Important advancements in the treatment of non-small cell lung cancer (NSCLC) have been achieved over the past two decades, increasing our understanding of the disease biology and mechanisms of ...tumour progression, and advancing early detection and multimodal care. The use of small molecule tyrosine kinase inhibitors and immunotherapy has led to unprecedented survival benefits in selected patients. However, the overall cure and survival rates for NSCLC remain low, particularly in metastatic disease. Therefore, continued research into new drugs and combination therapies is required to expand the clinical benefit to a broader patient population and to improve outcomes in NSCLC.
Worldwide, lung cancer is the most common cause of cancer-related deaths. Molecular targeted therapies and immunotherapies for non-small-cell lung cancer (NSCLC) have improved outcomes markedly over ...the past two decades. However, the vast majority of advanced NSCLCs become resistant to current treatments and eventually progress. In this Perspective, we discuss some of the recent breakthrough therapies developed for NSCLC, focusing on immunotherapies and targeted therapies. We highlight our current understanding of mechanisms of resistance and the importance of incorporating genomic analyses into clinical studies to decipher these further. We underscore the future role of neoadjuvant and maintenance combination therapy approaches to potentially cure early disease. A major challenge to successful development of rational combination therapies will be the application of robust predictive biomarkers for clear-cut patient stratification, and we provide our views on clinical research areas that could influence how NSCLC will be managed over the coming decade.
The treatment landscape of driver-negative non-small-cell lung cancer (NSCLC) is rapidly evolving. Immune-checkpoint inhibitors, specifically those targeting PD-1 or PD-L1, have demonstrated durable ...efficacy in a subset of patients with NSCLC, and these agents have become the cornerstone of first-line therapy. Approved immunotherapeutic strategies for treatment-naive patients now include monotherapy, immunotherapy-exclusive regimens or chemotherapy-immunotherapy combinations. Decision making in this space is complex given the absence of head-to-head prospective comparisons, although a thorough analysis of long-term efficacy and safety data from pivotal clinical trials can provide insight into the optimal management of each subset of patients. Indeed, histological subtype and the extent of tumour cell PD-L1 expression are paramount to regimen selection, although other clinicopathological factors and patient preferences might also be relevant in certain scenarios. Finally, several emerging biomarkers and novel therapeutic strategies are currently under investigation, and these might further refine the current treatment paradigm. In this Review, we discuss the current treatment landscape and detail our approach to first-line immunotherapy regimen selection for patients with advanced-stage, driver-negative NSCLC.
The past decade has been transformative for lung cancer patients, physicians, and scientists. The discovery of EGFR mutations that confer sensitivity to tyrosine kinase inhibitors in lung ...adenocarcinomas in 2004 heralded the beginning of the era of precision medicine for lung cancer. Indeed, it precipitated concerted efforts by many investigators to define molecular subgroups of lung cancer, characterize the genomic landscape of lung cancer subtypes, identify novel therapeutic targets, and define mechanisms of sensitivity and resistance to targeted therapies. The fruits of these efforts are visible every day now in lung cancer clinics: Patients receive molecular testing to determine whether their tumor harbors an actionable mutation, new and improved targeted therapies that can overcome resistance to first-generation drugs are in clinical trials, and drugs targeting the immune system are showing activity in patients. This extraordinary promise is tempered by the sobering fact that even the newest treatments for metastatic disease are rarely curative and are effective only in a small fraction of all patients. Ongoing and future efforts to find new vulnerabilities of lung cancers, unravel the complexity of drug resistance, increase the efficacy of immunotherapies, and perform biomarker-driven clinical trials are necessary to improve outcomes for patients with lung cancer.
Immune-checkpoint inhibitors (ICI), particularly inhibitors of the PD-1 axis, have altered the management of non-small cell lung cancer (NSCLC) over the last 10 years. First demonstrated to improve ...outcomes in second-line or later therapy of advanced disease, ICIs were shown to improve overall survival compared with chemotherapy in first-line therapy for patients whose tumors express PD-L1 on at least 50% of cells. More recently, combining ICIs with chemotherapy has been shown to improve survival in patients with both squamous and nonsquamous NSCLC, regardless of PD-L1 expression. However, PD-L1 and, more recently, tumor mutational burden have not proven to be straightforward indicative biomarkers. We describe the advances to date in utilizing these biomarkers, as well as novel markers of tumor inflammation, to ascertain which patients are most likely to benefit from ICIs. Ongoing translational work promises to improve the proportion of patients who benefit from these agents.
