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Druggable oncogene-driven non-small cell lung cancer has led to innovative systemic treatment options, improving patients' outcome. This benefit is not only achieved in the metastatic setting but also in the postsurgical setting, such as in lung cancers harboring a common sensitizing mutation or -rearrangement. To enhance the outcome of these patients, we need to understand the mechanisms of acquired resistance and evaluate the role of new drugs with novel mechanisms of action in the treatment landscape. In this chapter, we review treatment strategies of -mutant tumors in all stages, the mechanisms of acquired strategies, and novel therapies in this subset.

Purpose of ReviewThis review discusses the definitions, treatment modalities, management, future directions, and ongoing clinical trials of oligoprogressive disease in oncogene-driven and non-oncogene-driven NSCLC.Recent FindingsDuring the last decades, diagnostic and treatment modalities for oligometastatic NSCLC have advanced significantly, leading to improved survival. Additionally, our understanding of the tumor biology of oligoprogressive disease has expanded. However, despite the efforts of organizations, such as EORTC, ESTRO, and ASTRO proposing definitions for oligometastatic and oligoprogressive disease, heterogeneity in definitions persists in (ongoing) trials.SummaryRecognizing the significance of subclassification within oligoprogressive disease in NSCLC and the varying risks associated with subsequent metastatic spread, there is a call for tailored management strategies. A consensus on standardized criteria for the definition of oligoprogressive disease is urgently needed and will not only facilitate meaningful comparisons between studies but also pave the way for the development of personalized treatment plans that take into account the heterogeneous nature of oligoprogressive disease.

Treatment with 3 years of adjuvant osimertinib is considered a new standard in patients with completely resected stage I to IIIA NSCLC harboring a common sensitizing EGFR mutation. This therapeutic approach significantly prolonged the disease-free survival and the overall survival versus placebo and revealed a significant role in preventing the occurrence of brain metastases. However, many unanswered questions remain, including the optimal duration of this therapy, whether all patients benefit from adjuvant osimertinib, and the role of adjuvant chemotherapy in this population. Indeed, there is a renewed interest in neoadjuvant strategies with targeted therapies in resectable NSCLC harboring oncogenic drivers. In light of these considerations, we discuss the past and current treatment options, and the clinical challenges that should be addressed to optimize the treatment outcomes in this patient population.

BACKGROUND: For patients with advanced thymic epithelial tumours (TET), there is no standard second-line treatment after platinum-based chemotherapy. Although immune checkpoint blockers (ICB) are a potential treatment strategy, their efficacy seems limited with an increased risk of immune-related adverse events (ir-AEs), thus hampering their application in daily clinical practice.METHODS: We performed a meta-analysis to better evaluate the existing evidence about the activity and safety of ICB in the setting of unresectable or metastatic advanced TET previously treated with platinum-based chemotherapy.RESULTS: Six phase I/II trials met the eligibility criteria including a total of 166 evaluable patients (77% thymic carcinoma, 23% thymoma) evaluable for activity after being treated with pembrolizumab, nivolumab, avelumab or atezolizumab. The overall response rate to ICB was 18.4% (95% CI: 12.3-26.5), and the one-year progression-free survival rate and one-year overall survival rate were 26.0% (95% CI: 19.6-34.6) and 66.9% (95% CI: 59.6-75.2%), respectively. The incidence of grade 3-5 ir-AEs was 26.4%, with 17.1% in thymic carcinoma and 58.3% in thymoma.CONCLUSIONS: Despite the absence of a robust demonstration of efficacy in the context of randomised trials, our results suggest ICB as a potential strategy in patients with pretreated TET, mainly among patients with thymic carcinoma. Close monitoring is strongly advised to detect severe immune-toxicity.

PURPOSE: Pemetrexed is a chemotherapeutic drug in the treatment of non-small cell lung cancer and mesothelioma. Optimized dosing of pemetrexed based on renal function instead of body surface area (BSA) is hypothesized to reduce pharmacokinetic variability in systemic exposure and could therefore improve treatment outcomes. The aim of this study is to compare optimized dosing to standard BSA-based dosing.METHODS: A multicenter randomized (1:1) controlled trial was performed to assess superiority of optimized dosing versus BSA-based dosing in patients who were eligible for pemetrexed-based chemotherapy. The individual exposure to pemetrexed in terms of area under the concentration-time curve (AUC) was determined. The fraction of patients attaining to a predefined typical target AUC (164 mg × h/L ± 25%) was calculated.RESULTS: A total of 81 patients were included. Target attainment was not statistically significant different between both arms (89% vs. 84% (p = 0.505)). The AUC of pemetrexed was similar between the optimized dosing arm (n = 37) and the standard of care arm (n = 44) (155 mg × h/L vs 160 mg × h/L (p = 0.436).CONCLUSION: We could not show superiority of optimized dosing of pemetrexed in patients with an adequate renal function does not show added value on the attainment of a pharmacokinetic endpoint, safety, nor QoL compared to standard of care dosing.CLINICAL TRIAL NUMBER: Clinicaltrials.gov identifier: NCT03655821.

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.

