Determination of essential biomarkers in lung cancer: a real-world data study in Spain with demographic, clinical, epidemiological and pathological characteristics.

BACKGROUND: The survival of patients with lung cancer has substantially increased in the last decade by about 15%. This increase is, basically, due to targeted therapies available for advanced stages and the emergence of immunotherapy itself. This work aims to study the situation of biomarker testing in Spain. PATIENTS AND METHODS: The Thoracic Tumours Registry (TTR) is an observational, prospective, registry-based study that included patients diagnosed with lung cancer and other thoracic tumours, from September 2016 to 2020. This TTR study was sponsored by the Spanish Lung Cancer Group (GECP) Foundation, an independent, scientific, multidisciplinary oncology society that coordinates more than 550 experts and 182 hospitals across the Spanish territory. RESULTS: Nine thousand two hundred thirty-nine patients diagnosed with stage IV non-small cell lung cancer (NSCLC) between 2106 and 2020 were analysed. 7,467 (80.8%) were non-squamous and 1,772 (19.2%) were squamous. Tumour marker testing was performed in 85.0% of patients with non-squamous tumours vs 56.3% in those with squamous tumours (p-value < 0.001). The global testing of EGFR, ALK, and ROS1 was 78.9, 64.7, 35.6% respectively, in non-squamous histology. PDL1 was determined globally in the same period (46.9%), although if we focus on the last 3 years it exceeds 85%. There has been a significant increase in the last few years of all determinations and there are even close to 10% of molecular determinations that do not yet have targeted drug approval but will have it in the near future. 4,115 cases had a positive result (44.5%) for either EGFR, ALK, KRAS, BRAF, ROS1, or high PDL1. CONCLUSIONS: Despite the lack of a national project and standard protocol in Spain that regulates the determination of biomarkers, the situation is similar to other European countries. Given the growing number of different determinations and their high positivity, national strategies are urgently needed to implement next-generation sequencing (NGS) in an integrated and cost-effective way in lung cancer.

Brigatinib versus Crizotinib in ALK-Positive Non-Small-Cell Lung Cancer.

BACKGROUND: Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, has robust efficacy in patients with ALK-positive non-small-cell lung cancer (NSCLC) that is refractory to crizotinib. The efficacy of brigatinib, as compared with crizotinib, in patients with advanced ALK-positive NSCLC who have not previously received an ALK inhibitor is unclear. METHODS: In an open-label, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with advanced ALK-positive NSCLC who had not previously received ALK inhibitors to receive brigatinib at a dose of 180 mg once daily (with a 7-day lead-in period at 90 mg) or crizotinib at a dose of 250 mg twice daily. The primary end point was progression-free survival as assessed by blinded independent central review. Secondary end points included the objective response rate and intracranial response. The first interim analysis was planned when approximately 50% of 198 expected events of disease progression or death had occurred. RESULTS: A total of 275 patients underwent randomization; 137 were assigned to brigatinib and 138 to crizotinib. At the first interim analysis (99 events), the median follow-up was 11.0 months in the brigatinib group and 9.3 months in the crizotinib group. The rate of progression-free survival was higher with brigatinib than with crizotinib (estimated 12-month progression-free survival, 67% [95% confidence interval {CI}, 56 to 75] vs. 43% [95% CI, 32 to 53]; hazard ratio for disease progression or death, 0.49 [95% CI, 0.33 to 0.74]; P<0.001 by the log-rank test). The confirmed objective response rate was 71% (95% CI, 62 to 78) with brigatinib and 60% (95% CI, 51 to 68) with crizotinib; the confirmed rate of intracranial response among patients with measurable lesions was 78% (95% CI, 52 to 94) and 29% (95% CI, 11 to 52), respectively. No new safety concerns were noted. CONCLUSIONS: Among patients with ALK-positive NSCLC who had not previously received an ALK inhibitor, progression-free survival was significantly longer among patients who received brigatinib than among those who received crizotinib. (Funded by Ariad Pharmaceuticals; ALTA-1L ClinicalTrials.gov number, NCT02737501 .).

