The FLARE Score and Circulating Neutrophils in Patients with Cancer and COVID-19 Disease.

PURPOSE: Inflammation and neutrophils play a central role in both COVID-19 disease and cancer. We aimed to assess the impact of pre-existing tumor-related inflammation on COVID-19 outcomes in patients with cancer and to elucidate the role of circulating neutrophil subpopulations. METHODS: We conducted a multicenter retrospective analysis of 524 patients with cancer and SARS-CoV-2 infection, assessing the relationship between clinical outcomes and circulating inflammatory biomarkers collected before and during COVID-19 infection. Additionally, a single-center prospective cohort study provided data for an exploratory analysis, assessing the immunophenotype of circulating neutrophils and inflammatory cytokines. The primary endpoints were 30-day mortality and the severity of COVID-19 disease. RESULTS: Prior to COVID-19, 25% of patients with cancer exhibited elevated dNLR, which increased to 55% at the time of COVID-19 diagnosis. We developed the FLARE score, incorporating both tumor- and infection-induced inflammation, which categorized patients into four prognostic groups. The poor prognostic group had a 30-day mortality rate of 68%, significantly higher than the 23% in the favorable group (p < 0.0001). This score proved to be an independent predictor of early mortality. This prospective analysis revealed a shift towards immature forms of neutrophils and higher IL-6 levels in patients with cancer and severe COVID-19 infection. CONCLUSIONS: A pre-existing tumor-induced pro-inflammatory state significantly impacts COVID-19 outcomes in patients with cancer. The FLARE score, derived from circulating inflammatory markers, emerges as an easy-to-use, globally accessible, effective tool for clinicians to identify patients with cancer at heightened risk of severe COVID-19 complications and early mortality who might benefit most from immediate and intensive treatment strategies. Furthermore, our findings underscore the significance of immature neutrophils in the progression of COVID-19 in patients with cancer, advocating for further investigation into how these cells contribute to both cancer and COVID-19 disease.

Family history of cancer and lung cancer: Utility of big data and artificial intelligence for exploring the role of genetic risk.

OBJECTIVES: Lung Cancer (LC) is a multifactorial disease for which the role of genetic susceptibility has become increasingly relevant. Our aim was to use artificial intelligence (AI) to analyze differences between patients with LC based on family history of cancer (FHC). MATERIALS AND METHODS: From August 2016 to June 2020 clinical information was obtained from Thoracic Tumors Registry (TTR), a nationwide database sponsored by the Spanish Lung Cancer Group. In addition to descriptive statistical analysis, an AI-assisted analysis was performed. The German Technical Information Library supported the merging of data from the electronic medical records and database of the TTR. The results of the AI-assisted analysis were reported using Knowledge Graph, Unified Schema and descriptive and predictive analyses. RESULTS: Analyses were performed in two phases: first, conventional statistical analysis including 11,684 patients of those 5,806 had FHC. Median overall survival (OS) for the global population was 23 months (CI 95 %: 21.39-24.61) in patients with FHC versus 21 months (CI 95 %: 19.53-22.48) in patients without FHC (NFHC), p < 0.001. The second AI-assisted analysis included 5,788 patients of those 939 had FHC. 58.48 % of women with FHC had LC. 9.53 % of patients had an EGFR or HER2 mutation or ALK translocation and at least one relative with cancer. A family history of LC was associated with an increased risk of smoking-related LC. Non-smokers with a family history of LC were more likely to have an EGFR mutation in NSCLC. In Bayesian network analysis, 55 % of patients with a family history of LC and never-smokers had an EGFR mutation. CONCLUSION: In our population, the incidence of LC in patients with a FHC is higher in women and younger patients. FHC is a risk factor and predictor of LC development, especially in people ≤ 50 years. These results were confirmed by conventional statistics and AI-assisted analysis.

Analysis of Diagnostic Delay and its Impact on Lung Cancer Survival: Results From the Spanish Thoracic Tumor Registry.

