Endosonography With or Without Confirmatory Mediastinoscopy for Resectable Lung Cancer:A Randomized Clinical Trial

PURPOSE:Resectable non-small-cell lung cancer (NSCLC) with a high probability of mediastinal nodal involvement requires mediastinal staging by endosonography and, in the absence of nodal metastases, confirmatory mediastinoscopy according to current guidelines. However, randomized data regarding immediate lung tumor resection after systematic endosonography versus additional confirmatory mediastinoscopy before resection are lacking.METHODS:Patients with (suspected) resectable NSCLC and an indication for mediastinal staging after negative systematic endosonography were randomly assigned to immediate lung tumor resection or confirmatory mediastinoscopy followed by tumor resection. The primary outcome in this noninferiority trial (noninferiority margin of 8% that previously showed to not compromise survival, Pnoninferior &lt;.0250) was the presence of unforeseen N2 disease after tumor resection with lymph node dissection. Secondary outcomes were 30-day major morbidity and mortality.RESULTS:Between July 17, 2017, and October 5, 2020, 360 patients were randomly assigned, 178 to immediate lung tumor resection (seven dropouts) and 182 to confirmatory mediastinoscopy first (seven dropouts before and six after mediastinoscopy). Mediastinoscopy detected metastases in 8.0% (14/175; 95% CI, 4.8 to 13.0) of patients. Unforeseen N2 rate after immediate resection (8.8%) was noninferior compared with mediastinoscopy first (7.7%) in both intention-to-treat (Δ, 1.03%; UL 95% CIΔ, 7.2%; Pnoninferior =.0144) and per-protocol analyses (Δ, 0.83%; UL 95% CIΔ, 7.3%; Pnoninferior =.0157). Major morbidity and 30-day mortality was 12.9% after immediate resection versus 15.4% after mediastinoscopy first (P =.4940).CONCLUSION:On the basis of our chosen noninferiority margin in the rate of unforeseen N2, confirmatory mediastinoscopy after negative systematic endosonography can be omitted in patients with resectable NSCLC and an indication for mediastinal staging.</p

Non-small-cell lung cancer infiltrated with chronic myelomonocytic leukaemia: a molecular diagnostic challenge to recognise mixed cancers in a single biopsy

Molecular profiling techniques such as targeted next-generation sequencing (NGS) have become increasingly important in routine cancer diagnostics. Genomic alterations that are characteristic in certain malignancies are sometimes also detected in other cancers. Detection of rare variants may challenge the initial diagnosis or uncover a co-existing malignancy.1,2 We report on a non-small cell lung cancer (NSCLC) case with an oncogenic mutation in PIK3CA, and unusual mutations in both MET and IDH2, of which the last was shown to originate from tumor-infiltrating chronic myelomonocytic leukemia (CMML)

Safety and tolerability of stereotactic radiotherapy combined with durvalumab with or without tremelimumab in advanced non-small cell lung cancer, the phase I SICI trial

INTRODUCTION: This phase I study primarily addresses the safety and tolerability of Stereotactic radiotherapy on the primary tumor combined with double Immune Checkpoint Inhibition (SICI) in patients with non-small cell lung cancer (NSCLC). Increasing the release of neoantigens by radiotherapy might enhance response to immunotherapy. Especially, by targeting trunk mutations in the primary tumor. MATERIALS AND METHODS: In three sequential cohorts, immunotherapy regimes combined with stereotactic body radiotherapy (SBRT) on the primary tumor (1x20 Gy on 9 cc) were studied in stage IIIB/IV NSCLC patients progressing on chemotherapy. The first cohort (n = 3) received durvalumab. The second (n = 6) received a combination of tremelimumab and durvalumab followed by durvalumab monotherapy. The third cohort (n = 6) was similar except that the combination was reversed. Descriptive statistics were used to assess safety parameters and the exploratory outcomes of efficacy. Adverse events were reported using NCI CTCAE version 4.03. Exhaled breath was analyzed at baseline. RESULTS: Fifteen patients were included. Median irradiated volume was 9.13 cc, on a median primary tumor volume of 79 cc. There were seven patients with grade 1-2, and two patients with grade 3 treatment related adverse events. There was 1 dose limiting toxicity (colitis) with double immunotherapy. CONCLUSION: The combination of SBRT to the primary tumor and double immunotherapy in advanced NSCLC patients is safe and feasible

The additional diagnostic value of virtual bronchoscopy navigation in patients with pulmonary nodules: The NAVIGATOR study

