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.

Multidisciplinary approach for locally advanced non-small cell lung cancer (NSCLC): 2023 expert consensus of the Spanish Lung Cancer Group GECP.

INTRODUCTION: Recent advances in the treatment of locally advanced NSCLC have led to changes in the standard of care for this disease. For the selection of the best approach strategy for each patient, it is necessary the homogenization of diagnostic and therapeutic interventions, as well as the promotion of the evaluation of patients by a multidisciplinary oncology team. OBJECTIVE: Development of an expert consensus document with suggestions for the approach and treatment of locally advanced NSCLC leaded by Spanish Lung Cancer Group GECP. METHODS: Between March and July 2023, a panel of 28 experts was formed. Using a mixed technique (Delphi/nominal group) under the guidance of a coordinating group, consensus was reached in 4 phases: 1. Literature review and definition of discussion topics 2. First round of voting 3. Communicating the results and second round of voting 4. Definition of conclusions in nominal group meeting. Responses were consolidated using medians and interquartile ranges. The threshold for agreement was defined as 85% of the votes. RESULTS: New and controversial situations regarding the diagnosis and management of locally advanced NSCLC were analyzed and reconciled based on evidence and clinical experience. Discussion issues included: molecular diagnosis and biomarkers, radiologic and surgical diagnosis, mediastinal staging, role of the multidisciplinary thoracic committee, neoadjuvant treatment indications, evaluation of response to neoadjuvant treatment, postoperative evaluation, and follow-up. CONCLUSIONS: Consensus clinical suggestions were generated on the most relevant scenarios such as diagnosis, staging and treatment of locally advanced lung cancer, which will serve to support decision-making in daily practice.

Expert consensus to optimize the management of older adult patients with advanced EGFR-mutated non-small cell lung cancer

Lung cancer (LC) is associated with ageing, with the average age of affected individuals being approximately 70 years. However, despite a higher incidence and prevalence among older people, the older adult population is underrepresented in clinical trials. For LC with Epidermal Growth Factor Receptor (EGFR) mutations, there is no clear association of this mutation with age. Geriatric assessments (GAs) and a multidisciplinary approach are essential for defining the optimal treatment. In this consensus, a group of experts selected from the Oncogeriatrics Section of the Spanish Society of Medical Oncology (Sección de Oncogeriatría de la Sociedad Española de Oncología Médica—SEOM), the Spanish Lung Cancer Group (Grupo Español de Cáncer de Pulmón—GECP) and the Association for Research on Lung Cancer in Women (Asociación para la Investigación del Cáncer de Pulmón en Mujeres—ICAPEM) evaluate the scientific evidence currently available and propose a series of recommendations to optimize the management of older adult patients with advanced LC with EGFR mutations (AU)

Expert consensus to optimize the management of older adult patients with advanced EGFR-mutated non-small cell lung cancer.

Lung cancer (LC) is associated with ageing, with the average age of affected individuals being approximately 70 years. However, despite a higher incidence and prevalence among older people, the older adult population is underrepresented in clinical trials. For LC with Epidermal Growth Factor Receptor (EGFR) mutations, there is no clear association of this mutation with age. Geriatric assessments (GAs) and a multidisciplinary approach are essential for defining the optimal treatment. In this consensus, a group of experts selected from the Oncogeriatrics Section of the Spanish Society of Medical Oncology (Sección de Oncogeriatría de la Sociedad Española de Oncología Médica-SEOM), the Spanish Lung Cancer Group (Grupo Español de Cáncer de Pulmón-GECP) and the Association for Research on Lung Cancer in Women (Asociación para la Investigación del Cáncer de Pulmón en Mujeres-ICAPEM) evaluate the scientific evidence currently available and propose a series of recommendations to optimize the management of older adult patients with advanced LC with EGFR mutations.

Current and Emerging Treatment Options for Patients With Relapsed Small-cell Lung Carcinoma: A Systematic Literature Review.

