Circulating leukocyte-platelet complexes as a predictive biomarker for the development of immune-related adverse events in advanced non-small cell lung cancer patients receiving anti-PD-(L)1 blocking agents.

BACKGROUND: Anti-PD-(L)1 blocking agents can induce immune-related adverse events (irAEs), which can compromise treatment continuation. Since circulating leukocyte-platelet (PLT) complexes contribute to inflammatory and autoimmune diseases, we aimed to analyze the role of these complexes as predictors of irAEs in non-small cell lung cancer (NSCLC) patients receiving anti-PD-(L)1. MATERIALS AND METHODS: Twenty-six healthy donors (HD) and 87 consecutive advanced NSCLC patients treated with anti-PD-(L)1 were prospectively included. Percentages of circulating leukocyte-PLT complexes were analyzed by flow cytometry and compared between HD and NSCLC patients. The association of leukocyte-PLT complexes with the presence and severity of irAEs was analyzed. RESULTS: NSCLC patients had higher percentages of circulating leukocyte-PLT complexes. Higher percentages of monocytes with bound PLT (CD14 + PLT +) were observed in patients who received prior therapies while CD4 + T lymphocytes with bound PLT (CD4 + PLT +) correlated with platelets counts. The CD4 + PLT + high percentage group presented a higher rate of dermatological irAEs while the CD4 + PLT + low percentage group showed a higher rate of non-dermatological irAEs (p < 0.001). A lower frequency of grade ≥ 2 irAEs was observed in the CD4 + PLT + high percentage group (p < 0.05). Patients with CD4 + PLT + low and CD14 + PLT + high percentages presented a higher rate of grade ≥ 3 irAEs and predominantly developed non-dermatological irAEs (p < 0.01). CONCLUSIONS: Our results suggest that circulating leukocyte-PLT complexes and the combination of CD4 + PLT + and CD14 + PLT + percentages can be used as a predictive biomarker of the development and severity of irAEs in advanced NSCLC patients receiving anti-PD-(L)1 agents.

Prognostic effect of VEGF gene variants in metastatic non-small-cell lung cancer patients.

INTRODUCTION: Clinical and pathological characteristics are still considered prognostic markers in metastatic non-small-cell lung cancer (NSCLC) patients but they cannot explain all interindividual variability. Tumoral angiogenesis mediated by the vascular endothelial growth factor (VEGF) is critical for the progression and metastasis of the disease. We aimed to investigate the prognostic role of genetic variants within the VEGF pathway in patients with metastatic NSCLC. MATERIALS AND METHODS: We prospectively included 170 patients with metastatic NSCLC treated with first-line platinum-based chemotherapy. A comprehensive panel of single-nucleotide polymorphisms (SNPs) in genes belonging to the VEGF pathway (VEGFA, VEGFR1/FLT1, VEGFR2/KDR, GRB2, ITGAV, KISS1, KRAS, PRKCE, HIF1α, MAP2K4, MAP2K6, and MAPK11) were genotyped in blood DNA samples. SNPs were evaluated for association with overall survival (OS) and progression-free survival (PFS). RESULTS: In multivariate analyses adjusted for patient characteristics, we found that VEGFA rs2010963 and VEGFR2 rs2071559 were significantly associated with OS [Hazard Ratio (HR) 0.7 (0.5-0.9); p = 0.026 and HR 1.5 (1.1-2.3); p = 0.025, respectively]. Additionally, ITGAV rs35251833 and MAPK11 rs2076139 were significantly associated with PFS [HR 2.5 (1.4-4.3; p = 0.002 and HR 0.6 (0.5-0.9); p = 0.013, respectively]. CONCLUSION: Our findings reinforce the potential clinical value of germline variants in VEGFA and VEGFR2 and show for the first time variants in ITGAV and MAPK11 as promising prognostic markers in metastatic NSCLC patients receiving platinum-based chemotherapy.

Evidence from resected early-stage non-small cell lung cancer with EGFR mutation: a literature review.

