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We aimed to determine if advanced BRAF -mutant NSCLC has a higher thromboembolic events (TEE) rate than the expected. Between 2008 and 2021, 182 patients with BRAF -mutant advanced NSCLC (BRAF V600E, n = 70; BRAF non-V600E, n = 112) were retrospectively identified from 18 centers in Spain. Patients received chemotherapy (n = 147), immunotherapy (n = 69), targeted therapy (n = 42), and immunotherapy + chemotherapy (n = 26). Incidence rate of TEE was 26.4 % (95%CI: 19.9 %–32.9 %). A total of 72 TEE were documented among 48 patients, as 18 patients (37.5 %) developed more than one event. Median time to TEE onset was 2 months, 69 % of TEE occurred in the peridiagnostic period (+/− 90 days from cancer diagnosis), and in 16 pts. (33 %) TEE was the form of lung cancer presentation. Although most TEE were only venous (82 %; PE, n = 33; DVT, n = 16), arterial events were reported in 31 % and occurred earlier, or TEE presented in atypical locations (13.9 %). TEE were related to high hospitalization rate (59 %), recurrence (23 %), and mortality (10.4 %) despite appropriate anticoagulant/antiaggregant treatment. Median OS in patients without-TEE was 19.4 months (95%CI: 4.6–34.1), and significantly shorter in patients with arterial-TEE vs venous-TEE vs both of them: 9.9 months (95%CI: 0–23.5) vs 41.7 months (95%CI: 11.3–72.2 m) vs 2.7 months (95%CI: 2.1–3.3), p = 0.001. Neither clinical or molecular features (BRAF V600E / non-V600E), nor cancer treatment was associated to TEE occurrence. Khorana score underperformed to predict thrombosis at cancer diagnosis, as only 19.2 % of patients were classified as high-risk. Thrombotic events represent a new clinical feature of BRAF -mutant lung cancer. Patients with almost a 30 % incidence of TEE should be offered systematic anticoagulation. • Patients with BRAF -mutant lung cancer exhibit a high incidence of thrombosis. • Most thrombotic events occur during the peridiagnostic period. • A high percentage of patients experience more than one event. • Patients with thrombosis during the peridiagnostic period have worse survival. [ABSTRACT FROM AUTHOR]