Second-line treatment options are limited for patients with small-cell lung cancer (SCLC). We conducted a PRISMA-standard systematic literature review to evaluate the treatment landscape for patients with relapsed SCLC (PROSPERO number: CRD42022299759). Systematic searches of MEDLINE, Embase, and Cochrane Library were performed (October 2022) to identify publications (prior 5 years) from prospective studies of therapies for relapsed SCLC. Publications were screened against predetermined eligibility criteria; data were extracted to standardized fields. Publication quality was assessed using GRADE. The data were analyzed descriptively, grouped by drug class. Overall, 77 publications involving 6349 patients were included. Studies of tyrosine kinase inhibitors (TKIs) with established cancer indications accounted for 24 publications; topoisomerase I inhibitors for 15; checkpoint inhibitors (CPIs) for 11, and alkylating agents for 9 publications. The remaining 18 publications featured chemotherapies, small-molecule inhibitors, investigational TKIs and monoclonal antibodies, and a cancer vaccine. According to GRADE assessment, 69% of the publications reported low-/very-low-quality evidence; quality limitations included lack of randomization and small sample sizes. Only 6 publications/6 trials reported phase 3 data; 5 publications/2 trials reported phase 2/3 results. Overall, the clinical potential of alkylating agents and CPIs remained unclear; investigations of combination approaches and biomarker-directed usage are warranted. Phase 2 data from TKI trials were consistently promising; no phase 3 data were available. Phase 2 data for a liposomal formulation of irinotecan were promising. We confirmed an absence of promising investigational drug/regimens in late-stage development; thus, relapsed SCLC remains an area of high unmet need.

Aberrant Methylation of the Imprinted C19MC and MIR371-3 Clusters in Patients with Non-Small Cell Lung Cancer.

Epigenetic mechanisms have emerged as an important contributor to tumor development through the modulation of gene expression. Our objective was to identify the methylation profile of the imprinted C19MC and MIR371-3 clusters in patients with non-small cell lung cancer (NSCLC) and to find their potential target genes, as well as to study their prognostic role. DNA methylation status was analyzed in a NSCLC patient cohort (n = 47) and compared with a control cohort including COPD patients and non-COPD subjects (n = 23) using the Illumina Infinium Human Methylation 450 BeadChip. Hypomethylation of miRNAs located on chromosome 19q13.42 was found to be specific for tumor tissue. We then identified the target mRNA-miRNA regulatory network for the components of the C19MC and MIR371-3 clusters using the miRTargetLink 2.0 Human tool. The correlations of miRNA-target mRNA expression from primary lung tumors were analyzed using the CancerMIRNome tool. From those negative correlations identified, we found that a lower expression of 5 of the target genes (FOXF2, KLF13, MICA, TCEAL1 and TGFBR2) was significantly associated with poor overall survival. Taken together, this study demonstrates that the imprinted C19MC and MIR371-3 miRNA clusters undergo polycistronic epigenetic regulation leading to deregulation of important and common target genes with potential prognostic value in lung cancer.

Cost-effectiveness of atezolizumab versus pembrolizumab as first-line treatment in PD-L1-positive advanced non-small-cell lung cancer in Spain.

BACKGROUND: Atezolizumab has recently been approved for first-line treatment of high PD-L1 expression metastatic Non-Small-Cell Lung Cancer (NSCLC) patients with no EGFR or ALK mutations, on the basis of the IMpower110 trial. This study aims to estimate the cost-effectiveness of atezolizumab compared with pembrolizumab among these patients in Spanish settings, based on the results of the two cut-offs of the IMpower110 study. METHODS: A three-state partitioned-survival model was adapted to Spanish settings to calculate health outcomes and costs over a lifetime horizon. Clinical data for atezolizumab were collected from the interim and the exploratory results (data cut-off: Sept'18 and Feb'20, respectively) of the IMpower110 trial while a network meta-analysis was used to model pembrolizumab treatment. Utility data were collected from the trial. Direct medical costs were considered based on resources identified by experts. Costs and outcomes were discounted at 3% per year. Health outcomes were expressed as cost per Life Year (LY) and cost per Quality-Adjusted Life Year (QALY). Both deterministic and probabilistic sensitivity analyses were performed to assess the robustness of results. RESULTS: Over a lifetime horizon, the incremental results showed that atezolizumab generated similar health outcomes (LYs and QALYs) to pembrolizumab, with minimal differences depending on the cut-off used (+ 0.70 and + 0.42 LYs and QALYs with Sept'18 cut-off and - 0.80 and - 0.72 LYs and QALYs with Feb'20 cut-off). However, for both cut-offs, atezolizumab produced meaningfully less costs than pembrolizumab (€ - 54,261 with Sept'18 cut-off and € - 81,907 with Feb'20 cut-off). The sensitivity analyses carried out confirmed the robustness of the base-case results. CONCLUSIONS: The cost-effectiveness analysis, comparing the two cut-off of IMpower110, shows that atezolizumab provides similar health gains to pembrolizumab but at a lower cost for the first-line treatment of metastasic NSCLC patients in Spain.

