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Background: Lung cancer remains the leading cause of cancer-related mortality globally, predominantly affecting older individuals. Despite the increasing use of immune checkpoint inhibitors (ICIs) like nivolumab in non-small cell lung cancer (NSCLC), the efficacy and safety in elderly patients, particularly those aged 65 and above, remain underexplored due to their underrepresentation in clinical trials. Methods: This retrospective study analyzed data from 60 elderly patients (≥65 years) with metastatic NSCLC who received nivolumab as second-line or later therapy between January 2020 and May 2023. Results: The median age was 67 years, with a predominance of males (78%). Nivolumab was administered for a median of 8 cycles, with 33.3% of patients receiving 15 or more cycles. The median OS was 23 months, and the 1-, 3-, and 5-year survival rates were 93.3, 54.1, and 18.6%, respectively. Multivariate analysis identified adenocarcinoma histology, fewer than 15 cycles of nivolumab, and non-response to prior therapies as independent predictors of poor OS. Nivolumab treatment was generally well-tolerated, with 45% of patients experiencing at least grade 1 toxicity. Conclusions: Nivolumab is effective and well-tolerated in elderly patients with metastatic NSCLC, providing survival benefits comparable to those observed in younger populations. The number of treatment cycles and initial response to therapy are key determinants of survival, underscoring the importance of continued treatment in this age group. [ABSTRACT FROM AUTHOR]

Background: The aim of the study was to investigate a series of complete blood cell count-based biomarkers of systemic inflammation as predictors of clinical outcomes in patients who underwent first-line chemoimmunotherapy for advanced NSCLC. Methods: Consecutive patients with pathologically diagnosed stage III/IV NSCLC and PD-L1 < 50% who underwent first-line chemoimmunotherapy were retrospectively enrolled. The clinical outcomes used for biomarker evaluation were Objective Response Rate (ORR) and Overall Survival (OS). Results: Non-responders had significantly higher values of neutrophil to lymphocyte ratio (NLR, median: 5.36; IQR: 2.78–10.82 vs. 3.31; IQR: 2.15–4.12, p = 0.019), neutrophil to monocyte ratio (NMR, median: 14.00; IQR: 8.82–21.20 vs. 9.20; IQR: 7.45–11.20, p = 0.013), and systemic inflammation index (SII, median: 1395; IQR: 929–3334 vs. 945; IQR: 552–1373, p = 0.025), but only NLR and NMR remained independently associated with clinical response in multivariate logistic regression. In the univariate analysis, white blood cells (OR:1.2202; 95% CI: 1.0339–1.4400, p = 0.019), neutrophils (OR:1.2916; 95% CI: 1.0692–1.5604, p = 0.008), NLR (OR:1.3601: 95% CI: 1.0949–1.6896, p = 0.005) and NMR (OR:1.2159; 95% CI: 1.00396–1.4221, p = 0.015) were significantly associated with survival; Cox regression models confirmed that neutrophils, NLR, and MLR were independently associated with survival; NLR, at a cut-off value of 4.0, showed the better AUC (0.749) in predicting OS. Conclusions: Baseline complete blood cell count biomarkers, especially the NLR, can predict clinical outcomes in patients with advanced NSCLC treated with first-line chemoimmunotherapy. [ABSTRACT FROM AUTHOR]

Lung cancer stands as a malignant neoplasm bearing the highest burden of morbidity and mortality within the elderly population on a global scale. Among the lung cancer subtypes, non-small cell lung cancer (NSCLC) prevails as the most prevalent. As age advances, elderly patients often present with an increased prevalence of comorbidities, diminished organ reserve function, and alterations in drug pharmacokinetics, including absorption, distribution, metabolism, and clearance. These factors collectively contribute to a reduction in their capacity to tolerate therapeutic interventions. Regrettably, there exists a paucity of research data and evidence regarding the management of elderly patients afflicted by advanced lung cancer. This article endeavors to compile and elucidate strategies for the enhancement of treatment approaches, with the aim of aiding clinical decisionmaking. Prior to the selection of clinical treatmentmodalities for elderly patients with advanced NSCLC, a comprehensive assessment should be conducted, taking into account various facets, including tumor characteristics, patient age, physiological status, and the presence of comorbidities. The treatment strategy should be implemented in a tiered fashion, thereby affording the opportunity for the tailoring of individualized therapeutic approaches for elderly patients afflicted by advanced NSCLC. The demographic of elderly patients confronting advanced NSCLC presents a complex landscape marked by intricate underlying conditions, necessitating the imperative optimization of treatment strategies. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate the efficacy and safety of PD‐1/PD‐L1 inhibitors in treatment of elderly patients with advanced non‐small cell lung cancer (NSCLC). Methods: Patients with advanced NSCLC ≥70 years old who received PD‐1/PD‐L1 inhibitors in our hospital were retrospectively analyzed. According to age, the patient were stratified as follows: 70–75 years old, 76–80 years old, and >80 years old. Kaplan–Meier method was used for survival analysis, and univariate and multivariate Cox proportional hazards regression models were used to analyze the correlation between different clinical characteristics and survival. Results: A total of 58 elderly patients with advanced non‐small cell cancer were enrolled in this study. Patients aged 70–75, 76–80, and >80 years old were 32, 19, and 7, respectively. For the all, median OS was 17.0 months, and PFS was 7.0 months. PFS and OS did not differ according to age (P = 0.396, 0.054, respectively). Univariate analysis showed that PS of 0–1, stage III, first‐line therapy and irAEs were associated with longer PFS, and PS of 0–1, stage III, and first‐line therapy were associated with longer OS. Multivariate analysis showed that patients with stage III had longer PFS. PFS and OS of patients with PS ≥ 2 were significantly shorter than those of patients with PS of 0–1. Conclusions: In the present real‐world retrospective cohort, PD‐1/PD‐L1 inhibitors are effective and well tolerated in elderly patients with advanced NSCLC. Immunotherapy should be actively used as early as possible in older patients advanced NSCLC. [ABSTRACT FROM AUTHOR]

Background: Based on pharmacoeconomics, drug availability and actual treatment, optimal treatment regimens for Chinese non-small-cell lung carcinoma (NSCLC) patients over 70 years old are needed. Methods: This multicenter, single-arm pilot trial enrolled patients with advanced non-squamous NSCLC who refused systemic chemotherapy. Eligible patients received anlotinib (12 mg/day, d1-14, Q3W) until disease progression, intolerant toxicities, or withdrawal from the study. The primary endpoint was progression-free survival (PFS). Results: Forty-nine patients were screened between January 2019 and September 2021, of whom 40 patients were eligible. The median age was 76 years. With a median follow-up period of 16.20 (95% CI: 8.77, 25.10) months, the median PFS was 5.45 months (95% CI: 3.52-9.23) and the median overall survival was 10.32 months (95% CI: 6.44-12.78). Three patients achieved a partial response and 34 had stable disease, with an objective response rate of 7.5% and a disease control rate of 92.5%. Thirty-three (82.5%; 33/40) patients reported treatment-related adverse events (TRAEs) of any grade, and the incidence rate of grade ≥3 TRAEs was 35% (14/40). The most common grade ≥3 TRAEs were hypertension (4/40; 10.0%), hand-foot syndrome (3/40; 7.5%), and proteinuria (2/40; 5.0%). Conclusion: Anlotinib treatment was feasible and safe in Chinese elderly patients with advanced non-squamous NSCLC who did not receive any systemic chemotherapy. [ABSTRACT FROM AUTHOR]

