Circulating Osteopontin Predicts Clinical and Radiological Response in First-Line Treatment of Advanced Non-Small Cell Lung Cancer.

PURPOSE: Pembrolizumab-based regimens are conditioned by the expression of PD-L1, but durable response rate is limited by innate and acquired resistance mechanisms. Here, we focus on osteopontin (OPN), an upfront biomarker of senescence, which closely associated with natural history of non-small cell lung cancer (NSCLC). METHODS: Seventy-nine patients eligible to pembrolizumab regimens-alone or in combination with chemotherapy-as first-line treatment of advanced NSCLC were enrolled. Predictive value of OPN toward iRECIST progression disease (PD) was set as first outcome. Secondary ones included performance status (ECOG) at baseline, early (first and best) responses, and overall survival (OS). RESULTS: High Serum OPN characterized patients with worse ECOG-PS (p = 0.015) at baseline and subjects experienced PD/death at first (OR 1.17 [1.02 to 1.35]; p = 0.030) and best responses (0.04 [0.00 to 0.81]; p = 0.035). OPN was associated with time-to-progression (B -2.74 [-4.46 to -1.01]) and time-to death (-0.13 [-0.20 to -0.05]). Cox regression models unveil a predictive value for iRECIST-PD (HR 1.01 [1.00 to 1.02]; p = -0.005), RECIST-PD (HR 1.01 [1.00 to 1.02]; p = 0.017), and OS (HR 1.02 [1.01 to 1.03]; p = 0.001). These models were internally validated through bootstrap resampling and characterized by relevant discrimination ability at ROC curve analyses. CONCLUSION: Baseline levels of serum OPN is closely associated with performance status and short/long term outcomes in patients with advanced NSCLC, which are candidate to pembrolizumab-based regimens. As upfront biomarker of senescence, OPN may pave the way for future studies focusing on senescence patterns in NSCLC.

Diagnosis of lung cancer following emergency admission: Examining care pathways, clinical outcomes, and advanced NSCLC treatment in an Italian cancer Center.

Background: Lung cancer patients diagnosed following emergency admission often present with advanced disease and poor performance status, leading to suboptimal treatment options and outcomes. This study aimed to investigate the clinical and molecular characteristics, treatment initiation, and survival outcomes of these patients. Methods: We retrospectively analyzed data from 124 patients diagnosed with lung cancer following emergency admission at a single institution. Clinical characteristics, results of molecular analyses for therapeutic purpose, systemic treatment initiation, and survival outcomes were assessed. Correlations between patients' characteristics and treatment initiation were analyzed. Results: Median age at admission was 73 years, and 79.0 % had at least one comorbidity. Most patients (87.1 %) were admitted due to cancer-related symptoms. Molecular analyses were performed in 89.5 % of advanced non-small cell lung cancer (NSCLC) cases. In this subgroup, two-thirds (66.2 %) received first-line therapy. Median overall survival (OS) was 3.9 months for the entire cohort, and 2.9 months for patients with metastatic lung cancer. Among patients with advanced NSCLC, OS was significantly longer for those with actionable oncogenic drivers and those who received first-line therapy. Improvement of performance status during hospitalization resulted in increased probability of receiving first-line systemic therapy. Discussion: Patients diagnosed with lung cancer following emergency admission demonstrated poor survival outcomes. Treatment initiation, particularly for patients with actionable oncogenic drivers, was associated with longer OS. These findings highlight the need for proactive medical approaches, including improving access to molecular diagnostics and targeted treatments, to optimize outcomes in this patient population.

Prognostic Role of Soluble and Extracellular Vesicle-Associated PD-L1, B7-H3 and B7-H4 in Non-Small Cell Lung Cancer Patients Treated with Immune Checkpoint Inhibitors.