Five-Year Survival Outcomes With Nivolumab Plus Ipilimumab Versus Chemotherapy as First-Line Treatment for Metastatic Non-Small-Cell Lung Cancer in CheckMate 227.

PURPOSE: We present 5-year results from CheckMate 227 Part 1, in which nivolumab plus ipilimumab improved overall survival (OS) versus chemotherapy in patients with metastatic non-small-cell lung cancer, regardless of tumor programmed death ligand 1 (PD-L1) status. METHODS: Adults with stage IV/recurrent non-small-cell lung cancer without EGFR mutations or ALK alterations and with tumor PD-L1 ≥ 1% or < 1% (n = 1739) were randomly assigned. Patients with tumor PD-L1 ≥ 1% were randomly assigned to first-line nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. Patients with tumor PD-L1 < 1% were randomly assigned to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy. End points included exploratory 5-year results for efficacy, safety, and quality of life. RESULTS: At a minimum follow-up of 61.3 months, 5-year OS rates were 24% versus 14% for nivolumab plus ipilimumab versus chemotherapy (PD-L1 ≥ 1%) and 19% versus 7% (PD-L1 < 1%). The median duration of response was 24.5 versus 6.7 months (PD-L1 ≥ 1%) and 19.4 versus 4.8 months (PD-L1 < 1%). Among patients surviving 5 years, 66% (PD-L1 ≥ 1%) and 64% (PD-L1 < 1%) were off nivolumab plus ipilimumab without initiating subsequent systemic anticancer treatment by the 5-year time point. Survival benefit continued after nivolumab plus ipilimumab discontinuation because of treatment-related adverse events, with a 5-year OS rate of 39% (combined PD-L1 ≥ 1% and < 1% populations). Quality of life in 5-year survivors treated with nivolumab plus ipilimumab was similar to that in the general US population through the 5-year follow-up. No new safety signals were observed. CONCLUSION: With all patients off immunotherapy treatment for ≥ 3 years, nivolumab plus ipilimumab increased 5-year survivorship versus chemotherapy, including long-term, durable clinical benefit regardless of tumor PD-L1 expression. These data support nivolumab plus ipilimumab as an effective first-line treatment for patients with metastatic non-small-cell lung cancer.

Alectinib after failure to crizotinib in patients with ALK-positive non-small cell lung cancer: results from the Spanish early access program.

This retrospective observational study analyzed the clinical characteristics, treatment patterns and outcomes of 120 patients with advanced ALK-positive non-small-cell lung cancer (ALK+ NSCLC) according to data collected between November 2019 and October 2020 in 38 Spanish hospitals. Patients had progressed after 1-5 prior treatment lines (which included crizotinib in any prior line) and received subsequent therapy with alectinib in a local expanded access program. Median age was 58.7 years, 50% of patients were female, 64.1% had ECOG PS of 0-1, 85% presented stage IV, 95% had adenocarcinoma histology and 20.8% had brain metastases. After a median 9.6 months of alectinib treatment, objective response rate (ORR) was 54.5%, disease control rate (DCR) was 80%, median progression-free survival (PFS) was 9.4 months and median overall survival (OS) was 24.1 months. Patients with brain metastases achieved an intracranial DCR of 71.4%. Adverse events (AEs) were reported in 35.8% of patients (14.2% of AEs were grade ≥3). Over 40% of patients received some treatment after alectinib, most frequently lorlatinib (65.2%) and brigatinib (32.6%). This study provides information on real-world treatment patterns and confirms the tolerability and prolonged PFS and OS observed with alectinib in clinical trials, in unselected pretreated patients with advanced ALK+ NSCLC.