Background: Alectinib is first-line therapy in patients with stage IV non-small cell lung carcinoma (NSCLC) and an anaplastic lymphoma kinase (ALK) fusion. A shorter median progression-free survival (mPFS) was observed when alectinib minimum plasma concentrations during steady state (C min,SS) were below 435 ng/mL. This may suggest that patients should have an alectinib C min,SS ≥ 435 ng/mL for a more favorable outcome. This potential target could be attained by using therapeutic drug monitoring (TDM), i.e. adjusting the dose based on measured plasma trough concentrations. Hypothetically, this will increase mPFS, but this has not yet been evaluated in a randomized controlled trial (RCT). Therefore, the ADAPT ALEC trial is designed, with the primary objective to prolong mPFS in NSCLC patients treated with alectinib by using TDM. Methods: ADAPT ALEC is a multicenter, phase IV RCT, in which patients aged ≥ 18 years with advanced ALK positive (+) NSCLC eligible for alectinib in daily care are enrolled. Participants will be randomized (1:1 ratio) into intervention arm A (TDM) or B (control), stratified by brain metastases and prior ALK treatments. Starting dose in both arms is the approved flat fixed dose of alectinib 600 mg taken twice daily with food. In case of alectinib C min,SS < 435 ng/mL, arm A will receive increased doses of alectinib till C min,SS≥ 435 ng/mL when considered tolerable. The primary outcome is mPFS, where progressive disease is defined according to RECIST v1.1 or all-cause death and assessed by CT-scans and MRI brain. Secondary endpoints are feasibility and tolerability of TDM, patient and physician adherence, overall response rate, median overall survival, intracranial PFS, quality of life, toxicity, alectinib-M4 concentrations and cost-effectiveness of TDM. Exploratory endpoints are circulating tumor DNA and body composition. Discussion: The ADAPT ALEC will show whether treatment outcomes of patie

Introduction: Few data is available on whether brain metastases (BM) influence survival in patients with stage IV KRAS G12C mutated (KRAS G12C+ ) non-small cell lung cancer (NSCLC) treated with first-line immune checkpoint inhibitor (ICI) +/- chemotherapy ([chemo]-ICI). Methods: Data was retrospectively collected from the population-based Netherlands Cancer Registry. The cumulative incidence of intracranial progression, overall survival (OS) and progression free survival (PFS) was determined for patients with KRAS G12C+ stage IV NSCLC diagnosed January 1 - June 30, 2019, treated with first-line (chemo)-ICI. OS and PFS were estimated using Kaplan-Meier methods and BM+ and BM- groups were compared using log-rank tests. Results: Of 2489 patients with stage IV NSCLC, 153 patients had KRAS G12C+ and received first-line (chemo)-ICI. Of those patients, 35% (54/153) underwent brain imaging (CT and/or MRI), of which 85% (46/54) MRI. Half of the patients with brain imaging (56%; 30/54) had BM, concerning one-fifth (20%; 30/153) of all patients, of which 67% was symptomatic. Compared to BM-, patients with BM+ were younger and had more organs affected with metastasis. Around one-third (30%) of patients with BM+ had & GE;5 BM at diagnosis. Three quarters of patients with BM+ received cranial radiotherapy prior to start of (chemo)-ICI. The 1-year cumulative incidence of intracranial progression was 33% for patients with known baseline BM and 7% for those without (p = 0.0001). Median PFS was 6.6 (95% CI 3.0-15.9) and 6.7 (95% CI 5.1-8.5) months for BM+ and BM- (p = 0.80), respectively. Median OS was 15.7 (95% CI 6.2-27.3) and 17.8 (95% CI 13.4-22.0) months for BM+ and BM- (p = 0.77), respectively. Conclusion: Baseline BM are common in patients with metastatic KRAS G12C+ NSCLC. During (chemo)-ICI treatment, intracranial progression was more frequent in patients with known baseline BM, justifying regular imaging during treatment. In our study, presence of known baseline BM did n

INTRODUCTION In stage III non-small cell lung cancer (NSCLC), prophylactic cranial irradiation (PCI) reduces the brain metastases incidence and prolongs the progression-free survival without improving overall survival. PCI increases the risk of toxicity and is currently not adopted in routine care. Our objective was to assess the cost-effectiveness of PCI compared with no PCI in stage III NSCLC from a Dutch societal perspective. METHODS A cohort partitioned survival model was developed based on individual patient data from three randomized phase III trials (N = 670). Quality-adjusted life years (QALYs) and costs were estimated over a lifetime time horizon. A willingness-to-pay (WTP) threshold of €80,000 per QALY was adopted. Sensitivity and scenario analyses were performed to address parameter uncertainty and to explore what parameters had the greatest impact on the cost-effectiveness results. RESULTS PCI was more effective and costly (0.443 QALYs, €10,123) than no PCI, resulting in an incremental cost-effectiveness ratio (ICER) of €22,843 per QALY gained. The probability of PCI being cost-effective at a WTP threshold of €80,000 per QALY was 93%. The probability of PCI gaining three and six additional months of life were 76% and 56%. The scenario analysis adding durvalumab increased the ICER to €35,159 per QALY gained. Using alternative survival distributions had little impact on the ICER. Assuming fewer PCI fractions and excluding indirect costs decreased the ICER to €18,263 and €5554 per QALY gained. CONCLUSION PCI is cost-effective compared to no PCI in stage III NSCLC, and could therefore, from a cost-effectiveness perspective, be considered in routine care.