Immunotherapy has revolutionized the treatment of patients with non‐small cell lung cancer (NSCLC). High expression of tissue PD‐L1 (tPD‐L1) is currently the only approved biomarker for predicting treatment response. However, even tPD‐L1 low (1‐49%) and absent (<1%) patients might benefit from immunotherapy but, to date, there is no reliable biomarker, that can predict response in this particular patient subgroup. This study aimed to test whether tumour‐associated extracellular vesicles (EVs) could fill this gap. Using NSCLC cell lines, we identified a panel of tumour‐related antigens that were enriched on large EVs (lEVs) compared to smaller EVs. The levels of lEVs carrying these antigens were significantly elevated in plasma of NSCLC patients (n = 108) and discriminated them from controls (n = 77). Among the tested antigens, we focused on programmed cell death ligand 1 (PD‐L1), which is a well‐known direct target for immunotherapy. In plasma lEVs, PD‐L1 was mainly found on a population of CD45−/CD62P+ lEVs and thus seemed to be associated with platelet‐derived vesicles. Patients with high baseline levels of PD‐L1+ lEVs in blood showed a significantly better response to immunotherapy and prolonged survival. This was particularly true in the subgroup of NSCLC patients with low or absent tPD‐L1 expression, thus identifying PD‐L1‐positive lEVs in plasma as a novel predictive and prognostic marker for immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Cancer-associated thrombosis (CAT) and venous thromboembolism (VTE) are frequent cancer-related complications associated with high mortality; thus, this urges the identification of predictive markers. Immune checkpoint inhibitors (ICIs) used in cancer immunotherapy allow T-cell activation against cancer cells. Retrospective studies showed increased VTE following ICI administration in some patients. Non-small cell lung cancer (NSCLC) patients are at high risk of thrombosis and thus, the adoption of immunotherapy, as a first-line treatment, seems to be associated with coagulation-fibrinolysis derangement. Methods: We pharmacologically modulated NSCLC cell lines in co-culture with CD8+ T-cells (TCD8+) and myeloid-derived suppressor cells (MDSCs), isolated from healthy blood donors. The effects of ICIs Nivolumab and Ipilimumab on NSCLC cell death were assessed by annexin V and propidium iodide (PI) flow cytometry analysis. The potential procoagulant properties were analyzed by in vitro clotting assays and enzyme-linked immunosorbent assays (ELISAs). The metabolic remodeling induced by the ICIs was explored by 1H nuclear magnetic resonance (NMR) spectroscopy. Results: Flow cytometry analysis showed that TCD8+ and ICIs increase cell death in H292 and PC-9 cells but not in A549 cells. Conditioned media from NSCLC cells exposed to TCD8+ and ICI induced in vitro platelet aggregation. In A549, Podoplanin (PDPN) levels increased with Nivolumab. In H292, ICIs increased PDPN levels in the absence of TCD8+. In PC-9, Ipilimumab decreased PDPN levels, this effect being rescued by TCD8+. MDSCs did not interfere with the effect of TCD8+ in the production of TF or PDPN in any NSCLC cell lines. The exometabolome showed a metabolic remodeling in NSCLC cells upon exposure to TCD8+ and ICIs. Conclusions: This study provides some insights into the interplay of immune cells, ICIs and cancer cells influencing the coagulation status. ICIs are important promoters of coagulation, benefiting from TCD8+ mediation. The exometabolome analysis highlighted the relevance of acetate, pyruvate, glycine, glutamine, valine, leucine and isoleucine as biomarkers. Further investigation is needed to validate this finding in a cohort of NSCLC patients. [ABSTRACT FROM AUTHOR]

Non-small cell lung cancer (NSCLC) accounts for 80-85% of all lung cancers. In recent years, treatment with immune checkpoint inhibitors (ICIs) has gradually improved the survival rate of patients with NSCLC, especially those in the advanced stages. ICIs can block the tolerance pathways that are overexpressed by tumor cells and maintain the protective activity of immune system components against cancer cells. Emerging clinical evidence suggests that gut microbiota may modulate responses to ICIs treatment, possibly holding a key role in tumor immune surveillance and the efficacy of ICIs. Studies have also shown that diet can influence the abundance of gut microbiota in humans, therefore, dietary interventions and the adjustment of the gut microbiota is a novel and promising treatment strategy for adjunctive cancer therapy. This review comprehensively summarizes the effects of gut microbiota, antibiotics (ATBs), and dietary intervention on the efficacy of immunotherapy in NSCLC, with the aim of informing the development of novel strategies in NSCLC immunotherapy. [ABSTRACT FROM AUTHOR]

Lung cancer is a leading cause of cancer-related deaths worldwide. Epidermal growth factor receptor (EGFR) driver mutations are crucial for treatment decisions for patients with non-small cell lung cancer (NSCLC). This study aimed to assess the differences in EGFR mutation detection between two companion diagnostic (CDx) tests—the Oncomine Dx Target Test (ODxTT) and the AmoyDx Pan Lung Cancer PCR Panel—and their impact on treatment applicability. To this end, we used an in-house targeted sequencing dataset of 282 samples from 127 EGFR-mutated NSCLC patients to simulate the concordance between the EGFR variants targeted by the ODxTT and AmoyDx panel, the oncogenicity of the variants, and their therapeutic potential. Of the 216 EGFR mutations identified by the in-house panel, 51% were detectable by both CDx tests, 3% were specific to ODxTT, and 46% were not targeted by either test. Most non-targeted mutations did not have oncogenicity and were located outside exons 18–21. Notably, 95% of the mutations detectable by both tests had potential oncogenicity. Furthermore, among the 96 patients harboring actionable EGFR mutations, 97% had mutations detectable by both CDx tests and 1% by ODxTT, while 2% had mutations not covered by either test. These findings suggest that while both CDx tests are effective in detecting almost all actionable EGFR mutations, ODxTT provides slightly broader coverage. These results emphasize the importance of selecting appropriate CDx tests to inform treatment decisions for EGFR-positive NSCLC patients. [ABSTRACT FROM AUTHOR]

BACKGROUND: Differential diagnosis of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) in hospitalized patients is crucial for appropriate treatment choice. OBJECTIVE: To investigate the relevance of serum tumor markers (STMs) and their combinations for the differentiation of NSCLC and SCLC subtypes. METHODS: Between 2000 and 2003, 10 established STMs were assessed retrospectively in 311 patients with NSCLC, 128 with SCLC prior systemic first-line therapy and 51 controls with benign lung diseases (BLD), by automatized electrochemiluminescence immunoassay technology. Receiver operating characteristic (ROC) curves and logistic regression analyses were used to evaluate the diagnostic efficacy of both individual and multiple STMs with corresponding sensitivities at 90% specificity. Standards for Reporting of Diagnostic Accuracy (STARD guidelines) were followed. RESULTS: CYFRA 21-1 (cytokeratin-19 fragment), CEA (carcinoembryonic antigen) and NSE (neuron specific enolase) were significantly higher in all lung cancers vs BLD, reaching AUCs of 0.81 (95% CI 0.76–0.87), 0.78 (0.73–0.84), and 0.88 (0.84–0.93), respectively. By the three marker combination, the discrimination between benign and all malignant cases was improved resulting in an AUC of 0.93 (95% CI 0.90–0.96). In NSCLC vs. BLD, CYFRA 21-1, CEA and NSE were best discriminative STMs, with AUCs of 0.86 (95% CI 0.81–0.91), 0.80 (0.74–0.85), and 0.85 (0.79–0.91). The three marker combination also improved the AUC: 0.92; 95% CI 0.89–0.96). In SCLC vs. BLD, ProGRP (pro-gastrin-releasing peptide) and NSE were best discriminative STMs, with AUCs of 0.89 (95% CI 0.84–0.94) and 0.96 (0.93–0.98), respectively, and slightly improved AUC of 0.97 (95% CI 0.95–0.99) when in combination. Finally, discrimination between SCLC and NSCLC was possible by ProGRP (AUC 0.86; 95% CI 0.81–0.91), NSE (AUC 0.83; 0.78–0.88) and CYFRA 21-1 (AUC 0.69; 0.64–0.75) and by the combination of the 3 STMs (AUC 0.93; 0.91–0.96), with a sensitivity of 88% at 90% specificity. CONCLUSIONS: The results confirm the power of STM combinations for the differential diagnosis of lung cancer from benign lesions and between histological lung cancer subtypes. [ABSTRACT FROM AUTHOR]

Background: About 10% of NSCLCs are mutated in KRAS and impaired in STK11/LKB1, a genetic background associated with poor prognosis, caused by an increase in metastatic burden and resistance to standard therapy. LKB1 is a protein involved in a number of biological processes and is particularly important for its role in the regulation of cell metabolism. LKB1 alterations lead to protein loss that causes mitochondria and metabolic dysfunction that makes cells unable to respond to metabolic stress. Different studies have shown how it is possible to interfere with cancer metabolism using metformin and caloric restriction (CR) and both modify the tumor microenvironment (TME), stimulating the switch from "cold" to "hot". Given the poor therapeutic response of KRASmut/LKB1mut patients, and the role of LKB1 in cell metabolism, we examined whether the addition of metformin and CR enhanced the response to chemo or chemo-immunotherapy in LKB1 impaired tumors. Methods: Mouse cell lines were derived from lung nodules of transgenic mice carrying KRASG12D with either functional LKB1 (KRASG12D/LKB1wt) or mutated LKB1 (KRASG12D/LKB1mut). Once stabilized in vitro, these cell lines were inoculated subcutaneously and intramuscularly into immunocompetent mice. Additionally, a patient-derived xenograft (PDX) model was established by directly implanting tumor fragments from patient into immunocompromised mice. The mice bearing these tumor models were subjected to treatment with chemotherapy or chemo-immunotherapy, both as standalone regimens and in combination with metformin and CR. Results: Our preclinical results indicate that in NSCLC KRASmut/LKB1mut tumors, metformin and CR do enhance the response to chemo and chemo-immunotherapy, inducing a metabolic stress condition that these tumors are not able to overcome. Analysis of immune infiltrating cells did not bring to light any strong correlation between the TME immune-modulation and the tumor response to metformin and CR. Conclusion: Our in vitro and in vivo preliminary studies confirm our hypothesis that the addition of metformin and CR is able to improve the antitumor activity of chemo and chemoimmunotherapy in LKB1 impaired tumors, exploiting their inability to overcome metabolic stress. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitor (ICI) treatment has been linked to a variety of immune-related adverse events (irAEs), which can affect any organ system. The incidence and risk factors of irAEs have not been adequately evaluated among older adults with NSCLC. Methods: A cohort study was conducted using 1999–2019 SEER-Medicare data among beneficiaries aged ≥65 years with a diagnosis of NSCLC who received nivolumab, pembrolizumab, or atezolizumab. Incident irAEs were identified post-ICI initiation. Demographic, cancer-related characteristics, and clinical history risk factors of irAEs were evaluated with competing events considered. Results: A total of 8175 older NSCLC patients were included (with 46.8% experiencing irAEs). Pneumonitis (16.5%), hypothyroidism (10.5%), arrhythmia (11.18%), and acute kidney injury (AKI) (5.8%) were the most common irAEs. The median time to first irAE was 82days (IQR: 29–182days). The earliest onset of irAE occurrence was for hematologic irAEs, while the latest were gastrointestinal, dermatologic, and musculoskeletal irAEs. Fine–Gray regression modeling revealed significantly greater hazards of irAE occurrence in patients who received pembrolizumab at index, did not have CNS metastases, had a history of autoimmune disorder, and had chemotherapy in combination with ICI. Race, socioeconomic status, previous radiation therapy, and comorbidity burden were found to be associated with the occurrence of certain type of irAEs. Conclusion: A significant proportion of older patients with NSCLC develop an irAE after receiving ICI treatment. Factors related to cancer and treatment as well as demographics contribute to the increased risk of irAEs. Close monitoring and prediction of irAE among older patients receiving ICI is warranted. [ABSTRACT FROM AUTHOR]