BACKGROUND: Early detection is crucial to improve lung cancer survival rates. Delays in diagnosis might negatively impact the prognosis of the disease. This study aims to analyze the diagnostic delay in lung cancer patients and describe if there is an association between delay and survival. METHODS: The data source used was the Thoracic Tumor Registry of the Spanish Lung Cancer Group. This analysis was restricted to lung cancer cases with information on the first date of consultation by symptoms and date of diagnosis. The delay was calculated as the number of days between the two dates. A descriptive analysis was performed, and ordinal logistic regressions were fitted with delay as the dependent variable. Kaplan-Meier survival analysis and Cox regression were performed. RESULTS: 22,755 lung cancer cases were included. Never smokers were 1.16 (95%CI: 1.06-1.27) times more likely to register longer delay than smokers. Stage 0-I-II cases had a 3.09 (95%CI: 2.88-3.32) higher risk of longer delay compared to III-IV stages. Overall, 5-year survival rate after diagnosis was 23.64% (95%CI: 22.88-24.41). In those categorized as having the shortest delay 5-year survival was 17.67% (95%CI: 16.31-19.07) and in the extreme delay it was 32.98% (95%CI: 31.28-34.69) (p<0.001). Adjusted mortality risk was higher in those with the shortest delay (HR 1.36, CI95%: 1.30-1.43) in comparison with the extreme delay. CONCLUSIONS: Diagnostic delay is short among Spanish lung cancer patients, indicating a relatively quick diagnostic process. Extreme delays appear to be associated with higher survival rates, possibly attributed to slow-growing tumors, earlier stage at diagnosis or basically the natural history of this disease.

Advances in Immunotherapy for Malignant Pleural Mesothelioma: From Emerging Strategies to Translational Insights.

MPM stands as a rare malignancy necessitating improved therapeutic strategies due to its limited treatment choices and unfavorable prognosis. The advent of immune checkpoint inhibitors has heralded a paradigm shift in the therapeutic landscape of MPM, offering promising avenues across diverse clinical scenarios. In the context of advanced stages of the disease, Immune check-point inhibitors targeting programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-as-sociated protein 4 (CTLA-4), have exhibited encouraging potential in clinical trials, particularly manifesting efficacy among patients exhibiting disease progression following chemotherapy regimens. Innovative combination regimens, exemplified by the concurrent administration of nivolumab and ipilimumab, have demonstrated marked improvement in survival and patient's benefits. A deeper comprehension of the intricate genetic underpinnings of MPM, encompassing key mutations such as cyclin-dependent kinase inhibitor 2A (CDKN2A), neurofibromin 2 (NF2), and BRCA1-associated protein 1 (BAP1) mutations, has elucidated novel avenues for targeted therapeutic interventions. This review accentuates the transformative capacity of immunotherapy in revolutionizing the therapeutic outlook for MPM, thereby potentially translating into augmented survival rates and offering glimpses of new approaches on the horizon. Despite the persisting challenges, the synergistic crossroads of interdisciplinary research and collaborative clinical endeavors portend a hopeful landscape for MPM treatment.

El mesotelioma pleural maligno (MPM) es una neoplasia poco frecuente que requiere una mejora de las estrategias terapéuticas debido a sus limitadas opciones de tratamiento y a su pronóstico desfavorable. La llegada de los inhibidores de los puntos de control inmunitario ha supuesto un cambio de paradigma en el panorama terapéutico del MPM, ofreciendo vías prometedoras en diversos escenarios clínicos. En el contexto de los estadios avanzados de la enfermedad, los inhibidores de puntos de control inmunitario dirigidos contra la proteína de muerte celular programada 1 (PD-1) y la proteína 4 asociada a los linfocitos T citotóxicos (CTLA-4) han mostrado un potencial alentador en los ensayos clínicos, sobre todo por su eficacia en los pacientes con progresión de la enfermedad tras los regímenes de quimioterapia. Los regímenes combinados innovadores, ejemplificados por la administración concurrente de nivolumab e ipilimumab, han demostrado una mejora significativa de la supervivencia y de los beneficios para los pacientes. Una comprensión más profunda de los complejos fundamentos genéticos del MPM, que abarca mutaciones clave como el inhibidor de la cinasa dependiente de ciclina 2A (CDKN2A), la neurofibromina 2 (NF2) y las mutaciones de la proteína 1 asociada a BRCA1 (BAP1), ha dilucidado nuevas vías para el desarrollo de intervenciones terapéuticas dirigidas. Esta revisión acentúa la capacidad transformadora de la inmunoterapia para revolucionar las perspectivas terapéuticas en el MPM, lo que podría traducirse en un aumento de las tasas de supervivencia y ofrecer nuevos enfoques terapéuticos en el horizonte próximo. A pesar de los retos persistentes, el cruce sinérgico de la investigación interdisciplinar y los esfuerzos clínicos de colaboración auguran un panorama esperanzador en el tratamiento de los MPM.

