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.

Clinical Utility of Targeted Sequencing in Lung Cancer: Experience From an Autonomous Swedish Health Care Center.

OBJECTIVES: Mutation analysis by massive parallel sequencing (MPS) is routinely performed in the clinical management of lung cancer in Sweden. We describe the clinical and mutational profiles of lung cancer patients subjected to the first 1.5 years of treatment predictive MPS testing in an autonomous regional health care region. METHODS: Tumors from all patients with lung cancer who had an MPS test from January 2015 to June 2016 in the Skåne health care region in Sweden (1.3 million citizens) were included. Six hundred eleven tumors from 599 patients were profiled using targeted sequencing with a 26-gene exon-focused panel. Data on disease patterns and characteristics of the patients subjected to testing were assembled, and correlations between mutational profiles and clinical features were analyzed. RESULTS: MPS with the 26-gene panel revealed alterations in 92% of the 611 lung tumors, with the most frequent mutations detected in the nontargetable genes TP53 (62%) and KRAS (37%). Neither KRAS nor TP53 mutations were associated with disease pattern, chemotherapy response, progression-free survival, or overall survival in advanced-stage disease treated with platinum-based doublet chemotherapy as a first-line treatment. Among targetable genes, EGFR driver mutations were detected in 10% of the tumors, and BRAF p.V600 variants in 2.3%. For the 71 never smokers (12%), targetable alterations (EGFR mutations, BRAF p.V600, MET exon 14 skipping, or ALK/ROS1 rearrangement) were detected in 59% of the tumors. CONCLUSION: Although the increasing importance of MPS as a predictor of response to targeted therapies is indisputable, its role in prognostics or as a predictor of clinical course in nontargetable advanced stage lung cancer requires further investigation.

Vorinostat in patients with advanced malignant pleural mesothelioma who have progressed on previous chemotherapy (VANTAGE-014): a phase 3, double-blind, randomised, placebo-controlled trial.

BACKGROUND: Vorinostat is a histone deacetylase inhibitor that changes gene expression and protein activity. On the basis of the clinical benefit reported in patients with malignant pleural mesothelioma treated in a phase 1 study of vorinostat, we designed this phase 3 trial to investigate whether vorinostat given as a second-line or third-line therapy improved patients' overall survival. METHODS: This double-blind, randomised, placebo-controlled trial was done in 90 international centres. Patients with measurable advanced malignant pleural mesothelioma and disease progression after one or two previous systemic regimens were eligible. After stratification for Karnofsky performance status, histology, and number of previous chemotherapy regimens, patients were randomly assigned (1:1) by use of an interactive voice response system with a block size of four to either treatment with vorinostat or placebo. Patients received oral vorinostat 300 mg (or matching placebo) twice daily on days 1, 2, 3, 8, 9, 10, 15, 16, and 17 of a 21-day cycle. The primary endpoints were overall survival and safety and tolerability of vorinostat. The primary efficacy comparison was done in the intention-to-treat population, and safety and tolerability was assessed in the treated population. This trial is registered with ClinicalTrials.gov, number NCT00128102. FINDINGS: From July 12, 2005, to Feb 14, 2011, 661 patients were enrolled and randomly assigned to receive either vorinostat (n=329) or placebo (n=332) and included in the intention-to-treat analysis. Median overall survival for vorinostat was 30·7 weeks (95% CI 26·7-36·1) versus 27·1 weeks (23·1-31·9) for placebo (hazard ratio 0·98, 95% CI 0·83-1·17, p=0·86). The most common grade 3 or worse adverse events for patients treated with vorinostat were fatigue or malaise (51 [16%] patients in the vorinostat group vs 25 [8%] in the placebo group]) and dyspnoea (35 [11%] vs 45 [14%]). INTERPRETATION: In this randomised trial, vorinostat given as a second-line or third-line therapy did not improve overall survival and cannot be recommended as a therapy for patients with advanced malignant pleural mesothelioma. FUNDING: Merck & Co.

Diagnostic yield and efficacy of endobronchial ultrasound-guided transbronchial needle aspiration in mediastinal lymphadenopathy.

INTRODUCTION: Endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) is an emerging minimally invasive option for pathologic examination of intrathoracic lymphadenopathy as well as for staging lung cancer. OBJECTIVES: To evaluate the diagnostic yield and possible learning curve effects on diagnostic performance using EBUS-TBNA in mediastinal lymphadenopathy. METHODS: A retrospective analysis was performed on 243 consecutive patients who underwent EBUS-TBNA over a 4-year period. Demographic and clinical data and pathology results were analysed for different time frames in order to evaluate potential learning curve effects. The procedures were performed by two experienced bronchoscopists at a single university medical centre. RESULTS: Samples were representative in 83% (200/243) of the patients. The overall diagnostic yield was 66% (n = 161/243). The diagnostic accuracy of EBUS-TBNA for detecting malignancy was 98.0% and for lung cancer 98.5%. The sensitivity, specificity, positive and negative predictive values for lung cancer stage ≥N1 and malignant disease were 100% for the first three studied periods and slightly less favourable in the most recent study period. Representative samples were obtained more frequently in the latter study periods (P < 0.001). CONCLUSION: EBUS-TBNA is a safe method with a learning curve that is easily overcome, although previous experience with ultrasound may be necessary. The diagnostic yield of EBUS-TBNA is in accordance with previously reported yield of standard cervical mediastinoscopy. At present, however, the relationship between EBUS-TBNA and mediastinoscopy appears to be complementary rather than substitutive.