Prognostic model of long-term advanced stage (IIIB-IV) EGFR mutated non-small cell lung cancer (NSCLC) survivors using real-life data.

BACKGROUND: There is a lack of useful diagnostic tools to identify EGFR mutated NSCLC patients with long-term survival. This study develops a prognostic model using real world data to assist clinicians to predict survival beyond 24 months. METHODS: EGFR mutated stage IIIB and IV NSCLC patients diagnosed between January 2009 and December 2017 included in the Spanish Lung Cancer Group (SLCG) thoracic tumor registry. Long-term survival was defined as being alive 24 months after diagnosis. A multivariable prognostic model was carried out using binary logistic regression and internal validation through bootstrapping. A nomogram was developed to facilitate the interpretation and applicability of the model. RESULTS: 505 of the 961 EGFR mutated patients identified in the registry were included, with a median survival of 27.73 months. Factors associated with overall survival longer than 24 months were: being a woman (OR 1.78); absence of the exon 20 insertion mutation (OR 2.77); functional status (ECOG 0-1) (OR 4.92); absence of central nervous system metastases (OR 2.22), absence of liver metastases (OR 1.90) or adrenal involvement (OR 2.35) and low number of metastatic sites (OR 1.22). The model had a good internal validation with a calibration slope equal to 0.781 and discrimination (optimism corrected C-index 0.680). CONCLUSIONS: Survival greater than 24 months can be predicted from six pre-treatment clinicopathological variables. The model has a good discrimination ability. We hypothesized that this model could help the selection of the best treatment sequence in EGFR mutation NSCLC patients.

Immunotherapy with checkpoint inhibitors in non-small cell lung cancer: insights from long-term survivors.

Immune checkpoint inhibitors (ICIs) targeting the programmed cell death-1 (PD-1)-programmed cell death ligand-1 (PD-L1) axis have shown promising results in non-small cell lung cancer (NSCLC) patients, some of them with persistent responses to these agents that form a population of long-term survivors. Despite the variable definition of PD-L1 positivity in tumors, an association between expression and response has been reasonably consistent in advanced NSCLC. In addition, the clinical efficacy of ICIs seems to be related to the genomic landscape of the tumor in terms of mutational burden and clonal neoantigens. Furthermore, increasing evidence shows that excessive activation of the immune response elicited by ICIs, leading to immune-related toxicities, might be associated with an improved response to immunotherapy. There are still many unanswered questions about the proper use of these agents to maximize their efficacy, which may be improved through combination with radiation, chemotherapy, targeted therapies, or other immune mediators, including dual checkpoint blockade. To search for clues for addressing these challenges, this review focused on the characteristics and clinical features of long-term NSCLC survivors and the potential biomarkers of response to ICIs.

Lung cancer in Spanish women: The WORLD07 project.

The WORLD07 study was a female-specific database, to prospectively characterise the clinical, histological, molecular and treatment-related features in Spanish women with lung cancer. Data were collected from patients' medical records and patient interviews from October 2007 to December 2012. A total of 2,060 women were analysed: median age, 61.3 years; white, 98.6%; postmenopausal, 80.2%; and no smokers, 55% including never smokers and ex-smokers. A family history of cancer was found in 42.5% of patients, 12.0% of patients had had a previous history of cancer (breast cancer, 39.7%). Most patients (85.8%) were diagnosed of non-small-cell lung cancer (NSCLC), most commonly reported with adenocarcinoma (71.4%), which was stage IV at diagnosis in 57.6%. Median overall survival (OS) for the entire population was 24.0 months, with a 1- and 2-year survival rate of 70.7% and 50.0% respectively. Median OS in patients with small-cell lung cancer was 18.8 months versus 25.0 months in patients with NSCLC (p = 0.011). Lung cancer appears to be a biologically different disease in women. By collecting prospective information about characteristics of women with lung cancer attending university hospitals in Spain, we hope to highlight the need to develop strategies based on gender differences and influence future healthcare policy.

Lung Cancer in Never-Smoking Women: A Sub-Analysis of the Spanish Female-Specific Database WORLD07.

