NSCLC: from tumorigenesis, immune checkpoint misuse to current and future targeted therapy.

Non-small cell lung cancer (NSCLC) is largely promoted by a multistep tumorigenesis process involving various genetic and epigenetic alterations, which essentially contribute to the high incidence of mortality among patients with NSCLC. Clinical observations revealed that NSCLC also co-opts a multifaceted immune checkpoint dysregulation as an important driving factor in NSCLC progression and development. For example, a deregulated PI3K/AKT/mTOR pathway has been noticed in 50-70% of NSCLC cases, primarily modulated by mutations in key oncogenes such as ALK, EGFR, KRAS, and others. Additionally, genetic association studies containing patient-specific factors and local reimbursement criteria expose/reveal mutations in EGFR/ALK/ROS/BRAF/KRAS/PD-L1 proteins to determine the suitability of available immunotherapy or tyrosine kinase inhibitor therapy. Thus, the expression of such checkpoints on tumors and immune cells is pivotal in understanding the therapeutic efficacy and has been extensively studied for NSCLC treatments. Therefore, this review summarizes current knowledge in NSCLC tumorigenesis, focusing on its genetic and epigenetic intricacies, immune checkpoint dysregulation, and the evolving landscape of targeted therapies. In the context of current and future therapies, we emphasize the significance of antibodies targeting PD-1/PD-L1 and CTLA-4 interactions as the primary therapeutic strategy for immune system reactivation in NSCLC. Other approaches involving the promising potential of nanobodies, probodies, affibodies, and DARPINs targeting immune checkpoints are also described; these are under active research or clinical trials to mediate immune regulation and reduce cancer progression. This comprehensive review underscores the multifaceted nature, current state and future directions of NSCLC research and treatment.

Impact of PD-L1 Expression on the Overall Survival of Patients With Non-small Cell Lung Cancer Treated With Single-agent Pembrolizumab.

BACKGROUND/AIM: Cemiplimab in patients with non-small cell lung cancer (NSCLC) with PD-L1 (programmed death ligand type 1) expression ≥50% showed a significant improved overall survival (OS) with increasing expression of PD-L1. To our knowledge there exist no similar data published for pembrolizumab regarding the increased OS in relation to the PD-L1 expression. Therefore, the objective of our study was to determine whether improvement in OS reflects increased expression levels of PD-L1 (≥50%) in patients with NSCLC. PATIENTS AND METHODS: Retrospective data from 9 Czech and 1 Polish comprehensive oncology Centers were used. All patients with stage IV NSCLC and PD-L1 expression ≥50% treated with pembrolizumab in daily practice were included. The groups of patients according to the expression of PD-L1 were determined as follows: PD-L1 50-59%, 60-69%, 70-79%, 80-89% and 90-100%. The log-rank test and the Cox regression model were used to compare survival between study groups. RESULTS: A total of 617 patients were included in the study. We did not observe a statistically significant difference in OS between groups of patients with different levels of PD-L1 expression in the pooled comparison (p=0.445). Furthermore, we did not observe a statistically significant difference even when comparing OS in patients with PD-L1expression of 50-59% (reference) with the group of other patients according to the level of expression of PD-L1 in the Cox regression model including the effect covariates. CONCLUSION: PD-L1 expression showed no significant effect on OS in patients with NSCLC with PD-L1≥50% treated with pembrolizumab.

Effectiveness of first-line anticancer treatment may predict treatment response in further lines in stage III/IV patients with non-small cell lung cancer.

PURPOSE: The aim of our study was to evaluate if therapeutic success in the first-line of anticancer treatments in patients with NSCLC may predict treatment success in the following lines. METHODS: We analyzed the data of patients with NSCLC stage III/IV from the TULUNG registry separately for chemotherapy, TKIs, ALK inhibitors, and immunotherapy in the first line during the years 2011-2019. "Succesful treatment " was defined as PFS ≥ 6 months, a "good responder " was a patient with ˃50% of "successful treatment " lines. Treatment responses were analyzed separately for each drug group. Descriptive statistics, Fisher exact test, Pearson Chi-Squared test, log-rank test, and univariate/multivariate logistic regression models were used. RESULTS: The first-line TKI therapy was successful in 66.2%, while good responders accounted for 50.7% of the cohort and their rates were similar for all types of TKIs. First-line platinum-based chemotherapy was successful in 43.1% and 48.6% for combinations with pemetrexed and bevacizumab, respectively. Good responders accounted for 29.5% and 25.9%, respectively. In the group of ALK inhibitors, we observed treatment success in 52.3% of cases, while alectinib showed the highest effectiveness (up to 70%). Good responders constituted 50% of the group. In the first-line immunotherapy group, survival benefit was observed in 52.3%, and good responders constituted 52.3% of the cohort. CONCLUSION: We concluded that the treatment success in first-line therapies in patients with NSCLC may predict survival benefits in the subsequent lines, particularly in EGFR- or ALK-positive disease and immunotherapy-treated patients.