BACKGROUND AND OBJECTIVE: Non-small cell lung cancer (NSCLC) in early-stages (I-IIIA) with epidermal growth factor receptor (EGFR) mutation may have specific epidemiological, clinical characteristics and treatment implications. This review aims to summarise the available evidence on these particularities, especially focusing on patient characteristics, treatment outcomes and safety with EGFR-tyrosine-kinase inhibitor (TKI). METHODS: An exhaustive search of international bibliographic databases, as well as in abstracts of communications from major international congresses was performed for evidence related to EGFR-mutated NSCLC or early-stage NSCLC published in English before December 31st, 2023. KEY CONTENT AND FINDINGS: Early-stage NSCLC with EGFR mutation presents with a variable incidence depending on geographical aspects. The clinical, radiological and molecular features differ slightly from both early-stage NSCLC without EGFR mutation and advanced NSCLC with EGFR mutation. Adjuvant treatment with the third-generation EGFR-TKI osimertinib has led to improvements in disease-free survival and overall survival (OS) in these patients, representing a practice changing and a new standard of care in clinical practice. No new safety signals have been reported with EGFR-TKI in the adjuvant setting. Clinical trials are ongoing to explore new therapeutic options in the adjuvant and neoadjuvant setting as well as the optimal duration of adjuvant osimertinib. CONCLUSIONS: Detection of EGFR mutation in early-stage NSCLC is an important goal due to the different characteristics and additional therapeutic options that improve patient outcomes and follow-up.

Potential Role of Circulating PD-L1+ Leukocytes as a Predictor of Response to Anti-PD-(L)1 Therapy in NSCLC Patients.

PD-(L)1 inhibitors are part of the treatment strategy for non-small cell lung cancer (NSCLC) although its efficacy is limited to certain patients. Our study aimed to identify patients who might benefit from anti-PD-(L)1 inhibitors by analyzing the PD-L1 expression on circulating leukocytes and its evolution during treatment. One hundred thirteen NSCLC patients, according to their radiological response after 10-12 weeks of treatment, were classified into responders, stable, and progressive disease. Percentages of circulating PD-L1+ leukocytes, PD-L1+ platelets (PLTs), and leukocyte-PLT complexes were assessed using flow cytometry, and plasma concentrations of soluble immunomodulatory factors were quantified by ELISA. Responders exhibited significantly higher pre-treatment percentages of PD-L1+ neutrophils, PD-L1+ CD14+ cells, and PD-L1+ PLTs than progressors. The percentages of these populations decreased in responders post-treatment, contrasting with stables and progressors. PLTs notably contributed to PD-L1 expression in CD14+ cells and neutrophils. Plasma cytokine analysis revealed baseline differences only in IL-17 concentration among groups, whereas network analyses highlighted distinct association patterns between plasma molecules and PD-L1+ leukocytes after 10-12 weeks of treatment. Our findings suggest that pre-treatment assessment of circulating PD-L1+ neutrophils, PD-L1+ CD14+ cells, and PD-L1+ PLTs may be helpful in identifying NSCLC patients who are potential candidates for anti-PD-(L)1 therapy.

ERCC1 and ERCC2 Polymorphisms Predict the Efficacy and Toxicity of Platinum-Based Chemotherapy in Small Cell Lung Cancer.

Standard first-line chemotherapy in small cell lung cancer (SCLC) is based on the platinum plus etoposide combination. Despite a high objective response rate, responses are not durable and chemotherapy-induced toxicity may compromise treatment. Genetic variants in genes involved in the DNA-repair pathways and in etoposide metabolization could predict treatment efficacy and safety and help personalize platinum-based chemotherapy. Germline polymorphisms in XRCC1, ERCC1, ERCC2, ABCB1, ABCC3, UGT1A1 and GSTP1 genes were investigated in 145 patients with SCLC. The tumor expression of ERCC1 was determined using immunohistochemistry, and the tumor expression of ERCC1-XPF was determined via a proximity ligation assay. Survival analyses showed a statistically significant association between the ERCC1 rs11615 variant and median progression-free survival (PFS) in patients with limited-stage (LS) SCLC (multivariate: hazard ratio 3.25, [95% CI 1.38-7.70]; p = 0.007). Furthermore, we observed differences between the ERCC1-XPF complex and median PFS in LS-SCLC, although statistical significance was not reached (univariate: positive expression 10.8 [95% CI 4.09-17.55] months versus negative expression 13.3 [95% CI 7.32-19.31] months; p = 0.06). Safety analyses showed that the ERCC2 rs1799793 variant was significantly associated with the risk of grade ≥ 3 thrombocytopenia in the total cohort (multivariate: odds ratio 3.15, [95% CI 1.08-9.17]; p = 0.04). Our results provide evidence that ERCC1 and ERCC2 variants may predict the efficacy and safety of platinum-based chemotherapy in SCLC patients. LS-SCLC patients may benefit most from ERCC1 determination, but prospective studies are needed.