The WORLD07 study characterizes lung cancer in Spanish women. This analysis investigated lung cancer features in never-smoking women. Of 2072 women recruited, 2035 were analyzed. Patient characteristics and demographics were similar for current/former smokers and never smokers. Among never smokers, 38.3% were exposed to passive smoking. Non-small-cell lung cancer was the most common type (78.8% of current/former smokers and 96.1% of never smokers) and adenocarcinoma the most common histology (69.1% and 83.4% respectively). There was a high incidence of lung cancer in Spanish never-smoking women and a high proportion (about 50%) had mutant epidermal growth factor receptor.

Management of the adverse events of afatinib: a consensus of the recommendations of the Spanish expert panel.

Afatinib is an irreversible ErbB family blocker tyrosine kinase inhibitor (TKI), which has recently been approved for the treatment of patients with EGFR M+ non-small cell lung cancer. As observed with reversible EGFR TKIs, it can induce class-effect adverse events. Appropriate management of afatinib-related adverse events improves quality of life and clinical outcomes in these patients. Here we provide practical recommendations for the prophylaxis and treatment of the most common of these (e.g., diarrhea, rash, mucositis and others).

Improving quality of care by standardising patient data collection in electronic medical records in an oncology department in Spain.

BACKGROUND: Evaluation of quality of care in oncology is key in ensuring patients receive adequate treatment. American Society of Clinical Oncology's (ASCO) Quality Oncology Practice Initiative (QOPI) Certification Program (QCP) is an international initiative that evaluates quality of care in outpatient oncology practices. METHODS: We retrospectively reviewed free-text electronic medical records from patients with breast cancer (BR), colorectal cancer (CRC) or non-small cell lung cancer (NSCLC). In a baseline measurement, high scores were obtained for the nine disease-specific measures of QCP Track (2021 version had 26 measures); thus, they were not further analysed. We evaluated two sets of measures: the remaining 17 QCP Track measures, as well as these plus other 17 measures selected by us (combined measures). Review of data from 58 patients (26 BR; 18 CRC; 14 NSCLC) seen in June 2021 revealed low overall quality scores (OQS)-below ASCO's 75% threshold-for QCP Track measures (46%) and combined measures (58%). We developed a plan to improve OQS and monitored the impact of the intervention by abstracting data at subsequent time points. RESULTS: We evaluated potential causes for the low OQS and developed a plan to improve it over time by educating oncologists at our hospital on the importance of improving collection of measures and highlighting the goal of applying for QOPI certification. We conducted seven plan-do-study-act cycles and evaluated the scores at seven subsequent data abstraction time points from November 2021 to December 2022, reviewing 404 patients (199 BR; 114 CRC; 91 NSCLC). All measures were improved. Four months after the intervention, OQS surpassed the quality threshold and was maintained for 10 months until the end of the study (range, 78-87% for QCP Track measures; 78-86% for combined measures). CONCLUSIONS: We developed an easy-to-implement intervention that achieved a fast improvement in OQS, enabling our Medical Oncology Department to aim for QOPI certification.

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.

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.

BRAF mutational status is associated with survival outcomes in locally advanced resectable and metastatic NSCLC.

BACKGROUND: Immunotherapy-based treatments have demonstrated high efficacy in patients with advanced and locally advanced non-small-cell lung cancer (NSCLC). BRAF mutations affect a small but significant fraction of NSCLC. The efficacy of these therapies in this subgroup of patients is unknown. MATERIALS AND METHODS: Plasma and tissue samples from 116 resectable stage IIIA/B NSCLC patients, included in NADIM and NADIM II clinical trials (NADIM cohort), and from a prospective academic cohort with 84 stage IV NSCLC patients (BLI-O cohort), were analyzed by next-generation sequencing. RESULTS: The p.G464E, p.G466R, p.G466V, p.G469V, p.L597Q, p.T599I, p.V600E (n = 2) BRAF mutations, were identified in four (3.45 %) samples from the NADIM cohort, all of which were cases treated with neoadjuvant chemoimmunotherapy (CH-IO), and four (4.76 %) samples from the BLI-O cohort, corresponding to cases treated with first-line immunotherapy (n = 2) or CH-IO (n = 2). All these patients were alive and had no evidence of disease at data cut-off. Conversely, patients with BRAF wild-type (wt) tumors in the BLI-O cohort had a median progression-free survival (PFS) of 5.49 months and a median overall survival (OS) of 12.00 months (P-LogRank = 0.013 and 0.046, respectively). Likewise, PFS and OS probabilities at 36 months were 60.5 % and 76.1 % for patients with BRAF-wt tumors in the NADIM cohort. The pathological complete response (pCR) rate after neoadjuvant CH-IO in patients with BRAF-positive tumors (n = 4) was 100 %, whereas the pCR rate in the BRAF-wt population was 44.3 % (RR: 2.26; 95 % CI: 1.78-2.85; P < 0.001). CONCLUSION: BRAF mutations may be a good prognostic factor for advanced and locally advanced NSCLC patients undergoing immunotherapy-based treatments.