Overall Survival and Biomarker Analysis of Neoadjuvant Nivolumab Plus Chemotherapy in Operable Stage IIIA Non-Small-Cell Lung Cancer (NADIM phase II trial).

PURPOSE: Neoadjuvant chemotherapy plus nivolumab has been shown to be effective in resectable non-small-cell lung cancer (NSCLC) in the NADIM trial (ClinicalTrials.gov identifier: NCT03081689). The 3-year overall survival (OS) and circulating tumor DNA (ctDNA) analysis have not been reported. METHODS: This was an open-label, multicenter, single-arm, phase II trial in which patients with stage IIIA NSCLC, who were deemed to be surgically resectable, were treated with neoadjuvant paclitaxel (200 mg/m2 once a day) and carboplatin (area under curve 6) plus nivolumab (360 mg) once on day 1 of each 21-day cycle, for three cycles, followed by adjuvant nivolumab monotherapy for 1 year (240 mg once every 2 weeks for 4 months, followed by 480 mg once every 4 weeks for 8 months). The 3-year OS and ctDNA analysis were secondary objectives of the trial. RESULTS: OS at 36 months was 81.9% (95% CI, 66.8 to 90.6) in the intention-to-treat population, rising to 91.0% (95% CI, 74.2 to 97.0) in the per-protocol population. Neither tumor mutation burden nor programmed cell death ligand-1 staining was predictive of survival. Conversely, low pretreatment levels of ctDNA were significantly associated with improved progression-free survival and OS (hazard ratio [HR], 0.20; 95% CI, 0.06 to 0.63, and HR, 0.07; 95% CI, 0.01 to 0.39, respectively). Clinical responses according to RECIST v1.1 criteria did not predict survival outcomes. However, undetectable ctDNA levels after neoadjuvant treatment were significantly associated with progression-free survival and OS (HR, 0.26; 95% CI, 0.07 to 0.93, and HR, 0.04; 95% CI, 0.00 to 0.55, respectively). The C-index to predict OS for ctDNA levels after neoadjuvant treatment (0.82) was superior to that of RECIST criteria (0.72). CONCLUSION: The efficacy of neoadjuvant chemotherapy plus nivolumab in resectable NSCLC is supported by 3-year OS. ctDNA levels were significantly associated with OS and outperformed radiologic assessments in the prediction of survival.

Real-World Analysis of Nivolumab and Atezolizumab Efficacy in Previously Treated Patients with Advanced Non-Small Cell Lung Cancer.

Nivolumab (anti-PD-1 antibody) and atezolizumab (anti-PD-L1 antibody) have shown superior survival outcomes and improved adverse effects compared to standard chemotherapy in advanced non-small cell lung cancer (NSCLC) patients. However, the efficacy of both treatments has not been directly compared in clinical trials. This retrospective, single-centre study was performed from June 2015 to December 2020 and included a cohort of 158 previously treated patients with stage IV or recurrent NSCLC who received PD-1 (nivolumab) (n = 89) or PD-L1 (atezolizumab) (n = 69) inhibitors at the Virgen del Rocío Hospital in Seville. The objective response rate (ORR) was 22.5% in the nivolumab group and 14.5% in the atezolizumab group (p = 0.140). Multivariate analysis did not show significant differences between the two groups for PFS and OS (PFS hazard ratio (HR): 0.80, 95% confidence interval (CI): 0.55−1.17, p = 0.260; OS HR: 0.79, 95% CI: 0.52−1.21, p = 0.281). Adverse events of all grades occurred in 68 patients in the nivolumab group (76.4%) and in 34 patients in the atezolizumab group (49.3%) (p < 0.001). Atezolizumab and nivolumab did not show statistically significant differences in survival outcomes in patients with NSCLC, even when stratified by histological subtype (squamous versus nonsquamous). However, the safety analysis suggested a more favourable toxicity profile for atezolizumab.

Cost-effectiveness analysis of molecular diagnosis by next-generation sequencing versus sequential single testing in metastatic non-small cell lung cancer patients from a south Spanish hospital perspective.