Eftilagimod Alpha (a Soluble LAG-3 Protein) Combined With Pembrolizumab in Second-Line Metastatic NSCLC Refractory to Anti-Programmed Cell Death Protein 1/Programmed Death-Ligand 1-Based Therapy: Final Results from a Phase 2 Study.

Introduction: Eftilagimod alpha (efti), a soluble lymphocyte activation gene-3 protein, triggers antigen-presenting cell and T-cell (CD4+ and CD8+) activation and helps overcome resistance to programmed cell death protein 1 or programmed cell death-ligand 1 (PD-(L)1) inhibitors. We assessed efti plus pembrolizumab in second-line anti-PD-(L)1-refractory metastatic patients with NSCLC. Methods: After confirmed progression on anti-PD-(L)1-based first-line therapy, patients received efti (30 mg subcutaneously every 2 weeks for eight 3-week cycles and then every 3 weeks for up to 54 weeks) plus pembrolizumab (200 mg intravenously every 3 weeks for up to 105 weeks). The primary endpoint was the objective response rate by modified Response Evaluation Criteria in Solid Tumors version 1.1 for immune-based therapies. Secondary endpoints included disease control rate, progression-free survival, overall survival (OS), and tolerability. Exploratory endpoints included tumor growth kinetics and predefined subgroup analyses. Programmed cell death-ligand 1 tumor proportion score was assessed centrally. Results: Thirty-six patients were enrolled from April 2019 to August 2021 using Simon's two-stage design. Most patients (81.8%) had low or negative (<50%) PD-(L)1 tumor proportion score. First-line therapy was anti-PD-(L)1-based for all patients, combined with chemotherapy for 66.7%. The confirmed objective response and disease control rates were 8.3% and 33.3%. The median progression-free survival was 2.1 months and the median OS was 9.9 months. Patients exhibiting high PD-(L)1 expression or acquired resistance to PD-(L)1 inhibitors revealed superior response and survival outcomes, and OS was closely correlated with disease control. No treatment-emergent adverse event led to permanent discontinuation of study treatment. Conclusions: Efti plus pembrolizumab was well-tolerated and revealed signs of antitumor activity in patients with NSCLC resistant to PD-(L)1 inhibitors, warranting further investigation. Trial registration number: NCT03625323.

Malignant Pleural Effusion: A Multidisciplinary Approach.

Malignant pleural effusion (MPE) has become an increasingly prevalent complication in oncological patients, negatively impacting their quality of life and casting a shadow over their prognosis. Owing to the pathophysiological mechanisms involved and the heterogeneous nature of the underlying disease, this entity is both a diagnostic and therapeutic challenge. Advances in the understanding of MPE have led to a shift in the treatment paradigm towards a more personalized approach. This article provides a comprehensive review and update on the pathophysiology of MPE and describes the diagnostic tools and the latest advances in the treatment of this complex clinical entity.

El derrame pleural maligno (DPM) se ha convertido en una complicación cada vez más prevalente en los pacientes oncológicos, empeorando la calidad de vida y ensombreciendo el pronóstico de los mismos. Debido a los mecanismos fisiopatológicos involucrados y a la naturaleza heterogénea de la enfermedad subyacente, esta entidad representa un desafío diagnóstico y terapéutico. Los avances en la comprensión del DPM han originado un cambio en el paradigma del tratamiento hacia un enfoque más personalizado. Este artículo proporciona una revisión exhaustiva y una actualización sobre la fisiopatología del DPM, y describe las herramientas diagnósticas y los últimos avances en el tratamiento de esta compleja entidad clínica.

The S-REAL study: Spanish real-world data on unresectable stage III NSCLC patients treated with durvalumab after chemoradiotherapy.

OBJECTIVES: The S-REAL study aimed to assess the effectiveness of durvalumab as consolidation therapy after definitive chemoradiotherapy (CRT) in a real-world cohort of patients with locally advanced, unresectable stage III non-small cell lung cancer (LA-NSCLC) included in a Spanish early access program (EAP). METHODS: In this multicentre, observational, retrospective study we analysed data from patients treated in 39 Spanish hospitals, who started intravenous durvalumab (10 mg/kg every 2 weeks) between September 2017 and December 2018. The primary endpoint was progression-free survival (PFS). Secondary endpoints included patient characterization and adverse events of special interest (AESI). RESULTS: A total of 244 patients were followed up for a median of 21.9 months [range 1.2-34.7]. Median duration of durvalumab was 45.5 weeks (11.4 months) [0-145]. Median PFS was 16.7 months (95% CI 12.2-25). No remarkable differences in PFS were observed between patients with programmed cell death-ligand 1 (PD-L1) expression ≥ 1% or < 1% (16.7 versus 15.6 months, respectively). However, PFS was higher in patients who had received prior concurrent CRT (cCRT) versus sequential CRT (sCRT) (20.6 versus 9.4 months). AESIs leading to durvalumab discontinuation were registered in 11.1% of patients. CONCLUSIONS: These results are in line with prior published evidence and confirm the benefits of durvalumab in the treatment of LA-NSCLC patients in a real-world setting. We also observed a lower incidence of important treatment-associated toxicities, such as pneumonitis, compared with the pivotal phase III PACIFIC clinical study.

