Synergy between imputed genetic pathway and clinical information for predicting recurrence in early stage non-small cell lung cancer.

OBJECTIVE: Lung cancer exhibits unpredictable recurrence in low-stage tumors and variable responses to different therapeutic interventions. Predicting relapse in early-stage lung cancer can facilitate precision medicine and improve patient survivability. While existing machine learning models rely on clinical data, incorporating genomic information could enhance their efficiency. This study aims to impute and integrate specific types of genomic data with clinical data to improve the accuracy of machine learning models for predicting relapse in early-stage, non-small cell lung cancer patients. METHODS: The study utilized a publicly available TCGA lung cancer cohort and imputed genetic pathway scores into the Spanish Lung Cancer Group (SLCG) data, specifically in 1348 early-stage patients. Initially, tumor recurrence was predicted without imputed pathway scores. Subsequently, the SLCG data were augmented with pathway scores imputed from TCGA. The integrative approach aimed to enhance relapse risk prediction performance. RESULTS: The integrative approach achieved improved relapse risk prediction with the following evaluation metrics: an area under the precision-recall curve (PR-AUC) score of 0.75, an area under the ROC (ROC-AUC) score of 0.80, an F1 score of 0.61, and a Precision of 0.80. The prediction explanation model SHAP (SHapley Additive exPlanations) was employed to explain the machine learning model's predictions. CONCLUSION: We conclude that our explainable predictive model is a promising tool for oncologists that addresses an unmet clinical need of post-treatment patient stratification based on the relapse risk while also improving the predictive power by incorporating proxy genomic data not available for specific patients.

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.

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.

Small-Cell Lung Cancer Long-Term Survivor Patients: How to Find a Needle in a Haystack?

Small-cell lung cancer (SCLC) is an aggressive malignancy characterized by a rapid progression and a high resistance to treatments. Unlike other solid tumors, there has been a scarce improvement in emerging treatments and survival during the last years. A better understanding of SCLC biology has allowed for the establishment of a molecular classification based on four transcription factors, and certain therapeutic vulnerabilities have been proposed. The universal inactivation of TP53 and RB1, along with the absence of mutations in known targetable oncogenes, has hampered the development of targeted therapies. On the other hand, the immunosuppressive microenvironment makes the success of immune checkpoint inhibitors (ICIs), which have achieved a modest improvement in overall survival in patients with extensive disease, difficult. Currently, atezolizumab or durvalumab, in combination with platinum-etoposide chemotherapy, is the standard of care in first-line setting. However, the magnitude of the benefit is scarce and no predictive biomarkers of response have yet been established. In this review, we describe SCLC biology and molecular classification, examine the SCLC tumor microenvironment and the challenges of predictive biomarkers of response to new treatments, and, finally, assess clinical and molecular characteristics of long-term survivor patients in order to identify possible prognostic factors and treatment vulnerabilities.

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.

Pembrolizumab for the treatment of non-small-cell lung cancer.

BACKGROUND: We assessed the efficacy and safety of programmed cell death 1 (PD-1) inhibition with pembrolizumab in patients with advanced non-small-cell lung cancer enrolled in a phase 1 study. We also sought to define and validate an expression level of the PD-1 ligand 1 (PD-L1) that is associated with the likelihood of clinical benefit. METHODS: We assigned 495 patients receiving pembrolizumab (at a dose of either 2 mg or 10 mg per kilogram of body weight every 3 weeks or 10 mg per kilogram every 2 weeks) to either a training group (182 patients) or a validation group (313 patients). We assessed PD-L1 expression in tumor samples using immunohistochemical analysis, with results reported as the percentage of neoplastic cells with staining for membranous PD-L1 (proportion score). Response was assessed every 9 weeks by central review. RESULTS: Common side effects that were attributed to pembrolizumab were fatigue, pruritus, and decreased appetite, with no clear difference according to dose or schedule. Among all the patients, the objective response rate was 19.4%, and the median duration of response was 12.5 months. The median duration of progression-free survival was 3.7 months, and the median duration of overall survival was 12.0 months. PD-L1 expression in at least 50% of tumor cells was selected as the cutoff from the training group. Among patients with a proportion score of at least 50% in the validation group, the response rate was 45.2%. Among all the patients with a proportion score of at least 50%, median progression-free survival was 6.3 months; median overall survival was not reached. CONCLUSIONS: Pembrolizumab had an acceptable side-effect profile and showed antitumor activity in patients with advanced non-small-cell lung cancer. PD-L1 expression in at least 50% of tumor cells correlated with improved efficacy of pembrolizumab. (Funded by Merck; KEYNOTE-001 ClinicalTrials.gov number, NCT01295827.).