Background: Non-small cell lung cancer (NSCLC) accounts for the vast majority of all diagnosed lung cancers. According to their histology, most NSCLCs are considered non-squamous cell carcinoma (NSCC), and up to 85% of the latter may lack either one of the two main actionable oncogenic drivers (i.e., EGFR mutations and ALK rearrangements)., Objective: Our analysis aimed to describe the clinical and epidemiological characteristics of Spanish patients suffering from NSCC with no actionable oncogenic driver in daily clinical practice., Design: A retrospective, cross-sectional, descriptive analysis., Methods: We analyzed the records of all Spanish patients with advanced NSCC diagnosed between January 2011 and January 2020 and included in the Spanish Thoracic Tumor Registry database. We evaluated the presence of metastasis and molecular profiling at the time of diagnosis and treatments received. We also assessed overall survival (OS) and progression-free survival (PFS) according to first-line treatment., Results: One thousand seven hundred ninety-seven Spanish patients with NSCC were included. They were mainly men (73.2%), smokers (current [44.4%] and former [44.4%]) and presented adenocarcinoma histology (97.6%). Most patients had at least one comorbidity (80.4%) and one metastatic site (96.8%), and a non-negligible number of those tested were PD-L1 positive (35.2%). Notably, the presence of liver metastasis indicated a shorter median OS and PFS than metastasis in other locations (p < 0.001). Chemotherapy was more often prescribed than immunotherapy as first-, second-, and third-line treatment in that period. In first-line, the OS rates were similar in patients receiving either regimen, but PFS rates significantly better in patients treated with immunotherapy (p = 0.026). Also, a high number of patients did not reach second- and third-line treatment, suggesting the failure of current early diagnostic measures and therapies., Conclusions: This analysis of the most lethal tumor in Spain could highlight the strengths and the weaknesses of its clinical management and set the ground for further advances and research., Competing Interests: Declarations Conflict of interest All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/and declare: EC has served as an advisor or consultant for AstraZeneca, Boehringer Ingelheim, BMS, MSD, Novartis, Roche, and Takeda; he has served as a speaker for AstraZeneca, Boehringer Ingelheim, BMS, MSD, Novartis, Pfizer, Roche, and Takeda; he has received grant support from MSD and has received honoraria from BMS, Pfizer, Roche, and Takeda. DR-A has served as an advisor for MSD, Regeneron, BMS, GSK & Lilly has received honoraria for lectures from MSD, Roche, BMS, Novartis, Takeda, Lilly, and AstraZeneca; he has received support for attending meetings and/or travel from Roche, MSD, Novartis and Sanofi. RL has received consulting fees from Roche, AstraZeneca, Boehringer Ingelheim, Novartis, and BMS; He has received payment or honoraria for lectures from Kyowa Kirin, Pierre-Fabre, Takeda, AstraZeneca, BMS, Novartis, Roche, and Pfizer; he has received support for attending meetings and/or travel from MSD. BM has served as an advisor for Roche, BMS, MSD, Boehringer Ingelheim, Takeda, and Abbvie; he has received support for attending meetings and/or travel from Roche, Pfizer, Merck Serono, Boehringer-Ingelheim, and AstraZeneca. GS has received honoraria from Sanofi and has received support for attending meetings and/or travel from Gilead and MSD. MAS has received honoraria from Takeda and Roche and has received support for attending meetings and/or travel from Roche and PharmaMar. PC has received honoraria from Roche, Janssen, Pfizer, Takeda, and BMS and has received support for attending meetings and/or travel from Roche, Janssen, Pfizer, Takeda, and BMS. RB has served as an advisor for AstraZeneca, Roche, Amgen, and MSD; he has received honoraria from BMS, Roche, AstraZeneca, Lilly, MSD, and Pfizer; he has received support for attending meetings and/or travel from AstraZeneca and Roche. JLGL has served as an advisor for MSD, Janssen-Cilag, BMS, Boehringer Ingelheim, and Amgen; he has received payment as an expert testimony from MSD, Janssen-Cilag, BMS, Boehringer Ingelheim, and Amgen; he has received honoraria from MSD, AstraZeneca, Roche, Pfizer, Janssen-Cilag, Novartis, Astellas, and BMS; he has received support for attending meetings and/or travel from MSD, Takeda, BMS, Roche, Pfizer, and Janssen-Cilag. JBB has received grants from Pfizer and Roche; he has received honoraria from AstraZeneca, Pfizer, MSD, BMS, Roche, and Sanofi; he has received support for attending meetings and/or travel from MSD, Takeda, and Roche. AP has served as an advisor for AstraZeneca; he has received payment as an expert testimony from AstraZeneca, Takeda, Roche, BMS, MSD, and Merck; he has received honoraria from AstraZeneca, Takeda, Roche, BMS, MSD, and Merck; he has received support for attending meetings and/or travel from Takeda, AstraZeneca & Merck. MP has been awarded research grants from AstraZeneca, Roche, BMS, Boehringer-Ingelheim, and Takeda; he has served as a consultant for AstraZeneca, BMS, Boehringer-Ingelheim, Celgene, MSD, Roche, Takeda, and Thermo-Fisher. All other authors declare no conflicts of interest. Ethical approval and consent to participate Not required as this study only used anonymised and aggregated data. Consent for publication Not applicable. Informed consent The study was approved by Clinical Research Ethical Comitte from Puerta de Hierro Hospital, and patients alive in the moment their inclusion signed a informed consent., (© 2024. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