The treatment of non-small cell lung cancer (NSCLC) has changed dramatically with the advent of immune checkpoint inhibitors (ICIs). Despite encouraging results, their efficacy remains limited to a subgroup of patients. Circulating immune checkpoints in soluble (s) form and associated with extracellular vesicles (EVs) represent promising markers, especially in ICI-based therapeutic settings. We evaluated the prognostic role of PD-L1 and of two B7 family members (B7-H3, B7-H4), both soluble and EV-associated, in a cohort of advanced NSCLC patients treated with first- (n = 56) or second-line (n = 126) ICIs. In treatment-naïve patients, high baseline concentrations of sPD-L1 (>24.2 pg/mL) were linked to worse survival, whereas high levels of sB7-H3 (>0.5 ng/mL) and sB7-H4 (>63.9 pg/mL) were associated with better outcomes. EV characterization confirmed the presence of EVs positive for PD-L1 and B7-H3, while only a small portion of EVs expressed B7-H4. The comparison between biomarker levels at the baseline and in the first radiological assessment under ICI-based treatment showed a significant decrease in EV-PD-L1 and an increase in EV-B7H3 in patients in the disease response to ICIs. Our study shows that sPD-L1, sB7-H3 and sB7-H4 levels are emerging prognostic markers in patients with advanced NSCLC treated with ICIs and suggests potential EV involvement in the disease response to ICIs.

Molecular and Genetic Advances in Small Cell Lung Cancer Landscape: From Homogeneity to Diversity.

Small cell lung cancer (SCLC) has been historically considered a homogeneous disease and thus approached as a single entity when it comes to clinical studies design and new treatments developments. However, increasing knowledge in the genetic and molecular landscape of this disease challenges this concept, opening the possibility that different subtypes might show differential vulnerability to treatments. In this narrative review, we gather the most relevant advances in genetic and molecular characterization of SCLC, focusing on how these discoveries may be used to design the path for a personalized treatment approach. Indeed, we discuss the new classification based on differential protein expression, the prevalence and significance of oncogenic drivers (e.g., EGFR mutations and ALK rearrangements) in SCLC, the genetic characteristics of SCLC in patients with no smoking history, and the existing evidence supporting the use of liquid biopsy for capturing the heterogeneity of the disease. We use the keywords "small cell lung cancer", "SCLC", "EGFR", "ALK", "histological transformation", and "transcriptional factors" to identify original research manuscripts, clinical trials, case reports, and case series from PubMed.

Immune Checkpoint Blockade: A Strategy to Unleash the Potential of Natural Killer Cells in the Anti-Cancer Therapy.

Immune checkpoint inhibitors (ICIs) immunotherapy has represented a breakthrough in cancer treatment. Clinical use of ICIs has shown an acceptable safety profile and promising antitumor activity. Nevertheless, some patients do not obtain clinical benefits after ICIs therapy. In order to improve and cure an increasing number of patients, the field has moved toward the discovery of new ICIs expressed by cells of innate immunity with an elevated inherent antitumor activity, such as natural killer cells. This review will focus on the recent findings concerning the role of classical and non-classical immune checkpoint molecules and receptors that regulate natural killer cell function, as potential targets, and their future clinical application.

Immunotherapy-chemotherapy combinations for non-small cell lung cancer: current trends and future perspectives.

INTRODUCTION: In recent years, immunotherapy has become a pillar in the treatment of advanced, non-oncogene-addicted non-small cell lung cancer (NSCLC). Programmed death ligand 1 (PD-L1) expression is currently the only factor used to predict response to immunotherapy in clinical practice. Specifically, single-agent pembrolizumab as first-line therapy is approved for tumors with high expression of PD-L1 (≥50%) while immunotherapy and chemotherapy are approved for any PD-L1. However, combinations of immune-checkpoint inhibitors (ICIs) and other agents may confer higher benefit than immunotherapy alone in some circumstances. AREAS COVERED: We reviewed the available data regarding the combined use of ICIs and chemotherapy in patients with advanced, treatment-naïve NSCLC. In light of the benefit demonstrated in advanced disease, these combinations have been subsequently tested in other settings. We collected the most relevant findings regarding efficacy and safety of chemo-immunotherapy combinations in early and locally advanced NSCLC. EXPERT OPINION: Immune-chemotherapy combinations demonstrated benefit in the advanced setting, and this strategy in now being applied in the early and local advanced settings. A description of clinical and biological predictors of response is required in order to identify patients who may benefit the most from combination therapy.

