Overcoming CEP85L-ROS1, MKRN1-BRAF and MET amplification as rare, acquired resistance mutations to Osimertinib

Lung cancer is the most common cancer-related cause of death worldwide, most of which are non-small cell lung cancers (NSCLC). Epidermal growth factor receptor (EGFR) mutations are common drivers of NSCLC. Treatment plans for NSCLC, specifically adenocarcinomas, rely heavily on the presence or absence of specific actionable driver mutations. Liquid biopsy can guide the treatment protocol to detect the presence of various mechanisms of resistance to treatment. We report three NSCLC EGFR mutated cases, each treated with Osimertinib in a combination therapy regimen to combat resistance mechanisms. The first patient presented with EGFR L858R/L833V compound mutation with MET amplification alongside CEP85L-ROS1 fusion gene, the second with EGFR exon 19del and MKRN1-BRAF fusion, and the last EGFR L858R/V834L compound mutation with MET amplification. Each regimen utilized a tyrosine kinase inhibitor or monoclonal antibody in addition to osimertinib and allowed for a prompt and relatively durable treatment response

Cardiomyopathy Etiologies, Symptoms and Management

Cardiomyopathy can be defined as a structural and functional myocardial disorder that is commonly genetic rather than due to coronary artery, valvular or congenital heart disease. It can be subcategorized into dilated, hypertrophic, restrictive, unclassified, and arrhythmogenic right ventricular cardiomyopathy/dysplasia. They can be further subdivided into primary and secondary cardiomyopathy. Primary includes genetics (HOCM, ARVC/D), mixed (DCM, RCM) or acquired (stress-induced, myocarditis) causes; while secondary cardiomyopathy is derived from the involvement of other organ systems. Cardiomyopathies can be identified by echocardiogram to display the anatomic and functional changes related to each subtype including systolic or diastolic dysfunction. In certain instances, cardiac-MRI or CT are used to further elucidate its specific characteristics such as fatty infiltration and focal hypertrophy. Treatment is very diverse and catered to each individual case. This will all be further elaborated on in the following chapter

Metabolic Activity Assessment by 18F-Fluorodeoxyglucose Positron Emission Tomography in Patients after COVID-19 Vaccination

In the following report, we describe 11 patients with various diagnoses and different treatment statuses (newly diagnosed, receiving treatment, or follow-up) of oncological diseases (breast, lymphoma, melanoma, and head and neck cancers). The patients underwent PET-CT for disease staging or follow-up and it was noted that all patients had areas of hypermetabolic uptake in the axillary lymph-nodes of the ipsilateral upper extremity where the Pfizer-BioNTech coronavirus (COVID-19) vaccine was administered. Following further investigations, including an ultrasound (US), biopsies and an examination of medical records, it was concluded that these findings were the result of the vaccination and not a progression of pre-existing disease

An Unusual Presentation of HCC in a Patient with No Underlying Liver Disease: A Case Study

Pedunculated hepatocellular carcinoma (P-HCC) is a rare subtype of HCC. P-HCC may occur in patients without underlying liver cirrhosis and can be present with negative serum tumor markers. With a growing worldwide incidence of nonalcoholic fatty liver disease, non-cirrhotic HCC will likely become more prevalent. We report a patient presenting to the hospital with nonspecific symptoms of weight loss, abdominal discomfort, and early satiety. Abdomen palpation found a large firm mass in the right middle abdomen. Computed tomography imaging showed a large right abdominal mass without evidence of liver attachment. The patient underwent a diagnostic laparotomy where a single 17 cm exophytic mass originating from the left liver lobe was found and resected. Clear margins were attained, and pathology demonstrated HCC. Early diagnosis of HCC is critical to achieving curative treatment, and physicians should keep P-HCC in mind when presented with a similar patient

Radiological artificial intelligence - predicting personalized immunotherapy outcomes in lung cancer

Abstract Personalized medicine has revolutionized approaches to treatment in the field of lung cancer by enabling therapies to be specific to each patient. However, physicians encounter an immense number of challenges in providing the optimal treatment regimen for the individual given the sheer complexity of clinical aspects such as tumor molecular profile, tumor microenvironment, expected adverse events, acquired or inherent resistance mechanisms, the development of brain metastases, the limited availability of biomarkers and the choice of combination therapy. The integration of innovative next-generation technologies such as deep learning—a subset of machine learning—and radiomics has the potential to transform the field by supporting clinical decision making in cancer treatment and the delivery of precision therapies while integrating numerous clinical considerations. In this review, we present a brief explanation of the available technologies, the benefits of using these technologies in predicting immunotherapy response in lung cancer, and the expected future challenges in the context of precision medicine

Uncommon EGFR mutations on osimertinib, real-life data (UNICORN study): Updated results, brain efficacy, and resistance mechanisms.

BACKGROUND : About 10% of EGFR mutations (EGFRm) are ‘uncommon mutations’ (ucEGFRm). osimertinib is a 3rd generation EGFRi, active against common EGFRm. We aimed to collect real-world data about systemic and brain response and resistance mechanisms to osimertinib for ucEGFRm patients

UNcommon EGFR Mutations: International Case Series on Efficacy of Osimertinib in Real-Life Practice in First-LiNe Setting (UNICORN).