• A phase II randomized study of gefitinib versus gefitinib plus olaparib in 182 EGFR-mutation positive NSCLC patients. • The study included patients from Spain and Mexico. • Median progression-free survival was 10.9 months in the gefitinib compared to 12.8 months in the gefitinib plus olaparib arm. Progression-free survival (PFS) and response rate to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) varies in patients with non-small-cell lung cancer (NSCLC) driven by EGFR mutations, suggesting that other genetic alterations may influence oncogene addiction. Low BRCA1 mRNA levels correlate with longer PFS in erlotinib-treated EGFR -mutant NSCLC patients. Since the poly (ADP-ribose) polymerase (PARP) inhibitor, olaparib, may attenuate and/or prevent BRCA1 expression, the addition of olaparib to gefitinib could improve outcome in EGFR -mutant advanced NSCLC. GOAL was a multicenter, randomized phase IB/II study performed in two countries, Spain and Mexico. Eligible patients were 18 years or older, treatment-naïve, pathologically confirmed stage IV NSCLC, with centrally confirmed EGFR mutations and measurable disease. Patients were randomly allocated (1:1) to receive gefitinib 250 mg daily or gefitinib 250 mg daily plus olaparib 200 mg three times daily in 28-day cycles. The primary endpoint was PFS. Secondary endpoints included overall survival (OS), response rate, safety and tolerability. Between September 2013, and July 2016, 182 patients underwent randomization, 91 received gefitinib and 91 received gefitinib plus olaparib. There were no differences in gender, age, smoking status, performance status, presence of bone and brain metastases or type of EGFR mutation. Median PFS was 10.9 months (95 % CI 9.3–13.3) in the gefitinib arm and 12.8 months (95 % CI 9.1–14.7) in the gefitinib plus olaparib arm (HR 1.38, 95 % CI 1.00–1.92; p = 0.124). The most common adverse events were anemia, 78 % in gefitinib plus olaparib group, 38 % in gefitinib arm, diarrhea, 65 % and 60 %, and fatigue, 40 % and 32 %, respectively. The gefitinib plus olaparib combination did not provide significant benefit over gefitinib alone. The combination's safety profile showed an increase in hematological and gastrointestinal toxicity, compared to gefitinib alone, however, no relevant adverse events were noted. [ABSTRACT FROM AUTHOR]

Background Immunotherapy has become a standard treatment for lung cancer; however, the high cost makes it necessary to assess health outcomes. Objective The aim of this study was to evaluate the effectiveness, safety and economic cost of nivolumab in real-world clinical practice. Setting Fifteen regional and academic hospitals from Spain participated in this study. Methods This study was a retrospective, multicentre and observational study involving patients who experienced progression after first-line therapy for non-small-cell lung cancer and were treated with nivolumab between January 2016 and July 2017. Effectiveness and safety were evaluated by the oncologist, and the data from the electronic clinical records of the patients were collected by the research team. Economic cost was calculated using the cost of acquiring nivolumab for the public health system. Main outcome measures Effectiveness variables were overall survival (OS) and progression-free survival (PFS). The safety variable was the incidence of adverse events (AEs), and the cost per life-year gained (LYG) was the economic variable. Results A total of 221 patients were enrolled (83.7% men). The mean age was 64.5 years, and 84.6% of the patients had an Eastern Cooperative Oncology Group (ECOG) performance-status score of 0-1. Squamous tumours accounted for 59.7% of the total, and 78.7% of the patients presented a time since platinum therapy (TPT) > 6 months. The mean nivolumab dose was 216 mg (SD 211), and the treatment duration was 7.0 months (95% CI 5.8-8.1). The median PFS was 5.3 months (95% CI 3.2-7.3), and OS was 9.7 months (95% CI 7.6-11.8). The median PFS and OS values were statistically significantly superior for patients with an ECOG score of 0-1 and for patients with a TPT > 6 months. The median OS was also statistically significantly superior for patients with non-squamous histology. Regarding safety, 71% of the patients presented AEs of any grade, and in 18.6%, the nivolumab treatment had to be delayed or discontinued. The cost of nivolumab per patient was €19,910.00 (SD 19,369), and the cost per LYG was €110,026.00 (€77,557.00-€231,171.00). Conclusions This study confirms that the efficacy and safety of nivolumab treatment in a real population are comparable to the results obtained in clinical trials. A greater clinical benefit of nivolumab therapy was observed in patients with an ECOG score of 0-1, a TPT > 6 months or non-squamous histology. Despite the benefit observed, the cost per LYG is above the threshold of efficiency established by public health institutes. [ABSTRACT FROM AUTHOR]

