Substantial advances have been made in understanding critical molecular and cellular mechanisms driving tumor initiation, maintenance, and progression in non-small-cell lung cancer (NSCLC). Over the ...last decade, these findings have led to the discovery of a variety of novel drug targets and the development of new treatment strategies. Already, the standard of care for patients with advanced-stage NSCLC is shifting from selecting therapy empirically based on a patient's clinicopathologic features to using biomarker-driven treatment algorithms based on the molecular profile of a patient's tumor. This approach is currently best exemplified by treating patients with NSCLC with first-line tyrosine kinase inhibitors when their cancers harbor gain-of-function hotspot mutations in the epidermal growth factor receptor (EGFR) gene or anaplastic lymphoma kinase (ALK) gene rearrangements. These genotype-based targeted therapies represent the first step toward personalizing NSCLC therapy. Recent technology advances in multiplex genotyping and high-throughput genomic profiling by next-generation sequencing technologies now offer the possibility of rapidly and comprehensively interrogating the cancer genome of individual patients from small tumor biopsies. This advance provides the basis for categorizing molecular-defined subsets of patients with NSCLC in whom a growing list of novel molecularly targeted therapeutics are clinically evaluable and additional novel drug targets can be discovered. Increasingly, practicing oncologists are facing the challenge of determining how to select, interpret, and apply these new genetic and genomic assays. This review summarizes the evolution, early success, current status, challenges, and opportunities for clinical application of genotyping and genomic tests in therapeutic decision making for NSCLC.
Upfront tumour genotyping is now considered an essential step in guiding treatment decision-making in the management of patients with advanced-stage non-small-cell lung cancer (NSCLC) in light of the ...ever-expanding toolbox of targeted therapies and immune-checkpoint inhibitors. However, genotyping of tumour biopsy samples is not feasible for all patients and, therefore, genomic analysis of circulating tumour DNA (ctDNA) has emerged as a compelling non-invasive option. Current guidelines universally recommend genotyping and support the use of ctDNA testing in certain settings, although they often omit the detail necessary for integrating these tests into clinical care on an individual basis. In this Perspective, we describe the rationale, promise and challenges associated with ctDNA-based NSCLC genotyping and suggest a framework for the implementation of these assays into routine clinical practice. We also offer considerations for the interpretation of ctDNA genotyping results, which, particularly when using next-generation sequencing panels, can be nuanced. Through the addition of this new approach to clinical practice, we propose that oncologists might finally be able to utilize effective genotyping in nearly all patients with advanced-stage NSCLC.
Summary Background Atezolizumab is a humanised antiprogrammed death-ligand 1 (PD-L1) monoclonal antibody that inhibits PD-L1 and programmed death-1 (PD-1) and PD-L1 and B7-1 interactions, ...reinvigorating anticancer immunity. We assessed its efficacy and safety versus docetaxel in previously treated patients with non-small-cell lung cancer. Methods We did a randomised, open-label, phase 3 trial (OAK) in 194 academic or community oncology centres in 31 countries. We enrolled patients who had squamous or non-squamous non-small-cell lung cancer, were 18 years or older, had measurable disease per Response Evaluation Criteria in Solid Tumors, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients had received one to two previous cytotoxic chemotherapy regimens (one or more platinum based combination therapies) for stage IIIB or IV non-small-cell lung cancer. Patients with a history of autoimmune disease and those who had received previous treatments with docetaxel, CD137 agonists, anti-CTLA4, or therapies targeting the PD-L1 and PD-1 pathway were excluded. Patients were randomly assigned (1:1) to intravenously receive either atezolizumab 1200 mg or docetaxel 75 mg/m2 every 3 weeks by permuted block randomisation (block size of eight) via an interactive voice or web response system. Coprimary endpoints were overall survival in the intention-to-treat (ITT) and PD-L1-expression population TC1/2/3 or IC1/2/3 (≥1% PD-L1 on tumour cells or tumour-infiltrating immune cells). The primary efficacy analysis was done in the first 850 of 1225 enrolled patients. This study is registered with ClinicalTrials.gov , number NCT02008227. Findings