INTRODUCTION: Approximately 10% of EGFR mutations (EGFRmuts) are uncommon (ucEGFRmuts). We aimed to collect real-world data about osimertinib for patients with ucEGFRmuts. METHODS: This is a multicenter, retrospective study of ucEGFRmut (exon 20 insertions excluded) metastatic NSCLC treated with osimertinib as first EGFR inhibitor. The Response Evaluation Criteria in Solid Tumors and response assessment in neuro-oncology brain metastases brain objective response rate (ORR) were evaluated by the investigators. Median progression-free survival (mPFS), median overall survival, and median duration of response (mDOR) were calculated from osimertinib initiation. Mutations found at resistance were collected. RESULTS: A total of 60 patients were included (22 centers, nine countries), with median age of 64 years, 75% females, and 83% Caucasian. The largest subgroups were G719X (30%), L861Q (20%), and de novo Thr790Met (T790M) (15%). The ORR was 61%, mPFS 9.5 months, mDOR 17.4 months, and median overall survival 24.5 months. Regarding patients with no concurrent common mutations or T790M (group A, n = 44), ORR was 60%, mPFS 8.6 months, and mDOR 11 months. For G719X, ORR was 47%, mPFS 8.8 months, and mDOR 9.1 months. For L861Q, ORR was 80%, mPFS 16 months, and mDOR 16 months. For de novo T790M, ORR was 44%, mPFS 12.7 months, and mDOR 46.2 months. Compound EGFRmut including common mutations had better outcome compared with only ucEGFRmut. For 13 patients with a response assessment in neuro-oncology brain metastases-evaluable brain metastases, brain ORR was 46%. For 14 patients, rebiopsy results were analyzed: four patients with additional EGFR mutation (C797S, D585Y, E709K), three with new TP53 mutation, one with c-Met amplification, one with PIK3CA mutation, and one with neuroendocrine transformation. CONCLUSIONS: Osimertinib was found to have an activity in ucEGFRmut with a high rate of disease control systemically and intracranially. Several resistance mechanisms were identified. This report comprises, to the best of our knowledge, the largest data set of its kind

Real-world experience with capmatinib in MET exon 14-mutated non-small cell lung cancer (RECAP): a retrospective analysis from an early access program

Background: Patients with non-small cell lung cancer (NSCLC) presenting with mesenchymal–epithelial transition (MET) exon 14 skipping mutation have an unfavorable prognosis with standard treatments. Capmatinib is a selective MET inhibitor, which showed promising efficacy in this patient population in early trials. Methods: We performed a retrospective, international, multicenter efficacy and safety analysis in patients with NSCLC treated with capmatinib in an early access program between March 2019 and December 2021. Results: Data from 81 patients with advanced MET exon 14 mutated NSCLC treated with capmatinib in first- or later-line therapy were analyzed. Median age was 77 years (range, 48–91), 56% were women, 86% had stage IV disease, and 27% had brain metastases. For all patients, the objective response rate (ORR) to capmatinib was 58% (95% CI, 47–69), whereas it was 68% (95% CI, 50–82) in treatment-naïve and 50% (95% CI, 35–65) in pretreated patients. The median progression-free survival was 9.5 months (95% CI, 4.7–14.3), whereas it was 10.6 months (95% CI, 5.5–15.7) in first-line and 9.1 months (95% CI, 3.1–15.1) in pretreated patients. After a median follow-up of 11.0 months, the median overall survival was 18.2 months (95% CI, 13.2–23.1). In patients with measurable brain metastases (n = 11), the intracranial ORR was 46% (95% CI, 17–77). Capmatinib showed a manageable safety profile. Grade ⩾ 3 treatment-related adverse events included peripheral edema (13%), elevated creatinine (4%), and elevated liver enzymes (3%). Conclusion: In patients with MET exon 14 skipping mutation, capmatinib showed durable systemic and intracranial efficacy and a manageable safety profile. This analysis confirms previously reported phase II data in a real-world setting

Real-world experience with capmatinib in MET exon 14-mutated non-small cell lung cancer (RECAP) : a retrospective analysis from an early access program

Background: Patients with non-small cell lung cancer (NSCLC) presenting with mesenchymal-epithelial transition (MET) exon 14 skipping mutation have an unfavorable prognosis with standard treatments. Capmatinib is a selective MET inhibitor, which showed promising efficacy in this patient population in early trials. Methods: We performed a retrospective, international, multicenter efficacy and safety analysis in patients with NSCLC treated with capmatinib in an early access program between March 2019 and December 2021. Results: Data from 81 patients with advanced MET exon 14 mutated NSCLC treated with capmatinib in first- or later-line therapy were analyzed. Median age was 77 years (range, 48-91), 56% were women, 86% had stage IV disease, and 27% had brain metastases. For all patients, the objective response rate (ORR) to capmatinib was 58% (95% CI, 47-69), whereas it was 68% (95% CI, 50-82) in treatment-naive and 50% (95% CI, 35-65) in pretreated patients. The median progression-free survival was 9.5 months (95% CI, 4.7-14.3), whereas it was 10.6 months (95% CI, 5.5-15.7) in first-line and 9.1 months (95% CI, 3.1-15.1) in pretreated patients. After a median follow-up of 11.0 months, the median overall survival was 18.2 months (95% CI, 13.2-23.1). In patients with measurable brain metastases (n = 11), the intracranial ORR was 46% (95% CI, 17-77). Capmatinib showed a manageable safety profile. Grade &amp;gt; 3 treatment-related adverse events included peripheral edema (13%), elevated creatinine (4%), and elevated liver enzymes (3%). Conclusion: In patients with MET exon 14 skipping mutation, capmatinib showed durable systemic and intracranial efficacy and a manageable safety profile. This analysis confirms previously reported phase II data in a real-world setting.Funding Agencies|Karl Landsteiner Institute for Lung Research and Pulmonary Oncology</p