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.

Describing differences among populations of thoracic tumors patients under and over 80 years: Data analysis from the SLCG thoracic tumor registry.

OBJECTIVES: Cancer is a disease of old age; however, most studies usually included minority of patients fit elderly. The purpose is to investigate the clinical characteristics and genetic information of patients with thoracic tumors who are 80 years old or older compared to those under 80 years old. STUDY DESIGN AND METHODS: The Thoracic Tumor Registry (TTR) is a Spanish observational, prospective cohort study that included patients diagnosed with thoracic tumors. Data were collected from medical records related to sociodemographic, epidemiological, clinical, molecular/genetic, and treatment outcome variables. RESULTS: The total number of patients, recruited from August 2016 to April 2023, was 26.193 (93,1 % were younger than 80 years and 6,9 % were 80 years or older). In the group of older patients: the male ratio increased (72,9 % vs. 80 %); the number of elderly people who had never smoked or were ex-smokers increased (9,9 % vs. 21,1 % and 44,8 % vs. 61,3 %, respectively) and the number of current smokers decreased (43,3 % vs. 17,5 %); had higher ECOG performance status at diagnosis (for ECOG ≥ 2, 15 % vs. 32,9 %), and there were more patients with previous cancer (17,3 % vs. 28 %). The proportion of men is higher than that of women (73 % vs. 27 % in <80 years and 80 % vs. 20 % in ≥80 years). For all biomarkers, the proportion of patients who had a molecular determination was lower in older patients. There were no differences in terms of alterations in the biomarkers tested; except for EGFR, for which the positivity rate was higher in patients aged 80 years and older (25 % vs. 15,3 %). CONCLUSION: The proportion of older patients with targeted mutations is higher. So, at least at diagnosis, it should be proceeded in a standard way. Then, when it comes to treatment, comorbidities and patient's baseline situation should be considered. CLINICAL TRIAL REGISTRATION: NCT02941458.

Association Between Lung Immune Prognostic Index and Durvalumab Consolidation Outcomes in Patients With Locally Advanced Non-Small-Cell Lung Cancer.

INTRODUCTION: The LIPI, based on pretreatment derived neutrophils/[leukocytes-neutrophils] ratio (dNLR) and LDH, is associated with immune checkpoint inhibitors (ICI) outcomes in advanced non-small-cell lung cancer (NSCLC). We aimed to assess baseline LIPI correlation with durvalumab consolidation outcomes in the locally advanced setting. MATERIAL AND METHODS: Multicentre retrospective study (330 patients) with stage III unresectable NSCLC treated with durvalumab after chemo-radiotherapy between April 2015 and December 2020; 65 patients treated with chemo-radiotherapy only. Baseline LIPI characterized 3 groups: good (dNLR≤3+LDH≤ULN), intermediate (dNLR>3/LDH>ULN) and poor (dNLR>3+LDH>ULN). Primary endpoint was overall survival (OS). RESULTS: In the durvalumab cohort, median age was 67 years, 95% smokers, 98% with a performance status of 0-1; 60% had nonsquamous histology and 16% a PD-L1 expression <1%. Radiotherapy was delivered concurrently in 81%. LIPI was evaluable in 216 patients: 66% good, 31% intermediate, 3% poor. LIPI significantly correlated with median OS (median follow-up: 19 months): 18.1 months vs. 47.0 months vs. not reached in poor, intermediate and good LIPI groups, respectively (P = .03). A trend between objective response rate and LIPI groups was observed: 0% vs. 41% vs. 45%, respectively (P = .05). The pooled intermediate/poor LIPI group was associated with shorter OS (HR 1.97; P = .03) and higher risk of progressive disease (OR 2.68; P = .047). Survivals and response were not influenced in the control cohort. CONCLUSION: Baseline LIPI correlated with outcomes in patients with locally advanced NSCLC treated with durvalumab consolidation, but not in those who only received chemo-radiotherapy, providing further evidence of its prognostic and potential predictive role of ICI benefit in NSCLC.

Comparison of Clinical and Genetic Characteristics Between Younger and Older Lung Cancer Patients.