Between March 11, 2014, and April 29, 2015, 1225 patients were recruited. In the primary population, 425 patients were randomly assigned to receive atezolizumab and 425 patients were assigned to receive docetaxel. Overall survival was significantly longer with atezolizumab in the ITT and PD-L1-expression populations. In the ITT population, overall survival was improved with atezolizumab compared with docetaxel (median overall survival was 13·8 months 95% CI 11·8–15·7 vs 9·6 months 8·6–11·2; hazard ratio HR 0·73 95% CI 0·62–0·87, p=0·0003). Overall survival in the TC1/2/3 or IC1/2/3 population was improved with atezolizumab (n=241) compared with docetaxel (n=222; median overall survival was 15·7 months 95% CI 12·6–18·0 with atezolizumab vs 10·3 months 8·8–12·0 with docetaxel; HR 0·74 95% CI 0·58–0·93; p=0·0102). Patients in the PD-L1 low or undetectable subgroup (TC0 and IC0) also had improved survival with atezolizumab (median overall survival 12·6 months vs 8·9 months; HR 0·75 95% CI 0·59–0·96). Overall survival improvement was similar in patients with squamous (HR 0·73 95% CI 0·54–0·98; n=112 in the atezolizumab group and n=110 in the docetaxel group) or non-squamous (0·73 0·60–0·89; n=313 and n=315) histology. Fewer patients had treatment-related grade 3 or 4 adverse events with atezolizumab (90 15% of 609 patients) versus docetaxel (247 43% of 578 patients). One treatment-related death from a respiratory tract infection was reported in the docetaxel group. Interpretation To our knowledge, OAK is the first randomised phase 3 study to report results of a PD-L1-targeted therapy, with atezolizumab treatment resulting in a clinically relevant improvement of overall survival versus docetaxel in previously treated non-small-cell lung cancer, regardless of PD-L1 expression or histology, with a favourable safety profile. Funding F. Hoffmann-La Roche Ltd, Genentech, Inc.
A widespread approach to modern cancer therapy is to identify a single oncogenic driver gene and target its mutant-protein product (for example, EGFR-inhibitor treatment in EGFR-mutant lung cancers). ...However, genetically driven resistance to targeted therapy limits patient survival. Through genomic analysis of 1,122 EGFR-mutant lung cancer cell-free DNA samples and whole-exome analysis of seven longitudinally collected tumor samples from a patient with EGFR-mutant lung cancer, we identified critical co-occurring oncogenic events present in most advanced-stage EGFR-mutant lung cancers. We defined new pathways limiting EGFR-inhibitor response, including WNT/β-catenin alterations and cell-cycle-gene (CDK4 and CDK6) mutations. Tumor genomic complexity increases with EGFR-inhibitor treatment, and co-occurring alterations in CTNNB1 and PIK3CA exhibit nonredundant functions that cooperatively promote tumor metastasis or limit EGFR-inhibitor response. This study calls for revisiting the prevailing single-gene driver-oncogene view and links clinical outcomes to co-occurring genetic alterations in patients with advanced-stage EGFR-mutant lung cancer.
Cell-free DNA (cfDNA) sequencing provides a noninvasive method for obtaining actionable genomic information to guide personalized cancer treatment, but the presence of multiple alterations in ...circulation related to treatment and tumor heterogeneity complicate the interpretation of the observed variants.
We describe the somatic mutation landscape of 70 cancer genes from cfDNA deep-sequencing analysis of 21,807 patients with treated, late-stage cancers across >50 cancer types. To facilitate interpretation of the genomic complexity of circulating tumor DNA in advanced, treated cancer patients, we developed methods to identify cfDNA copy-number driver alterations and cfDNA clonality.
Patterns and prevalence of cfDNA alterations in major driver genes for non-small cell lung, breast, and colorectal cancer largely recapitulated those from tumor tissue sequencing compendia (The Cancer Genome Atlas and COSMIC;
= 0.90-0.99), with the principal differences in alteration prevalence being due to patient treatment. This highly sensitive cfDNA sequencing assay revealed numerous subclonal tumor-derived alterations, expected as a result of clonal evolution, but leading to an apparent departure from mutual exclusivity in treatment-naïve tumors. Upon applying novel cfDNA clonality and copy-number driver identification methods, robust mutual exclusivity was observed among predicted truncal driver cfDNA alterations (FDR = 5 × 10
for
and
), in effect distinguishing tumor-initiating alterations from secondary alterations. Treatment-associated resistance, including both novel alterations and parallel evolution, was common in the cfDNA cohort and was enriched in patients with targetable driver alterations (>18.6% patients).