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.

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.

Spatially preserved multi-region transcriptomic subtyping and biomarkers of chemoimmunotherapy outcome in extensive-stage small cell lung cancer.

BACKGROUND: Transcriptomic subtyping holds promise for personalized therapy in extensive-stage small-cell lung cancer (ES-SCLC). In this study, we aimed to assess intratumoral transcriptomic subtype diversity and to identify biomarkers of long-term chemoimmunotherapy benefit in human ES-SCLC. PATIENTS AND METHODS: We analyzed tumor samples from 58 ES-SCLC patients enrolled in two multicenter single-arm phase IIIb studies evaluating front-line chemoimmunotherapy in Spain: n=32 from the IMfirst trial, and n=26 from the CANTABRICO trial. We utilized the GeoMxTM DSP system to perform multi-region transcriptomic analysis. For subtype classification, we performed hierarchical clustering using the relative expression of ASCL1 (SCLC-A), NEUROD1 (SCLC-N), POU2F3 (SCLC-P), and YAP1 (SCLC-Y). RESULTS: Subtype distribution was similar between both cohorts, except for SCLC-P, not identified in the CANTABRICO_DSP cohort. A total of 44% of the patients in both cohorts had tumors with multiple co-existing transcriptional subtypes. Transcriptional subtypes or subtype heterogeneity were not associated with outcomes. Most potential targets did not show subtype-specific expression. Consistently in both cohorts, tumors from patients with long-term benefit (time to progression ³12 months) contained an IFNg-dominated mRNA profile, including enhanced capacity for antigen presentation. Hypoxia and glycolytic pathways were associated with resistance to chemoimmunotherapy. CONCLUSIONS: This work suggests that intratumoral heterogeneity, inconsistent association with outcome, and unclear subtype-specific target expression might be significant challenges for subtype-based precision oncology in SCLC. Pre-existing IFNg-driven immunity and mitochondrial metabolism seem correlates of long-term efficacy in this study, although the absence of a chemotherapy control arm precludes concluding that these are predictive features specific for immunotherapy.

Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial.