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.

Transbronchial and transesophageal fine-needle aspiration using a single ultrasound bronchoscope in the diagnosis of locoregional recurrence of surgically-treated lung cancer.

BACKGROUND: The present study sought to evaluate the usefulness of EBUS-TBNA in the diagnosis of locoregional recurrence of lung cancer in a cohort of lung cancer patients who were previously treated surgically, and describe our initial experience of EUS-B-FNA in this clinical scenario. METHODS: We retrospectively studied the clinical records of all patients with a previous surgically-treated lung cancer who were referred to our bronchoscopy unit after suspicion of locoregional recurrence. The diagnostic sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and overall accuracy of EBUS-TBNA for the diagnosis of locoregional recurrence were evaluated. RESULTS: Seventy-three patients were included. EBUS-TBNA confirmed malignancy in 40 patients: 34 confirmed to have locoregional recurrence, six had metachronous tumours. Of the 33 patients with non-malignant EBUS-TBNA; 2 had specific non-malignant diseases, 26 underwent radiological follow up and 5 patients underwent surgery. Of the 26 patients who had radiological follow up; 18 remained stable, three presented thoracic radiological progression and 5 presented extrathoracic progression. Of the 5 patients who underwent surgery; 3 had metachronous tumours, one confirmed to be a true negative and one presented nodal invasion. Seven patients underwent EUS-B-FNA, four of them confirmed to have recurrence. The sensitivity, specificity, NPV, PPV and overall accuracy of EBUS-TBNA for the diagnosis of locoregional recurrence were 80.9, 100, 69.2, 100 and 86.6% respectively. CONCLUSIONS: EBUS-TBNA is an accurate procedure for the diagnosis of locoregional recurrence of surgically-treated lung cancer. EUS-B-FNA combined with EBUS-TBNA broads the diagnostic yield of EBUS-TBNA alone.

SIADH-related hyponatremia in hospital day care units: clinical experience and management with tolvaptan.

Hyponatremia (Na ˂ 135 mmol/l) is the most frequent electrolyte disorder in clinical practice, and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the commonest cause of hyponatremia in cancer patients. Correcting hyponatremia in these patients can reduce morbidity and mortality, increase the response to anti-cancer agents, and help reduce hospital length of stay and costs. Tolvaptan is an oral medication used to treat SIADH-related hyponatremia patients that needs to be initiated at hospital so patients can have their serum sodium monitored. If tolvaptan could be initiated in hospital day care units (DCUs), performing the same tests, hospitalization could be avoided, quality of life improved, and costs reduced. This is the first publication where a panel of oncologists are sharing their experience and making some recommendations with the use of tolvaptan to treat SIADH-related hyponatremia in DCU after collecting and examining 35 clinical cases with these type of patients. The conclusion from this retrospective observational analysis is that the use of tolvaptan in DCU is safe and effective in the therapeutic management of SIADH-related hyponatremia.

Erlotinib-associated rash in patients with EGFR mutation-positive non-small-cell lung cancer treated in the EURTAC trial.

