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This document summarizes the key findings and insights from the 2023 European Society for Medical Oncology (ESMO) annual meeting, with a focus on thoracic oncology. It covers various topics such as immunotherapy-based therapy in nonmetastatic settings, radiotherapy in non-small cell lung cancer (NSCLC), and bispecific T-cell engagers in small cell lung cancer (SCLC). The report includes data from clinical trials and studies, highlighting the effectiveness and safety of different treatment approaches. It also mentions the approval of certain therapies by regulatory bodies and emphasizes the need for further research in specific patient subgroups. Authored by a team of experts, this report provides valuable insights and perspectives for library patrons conducting research in this field. [Extracted from the article]

The article provides an overview of key findings from the 2023 European Society for Medical Oncology (ESMO) annual meeting in the field of thoracic oncology, specifically focusing on targeted therapies for non-small cell lung cancer (NSCLC). The studies discussed highlight the safety and efficacy of various targeted therapies, such as adagrasib plus pembrolizumab for patients with a specific genetic mutation, and the combination of atezolizumab, bevacizumab, carboplatin, and paclitaxel for other genetic mutations. The article acknowledges the positive outcomes observed in these trials but also emphasizes the need for further research and understanding of these therapies. [Extracted from the article]

Background: The PACIFIC study showed that after radio-chemotherapy, patients with NSCLC derived a benefit in PFS and OS when treated with durvalumab. This effect was limited to patients with a PD-L1 expression of >1%, partly because the outcome in the observational control arm was surprisingly favorable. Thus, it could be speculated that a lack of PD-L1 expression confers a favorable outcome for patients with stage III NSCLC. Methods: Clinical data, PD-L1 expression, predictive blood markers, and the outcomes of 99 homogeneously treated patients with stage III NSCLC were retrospectively captured. Statistical analyses using the log rank test were performed. Results: The median OS of patients with an expression of PD-L1 < 1% was 20 months (CI 10.5–29.5) and the median OS of patients with an expression of PD-L1 ≥ 1% was 28 months (CI 16.5–39.2) (p = 0.734). The median PFS of patients with an expression of PD-L1 < 1% was 9 months (CI 6.3–11.6) and the median PFS of patients with an expression of PD-L1 ≥ 1% was 12 months (CI 9.8–14.2) (p = 0.112). Conclusions: The assumption that the lack of PD-L1 expression represents a favorable prognostic factor after radio-chemotherapy vs. PD-L1 expression > 1% was not confirmed. [ABSTRACT FROM AUTHOR]

Introduction: The timing of tumor-specific palliative therapy and its influence on the survival of patients with stage IV lung cancer remain unclear. Methods: 375 patients with stage IV lung cancer who experienced an early or delayed therapy (early or delayed therapy group [TG]) were investigated using histology and ECOG performance score (ECOG-PS)-related subgroups. Kaplan-Meier and Cox regression analyses were used for survival analyses. Results: Patients in the early TG had a significantly shorter median overall survival (OS) than those in the delayed TG (6 vs. 11 months). Patients with an ECOG-PS of ≥1 were significantly more present in the early TG than in the delayed TG (66.8 vs. 51.9%). But an early therapy was also significantly associated to a shorter median OS in ECOG-matched subgroups (ECOG-PS of 0, 7 vs. 23 months; ECOG ≥1, 6 vs. 8 months). An early therapy was associated to a significantly worse median OS in histological subgroups (NSCLC, 5 vs. 11 months; SCLC, 7 vs. 11 months) and was an independent risk factor in uni- and multivariate analyses. Conclusions: An early initiation of cancer-specific therapy was associated with a shorter survival time in palliative lung cancer patients, independent of the ECOG-PS and histological subtype. [ABSTRACT FROM AUTHOR]

Simple Summary: There is a need to better understand the effectiveness of new treatments, such as the recently approved nivolumab, in patients with locally advanced or metastatic non-small cell lung cancer in clinical practice. This study aims to report the characteristics and outcomes of 2784 patients with locally advanced or metastatic non-small cell lung cancer receiving nivolumab in second-line or later in France (ESME-AMLC) and Germany (CRISP) between 2015 and 2020. Two-year survival rates were 26.7% in patients with tumors with squamous histology and 32.8% in patients with non-squamous/others histologies in ESME-AMLC, and 20.9% and 18.9%, respectively, in CRISP. Poorer performance score and shorter duration from the previous line of therapy initiation were significantly associated with shorter treatment duration with nivolumab and overall survival. These real-world data provide insight into the characteristics of patients receiving nivolumab in France and Germany and confirm the efficacy of nivolumab previously observed in clinical trials. This study reports characteristics and outcomes in patients with locally advanced or metastatic non-small cell lung cancer (aNSCLC) receiving nivolumab in second-line or later (2L+) in France and Germany between 2015 and 2020. Patients with aNSCLC (stage IIIB–C/IV) receiving nivolumab in 2L+ were included from the retrospective Epidemiological Strategy and Medical Economics of Advanced and Metastatic Lung Cancer cohort (ESME-AMLC, France; 2015–2019) and Clinical Research platform Into molecular testing, treatment and outcome of non-Small cell lung carcinoma Patients (CRISP, Germany; 2016–2020). Overall, 2262 ESME-AMLC and 522 CRISP patients were included. Median treatment duration (95% confidence intervals) was 2.8 months (2.5–3.2) in squamous and 2.5 months (2.3–2.8) in non-squamous/others patients in ESME-AMLC, and 2.3 months (1.4–3.1) and 2.3 months (2.0–2.8), respectively in CRISP. One-year and two-year overall survival (OS) were 47.2% and 26.7% in squamous and 50.8% and 32.8% in non-squamous/others patients in ESME-AMLC, and 43.1% and 20.9%, and 37.7% and 18.9%, respectively in CRISP. Poorer performance score and shorter time from start of previous line of therapy initiation were significantly associated with shorter treatment duration and OS. This study confirms, in real-world clinical databases, the efficacy of nivolumab previously observed in clinical trials. [ABSTRACT FROM AUTHOR]

Background: The analysis of statutory health insurance (SHI) data is a little-used approach for understanding treatment and care as well as resource use of lung cancer (LC) patients in Germany. The aims of this observational, retrospective, longitudinal analysis of structured data were to analyze the healthcare situation of LC patients in Germany based on routine data from SHI funds, to develop an algorithm that sheds light on LC types (non-small cell / NSCLC vs. small cell / SCLC), and to gain new knowledge to improve needs-based care.Methods: Anonymized billing data of approximately four million people with SHI were analyzed regarding ICD-10 (German modification), documented medical interventions based on the outpatient SHI Uniform Assessment Standard Tariff (EBM) or the inpatient Operations and Procedure Code (OPS), and the dispensing of prescription drugs to outpatients (ATC classification). The study included patients who were members of 64 SHI funds between Jan-1st, 2015 and Dec-31st, 2016 and who received the initial diagnosis of LC in 2015 and 2016.Results: The analysis shows that neither the cancer type nor the cancer stage can be unambiguously described by the ICD-10 coding. Furthermore, an assignment based on the prescribed medication provides only limited information: many of the drugs are either approved for both LC types or are used off-label, making it difficult to assign them to a specific LC type. Overall, 25% of the LC patients were unambiguously identifiable as NSCLC vs SCLC based on the ICD-10 code, the drug therapy, and the billing data.Conclusions: The current coding system appears to be of limited suitability for drawing conclusions about LC and therefore the SHI patient population. This makes it difficult to analyze the healthcare data with the aim of gathering new knowledge to improve needs-based care. The approach chosen for this study did not allow for development of a LC differentiation algorithm based on the available healthcare data. However, a better overview of patient specific needs could make it possible to modify the range of services provided by the SHI funds. From this perspective, it makes sense, in a first step, to refine the ICD-10 system to facilitate NSCLC vs. SCLC classification. [ABSTRACT FROM AUTHOR]

Background: Oncology nurse navigators are integral members of multidisciplinary teams that manage patients with non--small cell lung cancer (NSCLC), including the 3%-4% of patients with mesenchymal-epithelial transition exon 14 (METex14) skipping mutation. This oncogenic driver confers a poor prognosis but sensitizes tumors to MET inhibitors. Tepotinib, an oral, selective MET inhibitor, showed robust, durable efficacy in METex14 NSCLC in the VISION trial. Objective: To support nurse navigators and other professionals managing these patients, we conducted an exploratory analysis of VISION to evaluate circulating tumor DNA (ctDNA) and MET-related biomarkers in liquid biopsy (LBx [ie, blood]) samples and their associations with clinical outcomes. Methods: Baseline, on-treatment and/or end-of-treatment (EOT) LBx from VISION were analyzed by ctDNA next-generation sequencing (NGS; Guardant360®) and enzyme-linked immunoassay for shed MET (sMET; a soluble form of the MET extracellular domain) and hepatocyte growth factor (HGF; the ligand for MET). Patients with baseline LBx NGS profiles (n=165) were classified as positive (L+) or negative (L-) for METex14 (all L- patients had METex14 by tissue NGS). On-treatment response was analyzed in L+ patients with 2 consecutive on-treatment samples (n=81). Confirmed molecular response (cMR) was defined as >75% depletion from baseline in METex14 variant allele frequency (VAF) in 2 consecutive on-treatment samples; molecular progression (MP) was defined as VAF increase from baseline in ≥1 on-treatment sample. Objective response rate (ORR), median duration of response (mDOR), median progression-free survival (mPFS), and median overall survival (mOS) were evaluated according to biomarker status. Mechanisms of acquired resistance were investigated in postprogression EOT samples. Data cut-off date was November 20, 2022. Results: Patients with high (>upper quartile, n=58) versus low (≤upper quartile, n=175) baseline HGF had numerically shorter mDOR and mPFS. Patients with low (≤lower quartile, n=61) versus high (>lower quartile, n=183) relative change in sMET from baseline had numerically higher ORR, mPFS, and mOS. In L- (n=51) versus L+ (n=114) patients, ORR was comparable, but mDOR and mPFS were longer. Seven of 10 patients with MET amplification, 1 of 5 patients with KRAS/NRAS mutation, 1 of 5 patients with PI3K/AKT pathway alterations, and 0 of 2 patients with EGFR mutations at baseline had objective response. Patients with tumor protein 53 (TP53) mutations (73/165) versus wild-type had comparable ORR but shorter mPFS (8.2 vs 11.3 mo, respectively). Patients with cMR (n=65 [80%]) versus MP (n=12 [15%]) had better outcomes (ORR: 63.1% vs 16.7%, respectively; mDOR: 18.5 vs 6.2 mo, respectively; mPFS: 11.2 vs 4.2 mo, respectively). At EOT, 9 of 73 patients (12%) had acquired MET kinase domain mutations and 9 of 73 (12%) had emerging alterations in KRAS, EGFR, MYC, BRAF, RB1, and ERBB2. Conclusions: In the largest on-treatment LBx biomarker dataset for an MET inhibitor in METex14 NSCLC, MR was associated with improved outcomes and TP53 mutation had negative prognostic significance. On-target secondary MET mutations and off-target bypass pathway activation were potential resistance mechanisms. These data can help to inform nurse navigators and other healthcare professionals managing patients receiving tepotinib for METex14 skipping NSCLC. [ABSTRACT FROM AUTHOR]

Background: Pemetrexed and cisplatin is a first-line standard in non-squamous non-small-cell lung cancer without targetable mutations. It became the backbone of checkpoint-inhibitor–chemotherapy combinations. Single high doses of cisplatin pose toxicity risks and require hyperhydration, potentially prolonging outpatient application. The aim of this study was to compare efficacy, safety and tolerability of split-dose cisplatin with the standard schedule. Methods: Patients with metastatic non-squamous non-small-cell lung cancer were randomly assigned to up to six 21-day cycles of pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 on day 1 (arm A), or pemetrexed 500 mg/m2 (day 1) and cisplatin 40 mg/m2 (day 1 + 8, arm B), followed by pemetrexed maintenance. Primary endpoint was objective response rate. Secondary objectives were overall survival, progression-free survival, time to progression, treatment compliance, toxicity profile, and quality of life. Results: We enrolled 130 patients (129 evaluable). Median cycle numbers in A and B were six (1–6) and five (1–6). Dose intensities were comparable between arms. More patients in A received pemetrexed maintenance (24.2% versus 11.1%). With 16 (24.2%) in A and 19 (30.2%) patients in B achieving objective responses [odds ratio 0.74 (0.34–1.62), p = 0.55] the primary endpoint was met. Overall survival was not different between arms (median 14.4 versus 14.9 months); [HR = 1.07; (0.68–1.68), p = 0.78]. Median progression-free survival was 7.0 months in A and 6.2 months in B [HR = 1.63; (1.17–2.38); p = 0.01]. Adverse events of CTCAE grade ⩾3, particularly hematological, were more frequent in B. No difference in grade 4 and 5 infections between arms was noted. Treatment-related asthenia and nausea/vomiting of any grade were more frequent in A. Global health status, fatigue and constipation measured on day 1 of cycle 4 demonstrated superior scores in B. Conclusion: Pemetrexed and split-dose cisplatin is safe and effective. Advantages of split-dose cisplatin with regard to specific toxicities allow personalization of this important chemotherapy backbone. Trial Registration: European Clinical Trials Database (EudraCT) number 2011-001963-37. [ABSTRACT FROM AUTHOR]

Clinical trial and real-world data in non-small-cell lung cancer indicate that 10-60% of patients that progressed on first- or second-generation EGFR-targeting tyrosine kinase inhibitors (TKI) do not receive systemic second-line therapy. In our article, we discuss efficacy, safety and treatment duration with different EGFR-TKIs and stress the need for delivery of the most efficacious therapy in the first-line. We also provide our perspective on analysis of circulating tumor DNA and the role of EGFR-TKI in combined therapies. Finally, we review new therapeutic options to overcome resistance to EGFR-TKI. We believe that overall treatment duration and access to different medications in subsequent lines of therapy should be considered when planning the optimal treatment strategy. [ABSTRACT FROM AUTHOR]

Background: The cancer vaccine Vx-001, which targets the universal tumour antigen TElomerase Reverse Transcriptase (TERT), can mount specific Vx-001/TERT572 CD8 + cytotoxic T cells; this immune response is associated with improved overall survival (OS) in patients with advanced/metastatic non-small cell lung cancer (NSCLC).Methods: A randomised, double blind, phase 2b trial, in HLA-A*201-positive patients with metastatic, TERT-expressing NSCLC, who did not progress after first-line platinum-based chemotherapy were randomised to receive either Vx-001 or placebo. The primary endpoint of the trial was OS.Results: Two hundred and twenty-one patients were randomised and 190 (101 and 89 patients in the placebo and the Vx-001 arm, respectively) were analysed for efficacy. There was not treatment-related toxicity >grade 2. The study did not meet its primary endpoint (median OS 11.3 and 14.3 months for the placebo and the Vx-001, respectively; p = 0.86) whereas the median Time to Treatment Failure (TTF) was 3.5 and 3.6 months, respectively. Disease control for >6months was observed in 30 (33.7%) and 26 (25.7%) patients treated with Vx-001 and placebo, respectively. There was no documented objective CR or PR. Long lasting TERT-specific immune response was observed in 29.2% of vaccinated patients who experienced a significantly longer OS compared to non-responders (21.3 and 13.4 months, respectively; p = 0.004).Conclusion: Vx-001 could induce specific CD8+ immune response but failed to meet its primary endpoint. Subsequent studies have to be focused on the identification and treatment of subgroups of patients able to mount an effective immunological response to Vx-001.Clinical Trial Registration: NCT01935154. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to describe the real-world treatment and overall survival (OS) of German patients with a diagnosis of advanced non-small cell lung cancer (aNSCLC), and to explore factors associated with the real-world mortality risk.Methods: This was a retrospective German claims data analysis of incident aNSCLC patients. Data were available from 01/01/2011 until 31/12/2016. Identification of eligible patients took place between 01/01/2012-31/12/2015, to allow for at least 1-year pre-index and follow-up periods. Inpatient and outpatient mutation test procedures after aNSCLC diagnosis were observed. Further, prescribed treatments and OS since first (incident) aNSCLC diagnosis and start of respective treatment lines were described both for all patients and presumed EGFR/ALK/ROS-1-positive patients. Factors associated with OS were analyzed in multivariable Cox regression analysis.Results: Overall, 1741 aNSCLC patients were observed (mean age: 66·97 years, female: 29·87%). The mutation test rate within this population was 26·31% (n = 458), 26·6% of these patients (n = 122) received a targeted treatment and were assumed to have a positive EGFR/ALK/ROS-1 test result. Most often prescribed treatments were pemetrexed monotherapy as 1 L (21·23% for all and 11·11% for mutation-positive patients) and erlotinib monotherapy as 2 L (25·83%/38·54%). Median OS since incident diagnosis was 351 days in all and 571 days in mutation-positive patients. In a multivariable Cox regression analysis, higher age, a stage IV disease, a higher number of chronic drugs in the pre-index period and no systemic therapy increased the risk of early death since first aNSCLC diagnosis. On the other hand, female gender and treatment with therapies other than chemotherapy were associated with a lower risk of early death.Conclusions: Despite the introduction of new treatments, the real-world survival prognosis for aNSCLC patients remains poor if measured based on an unselected real-world population of patients. Still, the majority of German aNSCLC patients do not receive a mutation test. [ABSTRACT FROM AUTHOR]

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Background. Afatinib, an irreversible ErbB family blocker, is approved for treatment of patients with previously untreated non-small cell lung cancer (NSCLC) harboring activating epidermal growth factor receptor (EGFR) mutations. Efficacy of afatinib in EGFR tyrosine kinase inhibitor-naï ve (TKI-naïve) patients with uncommon EGFR mutations (other than exon 19 deletions or exon 21 point mutations) has been reported; however, efficacy in TKI-pretreated patients with uncommon EGFR mutations is unknown. Materials and Methods. In the afatinib compassionate use program (CUP), patients with advanced or metastatic, histologically confirmed NSCLC progressing after at least one line of chemotherapy and one line of EGFR-TKI treatment were enrolled. Demographic data, mutation type, response rates, time to treatment failure (TTF), and safety in patients harboring uncommon EGFR mutations were reported. Results. In 60 patients (63% female, median age 63 years [range: 30-84 years]), a total of 66 uncommon EGFR mutations including 30 T790M mutations were reported (18.4% and 11%, respectively, of known EGFR mutations within the CUP). Most patients (67%) received afatinib as third- or fourth-line treatment. Median TTF was 3.8 months (range: 0.2 to >24.6 months; p = .244) in patients with uncommon mutations compared with 5.1 months (range: 0.1 to >21.1 months) in patients with common mutations (n = 165). Pronounced activity was observed with E709X mutations (TTF >12 months). No new safety signals were detected. Conclusion. Afatinib is clinically active and well tolerated in many TKI-pretreated NSCLC patients harboring uncommon EGFR mutations. Compared with results reported in TKI-naTve patients, activity was also indicated in patients with T790M and exon 20 insertion mutations. [ABSTRACT FROM AUTHOR]

Background: Pulmonary function may decline after induction chemotherapy and predict perioperative complications in non-small cell lung cancer (NSCLC). The influence of adjuvant chemotherapy is largely indeterminate. Objective: To assess whether adjuvant chemotherapy alters pulmonary function and impacts on treatment-related adverse events. Methods: In a trial on adjuvant chemotherapy (the TREAT trial), 132 patients with R0-resected NSCLC were randomised to 4 cycles of cisplatin-vinorelbine (CVb, n = 65) or cisplatin-pemetrexed (CPx, n = 67). Pulmonary function tests (forced expiratory volume in 1 s, FEV1, forced vital capacity, FVC, total lung capacity, TLC, diffusing capacity for carbon monoxide, DLCO, and blood gas analyses, BGA) were analysed before and 30 days after the last chemotherapy, and changes were calculated (Δ = mean differences). Results: Overall,FVC increased significantly (Δ +290 ml, n = 76; p < 0.0001), while TLC did not change (Δ +220 ml, n = 41; p = 0.174). For CPx, FEV1 increased significantly (Δ +150 ml, n = 47; p = 0.0017), but not for CVb (Δ +30 ml, n = 30). DLCO decreased only for CVb (-8%, n = 6) but not for CPx (-0.39%, n = 17; p = 0.58). BGA did not change (p = 0.99). In a Cox regression analysis, baseline pulmonary function did not influence treatment failure. Conclusions: Adjuvant chemotherapy seems not to result in a decrease of pulmonary function parameters. A significant FVC increase was probably due to ongoing postoperative improvement. Decline of DLCO was noted with CVb but not with CPx. Pulmonary function does not impact on treatment failure. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Erlotinib inhibits the tyrosine kinase of epidermal growth factor receptor (EGFR) and is successfully used in lung cancer treatment. EGFR is essential in skin development and function and may have a role in the pathogenesis of psoriasis. Cutaneous side effects are very common in patients treated with erlotinib, and therapeutic use of erlotinib in dermatological disorders has therefore not been considered. We report two cases of patients with lung cancer and concomitant psoriasis treated with erlotinib with complete resolution of the skin problems. We present a review of the current literature on the topic. [ABSTRACT FROM AUTHOR]

Background: Adjuvant chemotherapy has been proven to be beneficial for patients with early stage non-small cell lung cancer. However, toxicity and insufficient dose delivery have been critical issues with the chemotherapy used. Doublet regimens with pemetrexed, a multi-target folate inhibitor, and platin show clear activity in non-small cell lung cancer and are well tolerated with low toxicity rates and excellent delivery. Methods/Design: In this prospective, multi-center, open label randomized phase II study, patients with pathologically confirmed non-small cell lung cancer, stage IB, IIA, IIB, T3N1 will be randomized after complete tumor resection either to 4 cycles of the standard adjuvant vinorelbine and cisplatin regimen from the published phase III data, or to 4 cycles of pemetrexed 500 mg/m2 d1 and cisplatin 75 mg/m2 d1, q 3 weeks. Primary objective is to compare the clinical feasibility of these cisplatin doublets defined as non-occurrence of grade 4 neutropenia and/or thrombocytopenia > 7 days or bleeding, grade 3/4 febrile neutropenia and/or infection, grade 3/4 non-hematological toxicity, nonacceptance leading to premature withdrawal and no cancer or therapy related death. Secondary parameters are efficacy (time to relapse, overall survival) and drug delivery. Parameters of safety are hematologic and non-hematologic toxicity of both arms. Discussion: The TREAT trial was designed to evaluate the clinical feasibility, i.e. rate of patients without dose limiting toxicities or premature treatment withdrawal or death of the combination of cisplatin and pemetrexed as well as the published phase III regimen of cisplatin and vinorelbine. Hypothesis of the study is that reduced toxicities might improve the feasibility of drug delivery, compliance and the convenience of treatment for the patient and perhaps survival. [ABSTRACT FROM AUTHOR]

Simple Summary: Since the recent approval of osimertinib, a third generation tyrosine kinase inhibitor (TKI) targeting EGFR in non-small cell lung cancer (NSCLC), tracing the resistance mechanisms that yield to failure of osimertinib has become of interest. As the spectrum of osimertinib-resistance related genomic alterations appears significantly more diverse compared to first and second generation TKI, comprehensive, and preferably non-invasive molecular diagnostic methods are required for the detection of resistance mechanisms. In this study, we present molecular results of 56 NSCLC patients during disease progression on first and second line osimertinib treatment using a hybrid capture (HC) next generation sequencing (NGS) based liquid biopsy approach. We show examples of polyclonal resistance development which leads to the presence of multiple resistance mechanisms in the same patient, and highlight the clinical utility of HC NGS over single gene testing. Since 2009, several first, second, and third generation EGFR tyrosine kinase inhibitors (TKI) have been approved for targeted treatment of EGFR mutated metastatic non-small lung cancer (NSCLC). A vast majority of patients is improving quickly on treatment; however, resistance is inevitable and typically occurs after one year for TKI of the first and second generation. Osimertinib, a third generation TKI, has recently been approved for first line treatment in the palliative setting and is expected to become approved for the adjuvant setting as well. Progression-free survival (PFS) under osimertinib is superior to its predecessors but its spectrum of resistance alterations appears significantly more diverse compared to first and second generation EGFR TKI. As resistance mechanisms to osimertinib are therapeutically targetable in some cases, it is important to comprehensively test for molecular alterations in the relapse scenario. Liquid biopsy may be advantageous over tissue analysis as it has the potential to represent tumor heterogeneity and clonal diversification. We have previously shown high concordance of hybrid capture (HC) based next generation sequencing (NGS) in liquid biopsy versus solid tumor biopsies. In this study, we now present real-word data from 56 patients with metastatic NSCLC that were tested by liquid biopsy at the time of disease progression on mostly second line treated osimertinib treatment. We present examples of single and multiple TKI resistance mechanisms, including mutations in multiple pathways, copy number changes and rare fusions of RET, ALK, FGFR3 and BRAF. In addition, we present the added value of HC based NGS to reveal polyclonal resistance development at the DNA level encoding multiple EGFR C797S and PIK3CA mutations. [ABSTRACT FROM AUTHOR]

In recent years, Non-small cell lung cancer (NSCLC) has evolved into a prime example for precision oncology with multiple FDA-approved "precision" drugs. For the majority of NSCLC lacking targetable genetic alterations, immune checkpoint inhibition (ICI) has become standard of care in first-line treatment or beyond. PD-L1 tumor expression represents the only approved predictive biomarker for PD-L1/PD-1 checkpoint inhibition by therapeutic antibodies. Since PD-L1-negative or low-expressing tumors may also respond to ICI, additional factors are likely to contribute in addition to PD-L1 expression. Tumor mutation burden (TMB) has emerged as a potential candidate; however, it is the most complex biomarker so far and might represent a challenge for routine diagnostics. We therefore established a hybrid capture (HC) next-generation sequencing (NGS) assay that covers all oncogenic driver alterations as well as TMB and validated TMB values by correlation with the assay (F1CDx) used for the CheckMate 227 study. Results of the first consecutive 417 patients analyzed in a routine clinical setting are presented. Data show that fast reliable comprehensive diagnostics including TMB and targetable alterations are obtained with a short turn-around time. Thus, even complex biomarkers can easily be implemented in routine practice to optimize treatment decisions for advanced NSCLC. [ABSTRACT FROM AUTHOR]

• Local ablative therapy (LAT) improves survival in oligometastatic lung cancer (OMD) • Retrospective multicenter analysis from 5 certified German Lung Cancer centers. • The initial metastatic site determines the pattern of relapse. • Subsequent LAT for every recurrence is feasible for 25% of all patients. • Intracranial disease control determines survival and correlates to (repeated) LAT. Local ablative therapy (LAT) improves survival in oligometastatic lung cancer (OMD), but there is limited information on recurrence patterns, re-treatments and in particular the role of brain metastases during the course of disease. We therefore conducted a retrospective multicenter analysis to evaluate course of disease, sequence of therapies and predictors for long-term disease-control in the brain and survival endpoints. Clinical data of patients with synchronous, single organ OMD with ≤4 metastases were collected from 5 certified German lung cancer centers. All patients underwent thorough initial staging including a 18FDG-PET/CT scan, brain imaging and mediastinal staging, if necessary, and received LAT to all sites of disease. In total, 164 patients were included (median age 62 years [range 41–84], non-squamous histology 80%, N0-1 64%, single metastasis 84%), 103 had brain (cohort A), 61 extracranial metastases (cohort B). With a median follow-up of 66 months, 115 patients (70%) experienced recurrent disease with a different distribution of sites: In cohort A vs. B, brain relapses occurred in 56% vs. 18% and new distant metastases in 5% vs. 40%. In total, LAT for every relapse was possible for 25% (29/115) of the patients. Patients with initial and secondary onset brain metastases experienced long-term disease-control in the brain and subsequently favorable survival with the application of repeated LAT (disease in the brain controlled vs. not-controlled, HR 0.21, p < 0.001). Comparable long-term overall survival was observed in patients with no or isolated brain relapses (5-years OS 74% and 92%) in contrast to patients with extracranial relapses (5-years OS 19.6%, p < 0.001). Repeated LAT for recurrent synchronous single organ OMD results in a long-term favorable outcome. Disease control in the brain appears crucial and likely determines survival. [ABSTRACT FROM AUTHOR]

BRAF mutations have been subtyped in three functional classes with different oncogenic modes of action. The clinical impact of BRAF mutational subtypes in non–small-cell lung cancer (NSCLC) remains to be defined. So far, ambiguous results were reported from analyses of heterogeneous patient cohorts. We studied patients with metastatic or recurrent NSCLC who were sequentially enrolled in precision oncology programs at two large German lung cancer centres from 2009 to 2019. The study period allowed evaluating the specific impact of BRAF V600E-targeting. In a cohort of 72 patients, BRAF mutation subtyping revealed p.V600E mutations in 31 cases (43%), whereas 41 cases (57%) harboured 18 different BRAF mutational subtypes of functional classes II/III. Functionally relevant comutations were observed in 6.4% of class I, and 24.4% of class II/III BRAF mutations. Most patients were treated with chemotherapy. Targeted therapy was administered in 11 patients with a response rate of 72.7%. PD-1/PD-L1-immunotherapy was given in 14 patients with a response rate of 28.6%. Overall survival of patients with BRAF -mutated NSCLC was inferior (HR 1.38, p = 0.048) as compared to patients with BRAF wild-type cancers. Median time-to-treatment-failure with BRAF-targeting agents was shorter as compared to approved targeted therapy of other oncogenic drivers (HR 1.97, p = 0.05). Survival outcomes were not impacted by BRAF mutation subtype functional class. Patients with BRAF -mutated NSCLC have an inferior prognosis, which is not determined by BRAF mutation functional class. In contrast to NSCLC with other tractable driver mutations, BRAF -mutated NSCLC exhibit high susceptibility to immune checkpoint inhibitors. • PD-1/PD-L1 immunotherapy is effective in BRAF -mutant NSCLC. • Patients with BRAF -mutated NSCLC have inferior overall survival. • BRAF mutation functional class does not associate with clinical outcomes. [ABSTRACT FROM AUTHOR]