The impact of COVID-19 on consumption poverty in Mozambique.

This study assesses the impact of COVID-19 on household consumption poverty. To predict changes in income and the associated effects on poverty, we rely on existing estimated macroeconomic impacts. We assume two main impact channels: direct income/wage and employment losses. Our simulations suggest that consumption decreased by 7.1%-14.4% and that poverty increased by 4.3-9.9 percentage points in 2020. This points to a reversal of the positive poverty reduction trend observed in previous years. Poverty most certainly increased in the pre-COVID period due to other shocks, so Mozambique finds itself in a deepening struggle against poverty.

Novel approaches for the treatment of unresectable malignant pleural mesothelioma: A focus on immunotherapy and target therapy (Review).

Malignant pleural mesothelioma (MPM) is considered a relatively uncommon disease but its incidence is increasing worldwide. Patients affected by MPM have a very severe prognosis and have been often occupationally and environmentally exposed to asbestos. In recent years, checkpoint inhibitors have dramatically revolutionized the paradigm for the treatment of several malignancies. Several efforts have also been made to improve the survival outcomes of patients with MPM and after decades, the standard-of-care systemic treatment for unresectable MPM, based on first-line combination chemotherapy with cisplatin and pemetrexed, has changed. In addition to checkpoint inhibitors, other types of treatments, such as molecularly targeted therapy have been evaluated. However, to date, the results of these investigations are not very encouraging. The aim of the present review is to provide a comprehensive overview of the most relevant data of clinical trials regarding recent treatment strategies of MPM with a particular focus on immunotherapeutic and targeted approaches.

Radiation-Related Deregulation of TUBB3 and BRCA1/2 and Risk of Secondary Lung Cancer in Women With Breast Cancer.

INTRODUCTION: Breast cancer survivors are at increased risk of developing unrelated primary cancers, particularly lung cancer. Evidence indicates that sex hormones as well as a deregulation of DNA-repair pathways may contribute to lung cancer onset. We investigated whether the hormone status and expression of markers involved in DNA repair (BRCA1/2, ERCC1, and P53R2), synthesis (TS and RRM1), and cell division (TUBB3) might be linked to lung cancer risk. PATIENTS AND METHODS: Thirty-seven breast cancer survivors with unrelated lung cancer and 84 control subjects comprising women with breast cancer (42/84) or lung cancer (42/84) were enrolled. Immunohistochemistry on tumor tissue was performed. Geometric mean ratio was used to assess the association of marker levels with patient groups. RESULTS: Estrogen receptor was expressed in approximately 90% of the breast cancer group but was negative in the majority of the lung cancer group, a result similar to the lung cancer control group. Likewise, ER isoform ß was weakly expressed in the lung cancer group. Protein analysis of breast cancer versus control had a significantly lower expression of BRCA1, P53R2, and TUBB3. Likewise, a BRCA1 reduction was observed in the lung cancer group concomitant with a BRCA2 increase. Furthermore, BRCA2 and TUBB3 increased in ipsilateral lung cancer in women who had previously received radiotherapy for breast cancer. CONCLUSION: The decrease of DNA-repair proteins in breast cancer could make these women more susceptible to therapy-related cancer. The increase of BRCA2 and TUBB3 in lung cancer from patients who previously received radiotherapy for breast cancer might reflect a tissue response to exposure to ionizing radiation.

Correlation between B7-H4 and Survival of Non-Small-Cell Lung Cancer Patients Treated with Nivolumab.