BACKGROUND: The number of solitary pulmonary nodules to be evaluated is expected to increase and therefore we need to improve diagnostic and therapeutic tools to approach these nodules. To prevent patients from futile invasive procedures and receiving treatment without histological confirmation of cancer, we evaluated the value of virtual bronchoscopy navigation to obtain a diagnosis of the solitary pulmonary nodule in a real-world clinical setting. METHODS: In the NAVIGATOR single center, prospective, observational cohort study patients underwent a virtual bronchoscopy navigation procedure with or without guide sheet tunnelling to assess a solitary pulmonary nodule. Nodules were considered not accessible if a diagnosis could not be obtained by either by CT-guided transthoracic biopsy or conventional bronchoscopy. RESULTS: Between February 2021 and January 2022 35 patients underwent the virtual bronchoscopy navigation procedure. The overall diagnostic yield was 77% and was dependent on size of the nodule and chosen path, with highest yield in lesions with an airway path. Adverse events were few and manageable. CONCLUSION: Virtual bronchoscopy navigation with or without sheet tunnelling is a new technique with a good diagnostic yield, also in patients in whom previously performed procedures failed to establish a diagnosis and/or alternative procedures are considered not feasible based on expected yield and/or safety. Preventing futile or more invasive procedures like surgery or transthoracic punctures with a higher complication rate is beneficial for patients, and allowed treatment adaptation in two-third of the analyzed patient population

High dose osimertinib in patients with advanced stage EGFR exon 20 mutation-positive NSCLC: Results from the phase 2 multicenter POSITION20 trial

Introduction: Patients with life-threatening advanced non-small cell lung cancer (NSCLC) who harbor an exon 20 deletion and/or insertion mutation (EGFRex20 + ) have limited effective treatment options. The high dose 3rd generation tyrosine kinase inhibitor (TKI) osimertinib shows promising in vitro activity in EGFRex20 + NSCLC tumors. Methods: The POSITION20 is a single arm phase II, multicenter study investigating 160 mg osimertinib in patients with EGFRex20+, T790M negative NSCLC. We allowed patients to be treatment naïve and to have asymptomatic brain metastases. The primary endpoint was overall response rate (ORR). Secondary outcomes were duration of response (DoR), progression free survival (PFS), overall survival (OS), and treatment related adverse events (trAEs). Results: From June 2018 to October 2021, 25 patients were enrolled across five centers in the Netherlands. The median age was 70 years (range, 47–87), 20 patients (80%) were women, and the median number of previous lines of therapy was 1 (range, 0–3). The exon 20 mutations were clustered between A763 and L777. The most common exon 20 mutations were p.(N771_H773dup) (n = 3) and p.(A767_V769dup) (n = 3). The ORR was 28% (95% CI, 12–49%), including seven partial responses, with a median DoR of 5.3 months (range, 2.7–27.6). The median PFS was 6.8 months (95% CI, 4.6–9.1) and the median OS was 15.2 months (95% CI, 14.3–16.0). The most common trAEs were diarrhea (72%), dry skin (44%), and fatigue (44%). The primary reason for discontinuation was progressive disease in 14 patients (56%). Conclusion: The POSITION20 study showed modest antitumor activity in patients with EGFRex20 + NSCLC treated with 160 mg osimertinib, with a confirmed ORR of 28% and acceptable toxicity

High dose osimertinib in patients with advanced stage EGFR exon 20 mutation-positive NSCLC:Results from the phase 2 multicenter POSITION20 trial

Introduction: Patients with life-threatening advanced non-small cell lung cancer (NSCLC) who harbor an exon 20 deletion and/or insertion mutation (EGFRex20 + ) have limited effective treatment options. The high dose 3rd generation tyrosine kinase inhibitor (TKI) osimertinib shows promising in vitro activity in EGFRex20 + NSCLC tumors. Methods: The POSITION20 is a single arm phase II, multicenter study investigating 160 mg osimertinib in patients with EGFRex20+, T790M negative NSCLC. We allowed patients to be treatment naïve and to have asymptomatic brain metastases. The primary endpoint was overall response rate (ORR). Secondary outcomes were duration of response (DoR), progression free survival (PFS), overall survival (OS), and treatment related adverse events (trAEs). Results: From June 2018 to October 2021, 25 patients were enrolled across five centers in the Netherlands. The median age was 70 years (range, 47–87), 20 patients (80%) were women, and the median number of previous lines of therapy was 1 (range, 0–3). The exon 20 mutations were clustered between A763 and L777. The most common exon 20 mutations were p.(N771_H773dup) (n = 3) and p.(A767_V769dup) (n = 3). The ORR was 28% (95% CI, 12–49%), including seven partial responses, with a median DoR of 5.3 months (range, 2.7–27.6). The median PFS was 6.8 months (95% CI, 4.6–9.1) and the median OS was 15.2 months (95% CI, 14.3–16.0). The most common trAEs were diarrhea (72%), dry skin (44%), and fatigue (44%). The primary reason for discontinuation was progressive disease in 14 patients (56%). Conclusion: The POSITION20 study showed modest antitumor activity in patients with EGFRex20 + NSCLC treated with 160 mg osimertinib, with a confirmed ORR of 28% and acceptable toxicity