AIM: This analysis investigates incidence and time course of rash in the EURTAC study. MATERIALS & METHODS: Patients with EGFR mutation-positive non-small-cell lung cancer were randomized 1:1 to receive once daily erlotinib or 3-weekly cycles of chemotherapy. RESULTS: Of the 86 erlotinib-treated patients, 71 reported rash. Median time to first rash appearance was 0.7 months. Most patients (n = 65) had the same or lower grade rash at final assessment compared with initial assessment. Of the 21 patients with decreased rash grade between initial and final assessments, 61.9% received no erlotinib dose modification, 42.8% had no concomitant rash treatment. CONCLUSION: Most rash cases were mild, occurred within 1 month of erlotinib treatment, and rapidly improved without the need for erlotinib dose alterations.

HLA-I levels correlate with survival outcomes in response to immune checkpoint inhibitors in non-small cell lung cancer.

OBJECTIVES: Immune checkpoint inhibitors (ICIs) have provided a breakthrough in the treatment of non-small cell lung cancer (NSCLC) patients, but only some patients benefit substantively. Identifying definitive predictive biomarkers could overcome this limitation. MATERIALS AND METHODS: We selected 146 metastatic NSCLC patients treated with anti-PD-(L)1. Immunohistochemistry of HLA-I, PD-L1 and CD73 was performed in 122 tumor biopsies at diagnosis. The association with patients, tumor parameters, and the predictive value to ICI treatment were determined. RESULTS: In our cohort, 42 %, 25 %, and 21 % of the tumors exhibited high levels of HLA-I, PD-L1, and CD73, respectively. Lung adenocarcinomas displayed elevated CD73 levels, compared with lung squamous cell carcinomas (P = 0.026). High PD-L1 was significantly correlated with high levels of HLA-I (P = 0.005) and of CD73 (P = 0.025). Patients with high-level HLA-I tumors exhibited more favorable clinical outcomes following ICI, with a median overall survival of 30.7 months (95 % confidence interval [CI]: 18.3 months-not reached), compared with 18.2 months (95 % CI: 12.4-25.2 months) in patients with low-level HLA-I tumors (P = 0.016). The median progression-free survival (PFS) for patients with high-level HLA-I tumors was 18.5 months (95 % CI: 11.1-57.1 months), longer than patients with low-level HLA-I tumors, whose median PFS was 9.2 months (95 % CI: 7.2-11.9 months) (P = 0.006). In a multivariable analysis, high-level HLA-I was independently associated with lower risk of progression to ICI (HR = 0.46, 95 % CI 0.24-0.87; P = 0.018). CONCLUSIONS: High-level HLA-I were associated with better clinical outcomes to ICI in our cohort of NSCLC patients. Therefore, further investigations are warranted to refine this biomarker and validate its efficacy in prospective and larger set of patients.

Difficulties on the access to innovative targeted therapies for lung cancer in Spain.

PURPOSE: Spanish Lung Cancer Group (SLCG) conducted a review to analyze the barriers to access to innovative targeted therapies for non-small cell lung cancer (NSCLC) in clinical practice in Spain. METHODS: Review all relevant content published on websites of European Commission, European Medicines Agency, and Spanish Agency of Medicines and Medical Products regarding the authorization and access to oncology treatments. RESULTS: More than 20 targeted therapies are available to treat different molecular alterations in patients with NSCLC. European Commission has approved treatments for genomic alterations involving the following genes: ALK, RET, ROS1, EGFR, BRAF, NTRK, KRAS, MET. However, the availability of these therapies in Spain is not complete, as innovative treatments are not reimbursed or funded late, with only five of these alterations currently covered by National Health System. CONCLUSION: SLCG considers imperative to improve the access in Spain to innovative treatments for NSCLC to reduce inequity across European countries.

Advanced non-squamous NSCLC with no actionable oncogenic driver in Spain: a cross-sectional descriptive analysis of data from the Thoracic Tumor Registry.

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.

Canakinumab Versus Placebo in Combination With First-Line Pembrolizumab Plus Chemotherapy for Advanced Non-Small-Cell Lung Cancer: Results From the CANOPY-1 Trial.