Reliable predictors of benefit from immune checkpoint inhibitors in non-small-cell lung cancer (NSCLC) are still limited. We aimed to evaluate the association between the expression of selected molecules involved in immune response and clinical outcomes in NSCLC patients receiving nivolumab. In our study, the outcomes of 46 NSCLC patients treated with nivolumab in second or subsequent lines (Nivolumab Cohort) were compared with the expression of PD-L1, PD-L2, PD-1, B7-H3, and B7-H4 assessed by immunohistochemistry (IHC). Samples from 17 patients (37.0%) in the Nivolumab Cohort were positive for B7-H4 expression. At univariate analyses, only B7-H4 expression was associated with significantly decreased progression-free survival (PFS; 1.7 vs. 2.0 months; p = 0.026) and with a disadvantage in terms of overall survival (OS) close to statistical significance (4.4 vs. 9.8 months; p = 0.064). At multivariate analyses, B7-H4 expression was significantly associated with decreased PFS (hazard ratio (HR) = 2.28; p = 0.021) and OS (HR = 2.38; p = 0.022). Subsequently, B7-H4 expression was compared with clinical outcomes of 27 NSCLC patients receiving platinum-based chemotherapy (Chemotherapy Cohort), but no significant association was observed. Our results suggest a negative predictive role of B7-H4 in a population of NSCLC treated with immune checkpoint inhibitors, which deserves further research.

Integrated Somatic and Germline Whole-Exome Sequencing Analysis in Women with Lung Cancer after a Previous Breast Cancer.

Women treated for breast cancer (BC) are at risk of developing secondary tumors, such as lung cancer (LC). Since rare germline variants have been linked to multiple cancer development, we hypothesized that BC survivors might be prone to develop LC as a result of harboring rare variants. Sixty patients with LC with previous BC (the study population; SP) and 53 women with either BC or LC and no secondary cancer (control population; CP) were enrolled. Whole exome sequencing was performed in both tumors and unaffected tissues from 28/60 SP patients, and in germline DNA from 32/53 CP. Candidate genes were validated in the remaining individuals from both populations. We found two main mutational signature profiles: S1 (C>T) in all BCs and 16/28 LCs, and S2 (C>A) which is strongly associated with smoking, in 12/28 LCs. The burden test over rare germline variants in S1-LC vs CP identified 248 genes. Validation confirmed GSN as significantly associated with LC in never-smokers. In conclusion, our data suggest two signatures involved in LC onset in women with previous BC. One of these signatures is linked to smoking. Conversely, regardless of smoking habit, in a subgroup of BC survivors genetic susceptibility may contribute to LC risk.

CIMAvax-EGF, a therapeutic non-small cell lung cancer vaccine.

INTRODUCTION: Lung cancer represents the most common cause of cancer death worldwide. While the prognosis remains poor, immunotherapy is giving a positive impact on survival. Cancer vaccines represent a form of active immunotherapy that historically has given modest results in terms of efficacy. The overexpression of the EGFR by tumor cells was reported in more than half of cases of lung cancer, representing a mechanism of cancerogenesis. CIMAvax-EGF, a therapeutic vaccine for non-small cell lung cancer (NSCLC) developed in Cuba, consists of a human recombinant EGF able to induce antibodies against the autologous EGF, resulting in serum EGF withdrawal and lower EGF-EGFR interaction. Area covered: We critically reviewed the existing literature about CIMAvax-EGF, from the Pilot studies to the efficacy controlled studies. We also overviewed the ongoing trials. Expert opinion: CIMAvax-EGF demonstrated to be safe and immunogenic. In a phase III randomized study CIMAvax-EGF, used as a switch maintenance treatment after platinum-based chemotherapy, did not significantly improve survival. Current data are not sufficient to recommend CIMAvax-EGF as a treatment option for advanced stage NSCLC. Further studies, conducted in a context of worldwide standardized clinical practice, are needed to better define if a subpopulation of patients can benefit from the vaccination.

Serial Troponin for Early Detection of Nivolumab Cardiotoxicity in Advanced Non-Small Cell Lung Cancer Patients.