Pembrolizumab as first-line treatment for advanced NSCLC in older adults: A phase II clinical trial evaluating geriatric and quality-of-life outcomes.

OBJECTIVES: Since specific data on immunotherapy in older adults with advanced non-small cell lung cancer (aNSCLC) are scarce, we designed this study to determine the overall survival (OS) at one year of first-line pembrolizumab in patients older than 70 years with aNSCLC expressing PD-L1. Secondary objectives included progression-free survival, disease-specific survival, response rate, tolerability, quality of life (QoL) changes, and geriatric assessments. MATERIALS AND METHODS: A single-arm, open-label, phase II clinical trial was carried out by the Spanish Lung Cancer Group between February 2018 and November 2019 at ten active sites in Spain. We included patients 70 years old and older with histological or cytological documented stage IIIB or IV aNSCLC and PD-L1 expression ≥ 1%. Each subject received 200 mg of intravenous pembrolizumab every three weeks for a maximum of two years. RESULTS: 83 patients were recruited for the study and 74 were finally analysed. Most were male (N = 64, 86.5%) and former smokers (N = 51, 68.9%). 24 patients (32.4%) completed at least one year of treatment, 62 (83.7%) discontinued treatment, and 30 (40.5%) experienced disease progression. The median follow-up of our cohort was 18.0 months [range: 0.1-47.7] and 46 patients (62.2%) died during the period of study. The estimated OS at one year was 61.7% (95% CI: 49.6-71.8%) and the median OS of our cohort was 19.2 months (95% CI: 11.3-25.5). QoL tended to improve throughout the study, although the differences were not statistically significant. The main geriatric scores remained stable, except for a worsening in nutritional status (P = 0.004) and an improvement in frailty (P = 0.028). CONCLUSION: Our results support treating older adults with aNSCLC expressing PD-L1 with pembrolizumab in monotherapy. The stability of most geriatric scores and the positive trend on the patients' QoL should be highlighted, although our results did not reach statistical significance.

Immune-Related Adverse Events and Corticosteroid Use for Cancer-Related Symptoms Are Associated With Efficacy in Patients With Non-small Cell Lung Cancer Receiving Anti-PD-(L)1 Blockade Agents.

Background: Immune-related adverse events (irAEs) have been associated with improved efficacy in advanced non-small cell lung cancer (NSCLC) patients receiving anti-PD-(L)1 blockade agents, while the concurrent use of corticosteroids seems to worsen it. We evaluated outcomes in advanced NSCLC patients treated with anti-PD-(L)1 blockade agents in relation to the presence of irAEs and the reasons for using corticosteroids: whether for palliative cancer-related reasons or for the management of irAEs. Methods: Clinical outcomes in advanced NSCLC patients treated with anti-PD-(L)1 blockade agents were calculated with regard to the presence of irAEs and the use of corticosteroids. A landmark analysis was performed to avoid immortal time bias due to the time-dependent nature of irAEs. Results: Out of a total of 267 patients, the 56.9% of patients who experienced irAEs had significantly improved outcomes. In the landmark analysis, median progression-free survival (PFS) was 12.4 months for patients with irAEs vs. 4.1 months for patients without irAEs (p < 0.001), while median overall survival (OS) was 28.2 vs. 12.5 months, respectively (p < 0.001). Likewise, objective response and disease control rates were significantly higher in patients experiencing irAEs: 48.6 vs. 22.8% and 77.1 vs. 39.6% (p < 0.001), respectively. Median OS was significantly shorter for patients receiving ≥10 mg of prednisone equivalent daily for cancer-related symptoms than for the rest of patients (<10 mg prednisone equivalent daily or for management of irAEs): 6 vs. 15.9 months (p < 0.001). Conclusions: IrAEs were associated with improved efficacy in advanced NSCLC patients when a landmark analysis was applied. Patients receiving corticosteroids had significantly poorer outcomes when they were used for cancer-related symptoms.