Introduction There is a cumulative risk of 20-40% of developing brain metastases (BM) in solid cancers. Stereotactic radiotherapy (SRT) enables the application of high focal doses of radiation to a volume and is often used for BM treatment. However, SRT can cause adverse radiation effects (ARE), such as radiation necrosis, which sometimes cause irreversible damage to the brain. It is therefore of clinical interest to identify patients at a high risk of developing ARE. We hypothesized that models trained with radiomics features, deep learning (DL) features, and patient characteristics or their combination can predict ARE risk in patients with BM before SRT. Methods Gadolinium-enhanced T1-weighted MRIs and characteristics from patients treated with SRT for BM were collected for a training and testing cohort (N = 1,404) and a validation cohort (N = 237) from a separate institute. From each lesion in the training set, radiomics features were extracted and used to train an extreme gradient boosting (XGBoost) model. A DL model was trained on the same cohort to make a separate prediction and to extract the last layer of features. Different models using XGBoost were built using only radiomics features, DL features, and patient characteristics or a combination of them. Evaluation was performed using the area under the curve (AUC) of the receiver operating characteristic curve on the external dataset. Predictions for individual lesions and per patient developing ARE were investigated. Results The best-performing XGBoost model on a lesion level was trained on a combination of radiomics features and DL features (AUC of 0.71 and recall of 0.80). On a patient level, a combination of radiomics features, DL features, and patient characteristics obtained the best performance (AUC of 0.72 and recall of 0.84). The DL model achieved an AUC of 0.64 and recall of 0.85 per lesion and an AUC of 0.70 and recall of 0.60 per patient. Conclusion Machine learning models built on radiomics featu

The recently concluded European Lung Cancer Congress 2022 (ELCC22) showcased some very exciting data, with more than 200 abstracts presented during the meeting. Through this review, we focus on selected clinically relevant abstracts that in our opinion represent significant updates in the current management of non-small cell lung cancer (NSCLC). Here, we summarize the updates in surgical management, adjuvant therapy and therapy for advanced stage NSCLC and put these advances in context of current clinical standard of care.

Introduction: Synchronous oligometastatic non-small cell lung cancer (NSCLC) definition varies from 1 metastasis in 1 organ (tumour-node-metastasis 8 [TNM8]), 1-3 metastases (European Society for Medical Oncology [ESMO]),Methods: In December 2017, 10 real-life multidisciplinary team (MDT) discussed patients (good condition, no significant comorbidities, F-18-fluorodeoxyglucose positron emission tomography/brain magnetic resonance imaging staged, all <5 metastases, 9/10Results: Twenty-six of 33 experts (24 centres) replied: 8 medical oncologists, 7 pulmonologists, 7 radiation oncologists, 4 thoracic surgeons. Sixty-two percent of respondents discussed the cases with their MDT. One case had 100% oligometastatic consensus, and 3 cases had >90% consensus; the number of treatment proposals varied between 3 and 8. Radical treatment was more often offered in case of single metastasis or N0. Compared with 2012, there was a trend towards a more conservative oligometastatic definition and chemotherapy was more frequently included in the treatment proposal.Conclusions: Oligometastatic NSCLC definition was conservative. The number of organs, MLN status and radical treatment possibility seem to be components of daily practice oligometastatic definition. (C) 2019 Elsevier Ltd. All rights reserved.

Introduction: Although frequent in NSCLC, patients with brain metastases (BMs) are often excluded from immune checkpoint inhibitor (ICI) trials. We evaluated BM outcome in a less-selected NSCLC cohort.Methods: Data from consecutive patients with advanced ICI-treated NSCLC were collected. Active BMs were defined as new and/or growing lesions without any subsequent local treatment before the start of ICI treatment. Objective response rate (ORR), progression-free survival, and overall survival (OS) were evaluated. Multivariate analyses were performed by using a Cox proportional hazards model and logistic regression.Results: A total of 1025 patients were included; the median follow-up time from start of ICI treatment was 15.8 months. Of these patients, 255 (24.9%) had BMs (39.2% active, 14.3% symptomatic, and 27.4% being treated with steroids). Disease-specific Graded Prognostic Assessment (ds-GPA) score was known for 94.5% of patients (35.7% with a score of 0-1, 58.5% with a score of 1.5-2.5, and 5.8% with a score of 3). The ORRs with BM versus without BM were similar: 20.6% (with BM) versus 22.7% (without BM) (p = 0.484). The intracranial ORR (active BM with follow-up brain imaging [n = 73]) was 27.3%. The median progression-free survival times were 1.7 (95% confidence interval [CI]: 1.5-2.1) and 2.1 (95% CI: 1.9-2.5) months, respectively (p = 0.009). Of the patients with BMs, 12.7% had a dissociated cranial-extracranial response and two (0.8%) had brain pseudoprogression. Brain progression occurred more in active BM than in stable BM (54.2% versus 30% [p <0.001]). The median OS times were 8.6 months (95% CI: 6.8-12.0) with BM and 11.4 months (95% CI: 8.6-13.8) months with no BM (p = 0.035). In the BM subgroup multivariate analysis, corticosteroid use (hazard ratio [HR] = 2.37) was associated with poorer OS, whereas stable BMs (HR = 0.62) and higher ds-GPA classification (HR = 0.48-0.52) were associated with improved OS.Conclusion: In multiv

Introduction: Small cell lung cancer (SCLC) is a tumor with a poor prognosis, often diagnosed in an advanced stage. Despite aggressive treatment of early and locally advanced disease, SCLC often relapses. First line chemotherapy provides good response rates in advanced disease, but progression free and overall survival are limited. New drugs such as some targeted therapies and immune therapies are promising in SCLC. Areas covered: In this review, we discuss the preclinical rationale and trial data for targeted therapies and immune therapies in SCLC, with a specific focus on clinical trials. Expert commentary: Lack of identification of clear prognostic and predictive biomarkers has limited the advances in treatment efficacy. This has most likely been the main cause of failure for compounds tested so far. Due to the highly mutational profile and the rapid growth pattern of SCLC, immunotherapy combined with chemotherapy seems the most promising treatment option. Concerning targeted agents, achievements made so far are small, but DLL3-antibodies or combinations of PARPi and immunotherapy could be very promising. These promising strategies also need testing in limited disease.