BACKGROUND: Rare cases of severe myocarditis are reported during treatment with nivolumab. Troponin, a biomarker of cardiac damage, is a key component of the diagnostic workup of many cardiac disorders, including myocarditis. This study investigates the role of troponin to assess cardiac involvement during nivolumab therapy for non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: We evaluated 59 NSCLC patients, analyzing serum samples collected within a translational research study. Troponin above the upper normal limit (0.046 ng/mL) was defined as Tn+, whereas normal but detectable troponin (0.015-0.045) was defined as Tndet. Troponin alterations were interpreted on the grounds of the following elements: peak values and time curve, cardiac comorbidities, signs and symptoms coincident to troponin elevation, ECG, echocardiography, and disease progression. RESULTS: No patient had cardiovascular events. Among 362 available blood samples, Tn+ (max 0.317 ng/mL) was found in 13 determinations belonging to 6 patients. Seven other patients had isolated Tndet. In five patients, Tn+ was attributed to cardiac comorbidities, disease progression, or worsening clinical status. One patient without cardiac history and in good clinical condition had a sustained troponin increase-soon after the start of therapy-and after careful evaluation of all relevant elements, it was interpreted as a marker of nivolumab-related subclinical myocarditis. CONCLUSION: Tn+ may occur in NSCLC patients treated with nivolumab, but in most cases it does not indicate nivolumab cardiotoxicity. In some cases, however, a careful interpretation of troponin alteration, especially at the beginning of therapy, enables identification of subclinical myocarditis, thus allowing early cardiac treatment. IMPLICATIONS FOR PRACTICE: Myocarditis is a rare but serious adverse event of immune checkpoint blockade with nivolumab, which needs to be recognized as soon as possible. This article suggests that troponin, a user-friendly biomarker of myocardial cytotoxicity, might be useful for early detection of immune-mediated myocarditis. However, because troponin abnormalities might also be related to a number of conditions capable of causing myocardial oxygen demand-supply mismatch, a careful cardiac assessment should be performed in non-small cell lung cancer patients in order to properly interpret any troponin increase. According to the available evidence, monitoring troponin during the first weeks of treatment can be considered reasonable.

Prognostic role of the VeriStrat test in first line patients with non-small cell lung cancer treated with platinum-based chemotherapy.

OBJECTIVES: VeriStrat® is a blood-based test that utilizes matrix-assisted laser desorption/ionization time-of-flight (MALDI ToF) mass spectrometry to assign a binary classification of VeriStrat Good or VeriStrat Poor that is associated with treatment outcomes in cancer patients. A number of other studies have shown an association between VeriStrat status and clinical outcomes in second and subsequent lines of therapy. The prognostic properties of VeriStrat were demonstrated in the placebo arms of two randomized studies in non-small cell lung cancer (NSCLC): TOPICAL and BR.21; the predictive properties of the test were shown in a prospective randomized phase III study PROSE in the second line treatment of NSCLC with erlotinib versus chemotherapy. Motivated by these observations, we sought to extend the clinical utility of VeriStrat to standard first line chemotherapy and evaluated the performance of the test in a number of clinical studies of patients treated with platinum-based regimens. MATERIALS AND METHODS: We examine the performance of VeriStrat in three independent clinical trials where the test classification was acquired for prospectively collected baseline samples from 481 patients treated with platinum-based chemotherapy in first line. RESULTS: Across these trials, 66-70% of patients were classified as VeriStrat Good; patients classified as VeriStrat Good had significantly longer progression-free survival and overall survival than VeriStrat Poor patients, with hazard ratios ranging from 0.36 to 0.72 and 0.26 to 0.51, respectively. These results demonstrated that VeriStrat is a strong prognostic test in NSCLC patients treated with platinum-based regimens in the first line. CONCLUSION: VeriStrat provides valuable clinical information that may be used to support patient-physician conversations regarding prognosis and treatment options, and to identify a subset of patients who might benefit from other treatment strategies, possibly in the framework of clinical trials.