INTRODUCTION: The aim of this study was to analyze the clinical and genetic characteristics of young lung cancer cases, and to compare them with those of older cases. METHODS: We used the Thoracic Tumors Registry (TTR) as a data source representative of lung cancer cases diagnosed in Spain, and included all cases registered until 9/01/2023 which had information on age at diagnosis or the data needed to calculate it. We performed a descriptive statistical analysis and fitted logistic regressions to analyze how different characteristics influenced being a younger lung cancer patient. RESULTS: A total of 26,336 subjects were included. Lung cancer cases <50 years old had a higher probability of being women (OR: 1.38; 95% CI: 1.21-1.57), being in stage III or IV (OR: 1.32; 95% CI: 1.08-1.62), not having comorbidities (OR: 5.21; 95% CI: 4.59-5.91), presenting with symptoms at diagnosis (OR: 1.53; 95% CI: 1.29-1.81), and having ALK translocation (OR: 7.61; 95% CI: 1.25-46.32) and HER2 mutation (OR: 5.71; 95% CI: 1.34-24.33), compared with subjects ≥50 years. Among subjects <35 years old (n=61), our study observed a higher proportion of women (59.0% vs. 26.6%; p<0.001), never smokers (45.8% vs. 10.3%; p<0.001), no comorbidities (21.3% vs. 74.0%; p<0.001); ALK translocation (33.3% vs. 4.4%; p<0.001) and ROS1 mutation (14.3% vs. 2.3%; p=0.01), compared with subjects ≥35 years. CONCLUSIONS: Lung cancer displays differences by age at diagnosis which may have important implications for its clinical management.

Addressing lung cancer screening eligibility in Spain using 2013 and 2021 US Preventive Service Task Force criteria: cross-sectional study.

Objectives: The aim of the study was to ascertain the percentage of Spanish lung cancer cases that would fulfil the lung cancer screening inclusion criteria recommended by the United States Preventive Service Task Force (USPSTF) in 2013 and 2021. Methods: A cross-sectional study was carried out. All lung cancer cases registered in the Thoracic Tumor Registry with data on date of birth, date of diagnosis, smoking habit, number of pack-years and time elapsed since smoking cessation were included. Results: The study included 15 006 patients diagnosed with lung cancer in Spain between 2016 and 2022. Eligibility to participate in screening increased from 53.7% to 63.5% (an increase of 9.8%) according to the 2013 and 2021 recommendations, respectively. The percentage of eligible men rose by 9.2 percentage points with the 2021 versus 2013 recommendations, whereas this rise was 11.5 percentage points in women. Under the 2021 recommendations, 36.6% of women and 5.3% of men would not have fulfilled the screening inclusion criteria due to being never-smokers; 14.9% of women and 11.0% of men would not have fulfilled the age criterion; and 27.0% of ex-smokers among women compared to 35.6% among men would not have been eligible due to >15 years having elapsed since smoking cessation. Conclusions: In Spain, over one-third of lung cancer cases could not be detected through screening, by virtue of not meeting the most recent inclusion criteria stated by the USPSTF. The degree of fulfilment in a potential nationwide screening programme should be analysed, with the aim of establishing inclusion criteria in line with each country's context.

Real-world treatment patterns and survival outcomes for patients with stage III non-small cell lung cancer in Spain: a nationwide cohort study.

