Acquisition of immortality as a hallmark of malignant transformation is achieved by telomerase reactivation in the majority of human cancers. Point mutations in the telomerase reverse transcriptase (TERT) gene promoter were recently discovered as one fundamental driver of this process correlating with worse prognosis in several cancer types. The potential role of these mutations in human malignant pleural mesothelioma (MPM) aggressiveness was unknown far. Here we show that presence of TERT promoter mutations identifies a distinct MPM patient subgroup with extremely dismal prognosis. The respective MPM cell explants with TERT promoter mutations are characterized by a profoundly enhanced in vitro immortalization potential, reduced chromosomal instability and a specific mutation/deletion pattern compared to the wild-type counterparts. Consequently, our MPM-based results indicate a unique way of malignant transformation of TERT promoter-mutated tumors which has broad implications also for multiple other cancer types harboring this non-coding genomic alteration.Research.

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Introduction: Rearranged during transfection (RET) gene fusions are rare genetic drivers in non-small cell lung cancer (NSCLC). Selective RET-inhibitors such as selpercatinib have shown therapeutic activity in early clinical trials; however, their efficacy in the real-world setting is unknown. Methods: A retrospective efficacy and safety analysis was performed on data from RET fusion-positive NSCLC patients who participated in a selpercatinib access program (named patient protocol) between August 2019 and January 2021. Results: Data from 50 patients with RET fusion-positive advanced NSCLC treated with selpercatinib at 27 centers in 12 countries was analyzed. Most patients were Non-Asian (90%), female (60%), never-smokers (74%), with a median age of 65 years (range, 38–89). 32% of the patients had known brain metastasis at the time of selpercatinib treatment. Overall, 13 patients were treatment-naïve, while 37 were pretreated with a median of three lines of therapy (range, 1–8). The objective response rate (ORR) was 68% [95% confidence interval (CI), 53–81] in the overall population. The disease control rate was 92%. The median progression-free survival was 15.6 months (95% CI, 8.8–22.4) after a median follow-up of 9 months. In patients with measurable brain metastases ( n = 8) intracranial ORR reached 100%. In total, 88% of patients experienced treatment-related adverse events (TRAEs), a large majority of them being grade 1 or 2. The most common grade ⩾ 3 TRAEs were increased liver enzyme levels (in 10% of patients), prolonged QTc time (4%), abdominal pain (4%), hypertension (4%), and fatigue/asthenia (4%). None of patients discontinued selpercatinib treatment for safety reasons. No new safety concerns were observed, nor where there any treatment-related death. Conclusions: In this real-world setting, the selective RET-inhibitor selpercatinib demonstrated durable systemic and intracranial antitumor activity in RET fusion-positive NSCLC and was well tolerated.

Introduction: RANKL stimulates NF-kB-dependent cell-signalling and acts as the primary signal for bone resorption. Retrospective analysis of a large trial comparing denosumab versus zoledronic acid in bone metastatic solid tumours suggested significant overall survival (OS) advantage for lung cancer patients with denosumab. The randomised open-label phase III SPLENDOUR trial was designed to evaluate whether the addition of denosumab to standard first-line platinum-based doublet chemotherapy improves OS in advanced NSCLC. Methods:Stage IV NSCLC patients were randomised 1:1 to either chemotherapy with or without denosumab (120mg every 3-4 weeks), stratified by presence of bone metastases (at diagnosis), ECOG performance status, histology and region. To detect an OS increase from 9-11.25 months (HR=0.80), 847 OS events were required. The trial closed prematurely due to decreasing accrual rate.Results: 514 patients were randomised, 509 receiving ≥1 dose of assigned treatment (chemotherapy:252, chemotherapy-denosumab:257). Median age was 66.1 years, 71% male, 59% former smokers. Bone metastases were identified in 275(53%) patients. Median OS(95%CI) was 8.7(7.6-11.0) in the control versus 8.2(7.5-10.4) months in the chemotherapy-denosumab-arm, Addition of denosumab to first-line platinum-based doublet chemotherapy in advanced NSCLC 4 (HR=0.96;95%CI:[0.78-1.19]; 1-sided P=0.36). For patients with bone metastasis HR=1.02(95%CI:[0.77-1.35]), while for those without HR=0.90(95%CI:[0.66-1.23]). Grade≥3 adverse events were observed in 40.9%/5.2%/8.7% versus 45.5%/10.9%/10.5% of patients.Conditional power for OS benefit was ≤10%.Conclusions: Denosumab was well tolerated without unexpected safety concerns. There was no OS improvement for denosumab when added to chemotherapy in the ITT, and in the subgroups with and without bone metastases. Our data do not provide evidence of a clinical benefit for denosumab in NSCLC patients without bone metastases.

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.