BACKGROUND: To assess the cost-effectiveness of using next-generation sequencing (NGS) compared to sequential single-testing (SST) for molecular diagnostic and treatment of patients with advanced non-small cell lung cancer (NSCLC) from a Spanish single-center perspective, the Hospital Universitario Virgen del Rocio (HUVR). RESEARCH DESIGN AND METHODS: A decision-tree model was developed to assess the alterations detection alterations and diagnostic cost in patients with advanced NSCLC, comparing NGS versus SST. Model inputs such as testing, positivity rates, or treatment allocation were obtained from the literature and the clinical practice of HUVR experts through consultation. Several sensitivity analyses were performed to test the robustness of the model. RESULTS: Using NGS for molecular diagnosis of a 100-patients hypothetical cohort, 30 more alterations could be detected and 3 more patients could be enrolled in clinical-trials than using SST. On the other hand, diagnostic costs were increased up to €20,072 using NGS instead of SST. Using NGS time-to-results would be reduced from 16.7 to 9 days. CONCLUSIONS: The implementation of NGS at HUVR for the diagnostic of patients with advanced NSCLC provides significant clinical benefits compared to SST in terms of alterations detected, treatment with targeted-therapies and clinical-trial enrollment, and could be considered a cost-effective strategy.

Clinical and molecular parameters associated to pneumonitis development in non-small-cell lung cancer patients receiving chemoimmunotherapy from NADIM trial.

BACKGROUND: Pneumonitis (Pn) is one of the main immune-related adverse effects, having a special importance in lung cancer, since they share affected tissue. Despite its clinical relevance, Pn development remains an unpredictable treatment adverse effect, whose mechanisms are mainly unknown, being even more obscure when it is associated to chemoimmunotherapy. METHODS: In order to identify parameters associated to treatment related Pn, we analyzed clinical variables and molecular parameters from 46 patients with potentially resectable stage IIIA non-small-cell lung cancer treated with neoadjuvant chemoimmunotherapy included in the NADIM clinical trial (NCT03081689). Pn was defined as clinical or radiographic evidence of lung inflammation without alternative diagnoses, from treatment initiation to 180 days. RESULTS: Among 46 patients, 12 developed Pn (26.1%). Sex, age, smoking status, packs-year, histological subtype, clinical or pathological response, progression-free survival, overall survival and number of nivolumab cycles, were not associated to Pn development. Regarding molecular parameters at diagnosis, Pn development was not associated to programmed death ligand 1, TPS, T cell receptor repertoire parameters, or tumor mutational burden. However, patients who developed Pn had statistically significant lower blood median levels of platelet to monocyte ratio (p=0.012) and teratocarcinoma-derived growth factor 1 (p=0.013; area under the curve (AUC) 0.801), but higher median percentages of natural killers (NKs) (p=0.019; AUC 0.786), monocytes (p=0.017; AUC 0.791), MSP (p=0.006; AUC 0.838), PARN (p=0.017; AUC 0.790), and E-Cadherin (p=0.022; AUC 0.788). In addition, the immune scenario of Pn after neoadjuvant treatment involves: high levels of neutrophils and NK cells, but low levels of B and T cells in peripheral blood; increased clonality of intratumoral T cells; and elevated plasma levels of several growth factors (EGF, HGF, VEGF, ANG-1, PDGF, NGF, and NT4) and inflammatory cytokines (MIF, CCL16, neutrophil gelatinase-associated lipocalin, BMP-4, and u-PAR). CONCLUSIONS: Although statistically underpowered, our results shed light on the possible mechanisms behind Pn development, involving innate and adaptative immunity, and open the possibility to predict patients at high risk. If confirmed, this may allow the personalization of both, the surveillance strategy and the therapeutic approaches to manage Pn in patients receiving chemoimmunotherapy.

Pretreatment Tissue TCR Repertoire Evenness Is Associated with Complete Pathologic Response in Patients with NSCLC Receiving Neoadjuvant Chemoimmunotherapy.