Introduction: Patients with non-small cell lung cancer (NSCLC) experience leptomeningeal metastases (LM) in 3-9% of cases. Because overall survival (OS) and performance status are very poor, they are mostly excluded from clinical trials. Here, we evaluated survival of patients with NSCLC having LM treated with immune checkpoint inhibitors (ICIs).Methods: A prospectively collected list of patients with advanced NSCLC treated with ICIs between November 2012 and July 2018 in 7 European centres was merged. All patients with LM before ICI start were selected, data were retrospectively added and patients were classified according to the National Comprehensive Cancer Network (NCCN) LM prognostic classification (good/poor). Progression-free survival (PFS) and OS on ICIs were evaluated.Results: Nineteen of 1288 (1.5%) patients had LM; 73.7% had synchronous brain metastases; 73.7% had neurological symptoms at the start of ICIs and 52.6% were in the NCCN LM good prognosis group. Programmed death ligand-1 (PD-L1) expression was known for 42.1% of patients (87.5% positive). Median follow-up was 13 months from the start of ICIs, and median (95% confidence interval [CI]) PFS on ICIs was 2.0 (1.8-2.2) months. Six-month PFS rate was 21.0% and was significantly higher in the NCCN good versus poor prognostic group: 40% vs 0% (p = 0.05). Twelve-month PFS rate was 0%. Median (95% CI) OS from the start of ICIs was 3.7 (0.9-6.6) months. Six-month OS rate was 36.8%, and 12-month OS rate was 21.1%; both were not statistically significantly different for the good versus poor NCCN prognostic group (p = 0.40 and p = 0.56, respectively).Conclusion: Some patients with NSCLC having LM do benefit from ICI treatment; specifically, those in the NCCN LM good prognosis group can obtain a long survival. (C) 2019 Elsevier Ltd. All rights reserved.

Pemetrexed is an important component of first line treatment in patients with non-squamous non-small cell lung cancer. However, a limitation is the contraindication in patients with renal impairment due to hematological toxicity. Currently, it is unknown how to safely dose pemetrexed in these patients. The aim of our study was to elucidate the relationship between pemetrexed exposure and toxicity to support the development of a safe dosing regimen in patients with renal impairment. A population pharmacokinetic/pharmacodynamic analysis was performed based on phase II study results in three patients with renal dysfunction, supplemented with data from 106 patients in early clinical studies. Findings were externally validated with data of different pemetrexed dosing regimens. Alternative dosing regimens were evaluated using the developed model. We found that pemetrexed toxicity was driven by the time above a toxicity threshold concentration. The threshold for vitamin-supplemented patients was 0.110 mg/mL (95% CI: 0.092-0.146 mg/mL). It was observed that in patients with renal impairment (estimated glomerular filtration rate [eGFR]: <45 mL/min) the approved dose of 500 mg/m2 would yield a high probability of severe neutropenia in the range of 51.0% to 92.6%. A pemetrexed dose of 20 mg for patients (eGFR: 20 mL/min) is shown to be neutropenic-equivalent to the approved dose in patients with adequate renal function (eGFR: 90 mL/min), but would result in an approximately 13-fold lower area under the concentration-time curve. The pemetrexed exposure-toxicity relationship is explained by a toxicity threshold and substantially different from previously thought. Without prophylaxis for toxicity, it is unlikely that a therapeutic dose can be safely administered to patients with renal impairment.

Although targeted therapy is standard of care in a large subset of oncogenic addicted non-small cell lung cancers (NSCLC), until recently, this therapeutic approach has not been feasible for all genomic alterations such as for those tumors harboring Epidermal Growth Factor Receptor (EGFR) exon 20 insertion (ex20ins) mutations. Despite being the third most common EGFR mutation, a limited efficacy of firstand second-generation EGFR tyrosine kinase inhibitors (TKI) exists. This is related to the heterogeneity at the molecular level in EGFR ex20ins mutation variants and the finding that this mutation promotes active kinase conformation but does not increase the affinity for EGFR TKI. As a result, the prognosis of this population is diminished. Therefore, chemotherapy remained the most suitable strategy in this subset of EGFR mutant NSCLC patients. Recently, new treatment strategies have been reported in this landscape, either with new EGFR TKI or bispecific antibodies, which may establish a new standard of care in the coming future for these patients. Future research should focus on elu-cidating the oncogenic degree of all EGFR ex20ins variants, the potential role of combination strategies either with chemotherapy or immune checkpoint inhibitors, and the most appropriate first-line treatment strategy in this subgroup. Finally, the knowledge of mechanisms of acquired resistance to these new agents upon progression is a priority for personalising treatment at that time. It is in this framework, that we provide a thorough overview on this subject.