Together, these retrospective analyses of a large cfDNA sequencing data set reveal subclonal structures and emerging resistance in advanced solid tumors.
.
Background
Circulating cell‐free tumor DNA (ctDNA)‐based mutation profiling, if sufficiently sensitive and comprehensive, can efficiently identify genomic targets in advanced lung adenocarcinoma. ...Therefore, the authors investigated the accuracy and clinical utility of a commercially available digital next‐generation sequencing platform in a large series of patients with non–small cell lung cancer (NSCLC).
Methods
Plasma‐based comprehensive genomic profiling results from 8388 consecutively tested patients with advanced NSCLC were analyzed. Driver and resistance mutations were examined with regard to their distribution, frequency, co‐occurrence, and mutual exclusivity.
Results
Somatic alterations were detected in 86% of samples. The median variant allele fraction was 0.43% (range, 0.03%‐97.62%). Activating alterations in actionable oncogenes were identified in 48% of patients, including EGFR (26.4%), MET (6.1%), and BRAF (2.8%) alterations and fusions (ALK, RET, and ROS1) in 2.3%. Treatment‐induced resistance mutations were common in this cohort, including driver‐dependent and driver‐independent alterations. In the subset of patients who had progressive disease during EGFR therapy, 64% had known or putative resistance alterations detected in plasma. Subset analysis revealed that ctDNA increased the identification of driver mutations by 65% over standard‐of‐care, tissue‐based testing at diagnosis. A pooled data analysis on this plasma‐based assay demonstrated that targeted therapy response rates were equivalent to those reported from tissue analysis.
Conclusions
Comprehensive ctDNA analysis detected the presence of therapeutically targetable driver and resistance mutations at the frequencies and distributions predicted for the study population. These findings add support for comprehensive ctDNA testing in patients who are incompletely tested at the time of diagnosis and as a primary option at the time of progression on targeted therapies.
Circulating cell‐free tumor DNA‐based liquid biopsy using next‐generation sequencing detects a spectrum of targetable alterations at frequencies expected in patients with advanced non–small cell lung cancer. These findings support the concept of a plasma‐first algorithm at the time of progression on targeted therapy for this population.
As the leading cause of cancer death worldwide, lung cancer continues to impose a major burden on healthcare systems and cause significant challenges for clinicians and patients. Most patients ...present with advanced disease at the time of diagnosis and have a poor prognosis, with the vast majority surviving less than 5 years. Although new therapies have been introduced in recent years that target molecular disease drivers present in a subset of patients, there is a significant need for treatments able to improve response and extend survival while minimizing effects on quality of life. Recent evidence of clinical efficacy for immunotherapeutic approaches for lung cancer suggests that they will become the next major therapeutic advance for this disease. Non–small-cell lung cancer, which accounts for approximately 85% of lung cancer cases, has historically been considered a nonimmunogenic disease; however, as with several other malignancies, recent data show that much of this lack of immune responsiveness is functional rather than structural (i.e., possible to overcome therapeutically). This review explores the key elements of the immune system involved in non–small-cell lung cancer and briefly examines immunotherapeutic strategies in development to shift the balance of immune activity away from a tumor-induced immune-suppressive state toward an active antitumor immune response.
Summary Background Patients with squamous non-small-cell lung cancer that is refractory to multiple treatments have poor outcomes. We assessed the activity of nivolumab, a fully human IgG4 PD-1 ...immune checkpoint inhibitor antibody, for patients with advanced, refractory, squamous non-small-cell lung cancer. Methods We did this phase 2, single-arm trial at 27 sites (academic, hospital, and private cancer centres) in France, Germany, Italy, and USA. Patients who had received two or more previous treatments received intravenous nivolumab (3 mg/kg) every 2 weeks until progression or unacceptable toxic effects. The primary endpoint was the proportion of patients with a confirmed objective response as assessed by an independent radiology review committee. We included all treated patients in the analyses. This study is registered with ClinicalTrials.gov , number NCT01721759. Findings Between Nov 16, 2012, and July 22, 2013, we enrolled and treated 117 patients. 17 (14·5%, 95% CI 8·7–22·2) of 117 patients had an objective response as assessed by an independent radiology review committee. Median time to response was 3·3 months (IQR 2·2–4·8), and median duration of response was not reached (95% CI 8·31–not applicable); 13 (77%) of 17 of responses were ongoing at the time of analysis. 30 (26%) of 117 patients had stable disease (median duration 6·0 months, 95% CI 4·7–10·9). 20 (17%) of 117 patients reported grade 3–4 treatment-related adverse events, including: fatigue (five 4% of 117 patients), pneumonitis (four 3%), and diarrhoea (three 3%). There were two treatment-associated deaths caused by pneumonia and ischaemic stroke that occurred in patients with multiple comorbidities in the setting of progressive disease. Interpretation Nivolumab has clinically meaningful activity and a manageable safety profile in previously treated patients with advanced, refractory, squamous non-small cell lung cancer. These data support the assessment of nivolumab in randomised, controlled, phase 3 studies of first-line and second-line treatment. Funding Bristol-Myers Squibb.