PURPOSE: Characterization of the T-cell receptor (TCR) repertoire may be a promising source for predictive biomarkers of pathologic response to immunotherapy in locally advanced non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: In this study, next-generation TCR sequencing was performed in peripheral blood and tissue samples of 40 patients with NSCLC, before and after neoadjuvant chemoimmunotherapy (NADIM clinical trial, NCT03081689), considering their complete pathologic response (CPR) or non-CPR. Beyond TCR metrics, tissue clones were ranked by their frequency and spatiotemporal evolution of top 1% clones was determined. RESULTS: We have found a positive association between an uneven TCR repertoire in tissue samples at diagnosis and CPR at surgery. Moreover, TCR most frequently ranked clones (top 1%) present in diagnostic biopsies occupied greater frequency in the total clonal space of CPR patients, achieving an AUC ROC to identify CPR patients of 0.967 (95% confidence interval, 0.897-1.000; P = 0.001), and improving the results of PD-L1 tumor proportion score (TPS; AUC = 0.767; P = 0.026) or tumor mutational burden (TMB; AUC = 0.550; P = 0.687). Furthermore, tumors with high pretreatment top 1% clonal space showed similar immune cell populations but a higher immune reactive gene expression profile. Finally, the selective expansion of pretreatment tissue top 1% clones in peripheral blood of CPR patients suggests also a peripheral immunosurveillance, which could explain the high survival rate of these patients. CONCLUSIONS: We have identified two parameters derived from TCR repertoire analysis that could outperform PD-L1 TPS and TMB as predictive biomarkers of CPR after neoadjuvant chemoimmunotherapy, and unraveled possible mechanisms of CPR involving enhanced tumor immunogenicity and peripheral immunosurveillance.

Correlation of peripheral blood biomarkers with clinical outcomes in NSCLC patients with high PD-L1 expression treated with pembrolizumab.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are currently the standard therapy in advanced non-small cell lung cancer (NSCLC); however, there is no well-established prognostic biomarker. We investigated the relationship between survival outcomes and three peripheral blood biomarkers, including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and monocyte-to-lymphocyte ratio (MLR), as well as a new score termed the risk blood biomarker (RBB), calculated from the combination of the neutrophil-monocyte-to-lymphocyte ratio (NMLR) and white blood cell count (WBC). METHODS: This study included patients with stage IV or recurrent NSCLC confirmed with programmed death ligand 1 (PD-L1) expression ≥50% who received pembrolizumab monotherapy as first-line treatment at the Virgen del Rocío University Hospital in Seville, Spain. To establish the relationship between baseline peripheral blood biomarkers and survival outcomes, progression free survival (PFS) and overall survival (OS), we used the Kaplan-Meier method and multivariable Cox regression models. RESULTS: A total of 51 patients were included in this study. In multivariate analysis, baseline NLR and PLR showed a strong association with PFS [NLR hazard ratio (HR): 0.19, 95% confidence interval (CI): 0.09-0.44, P<0.001; PLR HR: 0.46, 95% CI: 0.23-0.92, P=0.03] and OS (NLR HR: 0.07, 95% CI: 0.02-0.19, P<0.001; PLR HR: 0.29, 95% CI: 0.13-0.67, P=0.004), and the MLR was associated with OS (MLR HR: 0.34, 95% CI: 0.15-0.76, P=0.01). According to the RBB score, groups with lower scores were associated with superior PFS (group 0: HR: 0.16, 95% CI: 0.06-0.41, P<0.001 and group 1: HR: 0.29, 95% CI: 0.12-0.73, P=0.01) and OS (group 0: HR: 0.04, 95% CI: 0.01-0.17, P<0.001 and group 1: HR: 0.15, 95% CI: 0.05-0.42, P<0.001). CONCLUSIONS: Low baseline NLR, MLR and PLR are significantly associated with better PFS, and low baseline NLR and PLR are associated with better OS. Additionally, we identified three subgroups of patients using the RBB score, and low scores were associated with improved survival outcomes and response to therapy.

Blood biomarkers associated to complete pathological response on NSCLC patients treated with neoadjuvant chemoimmunotherapy included in NADIM clinical trial.

