Introduction: Nazartinib, a novel third-generation EGFR-tyrosine kinase inhibitor, previously demonstrated antitumor activity and manageable safety in patients with EGFR-mut ant advanced non-small... Show moreIntroduction: Nazartinib, a novel third-generation EGFR-tyrosine kinase inhibitor, previously demonstrated antitumor activity and manageable safety in patients with EGFR-mut ant advanced non-small cell lung cancer (NSCLC) who received <= 3 prior lines of systemic ther-apy. Herein, we report phase 2 efficacy and safety of first-line nazartinib. Methods: This single-arm, open-label, global study enrolled treatment-naive adult patients with stage IIIB/IV NSCLC harboring EGFR-activating mutations (eg, L858R and/or ex19del). Patients with neurologically stable and controlled brain metastases were also eligible. Patients received oral nazartinib 150 mg once daily. The primary endpoint was Blinded Independent Review Committee (BIRC)-assessed overall response rate (ORR) per RECIST v1.1. Results: Forty-five patients received >= 1 dose of nazartinib. The median follow-up time from enrollment to data cutoff (November 1, 2019) was 30 months (range: 25-34). The BIRC-assessed ORR was 69% (95% CI, 53-82). The median progression-free survival (PFS) was 18 months (95% CI, 15-not estimable [NE]). The median overall survival was NE. In patients with baseline brain metastases (n = 18), the ORR and median PFS (95% CIs) were 67% (41-87) and 17 months (11-21). Seventeen of 18 patients had brain metastases as non-target lesions; the CNS lesions were absent/normalized in 9 of 17 (53%). Only 2 of 27 patients without baseline brain metastases developed new brain metastases postbaseline. Most frequent adverse events (>= 25%, any grade, all-causality) were diarrhea (47%), maculopapular rash (38%), pyrexia (29%), cough, and stomatitis (27% each). Conclusions: First-line nazartinib demonstrated promising efficacy, including clinically meaningful antitumor activity in the brain, and manageable safety in patients with EGFR-mutant NSCLC. (C) 2022 Published by Elsevier Ltd. Show less
Wanrooij, R.L.J. van; Bronswijk, M.; Kunda, R.; Everett, S.M.; Lakhtakia, S.; Rimbas, M.; ... ; Merwe, S.W. van der 2022
Main Recommendations 1 ESGE recommends a prolonged course of a prophylactic broad-spectrum antibiotic in patients with ascites who are undergoing therapeutic endoscopic ultrasound (EUS) procedures.... Show moreMain Recommendations 1 ESGE recommends a prolonged course of a prophylactic broad-spectrum antibiotic in patients with ascites who are undergoing therapeutic endoscopic ultrasound (EUS) procedures. Strong recommendation, low quality evidence. 2 ESGE recommends placement of partially or fully covered self-expandable metal stents during EUS-guided hepaticogastrostomy for biliary drainage in malignant disease. Strong recommendation, moderate quality evidence. 3 ESGE recommends EUS-guided pancreatic duct (PD) drainage should only be performed in high volume expert centers, owing to the complexity of this technique and the high risk of adverse events. Strong recommendation, low quality evidence. 4 ESGE recommends a stepwise approach to EUS-guided PD drainage in patients with favorable anatomy, starting with rendezvous-assisted endoscopic retrograde pancreatography (RV-ERP), followed by antegrade or transmural drainage only when RV-ERP fails or is not feasible. Strong recommendation, low quality evidence. 5 ESGE suggests performing transduodenal EUS-guided gallbladder drainage with a lumen-apposing metal stent (LAMS), rather than using the transgastric route, as this may reduce the risk of stent dysfunction. Weak recommendation, low quality evidence. 6 ESGE recommends using saline instillation for small-bowel distension during EUS-guided gastroenterostomy. Strong recommendation, low quality evidence. 7 ESGE recommends the use of saline instillation with a 19G needle and an electrocautery-enhanced LAMS for EUS-directed transgastric endoscopic retrograde cholangiopancreatography (EDGE) procedures. Strong recommendation, low quality evidence. 8 ESGE recommends the use of either 15- or 20-mm LAMSs for EDGE, with a preference for 20-mm LAMSs when considering a same-session ERCP. Strong recommendation, low quality evidence. Show less
Merwe, S.W. van der; Wanrooij, R.L.J. van; Bronswijk, M.; Everett, S.; Lakhtakia, S.; Rimbas, M.; ... ; Hooft, J.E. van 2021
Main Recommendations 1 ESGE recommends the use of endoscopic ultrasound-guided biliary drainage (EUS-BD) over percutaneous transhepatic biliary drainage (PTBD) after failed endoscopic retrograde... Show moreMain Recommendations 1 ESGE recommends the use of endoscopic ultrasound-guided biliary drainage (EUS-BD) over percutaneous transhepatic biliary drainage (PTBD) after failed endoscopic retrograde cholangiopancreatography (ERCP) in malignant distal biliary obstruction when local expertise is available. Strong recommendation, moderate quality evidence. 2 ESGE suggests EUS-BD with hepaticogastrostomy only for malignant inoperable hilar biliary obstruction with a dilated left hepatic duct when inadequately drained by ERCP and/or PTBD in high volume expert centers. Weak recommendation, moderate quality evidence. 3 ESGE recommends that EUS-guided pancreatic duct (PD) drainage should only be considered in symptomatic patients with an obstructed PD when retrograde endoscopic intervention fails or is not possible. Strong recommendation, low quality evidence. 4 ESGE recommends rendezvous EUS techniques over transmural PD drainage in patients with favorable anatomy owing to its lower rate of adverse events. Strong recommendation, low quality evidence. 