Background: Prophylactic cranial irradiation (PCI) reduces brain metastasis incidence in lung cancer, however with risk of neurocognitive decline. Nevertheless, risk factors for neurocognitive decline after PCI remain unclear.Methods: We systematically reviewed the PubMed database according to the PRISMA guideline. Inclusion criteria were: randomized clinical trials (RCTs) and observational/single arm trials evaluating PCI, including >= 20 patients, reporting neurocognitive test results for lung cancer. Primary aim: evaluate risk factors associated with neurocognitive decline after PCI.Results: Twenty records were eligible (8 different RCTs, 8 observational studies), including 3553 patients in total (858 NSCLC, 2695 SCLC) of which 73.6% received PCI. Incidence of mild/moderate cognitive decline after PCI varied from 8 to 89% (grading not always provided); for those without PCI, this was 3.4-42%. Interestingly, 23-95% had baseline cognitive impairment. Risk factors were often not reported. In one trial, both age (> 60 years) and higher PCI dose (36 Gy) including twice-daily PCI were associated with a higher risk of cognitive decline. In one trial, white matter abnormalities were more frequent in the concurrent or sandwiched PCI arm, but without significant neuropsychological differences. One trial identified hippocampal sparing PCI to limit the neurocognitive toxicities of PCI and another reported an association between hippocampal dose volume effects and memory decline. As neurocognition was a secondary endpoint in most RCTs, and was assessed by various instruments with often poor/moderate compliance, high-quality data is lacking.Conclusions: Age, PCI dose, regimen and timing might be associated with cognitive impairment after PCI in lung cancer patients, but high-quality data is lacking. Future PCI trials should collect and evaluate possible risk factors systematically.

Medical imaging plays a key role in evaluating and monitoring lung diseases such as chronic obstructive pulmonary disease (COPD) and lung cancer. The application of artificial intelligence in medical imaging has transformed medical images into mineable data, by extracting and correlating quantitative imaging features with patients' outcomes and tumor phenotype - a process termed radiomics. While this process has already been widely researched in lung oncology, the evaluation of COPD in this fashion remains in its infancy. Here we outline the main applications of radiomics in lung cancer and briefly review the workflow from image acquisition to the evaluation of model performance. Finally, we discuss the current assessments of COPD and the potential application of radiomics in COPD. (C) 2020 S. Karger AG, Basel

BACKGROUND: About 50% of non-small cell lung cancer (NSCLC) patients have metastatic disease at initial diagnosis, which limits their treatment options and, consequently, the 5-year survival rate (15%). Immune checkpoint inhibitors (ICI), either alone or in combination with chemotherapy, have become standard of care (SOC) for most good performance status patients. However, most patients will not obtain long-term benefit and new treatment strategies are therefore needed. We previously demonstrated clinical safety of the tumour-selective immunocytokine L19-IL2, consisting of the anti-ED-B scFv L19 antibody coupled to IL2, combined with stereotactic ablative radiotherapy (SABR). METHODS: This investigator-initiated, multicentric, randomised controlled open-label phase II clinical trial will test the hypothesis that the combination of SABR and L19-IL2 increases progression free survival (PFS) in patients with limited metastatic NSCLC. One hundred twenty-six patients will be stratified according to their metastatic load (oligo-metastatic: ≤5 or poly-metastatic: 6 to 10) and randomised to the experimental-arm (E-arm) or the control-arm (C-arm). The C-arm will receive SOC, according to the local protocol. E-arm oligo-metastatic patients will receive SABR to all lesions followed by L19-IL2 therapy; radiotherapy for poly-metastatic patients consists of irradiation of one (symptomatic) to a maximum of 5 lesions (including ICI in both arms if this is the SOC). The accrual period will be 2.5-years, starting after the first centre is initiated and active. Primary endpoint is PFS at 1.5-years based on blinded radiological review, and secondary endpoints are overall survival, toxicity, quality of life and abscopal response. Associative biomarker studies, immune monitoring, CT-based radiomics, stool collection, iRECIST and tumour growth rate will be performed. DISCUSSION: The combination of SABR with or without ICI and the immunocytokine L19-IL2 will be tested as 1st, 2nd or 3rd li

Although targeted therapy is standard of care in a large subset of oncogenic addicted non-small cell lung cancers (NSCLC), until recently, this therapeutic approach has not been feasible for all genomic alterations such as for those tumors harboring Epidermal Growth Factor Receptor (EGFR) exon 20 insertion (ex20ins) mutations. Despite being the third most common EGFR mutation, a limited efficacy of firstand second-generation EGFR tyrosine kinase inhibitors (TKI) exists. This is related to the heterogeneity at the molecular level in EGFR ex20ins mutation variants and the finding that this mutation promotes active kinase conformation but does not increase the affinity for EGFR TKI. As a result, the prognosis of this population is diminished. Therefore, chemotherapy remained the most suitable strategy in this subset of EGFR mutant NSCLC patients. Recently, new treatment strategies have been reported in this landscape, either with new EGFR TKI or bispecific antibodies, which may establish a new standard of care in the coming future for these patients. Future research should focus on elu-cidating the oncogenic degree of all EGFR ex20ins variants, the potential role of combination strategies either with chemotherapy or immune checkpoint inhibitors, and the most appropriate first-line treatment strategy in this subgroup. Finally, the knowledge of mechanisms of acquired resistance to these new agents upon progression is a priority for personalising treatment at that time. It is in this framework, that we provide a thorough overview on this subject.

