP for nivolumab in combination with EGFR-TKI vs treatment with either drug alone. Owing to the limitations of this study, the results warrant further confirmation. However, careful consideration should be given to the possibility of an increased risk of IP when EGFR-TKI is administered in combination with nivolumab, including concomitant and sequential use, and careful monitoring for IP is recommended.

Topics: Acrylamides; Afatinib; Aged; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Databases, Factual; ErbB Receptors; Erlotinib Hydrochloride; Female; Follow-Up Studies; Gefitinib; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Male; Middle Aged; Mutation; Nivolumab; Prognosis

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.

Topics: Acrylamides; Adenocarcinoma of Lung; Aged; Aniline Compounds; Antineoplastic Agents; Drainage; ErbB Receptors; Fatal Outcome; Female; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Mutation; Pleural Effusion, Malignant; Positron Emission Tomography Computed Tomography; Protein Kinase Inhibitors

Topics: Acrylamides; Aged; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Mutation; Piperazines

Topics: Acrylamides; Adult; Aniline Compounds; Antibodies, Monoclonal; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Nivolumab; Piperazines; Tomography, X-Ray Computed; Treatment Outcome

Topics: Acrylamides; Aged; Aniline Compounds; Female; Humans; Lung Diseases, Interstitial; Piperazines; Pulmonary Eosinophilia

A 75-year-old man with stage IV lung adenocarcinoma was treated with osimertinib due to disease progression despite having been administered erlotinib. Both an epidermal growth factor receptor (EGFR) L858R mutation on exon 21 and a T790M mutation on exon 20 were detected in a specimen from a recurrent primary tumor. Five weeks after osimertinib initiation, he developed general fatigue and dyspnea. Chest computed tomography scan revealed diffuse ground glass opacities and consolidation on both lungs. An analysis of the bronchoalveolar lavage fluid revealed marked lymphocytosis, and a transbronchial lung biopsy specimen showed a thickened interstitium with fibrosis and prominent lymphocytic infiltration. We diagnosed the patient to have interstitial lung disease induced by osimertinib.

Topics: Acrylamides; Adenocarcinoma; Adenocarcinoma of Lung; Aged; Aniline Compounds; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Erlotinib Hydrochloride; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Male; Neoplasm Recurrence, Local; Piperazines; Protein Kinase Inhibitors

We report a case of a 38-year-old woman who was diagnosed with stage IV lung adenocarcinoma, harboring an epidermal growth factor receptor (EGFR) L858R mutation on exon 21 and a T790 M mutation on exon 20. The patient was treated with osimertinib, a third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI) following treatment with nivolumab, an anti-Programmed Cell Death 1 (anti-PD1) antibody. After initiating osimertinib treatment, the patient began to complain of low-grade fever and shortness of breath without hypoxemia, and her chest radiograph and a CT scan revealed a remarkable antitumor response, although faint infiltrations were observed in the bilateral lung field. Bronchoalveolar lavage fluid mainly contained lymphocytes (CD4+/CD8+ ratio of 0.3), and a transbronchial lung biopsy specimen showed lymphocytic alveolitis with partial organization in several alveolar spaces. Therefore we diagnosed the patient with osimertinib-induced interstitial lung disease (ILD) after treatment with anti-PD1 antibody. We considered anti-PD1 therapies may be the risk factor of EGFR-TKI-induced ILD.

Topics: Acrylamides; Adenocarcinoma; Adenocarcinoma of Lung; Adult; Aniline Compounds; Antibodies, Monoclonal; Antineoplastic Agents; Drug Therapy, Combination; Female; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Nivolumab; Piperazines; Programmed Cell Death 1 Receptor; Protein Kinase Inhibitors; Tomography, X-Ray Computed

Topics: Acrylamides; Adenocarcinoma; Adenocarcinoma of Lung; Aged; Aniline Compounds; Antibodies, Monoclonal; Antineoplastic Agents; Female; Humans; Incidence; Lung Diseases, Interstitial; Lung Neoplasms; Male; Nivolumab; Piperazines

Topics: Acrylamides; Adult; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; Humans; Lung Diseases, Interstitial; Male

Osimertinib is an EGFR inhibitor licensed for the treatment of EGFR-mutant, T790M-positive NSCLC. Previously unreported, frequent transient asymptomatic pulmonary opacities were noted in patients during osimertinib therapy at the University of Colorado.. Computed tomography imaging and clinical notes on patients with NSCLC who had been treated with osimertinib at the University of Colorado were retrospectively reviewed.. Transient asymptomatic pulmonary opacities developed in seven of 20 patients (35%) while they were receiving osimertinib. The radiological patterns seen included ground-glass opacities with or without nodular consolidation. The median time to development of the first lesion was 8.7 weeks (range 1.6-43 weeks), the median time to resolution during continued osimertinib was 6 weeks (range 1-11 weeks).. Transient asymptomatic pulmonary opacities may be a previously unrecognized, benign feature associated with osimertinib therapy that may be mistaken for isolated pulmonary progression or the beginning of more severe pneumonitis. If new-onset pulmonary lesions, especially those associated with ground-glass appearances, are asymptomatic and localized and there is no evidence of disease progression elsewhere, it may be reasonable to continue treatment with osimertinib and monitor the lesions for resolution.

Topics: Acrylamides; Aged; Aniline Compounds; Antineoplastic Agents; Female; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Male; Middle Aged; Piperazines