Background: The burden of non-small cell lung cancer (NSCLC) remains high in Spain, with lung cancer accounting for 20% of cancer-related deaths annually. Programs such as the Spanish Thoracic Tumour Registry (TTR) and the global I-O Optimise initiative have been developed to observe patients in clinical practice with the aim of improving outcomes. This analysis examined treatment patterns and survival in patients with stage III NSCLC from the TTR. These patients represent a heterogenous group with complex treatment pathways. Methods: The TTR is an ongoing, observational, prospective, and retrospective cohort multicentre study (NCT02941458) that follows patients with thoracic cancer in Spain. Adults aged ≥18 years with stage IIIA/IIIB NSCLC enrolled in the TTR between 01 Jan 2010 and 31 Oct 2019 were included in this analysis. Initial treatment received was described by cancer stage and histology (squamous and non-squamous NSCLC). Kaplan-Meier estimates of progression-free survival (PFS) and overall survival (OS) were calculated over a 5-year period. Results: A total of 1,838 patients were included in the cohort, including 1,082 with stage IIIA (58.9%) and 756 with stage IIIB (41.1%). Median follow-up was 18.3 months. The median age of patients was 66 years, and most had non-squamous NSCLC (54.0%), were male (81.2%), and were active or former smokers (93.4%). Overall, 26.3% of patients received surgical resection (37.0% for stage IIIA and 11.1% for stage IIIB). The most frequent initial treatment received was concurrent chemoradiotherapy for stage IIIA (30.2%) and stage IIIB (37.0%) patients. Median OS was lower in patients with stage IIIB than stage IIIA (28 vs. 37 months) disease and was lower for patients with squamous than non-squamous histology (19 vs. 26 months). Median PFS and OS varied when patients were stratified by initial treatment. Conclusions: This TTR analysis describes the clinical reality surrounding the initial management and survival outcomes for stage III NSCLC in Spain and presents survival outcomes comparable with other real-world evidence. It provides insights into the diverse approaches used before the availability of immunotherapies and targeted treatments in the non-metastatic NSCLC setting.

Brief report: High incidence of peridiagnosis thromboembolic events in patients with BRAF-mutant lung cancer.

INTRODUCTION: We aimed to determine if advanced BRAF-mutant NSCLC has a higher thromboembolic events (TEE) rate than the expected. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

Perioperative Nivolumab and Chemotherapy in Stage III Non-Small-Cell Lung Cancer.

BACKGROUND: Approximately 20% of patients with non-small-cell lung cancer (NSCLC) receive a diagnosis of stage III disease. There is no current consensus regarding the most appropriate treatment for these patients. METHODS: In this open-label, phase 2 trial, we randomly assigned patients with resectable stage IIIA or IIIB NSCLC to receive neoadjuvant nivolumab plus platinum-based chemotherapy (experimental group) or chemotherapy alone (control group), followed by surgery. Patients in the experimental group who had R0 resections received adjuvant treatment with nivolumab for 6 months. The primary end point was a pathological complete response (0% viable tumor in resected lung and lymph nodes). Secondary end points included progression-free survival and overall survival at 24 months and safety. RESULTS: A total of 86 patients underwent randomization; 57 were assigned to the experimental group and 29 were assigned to the control group. A pathological complete response occurred in 37% of the patients in the experimental group and in 7% in the control group (relative risk, 5.34; 95% confidence interval [CI], 1.34 to 21.23; P = 0.02). Surgery was performed in 93% of the patients in the experimental group and in 69% in the control group (relative risk, 1.35; 95% CI, 1.05 to 1.74). Kaplan-Meier estimates of progression-free survival at 24 months were 67.2% in the experimental group and 40.9% in the control group (hazard ratio for disease progression, disease recurrence, or death, 0.47; 95% CI, 0.25 to 0.88). Kaplan-Meier estimates of overall survival at 24 months were 85.0% in the experimental group and 63.6% in the control group (hazard ratio for death, 0.43; 95% CI, 0.19 to 0.98). Grade 3 or 4 adverse events occurred in 11 patients in the experimental group (19%; some patients had events of both grades) and 3 patients in the control group (10%). CONCLUSIONS: In patients with resectable stage IIIA or IIIB NSCLC, perioperative treatment with nivolumab plus chemotherapy resulted in a higher percentage of patients with a pathological complete response and longer survival than chemotherapy alone. (Funded by Bristol Myers Squibb and others; NADIM II ClinicalTrials.gov number, NCT03838159; EudraCT number, 2018-004515-45.).

Adjuvant dabrafenib and trametinib for patients with resected BRAF -mutated melanoma: DESCRIBE-AD real-world retrospective observational study.