Comedication with corticosteroids and nonsteroidal antiphlogistics does not affect PD-L1 expression in non-small cell lung cancer.

Background: Programmed death-ligand 1 (PD-L1) expression is a standard predictor in the selection of immunotherapy for locally advanced/advanced non-small cell lung cancer (NSCLC). However, comedication with corticosteroids or non-steroidal anti-inflammatory drugs (NSAIDs) may influence the effectiveness of this treatment as documented in several previous studies. Due to certain molecular linkages between PD-L1 and corticosteroids or NSAIDs, we therefore addressed the question of whether there is a relationship between PD-L1 expression in NSCLC and the use of this comedication. Methods: This is a retrospective study using the Czech tumor registry LUng CAncer focuS (LUCAS), from which patient data were drawn. Independence of two categorical parameters was tested by Pearson's chi-square test. Results: In our group of 1,148 patients, we observed no significant relationship between PD-L1 expression and the use of corticosteroids or NSAIDs. Conclusions: According to our data, treatment with corticosteroids or NSAIDs during biopsy does not affect the expression of PD-L1 and it is therefore not necessary to take this treatment into account in this regard.

Can Previous Chemotherapy Affect the Outcome of Nivolumab Treatment in Non-small Cell Lung Cancer?

AIM: This study compared the results of nivolumab treatment in patients with pulmonary adenocarcinomas based upon previous chemotherapeutic regimens. PATIENTS AND METHODS: The data source for this retrospective study was the Czech VILP registry of patients with nivolumab-treated adenocarcinomas in second and higher lines of treatment. In relation to objective response rate, progression-free interval, and overall survival, three comparisons of patient were made: A: Those treated in first line with cisplatin and pemetrexed versus carboplatin with paclitaxel or vinorelbine; B: treatment with cisplatin and pemetrexed versus carboplatin with paclitaxel/vinorelbine and bevacizumab; and C: treatment in previous lines with pemetrexed (first-line cisplatin and pemetrexed plus those treated in second line with pemetrexed) versus treatment with taxane (first-line carboplatin and paclitaxel only plus those treated with second-line docetaxel). RESULTS: We observed no differences in objective response rate or progression-free survival between patients treated with the stated chemotherapeutic regimens. We observed a trend towards better overall survival for patients treated with carboplatin plus taxanes or vinorelbine with/without bevacizumab. CONCLUSION: From our overall survival data, a chemotherapeutic regimen of carboplatin plus taxanes or vinorelbine with/without bevacizumab might be a better partner for immunotherapy than a cisplatin and pemetrexed-based one.

Laboratory Parameters Associated With Inflammation Do Not Affect PD-L1 Expression in Non-small Cell Lung Cancer.

BACKGROUND/AIM: Due to some interconnectedness at the molecular level, this study assessed the possible influence of laboratory parameters associated with systemic inflammatory environment on programmed death-ligand 1 (PD-L1) expression in non-small cell lung carcinoma (NSCLC). PATIENTS AND METHODS: We assessed effects of c-reactive protein (CRP), albumin, haemoglobin, neutrophil, and lymphocyte levels on PD-L1 expression in NSCLC. Patient data were obtained retrospectively from LUCAS, the Czech registry of patients with lung carcinomas. Correlations of two continuous parameters (PD-L1 expression and laboratory parameters) were analysed by correlation coefficient. Differences in continuous parameters between two or more groups were tested by Mann-Whitney or Kruskal-Wallis tests. Independence of two categorical parameters was tested by chi-square test. RESULTS: We demonstrated no influence of the investigated laboratory parameters on PD-L1 expression in NSCLC, either in continuous or categorical division of variables. CONCLUSION: Inflammatory laboratory parameters at time of NSCLC diagnosis are unlikely to affect the determination of PD-L1 expression.

Real-life Effectiveness of Afatinib Versus Gefitinib in Patients With Non-small-cell Lung Cancer: A Czech Multicentre Study.