Introduction Lung cancer accounts for 20 % of cancer deaths in Spain. The most frequent subtype (87 %) is non-small cell lung cancer (NSCLC). Pemetrexed is a recently marketed drug added to NSCLC therapeutic arsenal. It seems to have become one of the most used options for the treatment of this condition over the last 3 years. Aim of the review To evaluate the efficacy and safety of pemetrexed in NSCLC, in the different therapy lines. Method A systematic search of published literature was conducted using the main databases (MEDLINE, EMBASE, the Cochrane Library and the Center for Reviews and Dissemination) and subsequently a search of referenced literature was performed. We included clinical trials, meta-analyses and systematic reviews. The evaluation of the quality of the articles was performed by pairs using specific assessment scales, Critical Appraisal Skills Program (CASP) adapted for CASP Spain. Then we extracted data on efficacy and safety according to the treatment line assessed. Results We identified 277 references. Finally, nine clinical trials and a meta-analysis complied with inclusion criteria. In first-line induction, treatment with pemetrexed associated with a platinum was similar in terms of efficacy to other alternative chemotherapy regimens, except in patients with non-squamous histology, in whom survival was higher in the experimental group. In maintenance treatment, greater efficacy was seen with pemetrexed in patients with non-squamous histology. In second-line treatment, there were no significant differences in terms of efficacy and safety for pemetrexed treatment versus other chemotherapy options. The most frequent adverse reactions were: hematological, gastrointestinal and neurological. All were significantly less frequent with pemetrexed versus other alternative therapies, except for liver toxicity. Conclusions Due to the high degree of uncertainty as to its efficacy in certain subgroups of patients, including conflicting data; to its recent incorporation, and therefore lack of safety data in the medium and long term, and the high budgetary impact of its incorporation into health systems, it seems reasonable to optimize its use, identifying those patients who may benefit most. [ABSTRACT FROM AUTHOR]

Simple Summary: Genetic variants identified in association with radiation therapy side effects in non-small-cell lung cancer patients require an independent validation. Therefore, the aim of our study was to replicate, in an independent cohort, the analyses of previously published studies associating single-nucleotide polymorphisms with radiation-induced oesophagitis. Following the original models, 2 of the 18 variants associated with radiation-induced oesophagitis in non-small-cell lung cancer patients were confirmed. Furthermore, we meta-analysed our cohort together with those of the reference studies. Twelve variants located in genes of inflammation and DNA double-strand break repair pathways remained associated with oesophagitis. These variants could be included in models for clinical prediction of radiation-induced oesophagitis to evaluate their performance. Several studies have identified single-nucleotide polymorphisms (SNPs) associated with adverse effects in non-small-cell lung cancer (NSCLC) patients treated with radiation therapy. Here, using an independent cohort, we aimed to validate the reported associations. We selected 23 SNPs in 17 genes previously associated with radiation-induced oesophagitis for validation in a cohort of 178 Spanish NSCLC patients. Of them, 18 SNPs were finally analysed, following the methods described in the original published studies. Two SNPs replicated their association with radiation-induced oesophagitis (rs7165790 located in the BLM gene: odds ratio (OR) = 0.16, 95% CI = 0.04–0.65, p-value = 0.010; rs4772468 at FGF14: OR = 4.36, 95% CI = 1.15–16.46, p-value = 0.029). The SNP rs2868371 at HSPB1 was also validated but displayed an opposite effect to the formerly described (OR = 3.72; 95% CI = 1.49–9.25; p-value = 0.004). Additionally, we tested a meta-analytic approach including our results and the previous datasets reported in the referenced publications. Twelve SNPs (including the two previously validated) retained their statistically significant association with radiation-induced oesophagitis. This study strengthens the role of inflammation and DNA double-strand break repair pathways in the risk prediction of developing radiation-induced oesophagitis in NSCLC patients. The validated variants are good candidates to be evaluated in risk prediction models for patient stratification based on their radiation susceptibility. [ABSTRACT FROM AUTHOR]

Vitamin D has been associated with risk, development, and progression of cancer. However, the genes involved in its metabolism are highly polymorphic, compromising its activity. The aim of this study is to evaluate the association between the gene polymorphisms involved in the metabolic pathway of vitamin D and survival in patients with non-small-cell lung cancer (NSCLC). The study was designed as an observational cohort which included 194 Caucasians patients from southern Spain with NSCLC. Real-time polymerase chain reaction was used to analyze the following polymorphisms: CYP27B1 rs4646536, rs3782130, and rs10877012; CYP24A1 rs6068816 and rs4809957; GC rs7041; CYP2R1 rs10741657; VDR rs1544410 (BsmI), rs11568820 (Cdx-2), rs2228570 (FokI), rs7975232 (ApaI), and rs731236 (TaqI). Progression-free survival (PFS) and overall survival were assessed. Cox regression showed that rs4646536 was associated with PFS in the general population ( p = 0.0233) and in the non-resected NSCLC subgroup ( p = 0.0233). In the resected NSCLC subgroup, rs11568820 was associated with OS ( p = 0.0129) and rs7041 with PFS ( p = 0.0447). In the non-resected NSCLC subgroup, rs6068816 was associated with PFS ( p = 0.0048) and OS ( p = 0.0089) and rs731236 and rs7975232 were associated with OS ( p = 0.0005) and PFS ( p = 0.0002), respectively. The other polymorphisms showed no effect on the results. The rs4646536, rs6068816, rs7041, rs11568820, rs731236, and rs7975232 polymorphisms are associated with survival in NSCLC and may have a substantial role as prognostic markers of the disease.