Medical imaging plays a key role in evaluating and monitoring lung diseases such as chronic obstructive pulmonary disease (COPD) and lung cancer. The application of artificial intelligence in medical imaging has transformed medical images into mineable data, by extracting and correlating quantitative imaging features with patients' outcomes and tumor phenotype - a process termed radiomics. While this process has already been widely researched in lung oncology, the evaluation of COPD in this fashion remains in its infancy. Here we outline the main applications of radiomics in lung cancer and briefly review the workflow from image acquisition to the evaluation of model performance. Finally, we discuss the current assessments of COPD and the potential application of radiomics in COPD. (C) 2020 S. Karger AG, Basel

Background: Prophylactic cranial irradiation (PCI) reduces brain metastasis incidence in lung cancer, however with risk of neurocognitive decline. Nevertheless, risk factors for neurocognitive decline after PCI remain unclear.Methods: We systematically reviewed the PubMed database according to the PRISMA guideline. Inclusion criteria were: randomized clinical trials (RCTs) and observational/single arm trials evaluating PCI, including >= 20 patients, reporting neurocognitive test results for lung cancer. Primary aim: evaluate risk factors associated with neurocognitive decline after PCI.Results: Twenty records were eligible (8 different RCTs, 8 observational studies), including 3553 patients in total (858 NSCLC, 2695 SCLC) of which 73.6% received PCI. Incidence of mild/moderate cognitive decline after PCI varied from 8 to 89% (grading not always provided); for those without PCI, this was 3.4-42%. Interestingly, 23-95% had baseline cognitive impairment. Risk factors were often not reported. In one trial, both age (> 60 years) and higher PCI dose (36 Gy) including twice-daily PCI were associated with a higher risk of cognitive decline. In one trial, white matter abnormalities were more frequent in the concurrent or sandwiched PCI arm, but without significant neuropsychological differences. One trial identified hippocampal sparing PCI to limit the neurocognitive toxicities of PCI and another reported an association between hippocampal dose volume effects and memory decline. As neurocognition was a secondary endpoint in most RCTs, and was assessed by various instruments with often poor/moderate compliance, high-quality data is lacking.Conclusions: Age, PCI dose, regimen and timing might be associated with cognitive impairment after PCI in lung cancer patients, but high-quality data is lacking. Future PCI trials should collect and evaluate possible risk factors systematically.

Background: Synchronous oligometastatic disease (sOM) has been described as a distinct disease entity; however, there is no consensus on OM definition (OM-d) in non esmall-cell lung cancer (NSCLC). A consensus group was formed aiming to agree on a common OM-d that could be used in future clinical trials. A European survey was circulated to generate questions and input for the consensus group meeting.Methods: A European Organisation for Research and Treatment of Cancer Lung Cancer Group (LCG)/sOM-d consensus group survey was distributed to LCG, sOM-d consensus group, and several European thoracic oncology societies' members.Results: 444 responses were analysed (radiation oncologist: 55% [n = 242], pulmonologist: 15% [n = 66], medical oncologist: 14% [n = 64]). 361 physicians (81%) aimed to cure sOM NSCLC patients and 82% (n=362) included the possibility of radical intent treatment in their sOM-d. The maximum number of metastases considered in sOM-d varied: 12% replied 1 metastasis, 42% = 5 metastases. 79% (n = 353) stated that number of organs involved was important for sOM-d, and most (80%, n = 355) considered that onlyConclusion: Although consensual answers were obtained, several issues remain unresolved and will require further research to agree on a sOM-d. (C) 2019 Elsevier Ltd. All rights reserved.

Introduction: Improved outcome has been shown in patients with synchronous oligometastatic (sOM) NSCLC when treated with radical intent. As a uniform definition of sOM NSCLC is lacking, we developed a definition and diagnostic criteria by a consensus process.Methods: A pan-European multidisciplinary consensus group was established. Consensus questions were built on the basis of current controversies, and definitions were extracted from a survey, cases and a systematic review. This statement was formulated during a consensus meeting.Results: It was determined that definition of sOM NSCLC is relevant when a radical treatment that may modify the disease course (leading to long-term disease control) is technically feasible for all tumor sites with acceptable toxicity. On the basis of the review, a maximum of five metastases and three organs was proposed. Mediastinal lymph node involvement was not counted as a metastatic site. Fludeoxyglucose F 18 positron emission tomography-computed tomography and brain imaging were considered mandatory. A dedicated liver magnetic resonance imaging scan was advised for a solitary liver metastasis, and thoracoscopy and biopsies of distant ipsilateral pleural sites were recommended for a solitary pleural metastasis. For mediastinal staging, fludeoxyglucose F 18 positron emission tomography-computed tomography was deemed the minimum requirement, with pathological confirmation recommended if this influences the treatment strategy. Biopsy of a solitary metastatic location was mandated unless the multidisciplinary team is of the opinion that the risks outweigh the benefits.Conclusion: A multidisciplinary consensus statement on the definition and staging of sOM NSCLC has been formulated. This statement will help to standardize inclusion criteria in future clinical trials. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Introduction: Non-small-cell lung cancer (NSCLC) guidelines advise to screen stage III NSCLC patients for brain metastases (BMs), preferably by magnetic resonance imaging (MRI) or when contraindicated or not accessible a dedicated contrast enhanced-computed tomography (dCE-CT), which can be incorporated in the staging (18)Fluodeoxoglucose-positron emission tomography ((18)FDG-PET-CE-CT). In daily practice, often a dCE-CT is performed instead of a MRI. The aim of the current study is to evaluate the additive value of MRI after dCE-CT, incorporated in the 18 FDG-PET-CE-CT.Patients and methods: It is an observational prospective multicentre study (NTR3628). Inclusion criteria included stage III NSCLC patients with a dCE-CT of the brain incorporated in the (18)FDG-PET and an additional MRI of the brain. Primary end-point is percentage of patients with BM on MRI without suspect lesions on dCE-CT. Secondary end-points are percentage of patients with BM on dCE-CT and percentage of patients with BMResults: Sixteen (7%) patients with extracranial stage III had BM on dCE-CT and were excluded. One hundred forty-nine patients were enrolled. 7/149 (4.7%) had BM on MRI without suspect lesions on dCE-CT. One hundred eighteen patients had a follow-up of at least 1 year (four with BM on baseline MRI); eight of the remaining 114 (7%) patients developed BMConclusion: Although in 7% of otherwise stage III NSCLC patients, BMs were detected on staging dCE-CT, MRI brain detected BMs in an additional 4.7%, which we consider clinically relevant. Within 1 year after a negative staging MRI, 7% developed BM. (C) 2019 Elsevier Ltd. All rights reserved.