BACKGROUND: Erlotinib has been shown to improve progression-free survival compared with chemotherapy when given as first-line treatment for Asian patients with non-small-cell lung cancer (NSCLC) with activating EGFR mutations. We aimed to assess the safety and efficacy of erlotinib compared with standard chemotherapy for first-line treatment of European patients with advanced EGFR-mutation positive NSCLC. METHODS: We undertook the open-label, randomised phase 3 EURTAC trial at 42 hospitals in France, Italy, and Spain. Eligible participants were adults (> 18 years) with NSCLC and EGFR mutations (exon 19 deletion or L858R mutation in exon 21) with no history of chemotherapy for metastatic disease (neoadjuvant or adjuvant chemotherapy ending ≥ 6 months before study entry was allowed). We randomly allocated participants (1:1) according to a computer-generated allocation schedule to receive oral erlotinib 150 mg per day or 3 week cycles of standard intravenous chemotherapy of cisplatin 75 mg/m(2) on day 1 plus docetaxel (75 mg/m(2) on day 1) or gemcitabine (1250 mg/m(2) on days 1 and 8). Carboplatin (AUC 6 with docetaxel 75 mg/m(2) or AUC 5 with gemcitabine 1000 mg/m(2)) was allowed in patients unable to have cisplatin. Patients were stratified by EGFR mutation type and Eastern Cooperative Oncology Group performance status (0 vs 1 vs 2). The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. We assessed safety in all patients who received study drug (≥ 1 dose). This study is registered with ClinicalTrials.gov, number NCT00446225. FINDINGS: Between Feb 15, 2007, and Jan 4, 2011, 174 patients with EGFR mutations were enrolled. One patient received treatment before randomisation and was thus withdrawn from the study; of the remaining patients, 86 were randomly assigned to receive erlotinib and 87 to receive standard chemotherapy. The preplanned interim analysis showed that the study met its primary endpoint; enrolment was halted, and full evaluation of the results was recommended. At data cutoff (Jan 26, 2011), median PFS was 9·7 months (95% CI 8·4-12·3) in the erlotinib group, compared with 5·2 months (4·5-5·8) in the standard chemotherapy group (hazard ratio 0·37, 95% CI 0·25-0·54; p < 0·0001). Main grade 3 or 4 toxicities were rash (11 [13%] of 84 patients given erlotinib vs none of 82 patients in the chemotherapy group), neutropenia (none vs 18 [22%]), anaemia (one [1%] vs three [4%]), and increased amino-transferase concentrations (two [2%] vs 0). Five (6%) patients on erlotinib had treatment-related severe adverse events compared with 16 patients (20%) on chemotherapy. One patient in the erlotinib group and two in the standard chemotherapy group died from treatment-related causes. INTERPRETATION: Our findings strengthen the rationale for routine baseline tissue-based assessment of EGFR mutations in patients with NSCLC and for treatment of mutation-positive patients with EGFR tyrosine-kinase inhibitors. FUNDING: Spanish Lung Cancer Group, Roche Farma, Hoffmann-La Roche, and Red Temática de Investigacion Cooperativa en Cancer.

SEOM-GECP Clinical guidelines for diagnosis, treatment and follow-up of small-cell lung cancer (SCLC) (2022).

Small-cell lung cancer (SCLC) is a highly aggressive malignancy comprising approximately 15% of lung cancers. Only one-third of patients are diagnosed at limited-stage (LS). Surgical resection can be curative in early stages, followed by platinum-etoposide adjuvant therapy, although only a minority of patients with SCLC qualify for surgery. Concurrent chemo-radiotherapy is the standard of care for LS-SCLC that is not surgically resectable, followed by prophylactic cranial irradiation (PCI) for patients without progression. For extensive-stage (ES)-SCLC, a combination of platinum and etoposide has historically been a mainstay of treatment. Recently, the efficacy of programmed death-ligand 1 inhibitors combined with chemotherapy has become the new front-line standard of care for ES-SCLC. Emerging knowledge regarding SCLC biology, including genomic characterization and molecular subtyping, and new treatment approaches will potentially lead to advances in SCLC patient care.

MET alterations in NSCLC-Current Perspectives and Future Challenges.

Targeted therapies have revolutionized the treatment and improved the outcome for oncogene-driven NSCLC and an increasing number of oncogenic driver therapies have become available. For MET-dysregulated NSCLC (especially MET exon 14 skipping mutations and MET-amplifications, which is one of the most common bypass mechanisms of resistance in oncogene-addicted NSCLC), several anti-MET-targeted therapies have been approved recently (MET exon 14 skipping mutation) and multiple others are in development. In this narrative review, we summarize the role of MET as an oncogenic driver in NSCLC, discuss the different testing methods for exon 14 skipping mutations, gene amplification, and protein overexpression, and review the existing data and ongoing clinical trials regarding targeted therapies in MET-altered NSCLC. As immunotherapy with or without chemotherapy has become the standard of care for advanced NSCLC, immunotherapy data for MET-dysregulated NSCLC are put into perspective. Finally, we discuss future challenges in this rapidly evolving landscape.

Immune-checkpoint inhibition for resectable non-small-cell lung cancer - opportunities and challenges.