5 ESGE recommends that, in patients at high surgical risk, EUS-guided gallbladder drainage (GBD) should be favored over percutaneous gallbladder drainage where both techniques are available, owing to the lower rates of adverse events and need for re-interventions in EUS-GBD. Strong recommendation, high quality of evidence. 6 ESGE recommends EUS-guided gastroenterostomy (EUS-GE), in an expert setting, for malignant gastric outlet obstruction, as an alternative to enteral stenting or surgery. Strong recommendation, low quality evidence. 7 ESGE recommends that EUS-GE may be considered in the management of afferent loop syndrome, especially in the setting of malignancy or in poor surgical candidates. Strong recommendation, low quality evidence. 8 ESGE suggests that endoscopic ultrasound-directed transgastric ERCP (EDGE) can be offered, in expert centers, to patients with a Roux-en-Y gastric bypass following multidisciplinary decision-making, with the aim of overcoming the invasiveness of laparoscopy-assisted ERCP and the limitations of enteroscopy-assisted ERCP. Weak recommendation, low quality evidence. Show less
BACKGROUNDAmong patients with non-small-cell lung cancer (NSCLC),METexon 14 skipping mutations occur in 3 to 4% andMETamplifications occur in 1 to 6%. Capmatinib, a selective inhibitor of the MET... Show moreBACKGROUNDAmong patients with non-small-cell lung cancer (NSCLC),METexon 14 skipping mutations occur in 3 to 4% andMETamplifications occur in 1 to 6%. Capmatinib, a selective inhibitor of the MET receptor, has shown activity in cancer models with various types of MET activation.METHODSWe conducted a multiple-cohort, phase 2 study evaluating capmatinib in patients withMET-dysregulated advanced NSCLC. Patients were assigned to cohorts on the basis of previous lines of therapy andMETstatus (METexon 14 skipping mutation orMETamplification according to gene copy number in tumor tissue). Patients received capmatinib (400-mg tablet) twice daily. The primary end point was overall response (complete or partial response), and the key secondary end point was response duration; both end points were assessed by an independent review committee whose members were unaware of the cohort assignments.RESULTSA total of 364 patients were assigned to the cohorts. Among patients with NSCLC with aMETexon 14 skipping mutation, overall response was observed in 41% (95% confidence interval [CI], 29 to 53) of 69 patients who had received one or two lines of therapy previously and in 68% (95% CI, 48 to 84) of 28 patients who had not received treatment previously; the median duration of response was 9.7 months (95% CI, 5.6 to 13.0) and 12.6 months (95% CI, 5.6 to could not be estimated), respectively. Limited efficacy was observed in previously treated patients withMETamplification who had a gene copy number of less than 10 (overall response in 7 to 12% of patients). Among patients withMETamplification and a gene copy number of 10 or higher, overall response was observed in 29% (95% CI, 19 to 41) of previously treated patients and in 40% (95% CI, 16 to 68) of those who had not received treatment previously. The most frequently reported adverse events were peripheral edema (in 51%) and nausea (in 45%); these events were mostly of grade 1 or 2.CONCLUSIONSCapmatinib showed substantial antitumor activity in patients with advanced NSCLC with aMETexon 14 skipping mutation, particularly in those not treated previously. The efficacy inMET-amplified advanced NSCLC was higher in tumors with a high gene copy number than in those with a low gene copy number. Low-grade peripheral edema and nausea were the main toxic effects. Show less
Desmoid tumours (also called deep or aggressive fibromatoses) are potentially life-threatening fibromatous lesions. Hereditary desmoid tumours arise in individuals affected by either familial... Show moreDesmoid tumours (also called deep or aggressive fibromatoses) are potentially life-threatening fibromatous lesions. Hereditary desmoid tumours arise in individuals affected by either familial adenomatous polyposis (FAP) or hereditary desmoid disease (HDD) carrying germline mutations in APC. Most sporadic desmoids carry somatic mutations in CTNNB1. Previous studies identified losses on 5q and 6q, and gains on 8q and 20q as recurrent genetic changes in desmoids. However, virtually all genetic changes were derived from sporadic tumours. To investigate the somatic alterations in FAP-associated desmoids and to compare them with changes occurring in sporadic tumours, we analysed 17 FAP-associated and 38 sporadic desmoids by array comparative genomic hybridisation and multiple ligation-dependent probe amplification. Overall, the desmoids displayed only a limited number of genetic changes, occurring in 44% of cases. Recurrent gains at 8q (7%) and 20q (5%) were almost exclusively found in sporadic tumours. Recurrent losses were observed for a 700 kb region at 5q22.2, comprising the APC gene (11%), a 2 Mb region at 6p21.2-p21.1 (15%), and a relatively large region at 6q15-q23.3 (20%). The FAP-associated desmoids displayed a significantly higher frequency of copy number abnormalities (59%) than the sporadic tumours (37%). As predicted by the APC germline mutations among these patients, a high percentage (29%) of FAP-associated desmoids showed loss of the APC region at 5q22.2, which was infrequently (3%) seen among sporadic tumours. Our data suggest that loss of region 6q15-q16.2 is an important event in FAP-associated as well as sporadic desmoids, most likely of relevance for desmoid tumour progression. Show less