BACKGROUND/AIM: We investigated efficacy differences for afatinib versus gefitinib in non-small-cell lung cancer (NSCLC) according to epidermal growth factor receptor (EGFR) mutations. PATIENTS AND METHODS: We retrospectively analysed data for 343 patients with NSCLC with performance status 1 having EGFR mutations treated with gefitinib or afatinib. Overall response rate (ORR) was tested by Fisher's exact test. Overall (OS) and progression-free (PFS) survival were estimated by Kaplan-Meier method. RESULTS: ORR did not differ in any group or subgroup. Among all patients, we observed significantly longer PFS for those treated with afatinib vs. gefitinib (median 13.4 vs. 9.5 months, p=0.026), but only a nonsignificant trend was observed for OS. We showed nonsignificant trends of better PFS and OS using afatinib for exon 19 deletion and L858R subgroups. We observed no significant PFS differences for other EGFR mutations but a nonsignificant trend towards better OS for those treated with afatinib. CONCLUSION: Afatinib led to longer PFS for patients with common EGFR mutations but not for those with rare mutations.

Comparison of Chemotherapeutic Regimens Frequently Used in Metastatic Non-squamous NSCLC Treatment.

BACKGROUND/AIM: Platinum-based chemotherapy with pemetrexed or paclitaxel/bevacizumab are regimens used in combination with checkpoint inhibitors in non-squamous non-small cell lung cancer (NSCLC) treatment. We conducted a real-world study to compare the outcomes of these chemotherapeutic regimens. PATIENTS AND METHODS: We investigated 1,534 patients with advanced non-squamous NSCLC treated with platin/pemetrexed (n=1212) or platin/paclitaxel/bevacizumab (n=322) in 9 cancer centres in the Czech Republic. RESULTS: The regimen containing platin/paclitaxel/bevacizumab showed significantly better overall response rate (ORR) compared to the platin/pemetrexed [40.8% vs. 32.7% (p=0.008)] in the overall population and [55.0% vs. 38.8% (p=0.002)] in the Eastern Cooperative Oncology Group performance status 0 group. There was no significant improvement in progression-free survival (PFS) and overall survival (OS) in either of these two groups of patients. CONCLUSION: In our real-world data analysis, patients treated with platin/paclitaxel/bevacizumab had better overall response rate (ORR), but not PFS or OS. Thus, both treatment regimens are similarly effective. Their selection should therefore be based on the potential side effects.

Prognostic Value of EGFR Exon-20 Insertions in Czech Patients With Advanced Non-small Cell Lung Cancer.

BACKGROUND/AIM: Per literature, patients with epidermal growth factor receptor (EGFR) exon-20 insertions respond poorly to tyrosine kinase inhibitors (TKIs). This study analyzed real-world data to examine the prognostic and predictive value of these mutations. PATIENTS AND METHODS: We conducted a retrospective cohort study using Czech TULUNG Registry data, with data on multiple mutation types, collected in 2011-2020. RESULTS: We analyzed 554 (95.85%) patients with EGFR exon-19 deletions or exon-21 L858R substitutions and 24 (4.15%) patients with exon-20 insertions who received first-line high-value therapies. We summarized clinical characteristics and outcomes in all patients and by cohort. The risk of progression was statistically significantly higher (86%) in the exon-20 insertion cohort compared to the cohort with other mutations. Although not statistically significant, the risk of death was 44% higher in patients with exon-20 insertions. CONCLUSION: Advanced NSCLC patients with rare EGFR exon-20 insertions have a high risk of progression.

Lung Cancer in Non-smokers in Czech Republic: Data from LUCAS Lung Cancer Clinical Registry.

BACKGROUND/AIM: LUCAS is a clinical lung cancer registry (ClinicalTrials.gov identifier is NCT04228237), prospectively collecting data from newly diagnosed lung cancer patients in seven pneumooncology centers in the Czech Republic, since June 1, 2018. The aim of the study was to assess the stage of the disease at the time of diagnosis, percentage of morphological types, survival, percentage of driving mutations, eligibility for radical surgery, and percentage of patients who undergo radical surgery, in the non-smoking population in comparison with smokers and former smokers. PATIENTS AND METHODS: The total number of patients in the registry at the time of the analysis was 2,743. Only 2,439 patients with complete records (smoking status, stage, and type of tumor) were included in this study. RESULTS: The analysis indicated that non-smokers are diagnosed at a later stage of the disease but they have a better survival rate than smokers. Fewer smokers with stage III disease who are eligible for radical surgery will undergo surgery compared to non-smokers with the same clinical stage. Driving mutations are more common in non-smokers, even after adjustment for the more frequent occurrence of adenocarcinoma in the group of non-smokers. CONCLUSION: The data from LUCAS registry are consistent with already known facts, suggesting that the LUCAS registry is a useful clinical tool.