Therapeutic strategies harnessing the immune system to eliminate tumour cells have been successfully used for several cancer types, including in patients with advanced-stage non-small-cell lung cancer (NSCLC). In these patients, immune-checkpoint inhibitors (ICIs) can provide durable responses and improve overall survival either as monotherapy, or combined with chemotherapy or other immunotherapeutic agents. However, the implementation of ICIs in early stage NSCLC has been hampered by the continuous struggle to develop robust end points to assess their efficacy in this setting, especially those enabling a fast and reproducible evaluation of the clinical activity of neoadjuvant strategies. Several trials are testing ICIs, alone or in combination with chemotherapy, in early stage NSCLC as an adjuvant, neoadjuvant or perioperative approach. As a novelty, most trials in the neoadjuvant setting have adopted pathological response as a primary end point. ICIs have been approved for use in the neoadjuvant and adjuvant settings on the basis of event-free survival and disease-free survival benefit, respectively; however, the correlation of these end points with overall survival remains unclear in these settings. Unresolved challenges for the optimal use of ICIs with curative intent include concerns about their applicability in daily clinical practice and about improving patient selection based on predictive biomarkers or assessment of pathological response and minimal residual disease. In this Review, we discuss the rationale, available strategies and current trial landscape for the implementation of ICIs in patients with resectable NSCLC, and we further elaborate on future approaches to optimize their clinical benefit.

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.

Molecular Epidemiology and Treatment Patterns of Patients With EGFR Exon 20-Mutant NSCLC in the Precision Oncology Era: The European EXOTIC Registry.

Introduction: Real-world evidence regarding molecular epidemiology and management patterns of patients with EGFR exon-20 mutated, advanced NSCLC outside the context of clinical trials is lacking. Methods: We created a European registry for patients with advanced EGFR exon 20-mutant NSCLC diagnosed from January 2019 to December 2021. Patients enrolled in clinical trials were excluded. Clinicopathologic and molecular epidemiology data were collected, and treatment patterns were recorded. Clinical end points according to treatment assignment were assessed using Kaplan-Meier curves and Cox regression models. Results: Data on 175 patients from 33 centers across nine countries were included in the final analysis. Median age was 64.0 (range: 29.7-87.8) years. Main features included female sex (56.3%), never or past smokers (76.0%), adenocarcinoma (95.4%), and tropism for bone (47.4%) and brain (32.0%) metastases. Mean programmed death-ligand 1 tumor proportional score was 15.8% (range: 0%-95%) and mean tumor mutational burden was 7.06 (range: 0-18.8) mutations per megabase. Exon 20 was detected in the tissue (90.7%), plasma (8.7%), or both (0.6%), using mostly targeted next-generation sequencing (64.0%) or polymerase chain reaction (26.0%). Mutations were mainly insertions (59.3%), followed by duplications (28.1%), deletions-insertions (7.7%), and the T790M (4.5%). Insertions and duplications were located mainly in the near loop (codons 767-771, 83.1%) and the far loop (codons 771-775, 13%) and only in 3.9% within the C helix (codons 761-766). Main co-alterations included mutations in TP53 (61.8%) and MET amplifications (9.4%). Treatment on mutation identification included chemotherapy (CT) (33.8%), CT-immunotherapy (IO) (18.2%), osimertinib (22.1%), poziotinib (9.1%), mobocertinib (6.5%), mono-IO (3.9%), and amivantamab (1.3%). Disease control rates were 66.2% with CT plus or minus IO, 55.8% with osimertinib, 64.8% with poziotinib, and 76.9% with mobocertinib. Corresponding median overall survival was 19.7, 15.9, 9.2, and 22.4 months, respectively. In multivariate analysis, type of treatment (new targeted agents versus CT ± IO) affected progression-free survival (p = 0.051) and overall survival (p = 0.03). Conclusions: EXOTIC represents the largest academic real-world evidence data set on EGFR exon 20-mutant NSCLC in Europe. Indirectly compared, treatment with new exon 20-targeting agents is likely to confer survival benefit than CT plus or minus IO.