Response to first-line pembrolizumab in metastatic KRAS-mutated non-small-cell lung cancer.

Aims: This retrospective study aims to identify a possible predictive role of KRAS mutations in non-small-cell lung cancer in response to first-line pembrolizumab, either as monotherapy or combined with chemotherapy. Methods: Patients received pembrolizumab alone (n = 213) or associated with chemotherapy (n = 81). Results: A mutation in the KRAS gene was detected in 27% of patients. In patients on pembrolizumab alone, median progression-free survival in KRAS-mutated cases was longer than in wild-type cases (11.3 vs 4.4 months; p = 0.019), whereas median overall survival did not reach statistical significance (22.1 vs 12.5 months; p = 0.119). Patients receiving chemo-immunotherapy with KRAS-positive tumors had a similar progression-free survival (9.7 vs 7.3 months; p = 0.435); overall survival data were immature. Conclusion: This study suggests a correlation between KRAS status and response to pembrolizumab.

Circulating tumor DNA to guide diagnosis and treatment of localized and locally advanced non-small cell lung cancer.

Liquid biopsy is a minimally invasive method for biomarkers detection in body fluids, particularly in blood, which offers an elevated and growing number of clinical applications in oncology. As a result of the improvement in the techniques for DNA analysis, above all next-generation sequencing (NGS) assays, circulating tumor DNA (ctDNA) has become the most informing tumor-derived material for most types of cancer, including non-small cell lung cancer (NSCLC). Although ctDNA concentration is higher in patients with advanced tumors, it can be detected even in patients with early-stage disease. Therefore, numerous clinical applications of ctDNA in the management of early-stage lung cancer are emerging, such as lung cancer screening, the identification of minimal residual disease (MRD), and the prediction of relapse before radiologic progression. Moreover, a high number of clinical trials are ongoing to better define the impact of ctDNA evaluation in this setting. Aim of this review is to offer a comprehensive overview of the most relevant implementations in using ctDNA for the management of early-stage lung cancer, addressing available data, technical aspects, limitations, and future perspectives.

Current treatment approaches for brain metastases in ALK/ROS1/NTRK-positive non-small-cell lung cancer.

INTRODUCTION: Oncogene-addicted non-small cell lung cancer (NSCLC) patients present a high incidence of CNS metastases either at diagnosis or during the course of the disease. In this case, patients present with worse prognosis and are often excluded from clinical trials unless brain metastases are pre-treated or clinically stable. AREAS COVERED: As a result of the discovery of several oncogenic drivers in ALK/ROS1/NTRK-positive NSCLC, targeted agents have been tested in several trials. We evaluate and compare the intracranial efficacy of available targeted agents in ALK/ROS1/NTRK-positive NSCLC based on subgroup analysis from pivotal trials. EXPERT OPINION: Last-generation ALK inhibitors have shown slightly superior intracranial activity but pivotal trials do not consider the same endpoints for intracranial efficacy, therefore data are not comparable. Local treatments for BM including surgical resection, stereotactic radiosurgery (SRS) and WBRT, should be integrated with systemic therapies basing on specific criteria like presence of oligoprogression or symptomatic progression.

The Era of Immunotherapy in Small-Cell Lung Cancer: More Shadows Than Light?

Small-cell lung cancer is an extremely chemo-sensitive disease; the addition of immunotherapy to chemotherapy has demonstrated a slight clinical benefit in pivotal trials, even with a statistically significant difference in terms of survival outcomes when compared to chemotherapy alone. In this scenario, the role of radiotherapy as a consolidation treatment in thoracic disease or as a prophylactic therapy in the brain should be clarified. In addition, due to the frailty and the poor prognostic characteristics of these patients, the need for predictive biomarkers that could support the use of immunotherapy is crucial. PD-L1 and TMB are not actually considered definitive biomarkers due to the heterogeneity of results in the literature. A new molecular classification of small-cell lung cancer based on the expression of key transcription factors seems to clarify the disease behavior, but the knowledge of this molecular subtype is still insufficient and the application in clinical practice far from reality; this classification could lead to a better understanding of SCLC disease and could provide the right direction for more personalized treatment. The aim of this review is to investigate the current knowledge in this field, evaluating whether there are predictive biomarkers and clinical patient characteristics that could help us to identify those patients who are more likely to respond to immunotherapy.