Prognostic impact of PD-1 and PD-L1 expression in malignant pleural mesothelioma: an international multicenter study.

BACKGROUND: Programmed cell death 1/programmed death ligand 1 (PD-1/PD-L1) immune-checkpoint blockade is a promising new therapeutic strategy in cancer. However, expression patterns and prognostic significance of PD-L1 and PD-1 are still controversial in human malignant pleural mesothelioma (MPM). METHODS: Formalin-fixed paraffin-embedded (FFPE) tumor samples from 203 MPM patients receiving standard treatment without immunotherapy were collected from 5 European centers. PD-L1 and PD-1 expression of tumor cells (TCs) and tumor-infiltrating lymphocytes (TILs) were measured by immunohistochemistry and correlated with clinical parameters and long-term outcome. RESULTS: High (>10%) PD-L1 TC and PD-1 TILs expressions were found in 18 (8%) and 39 (24%) patients, respectively. PD-L1 was rarely expressed by TILs [≥1%, n=13 (8%); >10%, n=1]. No significant associations were found between the PD-L1 or PD-1 expression of TCs or TILs and clinicopathological parameters such as stage or histological subtype. Notably, patients with high (>10%) TC-specific PD-L1 expression exhibited significantly worse median overall survival (OS) (6.3 vs. 15.1 months of those with low TC PD-L1 expression; HR: 2.51, P<0.001). In multivariate cox regression analysis adjusted for clinical parameters, high TC PD-L1 expression (>10%) proved to be an independent negative prognostic factor for OS (HR: 2.486, P=0.005). There was no significant correlation between PD-L1 or PD-1 expression of TILs and OS. CONCLUSIONS: In this multicenter cohort study, we demonstrate that high (>10%) PD-L1 expression of TCs independently predicts worse OS in MPM. Further studies are warranted to investigate the value of PD-L1/PD-1 expression as a marker for treatment response in MPM patients receiving immunotherapy.

Dabrafenib monotherapy in BRAF+ non-small cell lung cancer - our experience.

BACKGROUND: Activating BRAF mutations result in constitutive activation of the MAP kinase signaling cascade, stimulating cell proliferation. BRAF mutations are typical for malignant melanoma, but occur less frequently in other tumors, including in 1-2% cases of non-small cell lung cancer (NSCLC) [1,2]. CASE: We present two case reports of BRAF+ NSCLC patients, treated with 3rd line dabrafenib monotherapy on our department, and also brief review of available information about dabrafenib and its use in monotherapy of BRAF+ NSCLC. CONCLUSION: Monotherapy with BRAF inhibitors presents a viable alternative for BRAF+ NSCLC patients, incapable of combined therapy with trametinib. The lack of proper indication and reimbursement for NSCLC cases remains a problem, and individual treatment approval is required.

Giant lung metastasis of NRAS-mutant melanoma in a 24-year-old patient with a history of BRAF-mutant conventional melanoma harboring Spitzoid morphology: a case report.

BACKGROUND: Spitzoid melanocytic lesions represent a heterogeneous group of proliferations with ambiguous and overlapping terminology. The exact distinction of a Spitz nevus from a Spitzoid melanoma can be very difficult or, in some cases, impossible. Among the Spitzoid lesions, there is a lesion termed an atypical Spitz tumour (AST) that has intermediate histopathologic features between those of a Spitz nevus and a Spitzoid melanoma and thus uncertain malignant potential. There are several rare cases of patients with a Spitzoid melanoma initially misdiagnosed as a Spitz nevus or an AST with fatal consequences. It is, therefore, advised to perform a molecular characterization in cases where uncertain skin lesions are presented, as it may provide extended set of information with a possible impact on the treatment options. Furthermore, preventive measures, such as regular physical and skin examinations, as well as thorough scheduling of individual follow-up visits, are essential in patients with potentially malignant skin nevi. CASE REPORT: We report a case of a young adult female with a history of AST excision with a negative sentinel lymph node biopsy (SLNB) and insufficient follow-up. Four years after the primary dermatological diagnosis, she presented with a giant tumour in the right hemithorax. Radical en bloc resection of the tumour with right pneumonectomy and resection of the pericardium with reconstruction of the pericardium using mesh was performed. A definitive histopathological examination revealed a metastatic melanoma. The association of the previously diagnosed AST and subsequent appearance of melanoma metastases led to a retrospective re-evaluation of the initial lesion. The suspected diagnosis of Spitzoid melanoma, however, was not confirmed. Moreover, the molecular examination revealed a major discordance between the initial lesion and the lung tumour, which most likely excluded the possible association of the lung metastasis with the initial skin lesion. The initial skin lesion was a BRAF-mutant melanoma with Spitzoid features and termed as AST, while the giant lung metastasis was NRAS-mutant melanoma. The subsequent postoperative course was complicated by the appearance of brain metastases that were stereotactically irradiated. Nevertheless, despite complex specialised medical care, the patient's clinical condition rapidly deteriorated. By this time, no active oncological treatment was possible. The patient was delegated to local hospice for palliative care six months after the surgery and died three weeks later. CONCLUSIONS: Our patient was surgically treated at the age of 20 for AST and died four years later of metastatic NRAS-mutant melanoma most likely of different occult origin. Molecular characterization, as well as the close clinical follow-up should be always precisely performed in patients with uncertain skin lesions, such as AST.