Objectives: The CONVERT trial showed that twice-daily (BD) concurrent chemoradiotherapy should continue to be considered the standard of care in localised LS-SCLC. A survey was conducted to assess the impact of the CONVERT trial in clinical practice and to identify any relevant research questions for future trials in this setting.Methods and materials: An EORTC Group online survey of LS-SCLC practice was distributed to the EORTC LCG and to members of several European thoracic oncology societies between April and December 2018.Results: 198 responses were analysed. The majority of respondents (88%, n = 174) were aware of the CONVERT trial. Radiation oncologists comprised 56% of all respondents. Once-daily (OD) radiotherapy is still the most commonly used regimen, however the use of concurrent BD radiotherapy increased after the publication of CONVERT (n = 59/186, 32% prior to and n = 78/187, 42% after the publication, p = 0.053). The main reasons for not implementing BD after the CONVERT publication were logistical issues (n = 88, 44%), inconvenience for patients (n = 56, 28%), and the absence of a statistical survival difference between the two arms in CONVERT (n = 38, 19%). Brain MRI was used by 28% during staging but more than half (60%) of the respondents did not routinely image the brain during follow-up. The main research questions of interest in LS-SCLC were 1) integrating novel targeted therapies-immunotherapies (n =. 160, 81%), 2) PCI (+/- hippocampal sparing) vs. MRI surveillance (n = 140, 71%) and, 3) biomarker driven trials (n = 92, 46%).Conclusion: Once daily radiotherapy (60-66 Gy in 30-33 fractions) remains the most prescribed radiotherapy fractionation, despite the findings suggested by the CONVERT trial.

Introduction: Improved outcome has been shown in patients with synchronous oligometastatic (sOM) NSCLC when treated with radical intent. As a uniform definition of sOM NSCLC is lacking, we developed a definition and diagnostic criteria by a consensus process.Methods: A pan-European multidisciplinary consensus group was established. Consensus questions were built on the basis of current controversies, and definitions were extracted from a survey, cases and a systematic review. This statement was formulated during a consensus meeting.Results: It was determined that definition of sOM NSCLC is relevant when a radical treatment that may modify the disease course (leading to long-term disease control) is technically feasible for all tumor sites with acceptable toxicity. On the basis of the review, a maximum of five metastases and three organs was proposed. Mediastinal lymph node involvement was not counted as a metastatic site. Fludeoxyglucose F 18 positron emission tomography-computed tomography and brain imaging were considered mandatory. A dedicated liver magnetic resonance imaging scan was advised for a solitary liver metastasis, and thoracoscopy and biopsies of distant ipsilateral pleural sites were recommended for a solitary pleural metastasis. For mediastinal staging, fludeoxyglucose F 18 positron emission tomography-computed tomography was deemed the minimum requirement, with pathological confirmation recommended if this influences the treatment strategy. Biopsy of a solitary metastatic location was mandated unless the multidisciplinary team is of the opinion that the risks outweigh the benefits.Conclusion: A multidisciplinary consensus statement on the definition and staging of sOM NSCLC has been formulated. This statement will help to standardize inclusion criteria in future clinical trials. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Objectives: The CONVERT trial showed that twice-daily (BD) concurrent chemoradiotherapy should continue to be considered the standard of care in localised LS-SCLC. A survey was conducted to assess the impact of the CONVERT trial in clinical practice and to identify any relevant research questions for future trials in this setting.Methods and materials: An EORTC Group online survey of LS-SCLC practice was distributed to the EORTC LCG and to members of several European thoracic oncology societies between April and December 2018.Results: 198 responses were analysed. The majority of respondents (88%, n = 174) were aware of the CONVERT trial. Radiation oncologists comprised 56% of all respondents. Once-daily (OD) radiotherapy is still the most commonly used regimen, however the use of concurrent BD radiotherapy increased after the publication of CONVERT (n = 59/186, 32% prior to and n = 78/187, 42% after the publication, p = 0.053). The main reasons for not implementing BD after the CONVERT publication were logistical issues (n = 88, 44%), inconvenience for patients (n = 56, 28%), and the absence of a statistical survival difference between the two arms in CONVERT (n = 38, 19%). Brain MRI was used by 28% during staging but more than half (60%) of the respondents did not routinely image the brain during follow-up. The main research questions of interest in LS-SCLC were 1) integrating novel targeted therapies-immunotherapies (n =. 160, 81%), 2) PCI (+/- hippocampal sparing) vs. MRI surveillance (n = 140, 71%) and, 3) biomarker driven trials (n = 92, 46%).Conclusion: Once daily radiotherapy (60-66 Gy in 30-33 fractions) remains the most prescribed radiotherapy fractionation, despite the findings suggested by the CONVERT trial.