Squamous cell lung cancer (SCC) represents an area of unmet need in lung cancer research. For the past several years, therapeutic progress in SCC has lagged behind the now more common non-small cell ...lung cancer histologic subtype of adenocarcinoma. However, recent efforts to define the complex biology underlying SCC have begun to bear fruit in a multitude of ways, including characterization of previously unknown genomic and signaling pathways, delineation of new, potentially actionable molecular targets, and subsequent development of a large number of agents directed against unique SCC-associated molecular abnormalities. For the first time, SCC-specific prognostic gene signatures and predictive biomarkers of new therapeutic agents are emerging. In addition, recent and ongoing clinical trials, including the Lung-MAP master protocol, have been designed to facilitate approval of targeted therapy-biomarker combinations. In this comprehensive review, we describe the current status of SCC therapeutics, recent advances in the understanding of SCC biology and prognostic gene signatures, and the development of innovative new clinical trials, all of which offer new hope for patients with advanced SCC.
Summary Background Results from phase II studies in patients with stage IIIA non-small-cell lung cancer with ipsilateral mediastinal nodal metastases (N2) have shown the feasibility of resection ...after concurrent chemotherapy and radiotherapy with promising rates of survival. We therefore did this phase III trial to compare concurrent chemotherapy and radiotherapy followed by resection with standard concurrent chemotherapy and definitive radiotherapy without resection. Methods Patients with stage T1-3pN2M0 non-small-cell lung cancer were randomly assigned in a 1:1 ratio to concurrent induction chemotherapy (two cycles of cisplatin 50 mg/m2 on days 1, 8, 29, and 36 and etoposide 50 mg/m2 on days 1–5 and 29–33) plus radiotherapy (45 Gy) in multiple academic and community hospitals. If no progression, patients in group 1 underwent resection and those in group 2 continued radiotherapy uninterrupted up to 61 Gy. Two additional cycles of cisplatin and etoposide were given in both groups. The primary endpoint was overall survival (OS). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00002550. Findings 202 patients (median age 59 years, range 31–77) were assigned to group 1 and 194 (61 years, 32–78) to group 2. Median OS was 23·6 months (IQR 9·0–not reached) in group 1 versus 22·2 months (9·4–52·7) in group 2 (hazard ratio HR 0·87 0·70–1·10; p=0·24). Number of patients alive at 5 years was 37 (point estimate 27%) in group 1 and 24 (point estimate 20%) in group 2 (odds ratio 0·63 0·36–1·10; p=0·10). With N0 status at thoracotomy, the median OS was 34·4 months (IQR 15·7–not reached; 19 point estimate 41% patients alive at 5 years). Progression-free survival (PFS) was better in group 1 than in group 2, median 12·8 months (5·3–42·2) vs 10·5 months (4·8–20·6), HR 0·77 0·62–0·96; p=0·017); the number of patients without disease progression at 5 years was 32 (point estimate 22%) versus 13 (point estimate 11%), respectively. Neutropenia and oesophagitis were the main grade 3 or 4 toxicities associated with chemotherapy plus radiotherapy in group 1 (77 38% and 20 10%, respectively) and group 2 (80 41% and 44 23%, respectively). In group 1, 16 (8%) deaths were treatment related versus four (2%) in group 2. In an exploratory analysis, OS was improved for patients who underwent lobectomy, but not pneumonectomy, versus chemotherapy plus radiotherapy. Interpretation Chemotherapy plus radiotherapy with or without resection (preferably lobectomy) are options for patients with stage IIIA(N2) non-small-cell lung cancer. Funding National Cancer Institute, Canadian Cancer Society, and National Cancer Institute of Canada.
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