Despite the unprecedented tumor regression and long-term survival benefit observed with anti-programmed death (PD) anti-PD-1 or anti-B7-homolog 1 (B7-H1) therapy in patients with advanced cancers, a ...large portion of patients do not benefit from such treatment and a fraction of responders relapse. Current efforts to overcome resistance and improve efficacy of anti-PD therapy require a clear understanding of resistance and should precede current avenues using random combinations with available treatment regimens. Here, we categorized three types of resistance, namely target-missing, primary, and acquired resistance. This categorization requires reliable, accurate tissue sampling and appropriate interpretation of results based on the four classifications of tumor immunity in the microenvironment (TIME). We believe that fundamental understanding of these complex tumor-immune interactions and of the cellular and molecular mechanisms underlying these types of true resistance is the key for targeting the right targets in combination with or beyond anti-PD therapy in the future.
Recently, anti-PD therapy has taken center stage for the treatment of cancer, especially for solid tumors.
While anti-PD therapy is highly effective in some patients (response), others do not respond (resistance).
A proper understanding of the tumor microenvironment, both in terms of PD-L1/B7-H1 expression and of immune infiltration, is critical to separate true primary resistance from ‘target-missing’ resistance.
Additionally, acquired resistance may occur in some relapsing patients, although its causes and markers remain ill-defined.
Clear definitions and mechanistic understanding of these distinct resistances will be critical to improve the efficacy of cancer immunotherapy.
Decisions to continue or suspend therapy with immune checkpoint inhibitors are commonly guided by tumor dynamics seen on serial imaging. However, immunotherapy responses are uniquely challenging to ...interpret because tumors often shrink slowly or can appear transiently enlarged due to inflammation. We hypothesized that monitoring tumor cell death in real time by quantifying changes in circulating tumor DNA (ctDNA) levels could enable early assessment of immunotherapy efficacy.
We compared longitudinal changes in ctDNA levels with changes in radiographic tumor size and with survival outcomes in 28 patients with metastatic non-small cell lung cancer (NSCLC) receiving immune checkpoint inhibitor therapy. CtDNA was quantified by determining the allele fraction of cancer-associated somatic mutations in plasma using a multigene next-generation sequencing assay. We defined a ctDNA response as a >50% decrease in mutant allele fraction from baseline, with a second confirmatory measurement.
Strong agreement was observed between ctDNA response and radiographic response (Cohen's kappa, 0.753). Median time to initial response among patients who achieved responses in both categories was 24.5 days by ctDNA versus 72.5 days by imaging. Time on treatment was significantly longer for ctDNA responders versus nonresponders (median, 205.5 vs. 69 days;
< 0.001). A ctDNA response was associated with superior progression-free survival hazard ratio (HR), 0.29; 95% CI, 0.09-0.89;
= 0.03, and superior overall survival (HR, 0.17; 95% CI, 0.05-0.62;
= 0.007).
A drop in ctDNA level is an early marker of therapeutic efficacy and predicts prolonged survival in patients treated with immune checkpoint inhibitors for NSCLC.
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Disturbances in mechanisms that direct abnormal cells to undergo apoptosis frequently and critically contribute to tumorigenesis, yielding a logical target for potential therapeutic intervention. ...There is currently heightened interest in the extrinsic apoptosis pathway, with several proapoptotic receptor agonists (PARAs) in development. The PARAs include the ligand recombinant human Apo2L/TRAIL and agonistic mAbs. Mechanistic and preclinical data with Apo2L/TRAIL indicate exciting opportunities for synergy with conventional therapies and for combining PARAs with other molecularly targeted agents. Novel molecular biomarkers may help identify those patients most likely to benefit from PARA therapy.
The epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein that constitutes one of four members of the erbB family of tyrosine kinase receptors. Binding of EGFR to its cognate ...ligands leads to autophosphorylation of receptor tyrosine kinase and subsequent activation of signal transduction pathways that are involved in regulating cellular proliferation, differentiation, and survival. Although present in normal cells, EGFR is overexpressed in a variety of tumor cell lines and has been associated with poor prognosis and decreased survival. EGFR activation also plays a role in resistance to chemotherapy and radiation treatment in tumor cells. Over the past two decades, much effort has been directed at developing anticancer agents that can interfere with EGFR activity. The most common pharmacologic approaches to inhibiting EGFR have been to develop monoclonal antibodies and small-molecule inhibitors. Monoclonal antibodies block ligand binding to the extracellular domain, whereas the small-molecule inhibitors exert their effects at the intracellular portion of the receptor to prevent tyrosine kinase phosphorylation and subsequent activation of signal transduction pathways. A number of EGFR inhibitors have been developed that can arrest tumor growth and, in some cases, cause tumor regression. When used in combination with cytotoxic treatments, chemotherapy, and radiation, EGFR inhibitors have been able to potentiate their anticancer activity.
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