Downregulation of miR-99a/let-7c/miR-125b miRNA cluster predicts clinical outcome in patients with unresected malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is an aggressive tumor with a dismal overall survival (OS) and to date no molecular markers are available to guide patient management. This study aimed to identify a prognostic miRNA signature in MPM patients who did not undergo tumor resection. Whole miRNA profiling using a microarray platform was performed using biopsies on 27 unresected MPM patients with distinct clinical outcome: 15 patients had short survival (OS<12 months) and 12 patients had long survival (OS>36 months). Three prognostic miRNAs (mir-99a, let-7c, and miR-125b) encoded at the same cluster (21q21) were selected for further validation and tested on publicly available miRNA sequencing data from 72 MPM patients with survival data. A risk model was built based on these 3 miRNAs that was validated by quantitative PCR in an independent set of 30 MPM patients. High-risk patients had shorter median OS (7.6 months) as compared with low-risk patients (median not reached). In the multivariate Cox model, a high-risk score was independently associated with shorter OS (HR=3.14; 95% CI, 1.18-8.34; P=0.022). Our study identified that the downregulation of the miR-99a/let-7/miR-125b miRNA cluster predicts poor outcome in unresected MPM.

Circulating Cell-Free DNA and Circulating Tumor Cells as Prognostic and Predictive Biomarkers in Advanced Non-Small Cell Lung Cancer Patients Treated with First-Line Chemotherapy.

Cell-free DNA (cfDNA) and circulating tumor cells (CTCs) are promising prognostic and predictive biomarkers in non-small cell lung cancer (NSCLC). In this study, we examined the prognostic role of cfDNA and CTCs, in separate and joint analyses, in NSCLC patients receiving first line chemotherapy. Seventy-three patients with advanced NSCLC were enrolled in this study. CfDNA and CTC were analyzed at baseline and after two cycles of chemotherapy. Plasma cfDNA quantification was performed by quantitative PCR (qPCR) whereas CTCs were isolated by the ScreenCell Cyto (ScreenCell, Paris, France) device and enumerated according to malignant features. Patients with baseline cfDNA higher than the median value (96.3 hTERT copy number) had a significantly worse overall survival (OS) and double the risk of death (hazard ratio (HR): 2.14; 95% confidence limits (CL) = 1.24-3.68; p-value = 0.006). Conversely, an inverse relationship between CTC median baseline number (6 CTC/3 mL of blood) and OS was observed. In addition, we found that in patients reporting stable disease (SD), the baseline cfDNA and CTCs were able to discriminate patients at high risk of poor survival. cfDNA demonstrated a more reliable biomarker than CTCs in the overall population. In the subgroup of SD patients, both biomarkers identified patients at high risk of poor prognosis who might deserve additional/alternative therapeutic interventions.

Investigational drugs targeting fibroblast growth factor receptor in the treatment of non-small cell lung cancer.

INTRODUCTION: Fibroblast growth factor receptor (FGFR) due to its central role in regulating cell survival, is a promising target for cancer therapeutics. Dysregulation of the FGFR pathway has been observed in several malignancies, including non-small cell lung cancer (NSCLC) particularly in patients with squamous histology. Areas covered: The aim of this article is to review the most relevant findings of clinical trials investigating drugs targeting FGFR pathway: such as FGFR tyrosine kinase inhibitors (TKIs), FGFR monoclonal antibodies and FGF ligand traps in NSCLC patients. Expert opinion: At present, clinical activity of drugs targeting FGFR in NSCLC is disappointing. Further studies are needed in order to better identify patients who might benefit from these drugs and to clarify the mechanisms of resistance to these compounds.

Circulating Tumor DNA Reflects Tumor Metabolism Rather Than Tumor Burden in Chemotherapy-Naive Patients with Advanced Non-Small Cell Lung Cancer: 18F-FDG PET/CT Study.