Nonsmall cell lung cancer (NSCLC) predominantly affects the elderly since its incidence and mortality rates skyrocket beyond the age of 65. The landscape of NSCLC treatment has been revolutionized by immune checkpoint inhibitors (ICIs), which have emerged after a long and mostly inactive period of conventional treatment protocols. However, there is limited data on the exact effects of these chemicals on older patients, whose care can be complicated by a variety of conditions. This highlights the need to understand the efficacy of emerging cancer medicines in older patients. In this study, we will review the data of ICIs from clinical trials that were relevant to older people with NSCLC and poor performance status. We will also discuss the role of immunosenescence in immunotherapy and biomarkers in predicting the efficacy of ICIs in patients with advanced NSCLC. [ABSTRACT FROM AUTHOR]

Immunotherapy for non-small cell lung cancer (NSCLC) has advanced considerably over the past two decades. In particular, immune checkpoint inhibitors are widely used for treating NSCLC. However, the overall cure and survival rates of patients with NSCLC remain low. Therefore, continuous investigation into complementary treatments is necessary to expand the clinical advantages of immunotherapy to a larger cohort of patients with NSCLC. Recently, the distinctive role of the gut microbiota (GM) in the initiation, progression, and dissemination of cancer has attracted increasing attention. Emerging evidence indicates a close relationship between the gut and lungs, known as the gut-lung axis (GLA). In this review, we aim to provide a comprehensive summary of the current knowledge regarding the connection between the GM and the outcomes of immunotherapy in NSCLC, with particular focus on the recent understanding of GLA. Overall, promising GM-based therapeutic strategies have been observed to improve the effectiveness or reduce the toxicity of immunotherapy in patients with NSCLC, thus advancing the utilization of microbiota precision medicine. [ABSTRACT FROM AUTHOR]

There have been studies on antibiotic use concerning lung cancer and its potential impact on carcinogenesis and microbiome. However, subsequent research has failed to support these associations consistently. In terms of the potential carcinogenic of antibiotics on lung cancer, the available evidence has not been sufficient to draw any definitive conclusions. Maintaining immune homeostasis and preventing pathogen invasion is critically dependent on the microbiome. The subtle balance of the body microbiota, including the lungs, is susceptible to disruption by antibiotic use. There is an association between disruptions of the lung microbiome and respiratory diseases, including lung cancer, and decreased efficacy of treatments. Patients with lung cancer are often indicated for antibiotic treatment due to respiratory infections or other comorbidities. Pulmonary infections in the area of undetected lung tumors are not uncommon. They can be an early sign of malignancy, which may explain the association between antibiotic use and lung cancer diagnosis. Antibiotic use can also affect the effectiveness of immune checkpoint inhibitor therapy. Studies suggest that antibiotic use can impair the efficacy of immune checkpoint inhibitor therapy in lung cancer patients, particularly around the time when treatment is initiated. These findings require further study, understanding underlying mechanisms, and identifying microbiota signatures associated with treatment response. [ABSTRACT FROM AUTHOR]

The PACIFIC trial led to a new standard of care for patients with locally advanced lung cancer, but real-world practice has demonstrated that immune checkpoint inhibitor (ICI) pneumonitis can lead to significant clinical complications. This study aimed to examine the clinical predictors, outcomes, and healthcare utilization data in patients who received consolidation durvalumab. Using the Alberta Immunotherapy Database, NSCLC patients who received durvalumab in Alberta, Canada, from January 2018 to December 2021 were retrospectively evaluated. We examined incidence and predictive values of severe pneumonitis, with overall survival (OS) and time-to-treatment failure (TTF) using exploratory multivariate analyses. Of 189 patients, 91% were ECOG 0–1 and 85% had a partial response from chemoradiation prior to durvalumab. Median TTF and OS were not reached; 1-year OS was 82%. An amount of 26% developed any grade of pneumonitis; 9% had ≥grade 3 pneumonitis. Male gender and a pre-existing autoimmune condition were associated with severe pneumonitis. V20 was associated with any grade of pneumonitis. Pneumonitis development was found to be an independent risk factor for worse OS (p = 0.038) and TTF (p = 0.007). Our results suggest clinical and dosimetric predictive factors of durvalumab-associated pneumonitis. These results affirm the importance of careful patient selection for safe completion of consolidation durvalumab in real-world LA-NSCLC population. [ABSTRACT FROM AUTHOR]

The gastrointestinal microbiome has been shown to play a key role in determining the responses to cancer immunotherapy, including immune checkpoint inhibitor (ICI) therapy and CAR-T. In patients with non-small cell lung cancer (NSCLC), increasing evidence suggests that a microbiome composition signature is associated with clinical response to ICIs as well as with the development of immune-related adverse events. In support of this, antibiotic (ATB)-related dysbiosis has been consistently linked with the deleterious impact of ICI response, shortening the overall survival (OS) among patients on ATBs prior to ICI initiation. In parallel, several preclinical experiments have unravelled various strategies using probiotics, prebiotics, diet, and fecal microbiota transplantation as new therapeutic tools to beneficially shift the microbiome and enhance ICI efficacy. These approaches are currently being evaluated in clinical trials and have achieved encouraging preliminary results. In this article, we reviewed the recent studies on the gut microbiome as a potential biomarker and an adjuvant therapy to ICIs in NSCLC patients. [ABSTRACT FROM AUTHOR]

Outcome improvement in patients with driver-gene-negative advanced non-small cell lung cancer (NSCLC) has been significantly enhanced through targeting the immune system, specifically the PD-L1/PD-1 axis. Nevertheless, only a subset of patients with advanced NSCLC may derive benefits from immuno-monotherapy or immunotherapy combined with chemotherapy. Hence, in order to identify patients who will gain the maximum advantage from immunotherapy, it is crucial to investigate predictive biomarkers. This review provides a summary of the currently identified biomarkers associated with the extent of benefit from immuno-monotherapy or immunotherapy combined with chemotherapy in patients with advanced NSCLC. These biomarkers can be categorized into three groups: tumor-related, tumor-microenvironment-related, and host-factor-related.Tumor-related factors include PD-L1 expression, tumor mutational burden and specific genetic mutations, while tumor-microenvironment-related factors include extracellular vesicles and T-cell receptors, and host-related factors include systemic inflammation, circulating fatty acid profile, and the microbiome. [ABSTRACT FROM AUTHOR]

The emergence of immunotherapy, particularly programmed cell death 1 (PD-1) and programmed cell death ligand-1 (PD-L1) produced profound transformations for treating non-small cell lung cancer (NSCLC). Nevertheless, not all NSCLC patients can benefit from immunotherapy in clinical practice. In addition to limited response rates, exorbitant treatment costs, and the substantial threats involved with immunerelated adverse events, the intricate interplay between long-term survival outcomes and early disease progression, including early immune hyperprogression, remains unclear. Consequently, there is an urgent imperative to identify robust predictive and prognostic biological markers, which not only possess the potential to accurately forecast the therapeutic efficacy of immunotherapy in NSCLC but also facilitate the identification of patient subgroups amenable to personalized treatment approaches. Furthermore, this advancement in patient stratification based on certain biological markers can also provide invaluable support for themanagement of immunotherapy in NSCLC patients. Hence, in this review, we comprehensively examine the current landscape of individual biological markers, including PD-L1 expression, tumor mutational burden, hematological biological markers, and gene mutations, while also exploring the potential of combined biological markers encompassing radiological and radiomic markers, as well as prediction models that have the potential to better predict responders to immunotherapy in NSCLC with an emphasis on some directions that warrant further investigation which can also deepen the understanding of clinicians and provide a reference for clinical practice. [ABSTRACT FROM AUTHOR]