PURPOSE: The addition of checkpoint inhibitors to first-line treatment has prolonged survival of patients with non-small-cell lung cancer (NSCLC), but prognosis remains poor, with new treatment options needed. Canakinumab, a human, monoclonal anti-interleukin (IL)-1ß antibody, has potential to enhance the activity of PD-L1 inhibitors and chemotherapy (CT) by inhibiting protumor inflammation. METHODS: CANOPY-1 was a phase III, randomized, double-blind study comparing canakinumab (200 mg subcutaneously once every 3 weeks) versus placebo, both combined with pembrolizumab (200 mg intravenously once every 3 weeks) and platinum-based doublet CT, as first-line treatment for advanced/metastatic NSCLC without EGFR or ALK mutations. The primary end points were progression-free survival (PFS) and overall survival (OS). The secondary endpoints included overall response rate, safety, and patient-reported outcomes. RESULTS: Overall, 643 patients were randomly assigned to canakinumab (n = 320) or placebo (n = 323). With a median study follow-up of 6.5 months, the median PFS was 6.8 months with canakinumab versus 6.8 months with placebo (hazard ratio [HR], 0.85; 95% CI, 0.67 to 1.09; P = .102). With a median study follow-up of 21.2 months, the median OS was 20.8 months with canakinumab versus 20.2 months with placebo (HR, 0.87; 95% CI, 0.70 to 1.10; P = .123). No unexpected safety signals were observed for canakinumab combination. Infection rates were comparable between treatment and control arms. A higher frequency of neutropenia and ALT increase (grade ≤2) were reported in the treatment arm. Higher baseline C-reactive protein and IL-6 levels were associated with shorter PFS and OS. Patients treated with canakinumab had clinically meaningful delays in deterioration of lung cancer symptoms, including chest pain and coughing per LC13 and dyspnea per LC13 and C30. CONCLUSION: The addition of canakinumab to first-line pembrolizumab and CT did not prolong PFS or OS in patients with 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.

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.

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.

Characterization of a cohort of metastatic lung cancer patients harboring KRAS mutations treated with immunotherapy: differences according to KRAS G12C vs. non-G12C.

Approximately 20% of lung adenocarcinomas harbor activating mutations at KRAS, an oncogene with the ability to alter the tumor immune microenvironment. In this retrospective study, we examined 103 patients with KRAS-mutant lung adenocarcinoma who were treated with immunotherapy-based regimens and we evaluated the clinical outcomes according to PD-L1 expression and the type of KRAS mutation. Among all patients included, 47% carried KRAS G12C mutation whereas 53% harbored KRAS non-G12C mutations. PD-L1 status was available for 77% of cases, with higher expression among KRAS G12C tumors (p = 0.01). Better overall survival and progression-free survival were observed in high PD-L1 expression tumors, regardless of KRAS mutation type. The heterogeneous nature of KRAS-mutant tumors and the presence of other co-mutations may contribute to different outcomes to immunotherapy-based strategies.

Is oligoprogression a potentially curable disease in epidermal growth factor receptor mutant lung adenocarcinoma?

Third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have shown impressive results in EGFR mutant lung cancer (LC) patients in terms of disease control rate with a positive impact on overall survival. Nevertheless, after months of treatment with targeted therapy, progression inevitably occurs. Some patients develop oligoprogression and local treatment is required for optimal disease control while maintaining EGFR-TKIs. This work features a clinical case of a patient harboring an EGFR mutant LC undergoing oligoprogression to EGFR-TKIs, first into the brain and afterward to the primary tumor, requiring local ablative strategies, including primary tumor resection three years after the start of osimertinib. Currently, the patient is still alive and continues with a complete response upon EGFR-TKIs maintenance. Hence, oligoprogression, even in driven oncogenic tumors, represents a distinct biological entity and potential curative disease that deserves particular consideration in multidisciplinary tumor boards. In this case, tumor primary resection after three years of the initial diagnosis represents a paradigm shift in the treatment of EGFR mutant patients.