We aimed to evaluate the relationships between circulating tumor cells (CTCs) or plasma cell-free DNA (cfDNA) on one side and a comprehensive range of 18F-FDG PET/CT-derived parameters on the other side in chemotherapy-naive patients with advanced non-small cell lung cancer (NSCLC). Methods: From a group of 79 patients included in a trial evaluating the role of pretreatment circulating tumor markers as predictors of prognosis in chemotherapy-naive patients with advanced NSCLC, we recruited all those who underwent 18F-FDG PET/CT for clinical reasons at our institution before inclusion in the trial (and thus just before chemotherapy). For each patient, a peripheral blood sample was collected at baseline for the evaluation of CTCs and cfDNA. CTCs were isolated by size using a filtration-based device and then morphologically identified and enumerated; cfDNA was isolated from plasma and quantified by a quantitative polymerase chain reaction using human telomerase reverse transcriptase. The following 18F-FDG PET/CT-derived parameters were computed: maximum diameter of the primary lesion (T), of the largest lymph node (N), and of the largest metastatic lesion (M); SUVmax; SUVmean; size-incorporated SUVmax; metabolic tumor volume; and total lesion glycolysis. All parameters were independently measured for T, N, and M. The associations among CTCs, cfDNA, and 18F-FDG PET/CT-derived parameters were evaluated by multivariate-analysis. Patients were divided into 2 groups according to the presence of either limited metastatic involvement (M1a or M1b due to extrathoracic lymph nodes only) or disseminated metastatic disease. The presence or absence of metabolically active bone lesions was also recorded for each patient, and patient subgroups were compared. Results: Thirty-seven patients recruited in the trial matched our PET-based criteria (24 men; age, 64.5 ± 8.1 y). SUVmax for the largest metastatic lesion was the only variable independently associated with baseline cfDNA levels (P = 0.016). Higher levels of cfDNA were detected in the subgroup of patients with metabolically active bone lesions (P = 0.02), but no difference was highlighted when patients with more limited metastatic disease were compared with patients with disseminated metastatic disease. Conclusion: The correlation of cfDNA levels with tumor metabolism, but not with metabolic tumor volume at regional or distant levels, suggests that cfDNA may better reflect tumor biologic behavior or aggressiveness rather than tumor burden in metastatic NSCLC.

Releasing the brake: safety profile of immune check-point inhibitors in non-small cell lung cancer.

INTRODUCTION: Immune check-point inhibitors are now employed as single-agents in current practice for the treatment of advanced non-small cell lung cancer (NSCLC), while combinations of different inhibitors are being evaluated in clinical trials. Although the safety profile of these compounds, with particular reference to drugs targeting programmed death protein 1 (PD-1) and its ligand (PD-L1), is generally considered manageable, peculiar, immune-related toxicities may onset. Areas covered: This review focuses on the immune-related adverse events (irAEs) observed during immune check-point blockade in NSCLC and their management. The authors report the incidence of irAEs based on the currently available data involving NSCLC and provide recommendations on the general approach to irAEs, as well as indications for the most relevant site-specific events. Expert opinion: Since irAEs may involve a wide range of organs and systems and are potentially reversible if promptly treated, early diagnosis should always be achieved; this might be particularly challenging when other potential causes of toxicity are suspected, such as infections or concurrent treatments. Finally, drugs active on the PD-1/PD-L1 axis appear to be generally manageable even when they are administered to patients with relevant comorbidities, provided that adequate clinical monitoring is performed.

New systemic strategies for overcoming resistance to targeted therapies in non-small cell lung cancer.

INTRODUCTION: Although the achievements in the treatment of advanced non-small cell lung cancer (NSCLC) have been translated in improved disease control, response rate and survival, especially in the case of patients with targetable oncogenic drivers, acquired resistance is common after initial benefit; furthermore, primary resistance can occasionally be observed. Due to its clinical implications, the management of treatment-resistant NSCLC is a top topic of the current research, and many efforts are being put in the study of the mechanisms at the base of resistance and in the development of effective therapeutic countermeasures. Areas covered: This review aims at identifying the most relevant novel chemical therapies designed to overcome resistance in NSCLC, including recently approved agents, as well as compounds in clinical development. Expert opinion: An improved knowledge of the mechanisms causing resistance to treatments in NSCLC translates into effective innovative chemical therapies able to overcome such occurrence, and the paradigms of this progress are represented by novel inhibitors of the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK); however, the study of novel systemic therapies in this setting is challenging, and further efforts in this setting are highly needed.