BRAF and cMET exon 14 skipping are rare mutations of NSCLC. The treatment sequence in these cases for the first and second line is not clear. An international registry was created for patients with advanced NSCLC harboring BRAF or cMET exon 14 skipping mutations, diagnosed from January 2017 to June 2022. Clinicopathological and molecular data and treatment patterns were recorded. Data on 58 patients, from eight centers across five countries, were included in the final analysis. We found that 40 patients had the cMET exon 14 skipping mutation and 18 had the BRAF V600E mutation. In total, 53 and 28 patients received first- and second-line treatments, respectively, among which 52.8% received targeted therapy (TT) in the first line and 53.5% in the second line. The overall response rate (ORR) and disease control rate (DCR) for first-line treatment with TT vs. other treatment such as immune checkpoint inhibitors ± chemotherapy (IO ± CT) were 55.6% vs. 21.7% (p = 0.0084) and 66.7% vs. 39.1% (p = 0.04), respectively. The type of treatment in first-line TT vs. other affected time to treatment discontinuation (TTD) was 11.6 m vs. 4.6 m (p= 0.006). The overall survival for the whole group was 15.4 m and was not statistically affected by the type of treatment (19.2 m vs. 13.5 m; p = 0.83). [ABSTRACT FROM AUTHOR]

Over the last decade, the therapeutic scenario for advanced non-small-cell lung cancer (NSCLC) has undergone a major paradigm shift. Immune checkpoint inhibitors (ICIs) have shown a meaningful clinical and survival improvement in different settings of the disease. However, the real benefit of this therapeutic approach remains controversial in selected NSCLC subsets, such as those of the elderly with active brain metastases or oncogene-addicted mutations. This is mainly due to the exclusion or underrepresentation of these patient subpopulations in most pivotal phase III studies; this precludes the generalization of ICI efficacy in this context. Moreover, no predictive biomarkers of ICI response exist that can help with patient selection for this therapeutic approach. Here, we critically summarize the current state of ICI efficacy in the most common "special" NSCLC subpopulations. [ABSTRACT FROM AUTHOR]

Lung cancer has the highest mortality rate among all cancer types, resulting in over 1.8 million deaths annually. Immunotherapy utilizing immune checkpoint inhibitors (ICIs) has revolutionized the treatment of non-small cell lung cancer (NSCLC). ICIs, predominantly monoclonal antibodies, modulate co-stimulatory and co-inhibitory signals crucial for maintaining immune tolerance. Despite significant therapeutic advancements in NSCLC, patients still face challenges such as disease progression, recurrence, and high mortality rates. Therefore, there is a need for predictive biomarkers that can guide lung cancer treatment strategies. Currently, programmed death-ligand 1 (PD-L1) expression is the only established biomarker for predicting ICI response. However, its accuracy and robustness are not consistently reliable. This review provides an overview of potential biomarkers currently under development or in the validation stage that hold promise in improving the classification of responders and non-responders to ICI therapy in the near future. [ABSTRACT FROM AUTHOR]

(1) Background: Exon 20 insertion mutations (ex20ins) in EGFR and HER2 are uncommon driver mutations in non-small-cell lung cancer (NSCLC), with a poor prognosis and few targeted therapy options, and there are limited real-world data. Here, we report the clinicopathologic features and outcomes for patients with ex20ins NSCLC across British Columbia, Canada. (2) Methods: NSCLC patients with ex20ins in EGFR or HER2 were identified via tumour testing between 1 January 2016 and 31 December 2021 (n = 7233). Data were collected by chart review. Survival analyses were performed using the Kaplan–Meier method using the log-rank test. (3) Results: A total of 131 patients were identified. The median age was 66. Thirty-three percent of patients had brain metastases. For the EGFR cohort, the median OS was 18.6 months for patients who received any systemic therapy (ST) vs. 2.6 months for patients who did not (p < 0.001). Median OS was similar for patients treated with ex20ins-specific tyrosine kinase inhibitors (TKIs) vs. other STs (18.6 vs. 15.9 months; p = 0.463). The median first-line PFS was 4.1 vs. 7.4 months for patients treated with a TKI vs. other ST (p = 0.744). For the HER2 cohort, the median OS was 9.0 months for patients who received any ST vs. 4.9 months for patients who did not (p = 0.015). The median OS was 23.0 months for patients treated with an ex20ins TKI vs. 5.6 months for patients who were not (p = 0.019). The median first-line PFS was 5.4 vs. 2.1 months for patients treated with a TKI vs. other ST (p = 0.343). (4) Conclusions: Overall survival was significantly longer among ex20ins patients who received any systemic therapy vs. those who did not. Overall survival was significantly better among HER2 ex20ins patients who received ex20ins-specific TKIs. [ABSTRACT FROM AUTHOR]

Background: With remarkable success and few side effects, induction chemoimmunotherapy has been used to improve the prognosis of patients with resectable or potentially resectable non-small cell lung cancer (NSCLC), even in stage III disease. However, for patients who are medically inoperable, unresectable or refuse surgery after induction chemoimmunotherapy, it is unclear whether patients should be treated with concurrent chemoradiotherapy (cCRT) or radiotherapy (RT) alone considering patient safety and tolerability. This study aimed to determine whether cCRT is safe and superior to RT alone after chemoimmunotherapy for stage III NSCLC. Methods: Patients diagnosed with stage III NSCLC who received chemoimmunotherapy followed by cCRT/RT alone without surgery at Tianjin Cancer Hospital between November 2018 to December 2021 were retrospectively collected. Patients were divided into two groups: induction chemoimmunotherapy followed by cCRT (cCRT cohort) or RT alone (RT alone cohort). Kaplan-Meier method was used to estimate survival. Univariate and multivariate Cox regression models were adopted to estimate risk factors for PFS. Results: Sixty-five patients were included, with 44 (67.7%) received RT alone and 21 (32.3%) received cCRT. Patients in the cCRT group had significantly prolonged PFS (HR = 0.155, p = 0.004), LPFS (HR = 0.225, p = 0.029) and DMFS (HR = 0.028, p = 0.006) than those in the RT alone group. Albeit nonsignificant, a trend toward improved OS (HR = 0.030, p = 0.069) was also observed in the cCRT group. The multivariate analysis further confirmed that cCRT (HR = 0.141, p = 0.008) was the independent factor for promoting a favorable PFS. Treatment-related adverse events were similar between groups (p > 0.05). Patients with consolidation immunotherapy exhibited a trend of improved PFS (HR = 0.398, p = 0.274) and numerically better OS (HR = 0.018, p = 0.209) compared with those without. Conclusions: For patients with unresectable stage III NSCLC, cCRT following chemoimmunotherapy appears to be safe and may prolong survival compared with radiotherapy alone. Further investigations on the combination of chemoimmunotherapy and CRT are warranted. [ABSTRACT FROM AUTHOR]

Background: In the treatment of Non-Small Cell Lung Cancer (NSCLC) the combination of Immuno- Oncotherapy (IO) and chemotherapy (CT) has been found to be superior to IO or CT alone for patients' survival. Patients and clinicians are confronted with a preference sensitive choice between a more aggressive treatment with a greater negative effect on quality of life versus alternatives that are less effective but have fewer side effects. Objectives: The aims of this study were to: (a) quantify patients' preferences for relevant attributes related to Immuno-Oncotherapy treatment alternatives, and (b) evaluate the maximum acceptable risk (MAR)/Minimum acceptable benefit (MAB) that patients would accept for treatment alternatives. Methods: An online preference survey using discrete-choice experiment (DCE) was completed by NSCLC patients from two hospitals in Italy and Belgium. The survey asked patients' preferences for five patient- relevant treatment attributes. The DCE was developed using a Bayesian D-efficient design. DCE analyses were performed using mixed logit models. Information regarding patient demographics, health literacy, locus of control, and quality of life was also collected. Results: 307 patients (158 Italian, 149 Belgian), stage I to IV, completed the survey. Patients preferred treatments with a higher 5-year survival chance as the most important attribute over all the other attributes. Preference heterogeneity for the attribute weights depended on health literacy, patients' age and locus of control. Patients were willing to accept a substantially increased risks of developing side effects in exchange for the slightest increase (1%) in the chance of surviving at least 5 years from the diagnosis of cancer. Similarly, patients were willing to accept a switch in the mode of administration or complete loss of hair to obtain an increase in survival. Conclusion: In this study, the proportion of respondents who systematically preferred survival over all other treatment attributes was particularly high. Age, objective health literacy and locus of control accounted for heterogeneity in patients' preferences. Evidence on how NSCLC patients trade between survival and other NSCLC attributes can support regulators and other stakeholders on assessing clinical trial evidence and protocols, based on patients' conditions and socio-demographic parameters. [ABSTRACT FROM AUTHOR]