Aim:  To assess the cost-effectiveness of first-line treatment with dacomitinib compared with gefitinib in patients newly diagnosed with advanced NSCLC EGFR -positive in the context of Spain. Materials & methods: A partitioned survival model was developed including costs, utilities and disutilities to estimate quality-adjusted life-year (QALY) and incremental cost-effectiveness ratio when treating with dacomitinib versus gefitinib. Results: Dacomitinib presented higher QALYs (0.51) compared with gefitinib (0.45). Dacomitinib costs were €33,061 in comparison with €26,692 for gefitinib arm. An incremental cost-effectiveness ratio of €111,048 was obtained for dacomitinib. Conclusion: Dacomitinib was more effective in terms of QALYs gained than gefitinib. However, to obtain a cost-effectiveness alternative, a discount greater than 25% in dacomitinib acquisition cost is required.

In 2011, the Spanish Society of Medical Oncology (SEOM) and the Spanish Society of Pathology (SEAP) initiated a joint project to establish guidelines for biomarker testing in patients with advanced non-small-cell lung cancer based on the information available at the time. As this field is constantly evolving, these guidelines were updated in 2012 and 2015 and now in 2019. Current evidence suggests it should be mandatory to test all patients with this kind of advanced lung cancer for EGFR and BRAF mutations, ALK and ROS1 rearrangements and PD-L1 expression. The growing need to study other emerging biomarkers has promoted the routine use of massive sequencing (next-generation sequencing, NGS). However, the coordination of every professional involved and the prioritisation of the most suitable tests and technologies for each case remain a challenge., (Copyright © 2020 Sociedad Española de Anatomía Patológica. Publicado por Elsevier España, S.L.U. All rights reserved.)

In 2011 the Spanish Society of Medical Oncology (SEOM) and the Spanish Society of Pathology (SEAP) started a joint project to establish guidelines on biomarker testing in patients with advanced non-small-cell lung cancer (NSCLC) based on current evidence. As this field is constantly evolving, these guidelines have been updated, previously in 2012 and 2015 and now in 2019. Current evidence suggests that the mandatory tests to conduct in all patients with advanced NSCLC are for EGFR and BRAF mutations, ALK and ROS1 rearrangements and PD-L1 expression. The growing need to study other emerging biomarkers has promoted the routine use of massive sequencing (next-generation sequencing, NGS). The coordination of every professional involved and the prioritisation of the most suitable tests and technologies for each case remains a challenge.

Purpose: The analysis of epidermal growth factor receptor (EGFR) mutations in many patients with advanced non-small-cell lung cancer (aNSCLC) has provided the opportunity for successful treatment with specific, targeted EGFR tyrosine kinase inhibitors. However, this therapeutic decision may be challenging when insufficient tumor tissue is available for EGFR mutation testing. Therefore, blood surrogate samples for EGFR mutation analysis have been suggested., Methods: Data were collected from the Spanish cohort of patients in the large, non-interventional, diagnostic ASSESS study (NCT01785888) evaluating the utility of circulating free tumor-derived DNA from plasma for EGFR mutation testing. The incidence of EGFR mutation in Spain and the level of concordance between matched tissue/cytology and plasma samples were evaluated., Results: In a cohort of 154 eligible patients, EGFR mutations were identified in 15.1 and 11.0% of tumor and plasma samples, respectively. The most commonly used EGFR mutation testing method for the tumor tissue samples was the QIAGEN Therascreen ® EGFR RGQ PCR kit (52.1%). Fragment Length Analysis + PNA LNA Clamp was used for the plasma samples. The concordance rate for EGFR mutation status between the tissue/cytology and plasma samples was 88.8%; the sensitivity was 45.5%, and the specificity was 96.7%., Conclusions: The high concordance between the different DNA sources for EGFR mutation testing supports the use of plasma samples when tumor tissue is unavailable.