BRAF and MEK inhibitor, dabrafenib plus trametinib, adjuvant therapy is effective for high-risk resected melanoma patients with BRAF - V600 mutations. However, real-world evidence is limited. We aimed to determine the feasibility of this therapy in routine clinical practice. DESCRIBE-AD, a retrospective observational study, collected real-world data from 25 hospitals in Spain. Histologically confirmed and resected BRAF -mutated melanoma patients aged ≥18 years who were previously treated with dabrafenib plus trametinib adjuvant therapy, were included. The primary objectives were treatment discontinuation rate and time to discontinuation. The secondary objectives included safety and efficacy. From October 2020 to March 2021, 65 patients were included. Dabrafenib and trametinib discontinuation rate due to treatment-related adverse events (TRAEs) of any grade was 9%. Other reasons for discontinuation included patients' decisions (6%), physician decisions (6%), unrelated adverse events (3%), disease progression (5%), and others (5%). The median time to treatment discontinuation was 9 months [95% confidence interval (CI), 5-11]. G3-4 TRAEs occurred in 21.5% of patients, the most common being pyrexia (3%), asthenia (3%), and diarrhoea (3%). Unscheduled hospitalisations and clinical tests occurred in 6 and 22% of patients, respectively. After 20-month median follow-up (95% CI, 18-22), 9% of patients had exitus due to disease progression, with a 12-month relapse-free survival and overall survival rates of 95.3% and 100%, respectively. Dabrafenib and trametinib adjuvant therapy proved effective for melanoma patients in a real-world setting, with a manageable toxicity profile. Toxicity frequencies were low leading to low incidence of unscheduled medical visits, tests, and treatment discontinuations.

Second-line treatment outcomes after progression from first-line chemotherapy plus immunotherapy in patients with advanced non-small cell lung cancer.

INTRODUCTION: Chemotherapy plus immunotherapy is the standard of care for patients with metastatic NSCLC. No study has evaluated the outcomes of second-line chemotherapy treatments after progression following first-line chemo-immunotherapy. METHOD: This multicenter retrospective study evaluated the efficacy of second line (2L) chemotherapies after progression under first-line (1L) chemo-immunotherapy, measured by overall survival (2L-OS) and progression free survival (2L-PFS). RESULTS: A total of 124 patients were included. The mean age was 63.1 years, 30.6 % of the patients were female, 72.6 % had an adenocarcinoma and 43.5 % had a poor ECOG-performance status prior to 2L initiation. Sixty-four (52.0 %) patients were considered resistant to first line chemo-immunotherapy. (1L-PFS < 6 months). In 2L treatments, 57 (46.0 %) patients received taxane monotherapy, 25 (20.1 %) taxane plus anti-angiogenic, 12 (9.7 %) platinum-based chemotherapy and 30 (24.2 %) other chemotherapy. At a median follow-up of 8.3 months (95 %CI: 7.2-10.2), post initiation of 2L treatment, the median 2L-OS was 8.1 months (95 % CI: 6.4-12.7) and the median 2L-PFS was 2.9 months (95 %CI: 2.4-3.3). Overall, the 2L-objective response and 2L-disease control rates were 16.0 %, and 42.5 %, respectively. Taxane plus anti-angiogenic and platinum rechallenge achieved longest median 2L-OS: not reached (95 %CI: 5.8-NR) and 17.6 months (95 %CI 11.6-NR), respectively (p = 0.05). Patients resistant to the 1L treatment had inferior outcomes (2L-OS 5.1 months, 2L-PFS 2.3 months) compared with 1L responders (2L-OS 12.7 months, 2L-PFS 3.2 months). CONCLUSION: In this real-life cohort, 2L chemotherapy achieved modest activity following progression under chemo-immunotherapy. 1L-resistant patients remained a refractory population, highlighting a need for new 2L strategies.

SARS-CoV-2 infection in patients with melanoma: results of the Spanish Melanoma Group registry.

BACKGROUND: The Spanish Melanoma Group (GEM) developed a national registry of patients with melanoma infected by SARS-CoV-2 ("GRAVID"). METHODS: The main objective was to describe the COVID-19 fatality rate in patients with melanoma throughout the pandemic, as well as to explore the effect of melanoma treatment and tumor stage on the risk of COVID-19 complications. These are the final data of the register, including cases from February 2020 to September 2021. RESULTS: One hundred-fifty cases were registered. Median age was 68 years (range 6-95), 61 (40%) patients were females, and 63 (42%) patients had stage IV. Thirty-nine (26%) were on treatment with immunotherapy, and 17 (11%) with BRAF-MEK inhibitors. COVID-19 was resolved in 119 cases, including 85 (57%) patients cured, 15 (10%) that died due to melanoma, and 20 (13%) that died due to COVID-19. Only age over 60 years, cardiovascular disorders, and diabetes mellitus increased the risk of death due to COVID-19, but not advanced melanoma stage nor melanoma systemic therapies. Three waves have been covered by the register: February-May 2020, August-November 2020, and December 2020-April 2021. The first wave had the highest number of registered cases and COVID-19 mortality. CONCLUSION: Tumor stage or melanoma treatments are non-significant prognostic factors for COVID-19 mortality. During the pandemic in Spain there was a downward trend in the number of patients registered across the waves, as well as in the severity of the infection. GOV IDENTIFIER: NCT04344002.

