Hirva Mamdani

Over the past decade, lung cancer treatment has undergone a major paradigm shift. A greater understanding of lung cancer biology has led to the development of many effective targeted therapies as well as of immunotherapy. Immune checkpoint inhibitors (ICIs) have shown tremendous benefit in the treatment of non-small cell lung cancer (NSCLC) and are now being used as first-line therapies in metastatic disease, consolidation therapy following chemoradiation in unresectable locally advanced disease, and adjuvant therapy following surgical resection and chemotherapy in resectable disease. Despite these benefits, predicting who will respond to ICIs has proven to be difficult and there remains a need to discover new predictive immunotherapy biomarkers. Furthermore, resistance to ICIs in lung cancer is frequent either because of a lack of response or disease progression after an initial response. The utility of ICIs in the treatment of small cell lung cancer (SCLC) remains limited to first-line treatment of extensive stage disease in combination with chemotherapy with modest impact on overall survival. It is thus important to explore and exploit additional targets to reap the full benefits of immunotherapy in the treatment of lung cancer. Here, we will summarize the current state of immunotherapy in lung cancer, discuss novel targets, and explore the intersection between DNA repair defects and immunotherapy.

PURPOSE: To provide evidence-based recommendations updating the 2020 ASCO and Ontario Health (Cancer Care Ontario) guideline on systemic therapy for patients with stage IV non-small-cell lung cancer without driver alterations. METHODS: ASCO updated recommendations on the basis of an ongoing systematic review of randomized clinical trials from 2018 to 2021. RESULTS: This guideline update reflects changes in evidence since the previous update. Five randomized clinical trials provide the evidence base. Outcomes of interest include efficacy and safety. RECOMMENDATIONS: In addition to 2020 options for patients with high programmed death ligand-1 (PD-L1) expression (tumor proportion score [TPS] ≥ 50%), nonsquamous cell carcinoma (non-SCC), and performance status (PS) 0-1, clinicians may offer single-agent atezolizumab. With high PD-L1 expression (TPS ≥ 50%), non-SCC, and PS 0-1, clinicians may offer nivolumab and ipilumumab alone or nivolumab and ipilimumab plus chemotherapy. With negative (0%) and low positive PD-L1 expression (TPS 1%-49%), non-SCC, and PS 0-1, clinicians may offer nivolumab and ipilimumab alone or nivolumab and ipilimumab plus chemotherapy. With high PD-L1 expression, SCC, and PS 0-1, clinicians may offer single-agent atezolizumab. With high PD-L1 expression, squamous cell carcinoma (SCC), and PS 0-1, clinicians may offer nivolumab and ipilimumab alone or in combination with two cycles of platinum-based chemotherapy. With negative and low positive PD-L1 expression, SCC, and PS 0-1, clinicians may offer nivolumab and ipilimumab alone or in combination with two cycles of platinum-based chemotherapy. With non-SCC who received an immune checkpoint inhibitor and chemotherapy as first-line therapy, clinicians may offer second-line paclitaxel plus bevacizumab. With non-SCC, who received chemotherapy with or without bevacizumab and immune checkpoint inhibitor therapy, clinicians should offer the options of third-line single-agent pemetrexed, docetaxel, or paclitaxel plus bevacizumab.Additional information is available at www.asco.org/thoracic-cancer-guidelines.

Living guidelines are routinely updated guidelines that are developed for selected topic areas with rapidly evolving evidence that drives frequent change in clinical practice. These guidelines are updated on a regular schedule, based on the work of a standing panel that reviews the literature on a continuous basis. Updates will be made regularly and can be found at https://ascopubs.org/nsclc-da-living-guideline . PURPOSE To provide evidence-based recommendations updating the 2021 ASCO and Ontario Health (Cancer Care Ontario) guideline on systemic therapy for patients with stage IV non–small-cell lung cancer (NSCLC) with driver alterations. METHODS ASCO updated recommendations on the basis of an ongoing systematic review of randomized control trials from 2020 to 2021. RESULTS This guideline update reflects changes in evidence since the previous update. Two studies provide the evidence base. Outcomes of interest include efficacy and safety. RECOMMENDATIONS For patients with an anaplastic lymphoma kinase rearrangement, a performance status (PS) of 0-2, and previously untreated NSCLC, clinicians should offer alectinib or brigatinib or lorlatinib. For patients with an anaplastic lymphoma kinase rearrangement, a PS of 0-2, and previously untreated NSCLC, if alectinib, brigatinib, or lorlatinib are not available, clinicians should offer ceritinib or crizotinib. For patients with a RET rearrangement, a PS of 0-2, and previously untreated NSCLC, clinicians may offer selpercatinib or pralsetinib. In second line, for patients with a RET rearrangement who have not received RET-targeted therapy, clinicians may offer selpercatinib or pralsetinib. Additional information is available at www.asco.org/thoracic-cancer-guidelines .

Epigenetic modulation, including acetylation, methylation, phosphorylation, and ubiquitination, plays a pivotal role in regulation of gene expression. Histone acetylation-a balance between the activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs)-is one of the key epigenetic events. Our understanding of the role of HDACs in cancer is evolving. A number of HDAC isoenzymes are overexpressed in a variety of malignancies. Aberrant histone acetylation is associated with dysregulation of tumor suppressor genes leading to development of several solid tumors and hematologic malignancies. Pre-clinical studies have demonstrated that HDAC-1 gene expression is associated with lung cancer progression. Histone hypoacetylation is associated with more aggressive phenotype in adenocarcinoma of the lung. HDAC inhibitors (HDACi) have pleiotropic cellular effects and induce the expression of pro-apoptotic genes/proteins, cause cellular differentiation and/or cell cycle arrest, inhibit angiogenesis, and inhibit transition to a mesenchymal phenotype. Consequently, treatment with HDACi has shown anti-proliferative activity in non-small cell lung cancer (NSCLC) cell lines. Despite promising results in pre-clinical studies, HDACi have shown only modest single agent activity in lung cancer clinical trials. HDAC activation has been implicated as one of the mechanisms causing resistance to chemotherapy, molecularly targeted therapy, and immune checkpoint inhibition. Therefore, there is a growing interest in combining HDACi with these agents to enhance their efficacy or reverse resistance. In this paper, we review the available preclinical and clinical evidence for the use of HDACi in NSCLC. We also review the challenges precluding widespread clinical utility of HDACi as a cancer therapy and future directions.

The therapeutic landscape of lung cancer has expanded significantly over the past decade. Advancements in molecularly targeted therapies, strategies to discover and treat resistance mutations, and development of personalized cancer treatments in the context of tumor heterogeneity and dynamic tumor biology have made it imperative to obtain tumor samples on several different occasions through the course of patient treatment. While this approach is critical to the delivery of optimal cancer treatment, it is fraught with a number of barriers including the need for invasive procedures with associated complications, access to limited amount of tissue, logistical delays in obtaining the biopsy, high healthcare cost, and in many cases inability to obtain tissue because of technically difficult location of the tumor. Given multiple limitations of obtaining tissue samples, the use of blood-based biomarkers ("liquid biopsies") may enable earlier diagnosis of cancer, lower costs by avoiding complex invasive procedures, tailoring molecular targeted treatments, improving patient convenience, and ultimately supplement clinical oncologic decision-making. In this paper, we review various blood-based biomarkers including circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), tumor derived exosomes, tumor educated platelets (TEPs), and microRNA; and highlight current evidence for their use in detection and treatment of lung cancer.