Background: Synchronous oligometastatic disease (sOM) has been described as a distinct disease entity; however, there is no consensus on OM definition (OM-d) in non esmall-cell lung cancer (NSCLC). A consensus group was formed aiming to agree on a common OM-d that could be used in future clinical trials. A European survey was circulated to generate questions and input for the consensus group meeting.Methods: A European Organisation for Research and Treatment of Cancer Lung Cancer Group (LCG)/sOM-d consensus group survey was distributed to LCG, sOM-d consensus group, and several European thoracic oncology societies' members.Results: 444 responses were analysed (radiation oncologist: 55% [n = 242], pulmonologist: 15% [n = 66], medical oncologist: 14% [n = 64]). 361 physicians (81%) aimed to cure sOM NSCLC patients and 82% (n=362) included the possibility of radical intent treatment in their sOM-d. The maximum number of metastases considered in sOM-d varied: 12% replied 1 metastasis, 42% = 5 metastases. 79% (n = 353) stated that number of organs involved was important for sOM-d, and most (80%, n = 355) considered that onlyConclusion: Although consensual answers were obtained, several issues remain unresolved and will require further research to agree on a sOM-d. (C) 2019 Elsevier Ltd. All rights reserved.

Introduction: Synchronous oligometastatic non-small cell lung cancer (NSCLC) definition varies from 1 metastasis in 1 organ (tumour-node-metastasis 8 [TNM8]), 1-3 metastases (European Society for Medical Oncology [ESMO]),Methods: In December 2017, 10 real-life multidisciplinary team (MDT) discussed patients (good condition, no significant comorbidities, F-18-fluorodeoxyglucose positron emission tomography/brain magnetic resonance imaging staged, all <5 metastases, 9/10Results: Twenty-six of 33 experts (24 centres) replied: 8 medical oncologists, 7 pulmonologists, 7 radiation oncologists, 4 thoracic surgeons. Sixty-two percent of respondents discussed the cases with their MDT. One case had 100% oligometastatic consensus, and 3 cases had >90% consensus; the number of treatment proposals varied between 3 and 8. Radical treatment was more often offered in case of single metastasis or N0. Compared with 2012, there was a trend towards a more conservative oligometastatic definition and chemotherapy was more frequently included in the treatment proposal.Conclusions: Oligometastatic NSCLC definition was conservative. The number of organs, MLN status and radical treatment possibility seem to be components of daily practice oligometastatic definition. (C) 2019 Elsevier Ltd. All rights reserved.

Introduction: Non-small-cell lung cancer (NSCLC) guidelines advise to screen stage III NSCLC patients for brain metastases (BMs), preferably by magnetic resonance imaging (MRI) or when contraindicated or not accessible a dedicated contrast enhanced-computed tomography (dCE-CT), which can be incorporated in the staging (18)Fluodeoxoglucose-positron emission tomography ((18)FDG-PET-CE-CT). In daily practice, often a dCE-CT is performed instead of a MRI. The aim of the current study is to evaluate the additive value of MRI after dCE-CT, incorporated in the 18 FDG-PET-CE-CT.Patients and methods: It is an observational prospective multicentre study (NTR3628). Inclusion criteria included stage III NSCLC patients with a dCE-CT of the brain incorporated in the (18)FDG-PET and an additional MRI of the brain. Primary end-point is percentage of patients with BM on MRI without suspect lesions on dCE-CT. Secondary end-points are percentage of patients with BM on dCE-CT and percentage of patients with BMResults: Sixteen (7%) patients with extracranial stage III had BM on dCE-CT and were excluded. One hundred forty-nine patients were enrolled. 7/149 (4.7%) had BM on MRI without suspect lesions on dCE-CT. One hundred eighteen patients had a follow-up of at least 1 year (four with BM on baseline MRI); eight of the remaining 114 (7%) patients developed BMConclusion: Although in 7% of otherwise stage III NSCLC patients, BMs were detected on staging dCE-CT, MRI brain detected BMs in an additional 4.7%, which we consider clinically relevant. Within 1 year after a negative staging MRI, 7% developed BM. (C) 2019 Elsevier Ltd. All rights reserved.

Introduction: Patients with non-small cell lung cancer (NSCLC) experience leptomeningeal metastases (LM) in 3-9% of cases. Because overall survival (OS) and performance status are very poor, they are mostly excluded from clinical trials. Here, we evaluated survival of patients with NSCLC having LM treated with immune checkpoint inhibitors (ICIs).Methods: A prospectively collected list of patients with advanced NSCLC treated with ICIs between November 2012 and July 2018 in 7 European centres was merged. All patients with LM before ICI start were selected, data were retrospectively added and patients were classified according to the National Comprehensive Cancer Network (NCCN) LM prognostic classification (good/poor). Progression-free survival (PFS) and OS on ICIs were evaluated.Results: Nineteen of 1288 (1.5%) patients had LM; 73.7% had synchronous brain metastases; 73.7% had neurological symptoms at the start of ICIs and 52.6% were in the NCCN LM good prognosis group. Programmed death ligand-1 (PD-L1) expression was known for 42.1% of patients (87.5% positive). Median follow-up was 13 months from the start of ICIs, and median (95% confidence interval [CI]) PFS on ICIs was 2.0 (1.8-2.2) months. Six-month PFS rate was 21.0% and was significantly higher in the NCCN good versus poor prognostic group: 40% vs 0% (p = 0.05). Twelve-month PFS rate was 0%. Median (95% CI) OS from the start of ICIs was 3.7 (0.9-6.6) months. Six-month OS rate was 36.8%, and 12-month OS rate was 21.1%; both were not statistically significantly different for the good versus poor NCCN prognostic group (p = 0.40 and p = 0.56, respectively).Conclusion: Some patients with NSCLC having LM do benefit from ICI treatment; specifically, those in the NCCN LM good prognosis group can obtain a long survival. (C) 2019 Elsevier Ltd. All rights reserved.