Targeting molecular alterations in non-small-cell lung cancer: what's next?

In recent years, major advances have been achieved in our understanding of non-small-cell lung cancer (NSCLC) with oncogenic driver alterations and in the specific treatment of these with tyrosine kinase inhibitors. Currently, state-of-the-art management of patients with NSCLC (particularly adenocarcinoma or non-adenocarcinoma but with mild tobacco exposure) consists of the determination of EGFR, ALK, ROS1 and BRAF status, as they have US FDA and EMA approved targeted therapies. The increase in molecular knowledge of NSCLC and the development of drugs against other targets has settled new therapeutic indications. In this review we have incorporated the development around MET, KRAS and NTRK in the diagnosis of NSCLC given the therapeutic potential that they represent, as well as the drugs approved for these indications.

A prognostic score for patients with malignant pleural mesothelioma (MPM) receiving second-line immunotherapy or chemotherapy in the ETOP 9-15 PROMISE-meso phase III trial.

INTRODUCTION: Clinical and laboratory parameters associated with response for patients with advanced pre-treated malignant pleural mesothelioma (MPM) are lacking. We aimed to identify prognostic and predictive markers among patients with relapsed MPM who were randomised into the ETOP 9-15 PROMISE-meso phase III trial, evaluating pembrolizumab and chemotherapy. METHODS: Baseline clinical and laboratory parameters were investigated for prognostic or predictive value on progression-free survival (PFS) and overall survival (OS) in a retrospective analysis, based on the full cohort of 144 MPM patients. These consisted of immune-inflammatory indexes (neutrophil-lymphocyte ratio [NLR], systemic immune-inflammatory index [SII], lactate dehydrogenase [LDH]) along with other already known prognostic baseline characteristics and laboratory values. Cut-offs were chosen independently of outcome. Based on Cox multivariable analysis for PFS in the whole cohort, a risk factor model was built to illustrate the prognostic stratification of patients by the combination of the derived independent prognostic factors, taking into account the EORTC score, a validated prognostic score in MPM. All models were stratified by histology and adjusted by treatment. RESULTS: In the stratified multivariable analysis in the whole cohort, high SII (hazard ratio (HR) 2.06; 95%CI 1.39-3.05) and low haemoglobin (HR 1.62; 95%CI 1.06-2.50) were associated with worse PFS. Based on these two prognostic factors, a mesothelioma risk score (MRS) was constructed with three PFS risk prognosis categories: favourable, intermediate and poor with 0, 1 and 2 risk factors, respectively (corresponding percent of cohort: 24%, 34% and 42% and median PFS: 5.8, 4.2 and 2.1 months). The derived MRS stratified the prognosis for PFS and OS, overall and within each of the EORTC groups. No significant predictors of treatment benefit were identified. CONCLUSIONS: The proposed MRS is prognostic of patient outcome and it fine-tunes the prognosis of patients with pre-treated MPM alone or when used with the already established EORTC score.

Spanish Society of Thoracic Surgery (SECT) consensus document. Long-term follow-up for operated patients with lung cancer.

The most effective treatment for lung cancer is complete lung resection, although recurrences reach up to 10% and the appearance of second neoplasms, up to 6%. Therefore, the follow-up of these patients will be essential for the early detection and treatment of these events; however there is no definition of the form, time and cadence of these follow-ups. In this consensus document, we try to define them based on the available scientific evidence. A critical review of the literature is carried out (meta-analysis, systematic reviews, reviews, consensus recommendations of scientific societies, randomized controlled studies, non-randomized controlled studies, observational studies and case series studies) and communications to the main congresses on oncology and thoracic surgery in Spanish, English and French. The evidences found are classified following the GRADE system. It is defined according to the existing evidence that the patient resected for lung cancer should be followed up, as well as that this follow-up should be close during the first years and with CT (not being necessary to follow up with PET-CT, biomarkers or bronchoscopy). Cessation of smoking is also recommended in this follow-up.