BACKGROUND: Immunotherapy is being tested in early-stage non-small cell lung cancer (NSCLC), and achieving higher rates of complete pathological responses (CPR) as compared to standard of care. Early identification of CPR patients has vital clinical implications. In this study, we focused on basal peripheral immune cells and their treatment-related changes to find biomarkers associated to CPR. METHODS: Blood from 29 stage IIIA NSCLC patients participating in the NADIM trial (NCT03081689) was collected at diagnosis and post neoadjuvant treatment. More than 400 parameters of peripheral blood mononuclear cells (PBMCs) phenotype and plasma soluble factors were analyzed. RESULTS: Neoadjuvant chemoimmunotherapy altered more than 150 immune parameters. At diagnosis, 11 biomarkers associated to CPR were described, with an area under the ROC curve >0.70 and p-value <.05. CPR patients had significantly higher levels of CD4+ PD-1+ cells, NKG2D, and CD56 expression on T CD56 cells, intensity of CD25 expression on CD4+ CD25hi+ cells and CD69 expression on intermediate monocytes; but lower levels of CD3+ CD56- CTLA-4+ cells, CD14++ CD16+ CTLA-4+ cells, CTLA-4 expression on T CD56 cells and lower levels of b-NGF, NT-3, and VEGF-D in plasma compared to non-CPR. Post treatment, CPR patients had significantly higher levels of CD19 expression on B cells, BCMA, 4-1BB, MCSF, and PARC and lower levels of MPIF-1 and Flt-3L in plasma compared to non-CPR. CONCLUSIONS: Patients achieving CPR seem to have a distinctive peripheral blood immune status at diagnosis, even showing different immune response to treatment. These results reinforce the different biology behind CPR and non-CPR responses.

PD-(L)1 Inhibitors as Monotherapy for the First-Line Treatment of Non-Small-Cell Lung Cancer Patients with High PD-L1 Expression: A Network Meta-Analysis.

Programmed cell death-ligand 1 (PD-L1) has emerged as a potential biomarker for selection of patients more likely to respond to immunotherapy and as a prognostic factor in non-small cell lung cancer (NSCLC). In this network meta-analysis, we aimed to evaluate the efficacy of first-line anti-PD-(L)1 monotherapy in advanced NSCLC patients with high PD-L1 expression (≥50%) compared to platinum-based chemotherapy. We also evaluated efficacy outcomes according to tumor mutational burden (TMB). To that end, we conducted a systematic review. Six clinical trials with 2111 patients were included. In head-to-head comparisons, immunotherapy showed a significant improvement in progression-free survival (PFS: HRpooled = 0.69, 95% CI: 0.52-0.90, p = 0.007), overall survival (OS: HRpooled = 0.69, 95% CI: 0.61-0.78; p < 0.001) and overall response rate (ORR) (Risk ratio (RR)pooled = 1.354, 95% CI: 1.04-1.762, p = 0.024). In the assessment of relative efficacy for PFS through indirect comparisons, pembrolizumab (results from KEYNOTE-024) ranked highest followed by cemiplimab and atezolizumab, with statistical significance determined for some of the drugs. In terms of OS, cemiplimab ranked highest followed by atezolizumab and pembrolizumab, although non-significant OS was determined for these drugs. In conclusion, PD-(L)1 inhibitor monotherapy improves efficacy outcomes in the first line setting of advanced NSCLC patients with high PD-L1 expression. Evaluations with longer follow up are still needed to determine the superiority of any specific drug.

Primary and Acquired Resistance to Immunotherapy in Lung Cancer: Unveiling the Mechanisms Underlying of Immune Checkpoint Blockade Therapy.

After several decades without maintained responses or long-term survival of patients with lung cancer, novel therapies have emerged as a hopeful milestone in this research field. The appearance of immunotherapy, especially immune checkpoint inhibitors, has improved both the overall survival and quality of life of patients, many of whom are diagnosed late when classical treatments are ineffective. Despite these unprecedented results, a high percentage of patients do not respond initially to treatment or relapse after a period of response. This is due to resistance mechanisms, which require understanding in order to prevent them and develop strategies to overcome them and increase the number of patients who can benefit from immunotherapy. This review highlights the current knowledge of the mechanisms and their involvement in resistance to immunotherapy in lung cancer, such as aberrations in tumor neoantigen burden, effector T-cell infiltration in the tumor microenvironment (TME), epigenetic modulation, the transcriptional signature, signaling pathways, T-cell exhaustion, and the microbiome. Further research dissecting intratumor and host heterogeneity is necessary to provide answers regarding the immunotherapy response and develop more effective treatments for lung cancer.

Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial.

BACKGROUND: Non-small-cell lung cancer (NSCLC) is terminal in most patients with locally advanced stage disease. We aimed to assess the antitumour activity and safety of neoadjuvant chemoimmunotherapy for resectable stage IIIA NSCLC. METHODS: This was an open-label, multicentre, single-arm phase 2 trial done at 18 hospitals in Spain. Eligible patients were aged 18 years or older with histologically or cytologically documented treatment-naive American Joint Committee on Cancer-defined stage IIIA NSCLC that was deemed locally to be surgically resectable by a multidisciplinary clinical team, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received neoadjuvant treatment with intravenous paclitaxel (200 mg/m2) and carboplatin (area under curve 6; 6 mg/mL per min) plus nivolumab (360 mg) on day 1 of each 21-day cycle, for three cycles before surgical resection, followed by adjuvant intravenous nivolumab monotherapy for 1 year (240 mg every 2 weeks for 4 months, followed by 480 mg every 4 weeks for 8 months). The primary endpoint was progression-free survival at 24 months, assessed in the modified intention-to-treat population, which included all patients who received neoadjuvant treatment, and in the per-protocol population, which included all patients who had tumour resection and received at least one cycle of adjuvant treatment. Safety was assessed in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03081689, and is ongoing but no longer recruiting patients. FINDINGS: Between April 26, 2017, and Aug 25, 2018, we screened 51 patients for eligibility, of whom 46 patients were enrolled and received neoadjuvant treatment. At the time of data cutoff (Jan 31, 2020), the median duration of follow-up was 24·0 months (IQR 21·4-28·1) and 35 of 41 patients who had tumour resection were progression free. At 24 months, progression-free survival was 77·1% (95% CI 59·9-87·7). 43 (93%) of 46 patients had treatment-related adverse events during neoadjuvant treatment, and 14 (30%) had treatment-related adverse events of grade 3 or worse; however, none of the adverse events were associated with surgery delays or deaths. The most common grade 3 or worse treatment-related adverse events were increased lipase (three [7%]) and febrile neutropenia (three [7%]). INTERPRETATION: Our results support the addition of neoadjuvant nivolumab to platinum-based chemotherapy in patients with resectable stage IIIA NSCLC. Neoadjuvant chemoimmunotherapy could change the perception of locally advanced lung cancer as a potentially lethal disease to one that is curable. FUNDING: Bristol-Myers Squibb, Instituto de Salud Carlos III, European Union's Horizon 2020 research and innovation programme.

The Roles of Imprinted SLC22A18 and SLC22A18AS Gene Overexpression Caused by Promoter CpG Island Hypomethylation as Diagnostic and Prognostic Biomarkers for Non-Small Cell Lung Cancer Patients.

Genomic imprinting is a process that involves one gene copy turned-off in a parent-of-origin-dependent manner. The regulation of imprinted genes is broadly dependent on promoter methylation marks, which are frequently associated with both oncogenes and tumor suppressors. The purpose of this study was to assess the DNA methylation patterns of the imprinted solute-carrier family 22 member 18 (SLC22A18) and SLC22A18 antisense (SLC22A18AS) genes in non-small cell lung cancer (NSCLC) patients to study their relevance to the disease. We found that both genes were hypomethylated in adenocarcinoma and squamous cell carcinoma patients. Due to this imprinting loss, SLC22A18 and SLC22A18AS were found to be overexpressed in NSCLC tissues, which is significantly more evident in lung adenocarcinoma patients. These results were validated through analyses of public databases of NSCLC patients. The reversed gene profile of both genes was achieved in vitro by treatment with ademetionine. We then showed that high SLC22A18 and SLC22A18AS expression levels were significantly associated with worsening disease progression. In addition, low levels of SLC22A18AS were also correlated with better overall survival for lung adenocarcinoma patients. We found that SLC22A18 and SLC22A18AS knockdown inhibits cell proliferation in vitro. All these results suggest that both genes may be useful as diagnostic and prognostic biomarkers in NSCLC, revealing novel therapeutic opportunities.