Real-life effectiveness of first-line anticancer treatments in stage IIIB/IV NSCLC patients: Data from the Czech TULUNG Registry.

BACKGROUND: Data regarding real-life effectiveness of any treatment may improve clinical decision-making. The aim of this study was to evaluate real-life effectiveness of tyrosin-kinase inhibitors, bevacizumab and pemetrexed as first-line treatments in patients with advanced/metastatic non-small cell lung cancer (NSCLC). METHODS: We analyzed data of 2157 patients of the Czech TULUNG Registry of patients with advanced/metastatic NSCLC who received modern-era treatments between 2011 and 2018. Patients treated with gefitinib, erlotinib, afatinib, bevacizumab (+ maintenance), pemetrexed (+ maintenance) as first-line therapy were included in the study. A systematic literature search separately identified clinical trials suitable for calculation of comparator pooled OS and PFS for each regimen. For each subgroup, basic characteristics and survival data (Kaplan-Meier estimates) are shown. We propose the "index of real-life effectiveness" (IRE), a ratio of real-life OS/PFS and comparator pooled OS/PFS. Univariate and multivariate logistic regression identified factors were associated with longer OS (ie, IRE>1.1). RESULTS: Survival analysis showed median OS of 23 months for erlotinib, 29.3 months for afatinib, 19.6 months for gefitinib, 12.2 months for pemetrexed, 17.5 months for pemetrexed maintenance, 15.8 months for bevacizumab and 15.8 months for bevacizumab maintenance. Calculated IREs for OS for the regimens were: erlotinib 1.013, afatinib 1.184, gefitinib 0.736, pemetrexed 1.188, pemetrexed maintenance 1.294, bevacizumab 1.178, and bevacizumab maintenance 1.189. Multivariate regression analysis showed that these factors were associated with longer OS: lower PS for afatinib; lower PS, absence of adverse events and female sex for bevacizumab; and lower PS and female sex for pemetrexed. CONCLUSIONS: This study clearly demonstrated that real-life effectiveness of certain treatment regimens may strongly differ in various populations/health care systems, and comparison between TULUNG data and pooled survival data from trials showed higher real-life effectiveness for most of the studied first-line regimens. Lower ECOG PS, younger age, female sex and adverse events were associated with longer survival in most regimens. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: Comparison between TULUNG data and pooled survival data from trials showed higher real-life effectiveness for most of the studied first-line regimens; for most regimens, lower ECOG PS, younger age, female sex and adverse events were associated with longer survival. WHAT THIS STUDY ADDS: Real-life effectiveness of certain treatment regimens may strongly differ in various populations/health care systems.

Impact of Concomitant Medication Administered at the Time of Initiation of Nivolumab Therapy on Outcome in Non-small Cell Lung Cancer.

AIM: To investigate potential association between administration of corticosteroids, antibiotics, probiotics, proton pump inhibitors, non-steroidal anti-inflammatory drugs (NSAID), statins and metformin and outcome in patients with non-small cell lung cancer (NSCLC) treated with nivolumab. PATIENTS AND METHODS: A total of 224 patients with advanced NSCLC treated at nine comprehensive cancer centers were analyzed in this national retrospective study. Survival statistics were evaluated using Kaplan-Meier method and Cox analysis. RESULTS: Only corticosteroid use had a significant negative effect on the objective response rate. In the univariate analysis, there was no significant effect of the studied concomitant medications on the efficacy of nivolumab. In a subsequent multifactorial analysis, a possible positive effect of the concomitant use of NSAID at the initiation of nivolumab treatment was revealed. CONCLUSION: The results of the present retrospective exploratory analysis underscore the importance of knowing the exact type of concomitant medication, the route of administration, the dose of medication, and the region of the ongoing study. The present data indicated a significantly higher rate of progression in patients treated with corticosteroids and the possible positive effect of NSAID use at the initiation of nivolumab treatment.