Background: Immunotherapy alone (mono-IT) or combined with chemotherapy (chemo-IT) has recently become the cornerstone of first-line treatment for advanced non-small cell lung cancer (NSCLC) patients. Here, real-world outcomes of first-line mono-IT and chemo-IT of advanced NSCLC treated within routine clinical practice at a single academic center in the Central Eastern European (CEE) region are presented. Materials and methods: A total of 176 consecutive patients with advanced NSCLC treated with mono-IT (118 patients) or chemo-IT (58 patients) were included. At the participating institution, all medical data relevant for providing oncology care are collected prospectively and in a standardized manner using purposely created pro-forms. Adverse events (AEs) were recorded and graded according to Common Terminology Criteria for Adverse Events (CTCAE). The Kaplan-Meier method was used to estimate median overall survival (mOS) and median duration of treatment (mDOT). Results: The 118 patients in the mono-IT cohort had a median age of 64 years, most were male (59%), 20% had ECOG PS =2, and 14% had controlled CNS metastases at baseline. With a median follow-up time (mFU) of 24.1 months, the mOS was 19.4 months (95% CI, 11.1-27.6), and the mDOT was 5.0 months (95% CI, 3.5-6.5). The 1-year OS was 62%. The 58 patients in the chemo-IT cohort had a median age of 64 years, most were male (64%), 9% had ECOG PS =2, and 7% had controlled CNS metastases at baseline. With a mFU of 15.5 months, the mOS was 21.3 months (95% CI, 15.9-26.7), and the mDOT was 12.0 months (95% CI, 8.3-15.6). The 1-year OS was 75%. Adverse events of severe grade were recorded in 18% and 26% of patients, and immunotherapy discontinuation due to AEs occurred in 19% and 9% in the mono-IT and chemo-IT groups, respectively. No treatment-related deaths were recorded. Conclusion: The results from the present real-world observational study from a CEE country suggest similar effectiveness and safety of first-line mono-IT and chemo-IT in patients with advanced NSCLC to those observed in randomized clinical trials. However, continuous follow-up will offer better insight into the magnitude of long-term benefits in routine clinical practice. [ABSTRACT FROM AUTHOR]

The majority of epidermal growth factor receptor (EGFR) mutations (85–90%) are exon 19 deletions and L858R point mutations of exon 21, characterized by high sensitivity to EGFR-tyrosine kinase inhibitors (TKIs). Less is known about uncommon mutations (10–15% of EGFR mutations). The predominant mutation types in this category include exon 18 point mutations, exon 21 L861X, exon 20 insertions, and exon 20 S768I. This group shows a heterogeneous prevalence, partly due to different testing methods and to the presence of compound mutations, which in some cases can lead to shorter overall survival and different sensitivity to different TKIs compared to simple mutations. Additionally, EGFR-TKI sensitivity may also vary depending on the specific mutation and the tertiary structure of the protein. The best strategy remains uncertain, and the data of EGFR-TKIs efficacy are based on few prospective and some retrospective series. Newer investigational agents are still under study, and there are no other approved specific treatments targeting uncommon EGFR mutations. Defining the best treatment option for this patient population remains an unmet medical need. The objective of this review is to evaluate existing data on the outcomes, epidemiology, and clinical characteristics of lung cancer patients with rare EGFR mutations, with a focus on intracranial activity and response to immunotherapy. [ABSTRACT FROM AUTHOR]

Purpose: Immune-checkpoint inhibitors (ICIs) are effective against advanced non-small cell lung cancer (NSCLC). However, whether the efficacy and safety of ICI treatment in elderly patients are similar to those in younger patients is unclear. This study was designed to address this question. Methods: We enrolled patients who received ICI monotherapy in Japan between December 2015 and December 2017; those =75 years of age comprised the elderly group. We compared the efficacy and safety of ICI monotherapy in elderly patients with those in younger patients and explored prognostic factors in elderly patients. Results: We enrolled 676 patients; 137 (20.3%) were assigned to the elderly group. The median age of the elderly and younger groups was 78 (range, 75-85) and 66 (range, 34-74) years. The median progression-free survival (4.8 months vs. 3.3 months, p = 0.1589) and median overall survival (12.3 months vs. 13.0 months, p = 0.5587) were similar between the elderly and younger groups. Multivariate analysis revealed that a significantly better OS in the elderly group was associated with better responses to first-or second-line ICI treatment (p = 0.011) and more immune-related adverse events (irAEs) (p = 0.02). IrAEs that led to ICI discontinuation occurred in 34 of 137 patients (24.8%) in the elderly group, and their survival was significantly higher than that in those who did not have irAEs. Conclusion: ICI is also effective in elderly NSCLC patients, and treatment discontinuation due to irAEs may be a good prognostic marker. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors (ICI)-based combination strategies have improved the survival outcomes in advanced non-small cell lung cancers; however, data regarding their efficacy remains limited for uncommon histological types, including large-cell carcinoma (LCC) and large-cell neuroendocrine carcinoma (LCNEC). Methods: We retrospectively analyzed a total of 60 patients with advanced LCC and LCNEC – 37 treatment-naïve and 23 pre-treated – who received pembrolizumab with or without chemotherapy. Treatment and survival outcomes were analyzed. Results: Of the 37 treatment-naïve patients who received first-line pembrolizumab combined with chemotherapy, the 27 patients with LCC had an overall response rate (ORR) of 44.4% (12/27) and a disease control rate (DCR) of 88.9% (24/27); whereas 10 patients with LCNEC had an ORR of 70% (7/10) and DCR of 90% (9/10). The median progression-free survival (mPFS) was 7.0 months (95% confidence intervals [CI]: 2.2–11.8) and median overall survival (mOS) was 24.0 months (95%CI: 0.0–50.1) for first-line pembrolizumab plus chemotherapy of LCC (n = 27), whereas mPFS was 5.5 months (95%CI: 2.3–8.7) and mOS was 13.0 months (95%CI: 11.0–15.0) for first-line pembrolizumab plus chemotherapy of LCNEC (n = 10). Of the 23 pre-treated patients who received subsequent-line pembrolizumab with or without chemotherapy, mPFS was 2.0 months (95% CI: 0.6–3.4) and mOS was 4.5 months (95% CI: 0.0–9.0) for LCC and mPFS was 3.8 months (95% CI: 0.0–7.6) and mOS was not reached for LCNEC. Conclusion: Our study provides real-world clinical evidence of the anti-tumor activity of pembrolizumab plus chemotherapy in advanced LCC and LCNEC, indicating that this regimen could serve as a treatment option, particularly as first-line therapy, for improving the survival outcomes of patients with these rare histological subtypes of lung cancer. Trial registration: NCT05023837(ESPORTA, 27/08/2021). Highlights: • Rare lung cancer subtypes, LCC and LCNEC, benefits from immunochemotherapy. • Disease control of LCC and LCNEC is achieved with 1L pembrolizumab plus chemotherapy. • 1L pembrolizumab plus chemotherapy imparts better survival outcomes for LCC/LCNEC. [ABSTRACT FROM AUTHOR]

Background: Many trials supported pembrolizumab as a first-line monotherapy to significantly improve overall survival (OS) in selected patients with previously untreated metastatic Non–Small Cell Lung Cancer (mNSCLC) and a PD-L1 TPS of ≥50% without EGFR/ALK mutations. The aim of this study was to reveal the correlation between OS and adverse events in real-world settings after 42 months. Methods: This retrospective observational study involved 98 patients with mNSCLC, TPS ≥ 50%, and no EGFR/ALK aberrations. Patients were treated with pembrolizumab (200 mg q3w) as a first-line treatment. Clinical data, including PD-L1 expression, Performance Status (ECOG-PS), treatment duration, toxicity, and outcomes were retrieved from local electronic medical records and from the Italian Regulatory Agency Registry. Results: The cohort's main characteristics were as follows: median age 73 [44-89] years, 64.3% were male and 35.7% were female, an ECOG-PS score of 0 (n = 73) and 1 or 2 (n = 25), and a PD-L1 > 90% in 29.6% of patients. The entire cohort had stage IV NSCLC at diagnosis. The median number of cycles was 8.5 at a median follow-up of 13 months. The median OS of 13.6 months (95% CI: 11.7-NA) was not influenced by sex and PD-L1, but was significantly associated with ECOG-PS (p = 0.02). Immune-Related Adverse Events (irAEs) occurred in 77.5% of patients (30.1% cutaneous, 27.5% gastrointestinal, and 20.4% endocrinological), but no grade 4 or 5 irAEs were identified. Patients experiencing any type of toxicity had a significantly longer median OS (20.39 months, 95% CI: 13.08-NA) than those with no toxicities (6.46 months, 95% CI: 1.41-NA, p = 0.006). Conclusion: The percentage of irAEs detected was comparable to that reported in KEYNOTE-024 and KEYNOTE-042. These real-world findings demonstrated the significant correlation between OS and cutaneous toxicities. [ABSTRACT FROM AUTHOR]

Background: The efficacy of nivolumab and atezolizumab in advanced pre-treated NSCLC was documented in prospective trials. We aim to confirm the benefits and indicate predictive factors for immunotherapy in daily practice. Methods: This study was a retrospective analysis. The median PFS and OS were estimated using the Kaplan-Meier method. The log-rank test was used for comparisons. Multivariate analyses were performed using the Cox regression method. Results: A total of 260 patients (ECOG 0-1) with advanced NSCLC (CS III-IV) were eligible to receive nivolumab or atezolizumab as second-line treatment. Median PFS and OS were three months (95% confidence interval [CI] 2.57–3.42) and 10 months (95% CI 8.03–11.96), respectively, for the overall population. The median OS for the atezolizumab arm was eight months (95% CI 5.89–10.1), while for the nivolumab group, it was 14 months (95% CI 10.02–17.97) (p = 0.018). The sum of all measurable changes >100.5 mm (p = 0.007; HR = 1.003, 95% CI 1.001–1.005), PLT > 281.5 G/l (p < 0.001; HR = 1.003, 95% CI 1.001–1.003) and bone metastases (p < 0.004; HR = 1.58, 95% CI 1.04–2.38) were independent negative prognostic factors for OS in multivariate analysis. Based on preliminary analyses, a prognostic index was constructed to obtain three prognostic groups. Median OS in the subgroups was 16 months (95% CI 13.3–18.7), seven months (95% CI 4.83–9.17) and four months (95% CI 2.88–5.13), respectively (p < 0.001). Conclusions: Nivolumab and atezolizumab provided clinical benefit in real life. Clinical and laboratory factors may help to identify subgroups likely to benefit. The use of prognostic indices may be valuable in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Current prognosis in oncology is reduced to the tumour stage and performance status, leaving out many other factors that may impact the patient's management. Prognostic stratification of early stage non-small-cell lung cancer (NSCLC) patients with poor prognosis after surgery is of considerable clinical relevance. The objective of this study was to identify clinical factors associated with long-term overall survival in a real-life cohort of patients with stage I-II NSCLC and develop a prognostic model that identifies features associated with poor prognosis and stratifies patients by risk. Methods: This is a cohort study including 505 patients, diagnosed with stage I-II NSCLC, who underwent curative surgical procedures at a tertiary hospital in Madrid, Spain. Results: Median OS (in months) was 63.7 (95% CI, 58.7-68.7) for the whole cohort, 62.4 in patients submitted to surgery and 65 in patients submitted to surgery and adjuvant treatment. The univariate analysis estimated that a female diagnosed with NSCLC has a 0.967 (95% CI 0.936 - 0.999) probability of survival one year after diagnosis and a 0.784 (95% CI 0.712 - 0.863) five years after diagnosis. For males, these probabilities drop to 0.904 (95% CI 0.875 - 0.934) and 0.613 (95% CI 0.566 - 0.665), respectively. Multivariable analysis shows that sex, age at diagnosis, type of treatment, ECOG-PS, and stage are statistically significant variables (p<0.10). According to the Cox regression model, age over 50, ECOG-PS 1 or 2, and stage ll are risk factors for survival (HR>1) while adjuvant chemotherapy is a good prognostic variable (HR<1). The prognostic model identified a high-risk profile defined by males over 71 years old, former smokers, treated with surgery, ECOGPS 2. Conclusions: The results of the present study found that, overall, adjuvant chemotherapy was associated with the best long-term OS in patients with resected NSCLC. Age, stage and ECOG-PS were also significant factors to take into account when making decisions regarding adjuvant therapy. [ABSTRACT FROM AUTHOR]

Biomarkers of systemic inflammation/nutritional status have been associated with outcomes in advanced-stage non-small-cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs). However, most of them were not tested in cohorts of patients treated with ICIs in combination with chemotherapy (CT) (ICI + CT) or with CT alone, making it impossible to discriminate a predictive from a prognostic effect. We conducted a single-center retrospective study to search for associations between various baseline biomarkers/scores that reflected the systemic inflammation/nutritional status (Lung Immune Prognostic Index, Modified Lung Immune Prognostic Index, Scottish Inflammatory Prognostic Score, Advanced Lung Cancer Inflammation Index, EPSILoN, Prognostic Nutritional Index, Systemic Immune-Inflammation Index, Gustave Roussy Immune Score, Royal Marsden Hospital Prognostic Score, Lung Immuno-oncology Prognostic Score 3, Lung Immuno-oncology Prognostic Score 4, score published by Holtzman et al., and Glasgow Prognostic Score) and outcomes in metastatic NSCLC treated in a first-line setting either with ICI in monotherapy (cohort 1; n = 75), ICI + CT (cohort 2; n = 56), or CT alone (cohort 3; n = 221). In the three cohorts, the biomarkers/scores were moderately associated with overall survival (OS) and progression-free survival (PFS). Their prognostic performance was relatively poor, with a maximum c-index of 0.66. None of them was specific to ICIs and could help to choose the best treatment modality. The systemic inflammation/nutritional status, associated with outcomes independently of the treatment, is therefore prognostic but not predictive in metastatic NSCLC. [ABSTRACT FROM AUTHOR]

Immunotherapy has revolutionized the treatment paradigm of non-small cell lung cancer and improved patients' prognosis. Immune checkpoint inhibitors have quickly become standard frontline treatment for metastatic non-oncogene addicted disease, either as a single agent or in combination strategies. However, only a few patients have long-term benefits, and most of them do not respond or develop progressive disease during treatment. Thus, the identification of reliable predictive and prognostic biomarkers remains crucial for patient selection and guiding therapeutic choices. In this review, we provide an overview of the current strategies, highlighting the main clinical challenges and novel potential biomarkers. [ABSTRACT FROM AUTHOR]

Introduction: Artificial Intelligence (AI) methods are being increasingly investigated as a means to generate predictive models applicable in the clinical practice. In this study, we developed a model to predict the efficacy of immunotherapy (IO) in patients with advanced non-small cell lung cancer (NSCLC) using eXplainable AI (XAI) Machine Learning (ML) methods. Methods: We prospectively collected real-world data from patients with an advanced NSCLC condition receiving immune-checkpoint inhibitors (ICIs) either as a single agent or in combination with chemotherapy. With regards to six different outcomes - Disease Control Rate (DCR), Objective Response Rate (ORR), 6 and 24-month Overall Survival (OS6 and OS24), 3-months Progression-Free Survival (PFS3) and Time to Treatment Failure (TTF3) - we evaluated five different classification ML models: CatBoost (CB), Logistic Regression (LR), Neural Network (NN), Random Forest (RF) and Support Vector Machine (SVM). We used the Shapley Additive Explanation (SHAP) values to explain model predictions. Results: Of 480 patients included in the study 407 received immunotherapy and 73 chemo- and immunotherapy. From all the ML models, CB performed the best for OS6 and TTF3, (accuracy 0.83 and 0.81, respectively). CB and LR reached accuracy of 0.75 and 0.73 for the outcome DCR. SHAP for CB demonstrated that the feature that strongly influences models' prediction for all three outcomes was Neutrophil to Lymphocyte Ratio (NLR). Performance Status (ECOG-PS) was an important feature for the outcomes OS6 and TTF3, while PD-L1, Line of IO and chemo-immunotherapy appeared to be more important in predicting DCR. Conclusions: In this study we developed a ML algorithm based on real-world data, explained by SHAP techniques, and able to accurately predict the efficacy of immunotherapy in sets of NSCLC patients. [ABSTRACT FROM AUTHOR]

Background: To determine whether antibiotic use before chemotherapy is associated with chemotherapy responses and patient outcomes among NSCLC patients and define the optimal interval between chemotherapy initiation and antibiotic treatment. Materials and methods: One thousand four hundred and four advanced NSCLC patients receiving first-line platinum-based doublets therapy were retrospectively analyzed. Kaplan--Meier curve evaluated the impact of antibiotic use and type of antibiotics on the survival of patients. The factors affect the patient's prognosis were further confirmed by Cox regression. The optimal interval between antibiotic treatment and the initiation of chemotherapy was determined by the X-tile program. Results: NSCLC patients of 33.5% advanced underwent broad-spectrum antibiotic treatment prior to chemotherapy. In the chemotherapy only (Chemo) and chemotherapy plus antiangiogenesis (Chemo-angio) treatment groups, prior antibiotic treatment was associated with worse OS (Chemo: 13.8 vs. 17.6 months, p < 0.001; Chemo-angio:11.9 vs. 18.1 months, p = 0.012) and PFS (Chemo: 3.7 vs. 5.8 months, p < 0.001; Chemo-angio: 3.1 vs. 5.9 months, p < 0.001). Cox regression analysis revealed prior antibiotic administration as an independent predictor of OS and PFS (HR for PFS/OS: 1.925/1.452, both p < 0.001). Antibiotic usage duration (HR for PFS/OS: 1.030/1.036, p = 0.009/0.001) and type (PFS/OS: p < 0.001/p = 0.01) also showed significant association with patient prognosis, with calculated interval time cutoff values of 2, 4, and 2 days for fluoroquinolones, β-lactamase inhibitors, and cephalosporins, respectively. Conclusion: Antibiotic use before first-line chemotherapy was associated with poor results in advanced NSCLC patients; treatment length and type being strongly correlated with patient outcomes. Appropriate prolongation of the time between two treatments may enhance patient survival. Further prospective research is however necessary. [ABSTRACT FROM AUTHOR]

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Background: Immune checkpoint inhibitors (ICIs) have changed the treatment landscape of several cancer types. However, data are lacking with regard to the clinical responsiveness of ICIs in patients with advanced non-small cell lung cancer (NSCLC) after standard first-line chemotherapy. Therefore, we aimed to evaluate the clinical efficacy of ICI alone or in combination with chemotherapy for patients with advanced NSCLC after first-line platinum-based chemotherapy. Methods: We retrospectively collected patients with confirmed advanced NSCLC who underwent ICI monotherapy or ICI plus chemotherapy after first-line platinum-based chemotherapy between January 2018 and December 2020. A propensity score matching analysis was used to balance baseline characteristics between the two treatment groups. Kaplan-Meier methods and multivariable Cox regressions were used for survival analyses. Results: Among 832 eligible patients, 222 received ICI monotherapy and 610 received ICI plus chemotherapy. The median overall survival (OS) of patients who received ICI plus chemotherapy was 16.0 months compared with 13.1 months in patients who received ICI monotherapy (HR: 0.64, 95% CI: 0.49- 0.85, P = 0.002). After 1:1 propensity score matching, all baseline characteristics were well-balanced between the two treatment groups. Patients who received ICI plus chemotherapy had significantly longer OS than those who received ICI monotherapy (NR vs. 13.1 months, HR: 0.50, 95% CI: 0.34-0.71, P < 0.001). Meanwhile, the median time to treatment discontinuation was 4.4 months in the ICI-chemo group and 3.5 months in the ICI-mono group (HR: 0.72, 95% CI: 0.58-0.89, P = 0.002). The multivariate analysis indicated that treatment regimen was an independent prognostic factor for OS (HR: 0.488, 95% CI: 0.337-0.707, P < 0.001). Moreover, a nomogram that integrated both treatment regimens and clinicopathological factors was created for survival prediction. Conclusion: Our study indicated that patients with advanced NSCLC who received ICI plus chemotherapy after first-line platinum-based chemotherapy tended to have longer OS than those who received ICI monotherapy. The multivariate analysis showed that treatment regimen was an independent prognostic factor for OS. Future prospective studies are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

PD-L1 in tumor cells is the only used biomarker for anti PD1/PD-L1 immunecheckpoints inhibitors (ICI) in Non Small Cell Lung Cancer (NSCLC) patients. However, this parameter is inaccurate to predict response, especially in patients with low tumor PD-L1. Here, we evaluated circulating EVs as possible biomarkers for ICI in advanced NSCLC patients with low tumoral PD-L1. EVs were isolated from plasma of 64 PD-L1 low, ICI-treated NSCLC patients, classified either as responders (R; complete or partial response by RECIST 1.1) or non-responders (NR). EVs were characterized following MISEV guidelines and by flow cytometry. T cells from healthy donors were triggered in vitro using patients' EVs. Unsupervised statistical approach was applied to correlate EVs' and patients' features to clinical response. R-EVs showed higher levels of tetraspanins (CD9, CD81, CD63) than NR-EVs, significantly associated to better overall response rate (ORR). In multivariable analysis CD81-EVs correlated with ORR. Unsupervised analysis revealed a cluster of variables on EVs, including tetraspanins, significantly associated with ORR and improved survival. R-EVs expressed more costimulatory molecules than NR-EVs although both increased T cell proliferation and partially, activation. Tetraspanins levels on EVs could represent promising biomarkers for ICI response in NSCLC. [ABSTRACT FROM AUTHOR]

Despite the recent increase in the number of types of treatments, non-small-cell lung cancer (NSCLC) remains the major cause of death from cancer worldwide. So, there is an urgent need to develop new therapeutic strategies. The HER2 gene codes for tyrosine kinase receptor whose alterations are known to drive carcinogenesis. HER2 alterations, including amplification, mutations, and overexpression, have been mainly described in breast and gastric cancers, but up to 4% of NSCLC harbor actionable HER2 mutations. HER2-targeted therapy for NSCLC with trastuzumab, pertuzumab, and trastuzumab emtansine has failed to demonstrate an improvement in survival. Nevertheless, recent data from phase II trials have shed light on promising specific therapies for HER2-mutant NSCLC such as trastuzumab deruxtecan. Herein, we aimed to provide an updated review on the biology, epidemiology, molecular testing, and therapeutic strategies for NSCLC with HER2 molecular alterations. [ABSTRACT FROM AUTHOR]

The impact of baseline versus intercurrent steroids on the efficacy of upfront chemotherapy plus pembrolizumab (CT-ICI) for advanced non-small cell lung cancer (NSCLC) patients is unclear. We conducted a retrospective study on metastatic NSCLC patients treated with upfront CT-ICI at our institution between March 2020 and December 2021. The use of steroids was considered as the administration of at least 10 mg of prednisone equivalent. Of 101 patients, 36 (35.6%) received steroid therapy at baseline, and 18 (17.8%) started steroids on treatment. Overall, median progression-free survival (mPFS) was 6.5 months (95% CI, 5.9–8.9) and median overall survival (mOS) was 18.2 months (95% CI, 8.9-NR). Patients taking baseline steroids had significantly shorter survival than those not taking them and those assuming intercurrent steroids (mPFS 5.0 vs. 9.2 vs. 7.3 months, p < 0.001; mOS 7.0 months vs. not reached, p < 0.001). Baseline steroids were significantly associated with poorer survival outcomes in the multivariate model (OS HR 2.94, p = 0.02; PFS HR 3.84, p > 0.001). Conversely, intercurrent prescription did not reach a significant value regardless of other pivotal variables included in the model. Baseline steroid administration was associated with a detrimental effect on survival outcomes in NSCLC patients treated with CT-ICI. The role of intercurrent steroid administration should be further explored in larger studies. [ABSTRACT FROM AUTHOR]

Background and Objectives: Advanced non-small-cell lung cancer (NSCLC) has led to a high number of mortalities. Immunotherapy, as a first-line treatment in advanced NSCLC, currently has no clarity regarding its prognostic markers to assess the treatment outcome. This systematic review aimed to evaluate neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as prognostic markers in advanced NSCLC patients treated with immunotherapy. Materials and Methods: This systematic review was conducted using the PRISMA guidelines, starting from screening for relevant studies from several databases. Each included cohort study was further assessed by using the Newcastle–Ottawa Quality Assessment Scale, and the available data were extracted for qualitative and quantitative synthesis in pooled and subgroup analysis. Results: A total of 1719 patients were included in this meta-analysis. Hazard ratio (HR) outcomes for progression-free survival (PFS) and overall survival (OS) for NLR and PLR showed significant results, supporting NLR and PLR as prognostic markers (NLR: HR PFS 2.21 [95% CI: 1.50–3.24; p < 0.0001] and HR OS 2.68 [95% CI: 2.24–3.6; p < 0.0001]; PLR: HR PFS 1.57 [95% CI: 1.33–1.84; p < 0.00001] and HR OS 2.14 [95% CI: 1.72–2.67; p < 0.00001]). Subgroup analysis with a cut-off value of 5 for NLR and 200 for PLR also demonstrated notable outcomes. Higher NLR and PLR levels are associated with poor prognostic. Conclusions: There is considerable evidence regarding both markers as prognostic markers in NSCLC patients treated with immunotherapy. However, further studies with more homogeneous baseline characteristics are required to confirm these findings. [ABSTRACT FROM AUTHOR]

Background. Immunotherapy represented by PD-1 blockades had become the standard of care for advanced non-small cell lung cancer (NSCLC) gradually. Unfortunately, several PD-1 inhibitor-related studies excluded elderly patients with NSCLC over 75 years of age, resulting in relatively limited evidence regarding the efficacy and safety of PD-1 in elderly patients with NSCLC clinically. Objective. This study aimed to identify the effectiveness and safety of PD-1 blockade monotherapy among elderly patients with advanced NSCLC. Methods. Elderly patients with advanced NSCLC (≥65 years) who received PD-1 blockade monotherapy from September 2018 to December 2021 were screened retrospectively, and a total of 68 elderly patients with NSCLC were eligible for inclusion ultimately. The PD-1 blockades in the study were the available PD-1 monoclonal antibodies that had been approved for marketing in China, including camrelizumab, sintilimab, pembrolizumab, and nivolumab. The effectiveness and safety of the patients was collected retrospectively. Additionally, the correlation between prognosis and baseline characteristic subgroups was analyzed to identify the potential risk factors for progression-free survival (PFS). Results. The median age of the 68 elderly patients with advanced NSCLC was 73 years (range: 65–82 years). Best overall response during PD-1 blockade administration suggested that no patients were found with complete response, partial response was found in 14 patients, stable disease was noted in 29 patients, and 25 patients had progressive disease, yielding an objective response rate (ORR) of 20.6% (95%CI: 11.7%–32.1%) and a disease control rate (DCR) of 63.2% (95%CI: 50.7%–74.6%). Furthermore, prognostic analysis exhibited that the median progression-free survival (PFS) of the 68 patients with advanced NSCLC was 3.5 months (95%CI: 2.4–4.6) and the median overall survival (OS) was 10.5 months (95%CI: 6.3–14.7). Additionally, a total of 48 patients were observed with the treatment-related adverse reaction (70.6%) of the 68 elderly patients with NSCLC, and the incidence of grade 3 or above adverse reactions was 16.2%. Specifically, the most common adverse reactions were fatigue, diarrhea, rash, and abnormal liver function with the incidence of 25.0%, 22.1%, 16.2%, and 14.7%, respectively. Exploratory analysis between PFS and baseline characteristic subgroups suggested that ECOG performance status and number of metastatic lesions might be independent factors for PFS. Conclusion. PD-1 blockade monotherapy exhibited potential effectiveness and acceptable toxicity for elderly patients with NSCLC. ECOG performance status and number of metastatic lesions might be potential risk factors to predict the PFS of elderly patients with advanced NSCLC. [ABSTRACT FROM AUTHOR]

Metformin has been found to have inhibitory effects on a variety of tumors. However, its effects on non-small cell lung cancer (NSCLC) remain unclear. We demonstrated that metformin could inhibit the proliferation of A549 and H1299 cells. RNA transcriptome sequencing revealed that PDL1 was significantly downregulated in both cell types following treatment with metformin (P < 0.001). Jaspar analysis and chromatin immunoprecipitation showed that CEBPB could directly bind the promoter region of PDL1. Western blotting showed that protein expression of the isoforms CEBPB-LAP*, CEBPB-LAP, and CEBPB-LIP was significantly upregulated and the LIP/LAP ratio was increased. Gene chip analysis showed that PDL1 was significantly upregulated in A549-CEBPB-LAP cells and significantly downregulated in A549-CEBPB-LIP cells (P < 0.05) compared with CEBPB-NC cells. Dual-luciferase reporter gene assay showed that CEBPB-LAP overexpression could promote transcription of PDL1 and CEBPB-LIP overexpression could inhibit the process. Functional assays showed that the changes in CEBPB isoforms affected the function of NSCLC cells. Western blotting showed that metformin could regulate the function of NSCLC cells via AMPK–CEBPB–PDL1 signaling. Animal experiments showed that tumor growth was significantly inhibited by metformin, and atezolizumab and metformin had a synergistic effect on tumor growth. A total of 1247 patients were retrospectively analyzed, including 166 and 1081 patients in metformin and control groups, respectively. The positive rate of PDL1 was lower than that of the control group (HR = 0.338, 95% CI = 0.235–0.487; P < 0.001). In conclusion, metformin inhibited the proliferation of NSCLC cells and played an anti-tumor role in an AMPK–CEBPB–PDL1 signaling-dependent manner. [ABSTRACT FROM AUTHOR]

Introduction: Immune checkpoint inhibitors (ICIs) have now become the standard therapy for malignancies like non-small cell lung cancer and classical Hodgkin's lymphoma. ICIs are associated with unique immune-related adverse events (irAEs) caused by dysregulated immune activation. Treatment of lower gastrointestinal (GI) tract irAEs, such as colitis, is more common. However, for upper gastrointestinal tract irAEs, there is a lack of consensus in terms of globally standardized disease classification and treatment guidelines. Here, we report a case of sintilimab-induced acute erosive hemorrhagic gastritis. Case Presentation: A 54-year-old man with metastatic NSCLC (PT2N2M1 stage IV) underwent treatment with eight courses of sintilimab + bevacizumab, followed by maintenance therapy with sintilimab alone. However, he presented with epigastric pain and melena at the end of the first sintilimab treatment, and the symptoms occurred repeatedly after regular treatment with acute erosive hemorrhagic gastritis. Repeat esophagogastroduodenoscopy (EGD) showed severe hemorrhagic gastritis; symptomatic relief and improvement in EGD images were noted for as long as he was being treated with steroids, methylprednisolone sodium. Conclusion: As far as we are aware, we here describe the first case of sintilimab-associated acute erosive hemorrhagic gastritis, an upper gastrointestinal toxicity event. Throughout the treatment progression, differential diagnosis, multidisciplinary discussion, and the use of immunosuppressants were instrumental in clarifying the diagnosis and were crucial to the prognosis of the patient and continued treatment with ICIs. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICI) have revolutionized the management of locally advanced and advanced non-small lung cancer (NSCLC). With an improvement in the overall survival (OS) as both first- and second-line treatments, ICIs, and especially programmed-death 1 (PD-1) and programmed-death ligands 1 (PD-L1), changed the landscape of thoracic oncology. The PD-L1 level of expression is commonly accepted as the most used biomarker, with both prognostic and predictive values. However, even in a low expression level of PD-L1, response rates remain significant while a significant number of patients will experience hyperprogression or adverse events. The dentification of such subtypes is thus of paramount importance. While several studies focused mainly on the prediction of the PD-L1 expression status, others aimed directly at the development of prediction/prognostic models. The response to ICIs depends on a complex physiopathological cascade, intricating multiple mechanisms from the molecular to the macroscopic level. With the high-throughput extraction of features, omics approaches aim for the most comprehensive assessment of each patient. In this article, we will review the place of the different biomarkers (clinical, biological, genomics, transcriptomics, proteomics and radiomics), their clinical implementation and discuss the most recent trends projecting on the future steps in prediction modeling in NSCLC patients treated with ICI. [ABSTRACT FROM AUTHOR]

LKB1 (liver kinase B1) is a master regulator of several processes such as metabolism, proliferation, cell polarity and immunity. About one third of non-small cell lung cancers (NSCLCs) present LKB1 alterations, which almost invariably lead to protein loss, resulting in the absence of a potential druggable target. In addition, LKB1-null tumors are very aggressive and resistant to chemotherapy, targeted therapies and immune checkpoint inhibitors (ICIs). In this review, we report and comment strategies that exploit peculiar co-vulnerabilities to effectively treat this subgroup of NSCLCs. LKB1 loss leads to an enhanced metabolic avidity, and treatments inducing metabolic stress were successful in inhibiting tumor growth in several preclinical models. Biguanides, by compromising mitochondria and reducing systemic glucose availability, and the glutaminase inhibitor telaglenastat (CB-839), inhibiting glutamate production and reducing carbon intermediates essential for TCA cycle progression, have provided the most interesting results and entered different clinical trials enrolling also LKB1-null NSCLC patients. Nutrient deprivation has been investigated as an alternative therapeutic intervention, giving rise to interesting results exploitable to design specific dietetic regimens able to counteract cancer progression. Other strategies aimed at targeting LKB1-null NSCLCs exploit its pivotal role in modulating cell proliferation and cell invasion. Several inhibitors of LKB1 downstream proteins, such as mTOR, MEK, ERK and SRK/FAK, resulted specifically active on LKB1 -mutated preclinical models and, being molecules already in clinical experimentation, could be soon proposed as a specific therapy for these patients. In particular, the rational use in combination of these inhibitors represents a very promising strategy to prevent the activation of collateral pathways and possibly avoid the potential emergence of resistance to these drugs. LKB1-null phenotype has been correlated to ICIs resistance but several studies have already proposed the mechanisms involved and potential interventions. Interestingly, emerging data highlighted that LKB1 alterations represent positive determinants to the new KRAS specific inhibitors response in KRAS co-mutated NSCLCs. In conclusion, the absence of the target did not block the development of treatments able to hit LKB1 -mutated NSCLCs acting on several fronts. This will give patients a concrete chance to finally benefit from an effective therapy. [ABSTRACT FROM AUTHOR]