osimertinib and Pleural-Effusion--Malignant

Many advanced cases of cancer show central nervous system, pleural, or peritoneal involvement. In this study, we prospectively analyzed if cerebrospinal fluid (CSF), pleural effusion (PE), and/or ascites (ASC) can be used to detect driver mutations and guide treatment decisions. We collected 42 CSF, PE, and ASC samples from advanced non-small-cell lung cancer and melanoma patients. Cell-free DNA (cfDNA) was purified and driver mutations analyzed and quantified by PNA-Q-PCR or next-generation sequencing. All 42 fluid samples were evaluable; clinically relevant mutations were detected in 41 (97.6%). Twenty-three fluids had paired blood samples, 22 were mutation positive in fluid but only 14 in blood, and the abundance of the mutant alleles was significantly higher in fluids. Of the 34 fluids obtained at progression to different therapies, EGFR resistance mutations were detected in nine and ALK acquired mutations in two. The results of testing of CSF, PE, and ASC were used to guide treatment decisions, such as initiation of osimertinib treatment or selection of specific ALK tyrosine-kinase inhibitors. In conclusion, fluids close to metastatic sites are superior to blood for the detection of relevant mutations and can offer valuable clinical information, particularly in patients progressing to targeted therapies.

Topics: Acrylamides; Aged; Anaplastic Lymphoma Kinase; Aniline Compounds; Ascitic Fluid; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Female; HT29 Cells; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Neoplasm Proteins; Pleural Effusion, Malignant; Prospective Studies

Progression-free survival (PFS) of patients with non-small-cell lung cancer with pleural or pericardial effusion is expected to be prolonged with combination use of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor plus bevacizumab compared with that with an EGFR-tyrosine kinase inhibitor alone. Phase I clinical trial data have been reported for combined treatment with osimertinib plus bevacizumab and demonstrated their safety, but the efficacy remains unclear, particularly in patients with pleural or pericardial effusion. This is an ongoing single arm, prospective, open-label, multicenter, phase II trial to evaluate the efficacy and safety of osimertinib plus bevacizumab combination therapy in EGFR mutation-positive patients with untreated or recurrent non-small-cell lung cancer and pleural and/or pericardial effusion. Osimertinib will be administered orally once daily at a dose of 80 mg. One cycle consists of 21 days. Bevacizumab 15 mg/kg will be administered by drip infusion on Day 1 of each cycle. Treatment will be continued until progressive disease or any of the discontinuation criteria are met. The primary endpoint will be the 1-year PFS rate. Secondary endpoints are response rate, PFS, overall survival, survival not requiring pleural/pericardial drainage, and safety. Osimertinib plus bevacizumab combination therapy is expected to prolong PFS and reduce adverse events. TRIAL REGISTRATION NUMBER: UMIN000028071.

Topics: Acrylamides; Adult; Aged; Aged, 80 and over; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Female; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Pericardial Effusion; Pleural Effusion, Malignant; Prospective Studies; Risk; Survival Analysis; Young Adult

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Carcinoma, Small Cell; Humans; Indoles; Lung Neoplasms; Pleural Effusion; Pleural Effusion, Malignant; Pyrimidines

3rd-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), including osimertinib, have reasonable efficacy in non-small-cell lung cancers (NSCLC) with EGFR mutations. However, the efficacy of osimertinib in NSCLC patients with fluids, such as pleural, pericardial and abdominal effusions, is unclear. We evaluated the efficacy of osimertinib in this specific setting. NSCLC patients harboring EGFR T790 M mutations who experienced progressive disease after first EGFR-TKI treatment and started osimertinib treatment between April 2016 and August 2018 were retrospectively screened. In particular, we assessed the efficacy of osimertinib for NSCLC with EGFR T790 M mutations in patients who were diagnosed with EGFR T790 M mutation by malignant effusion. Among 90 patients with EGFR T790 M mutation who started osimertinib treatment after EGFR-TKI failure, 21 were diagnosed from malignant effusions excluding cerebrospinal fluid (F group) and 69 using other methods including tissue biopsies (NF group). Patient characteristics were well-balanced between the two groups. Overall response was 50%, and significantly worse in the F group (29%) than the NF group (57%; P = 0.025). Median progression-free survival with osimertinib treatment in the F group (7.1 months, 95% confidence interval [CI]: 2.3-14.0) was significantly shorter than that in the NF group (11.9 months, 95% CI: 9.5-16.0; P = 0.046)). Median drainage-free time was 10.9 months (95% CI: 1.4 months- not reached). The present study showed that the efficacy of osimertinib for NSCLC in which EGFR T790 M mutation is detected by malignant effusion may be less than in EGFR T790 M-mutated NSCLC detected by other methods.

Topics: Acrylamides; Adult; Aged; Aged, 80 and over; Aniline Compounds; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; ErbB Receptors; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Pleural Effusion, Malignant; Prognosis; Retrospective Studies; Survival Rate

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

AZD9291 (osimertinib) is designed for acquired T790M mutation after first- and second-generation EGFR) tyrosine kinase inhibitors have been used. Some of the resistance mechanisms that present after osimertinib treatment, including a newly acquired EGFR C797S mutation, have been identified. It is unclear, however, whether the bypass pathway is also a mechanism of resistance in patients after osimertinib treatment.. Cells from malignant pleural effusion were collected and cultured at the time of progression in a patient being treated with osimertinib. Tumor genotyping was done by matrix-assisted laser desorption ionization-time of flight mass spectrometry. EGFR, AKT, MEK, and ERK phosphorylation were determined. An anchorage-dependent colony formation assay was used for drug sensitivity.. An acquired mutation, BRAF V600E, was found in the patient at the time of progression while being treated with osimertinib. Cells grown from malignant pleural effusion were sensitive to BRAF V600E inhibitor and were more vulnerable to a combination treatment with osimertinib.. A potential mechanism of acquired resistance to osimertinib in patients with T790M is through the BRAF pathway. Simultaneous blockade of the BRAF and EGFR had a significant inhibitory effect.

Topics: Acrylamides; Adenocarcinoma; Adult; Aniline Compounds; Bone Neoplasms; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Male; Mutation; Neoplasm Staging; Phosphorylation; Piperazines; Pleural Effusion, Malignant; Prognosis; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf