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Activating EGFR mutations are commonly observed in non-small cell lung cancer (NSCLC). About 4-10 % of all activating epidermal growth factor receptor (EGFR) mutations are heterogenous in-frame deletion and/or insertion mutations clustering within exon 20 (EGFRex20+). NSCLC patients with EGFRex20+ mutations are treated as a single disease entity, irrespective of the type and location of the mutation. Here, we provide a comprehensive assessment of the literature reporting both in vitro and clinical drug sensitivity across different EGFRex20+ mutations. The activating A763_Y764insFQEA mutation has a better tumor response in comparison with mutations in the near- and far regions directly following the C-helix and should therefore be treated differently. For other EGFRex20+ mutations marked differences in treatment responses have been reported indicating the need for a classification beyond the exon-based classification. A further classification can be achieved using a structure-function modeling approach and experimental data using patient-derived cell lines. The detailed overview of TKI responses for each EGFRex20+ mutation can assist treating physicians to select the most optimal drug for individual NSCLC patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Patient-reported smoking history is frequently used as a stratification factor in NSCLC-directed clinical research. Nevertheless, this classification does not fully reflect the mutational processes in a tumor. Next-generation sequencing can identify mutational signatures associated with tobacco smoking, such as single-base signature 4 and indel-based signature 3. This provides an opportunity to redefine the classification of smoking- and nonsmoking-associated NSCLC on the basis of individual genomic tumor characteristics and could contribute to reducing the lung cancer stigma., Methods: Whole genome sequencing data and clinical records were obtained from three prospective cohorts of metastatic NSCLC (N = 316). Relative contributions and absolute counts of single-base signature 4 and indel-based signature 3 were combined with relative contributions of age-related signatures to divide the cohort into smoking-associated ("smoking high") and nonsmoking-associated ("smoking low") clusters., Results: The smoking high (n = 169) and smoking low (n = 147) clusters differed considerably in tumor mutational burden, signature contribution, and mutational landscape. This signature-based classification overlapped considerably with smoking history. Yet, 26% of patients with an active smoking history were included in the smoking low cluster, of which 52% harbored an EGFR/ALK/RET/ROS1 alteration, and 4% of patients without smoking history were included in the smoking high cluster. These discordant samples had similar genomic contexts to the rest of their respective cluster., Conclusions: A substantial subset of metastatic NSCLC is differently classified into smoking- and nonsmoking-associated tumors on the basis of smoking-related mutational signatures than on the basis of smoking history. This signature-based classification more accurately classifies patients on the basis of genome-wide context and should therefore be considered as a stratification factor in clinical research., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Sotorasib is a specific, irreversible inhibitor of the GTPase protein, KRAS G12C . We compared the efficacy and safety of sotorasib with a standard-of-care treatment in patients with non-small-cell lung cancer (NSCLC) with the KRAS G12C mutation who had been previously treated with other anticancer drugs., Methods: We conducted a randomised, open-label phase 3 trial at 148 centres in 22 countries. We recruited patients aged at least 18 years with KRAS G12C -mutated advanced NSCLC, who progressed after previous platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor. Key exclusion criteria included new or progressing untreated brain lesions or symptomatic brain lesions, previously identified oncogenic driver mutation other than KRAS G12C for which an approved therapy is available (eg EGFR or ALK), previous treatment with docetaxel (neoadjuvant or adjuvant docetaxel was allowed if the tumour did not progress within 6 months after the therapy was terminated), previous treatment with a direct KRAS G12C inhibitor, systemic anticancer therapy within 28 days of study day 1, and therapeutic or palliative radiation therapy within 2 weeks of treatment initiation. We randomly assigned (1:1) patients to oral sotorasib (960 mg once daily) or intravenous docetaxel (75 mg/m 2 once every 3 weeks) in an open-label manner using interactive response technology. Randomisation was stratified by number of previous lines of therapy in advanced disease (1 vs 2 vs >2), ethnicity (Asian vs non-Asian), and history of CNS metastases (present or absent). Treatment continued until an independent central confirmation of disease progression, intolerance, initiation of another anticancer therapy, withdrawal of consent, or death, whichever occurred first. The primary endpoint was progression-free survival, which was assessed by a blinded, independent central review in the intention-to-treat population. Safety was assessed in all treated patients. This trial is registered at ClinicalTrials.gov, NCT04303780, and is active but no longer recruiting., Findings: Between June 4, 2020, and April 26, 2021, 345 patients were randomly assigned to receive sotorasib (n=171 [50%]) or docetaxel (n=174 [50%]). 169 (99%) patients in the sotorasib group and 151 (87%) in the docetaxel group received at least one dose. After a median follow-up of 17·7 months (IQR 16·4-20·1), the study met its primary endpoint of a statistically significant increase in the progression-free survival for sotorasib, compared with docetaxel (median progression-free survival 5·6 months [95% CI 4·3-7·8] vs 4·5 months [3·0-5·7]; hazard ratio 0·66 [0·51-0·86]; p=0·0017). Sotorasib was well tolerated, with fewer grade 3 or worse (n=56 [33%] vs n=61 [40%]) and serious treatment-related adverse events compared with docetaxel (n=18 [11%] vs n=34 [23%]). For sotorasib, the most common treatment-related adverse events of grade 3 or worse were diarrhoea (n= 20 [12%]), alanine aminotransferase increase (n=13 [8%]), and aspartate aminotransferase increase (n=9 [5%]). For docetaxel, the most common treatment-related adverse events of grade 3 or worse were neutropenia (n=13 [9%]), fatigue (n=9 [6%]), and febrile neutropenia (n=8 [5%])., Interpretation: Sotorasib significantly increased progression-free survival and had a more favourable safety profile, compared with docetaxel, in patients with advanced NSCLC with the KRAS G12C mutation and who had been previously treated with other anticancer drugs., Funding: Amgen., Competing Interests: Declaration of interests AJdL reports financial interests, institutional, research grant from BMS, MSD, Boehringer, AstraZeneca; non-financial interests, other from Merck Serono, Roche. MLJ reports financial interests, institutional, research grant from AbbVie, Acerta, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, AstraZeneca, Atreca, BeiGene, BerGenBio, BioAtla, Boehringer Ingelheim, Calithera Biosciences, Corvus Pharmaceuticals, Curis, CytomX, Daiichi Sankyo, Dracen Pharmaceuticals, Dynavax, Lilly, EMD Serono, Erasca, Exelixis, Fate Therapeutics, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Harpoon, Helsinn Healthcare, Hengrui Therapeutics, Hutchison MediPharma, IDEAYA Biosciences, IGM Biosciences, Immunocore, Incyte, Janssen, Kadmon Pharmaceuticals, Loxo Oncology, Lycera, Memorial Sloan-Kettering, Merck, Merus, NeoImmune Tech, Neovia Oncology, Novartis, Numab Therapeutics, Nuvalent, OncoMed Pharmaceuticals, Pfizer, PMV Pharmaceuticals, Regeneron Pharmaceuticals, Relay Therapeutics, Revolution Medicines, Ribon Therapeutics, Rubius Therapeutics, Sanofi, Seven and Eight Biopharmaceuticals/Birdie Biopharmaceuticals, Shattuck Labs, Silicon Therapeutics, Stem CentRx, Syndax Pharmaceuticals, Takeda Pharmaceuticals, Tarveda Therapeutics, TCR2 Therapeutics, Tempest Therapeutics, Tizona Therapeutics, Tmunity Therapeutics, Turning Point Therapeutics, University of Michigan, Vyriad, WindMIL, Y-mAbs Therapeutics, Black Diamond, Carisma Therapeutics, Elicio Therapeutics, EQRx, Immunitas Therapeutics, Kartos Therapeutics, Mirati Therapeutics, Palleon Pharmaceuticals, Rain Therapeutics; financial interests, institutional, consulting fees from AbbVie, Amgen, Astellas, AstraZeneca, Axelia Oncology, Black Diamond, Calithera Biosciences, Checkpoint Therapeutics, CytomX Therapeutics, Daiichi Sankyo, EcoR1, Editas Medicine, Eisai, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, IDEAYA Biosciences, iTeos Therapeutics, Janssen, Lilly, Merck, Mirati Therapeutics, Molecular Axiom, Novartis, Oncorus, Regeneron Pharmaceuticals, Ribon Therapeutics, Sanofi-Aventis, Turning Point Therapeutics, VBL Therapeutics, Takeda Pharmaceuticals, Arrivant, Pyramid Biosciences, Revolution Medicines, Seagen. JM reports financial interests, personal fees from Amgen, AstraZeneca, Roche, Pierre Fabre, Pfizer; financial interests, institutional, research grant from AstraZeneca, Roche, Pierre Fabre; advisory board for Merck, Roche, AstraZeneca, MSD, BMS, Pfizer, Hengrui Therapeutics, Daiichi, Boehringer, Pierre Fabre, Amgen. A MCD reports other, institutional, advisory board for Amgen, Bayer, Boehringer Ingelheim, Roche, Sanofi; other, institutional, invited speaker for AstraZeneca, Janssen, Eli Lilly, Pfizer, Takeda; financial interests, institutional, research grant from Amgen; financial interests, institutional, principal investigator, local PI for Amgen, Daiichi, JNJ, Eli Lilly, Mirati Therapeutics; financial interests, institutional, principal investigator, coordinating PI for Roche; financial interests, institutional, other, steering committee member for Roche. GM reports financial interests, personal, other, consulting fees from Roche Hellas, Novartis Greece, BMS Greece, MSD Greece, AstraZeneca Greece, Takeda Hellas, Janssen Greece, GSK Greece, Amgen Hellas, Sanofi Greece, Boehringer Greece; financial interests, personal, other, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Roche Hellas, Novartis Greece, BMS Greece, MSD Greece, AstraZeneca Greece, Takeda Hellas, Pierre Fabre Greece, Janssen Greece, GSK Greece, Amgen Hellas, Sanofi Greece, Boehringer Greece; financial interests, personal, other, payment for expert testimony from Roche Hellas, Novartis Greece, BMS Greece, MSD Greece, AstraZeneca Greece, Takeda Hellas, Pierre Fabre Greece, Janssen Greece, GSK Greece, Amgen Hellas, Sanofi Greece, Boehringer Greece; financial interests, personal, other, support for attending meetings and/or travel from Roche Hellas, Novartis Greece, BMS Greece, MSD Greece, AstraZeneca Greece, Takeda Hellas, Pierre Fabre Greece, Janssen Greece, GSK Greece, Amgen Hellas, Sanofi Greece, Boehringer Greece; financial interests, personal, other, participation on a data safety monitoring board or advisory board for Roche Hellas, Novartis Greece, BMS Greece, MSD Greece, AstraZeneca Greece, Takeda Hellas, Janssen Greece, GSK Greece, Amgen Hellas, Sanofi Greece, Boehringer Greece; financial interests, personal, other, leadership or fiduciary role in other board, society, committee or advocacy group, unpaid for European Society for Medical Oncology working groups (Educational Publication Working Group, Adolescents and Young Adults working group); financial interests, institutional, principal investigator for Roche Hellas, Novartis Greece, BMS Greece, MSD Greece, AstraZeneca Greece, Gilead Greece, GSK Greece, Amgen Hellas, Sanofi Greece. MP reports financial interests, personal, advisory board for AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Eisei, MSD, Novartis, Pfizer, Roche, Takeda, Merck, Sanofi, Bayer, Amgen; financial interests, personal, other, travel grant from AstraZeneca, BMS, Boehringer Ingelheim, Roche, Takeda, Vifor; financial interests, personal, speaker fees from Janssen, Nestle. JW reports financial interests, personal, advisory board, lectures fees from Amgen, AstraZeneca, Bayer, Blueprint, BMS, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Merck, Janssen, Lilly, Loxo, MSD, Novartis, Pfizer, Roche, Seattle Genetics, Takeda, Turning Point, Nuvalent; financial interests, institutional, research grant from BMS, Janssen, Novartis, Pfizer. MS reports financial interests, institutional, research grant from AstraZeneca, Bristol Myers Squibb; financial interests, personal, consulting fees from Amgen, AstraZeneca, BIOCAD, Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Merck Serono, Novartis, Roche, Sanofi, Takeda; financial interests, personal, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, Novartis; financial interests, personal, support for attending meetings and/or travel from BIOCAD, Bristol Myers Squibb, Boehringer Ingelheim, Janssen, Novartis; financial interests, personal, participation on a data safety monitoring board or advisory board for Amgen, Bristol Myers Squibb, Novartis, Sanofi, GlaxoSmithKline, Merck Serono. HL reports financial interests, other, personal fees from Daiichi Sankyo, AstraZeneca, Pfizer, Novartis, Amgen, MSD, Roche, BMS, Eli Lilly, Boehringer Ingelheim. FS reports financial interests, personal, other, consulting fees from AstraZeneca, Amgen, Novartis, BeiGene Guardant Health, BerGenBio, Navire Pharma, Tango Therapeutics, Calithera Biosciences; financial interests, personal, other, lecture fees from European Society for Medical Oncology, Japanese Lung Cancer Society, Medscape, Intellisphere, VSPO McGill Universite de Montreal, RV Mais Promoção Eventos Ltda, MJH Life Sciences, IDEOlogy Health, MI&T, PER, LLC, CURIO; financial interests, personal, other, fees for travel, food and beverage from Dava Oncology, Tango Therapeutics, American Association for Cancer Research, International Association for the Study of Lung Cancer (IASLC), MJH Life Sciences, IDEOlogy Health, MI&T, PER, LLC, CURIO; financial interests, personal, stocks/shares, stock or stock options for BioNTech SE, Moderna (completed 2020); financial interests, institutional, research grant from Amgen, Mirati Therapeutics, Revolution Medicines, Pfizer, Novartis, Merck & Co; participation on a data safety monitoring board or advisory board for AstraZeneca, Amgen, Novartis, BeiGene, Guardant Health, BerGenBio; Calithera Biosciences. YY reports no relationships to disclose. S-WK reports no relationships to disclose. HL reports financial interests, personal, other, consulting fees from Roche, Novartis, BMS, MSD, AstraZeneca, Takeda, GSK, Merck, Amgen, Boehringer, Pfizer, Lilly; financial interests, personal, other, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Roche, Novartis, BMS, MSD, AstraZeneca, Takeda, AbbVie, GSK, Amgen, Boehringer, Pfizer, Lilly; financial interests, personal, other, payment for expert testimony from Roche, Novartis, BMS, MSD, AstraZeneca, Takeda, GSK, Amgen, Boehringer, Pfizer, Lilly; financial interests, personal, other, support for attending meetings and/or travel from Roche, Novartis, BMS, MSD, AstraZeneca, GSK, Amgen, Boehringer, Pfizer; financial interests, personal, participation on a data safety monitoring board or advisory board for Roche, Novartis, BMS, MSD, AstraZeneca, Takeda, GSK, Amgen, Boehringer, Pfizer, Lilly; other, personal, leadership role, W4O Core Committee – Unpaid for European Society for Medical Oncology; other, personal, leadership role, President of the Scientific Committee and Member of the Board of Directors – Unpaid for Hellenic Cooperative Oncology Group; other, personal, leadership role, member of board of directors – unpaid for Hellenic Foundation for Cancer Research, FairLife LCC; Other, personal, leadership role, legal representative member of board of directors - unpaid for W4O-Hellas; financial interests, personal and institutional, principal investigator, pi in sponsored clinical trials, personal and institutional fees from Bristol Myers Squibb, Boehringer Ingelheim, Roche, AbbVie, Lilly, Novartis, AstraZeneca, Amgen, PPD, Parexel ILR, Qualitis, Health Data Specialist. SN reports financial interests, personal, advisor/speaker bureau for AstraZeneca, BI, MSD, Roche, Sanofi, Pfizer, Takeda, Thermo Fisher, Novartis; financial interests, personal, speaker bureau for BeiGene. AJvdW reports financial interests, institutional, research grant from AstraZeneca, Boehringer-Ingelheim, Pfizer, Roche, Takeda; financial interests, fees to institution from AstraZeneca, Boehringer-Ingelheim, Pfizer, Roche, Takeda, Janssen Cilag, Lilly, Amgen, Merck. YC reports other, personal, speaker faculty for Amgen, AstraZeneca, Bristol Myers Squibb, Guardant Health, Jazz Pharmaceuticals, Pfizer, Takeda; other, personal, advisory board for AstraZeneca, Bristol Myers Squibb, Mirati Therapeutics; financial interests, institutional, principal investigator, local PI for Amgen, AstraZeneca, Bristol Myers Squibb, EMD/Serono, Helsinn, Ipsen, Merck. SP reports financial interests, institutional, support for study conduct and medical writing from AstraZeneca; financial interests, institutional, principal investigator, coordinating PI for Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, GlaxoSmithKline, Merck Sharp and Dohme, Roche/Genentech. Financial interests, institutional, consulting fees from AbbVie, AiCME, Amgen, Arcus, AstraZeneca, Bayer, BeiGene, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, F-Star, Fishawack, Foundation Medicine, Genzyme, Gilead, GlaxoSmithKline, Illumina, Imedex, IQVIA, Incyte, Ipsen, iTeos, Janssen, Medscape, Medtoday, Merck Sharp and Dohme, Merck Serono, Merrimack, Novartis, Novocure, OncologyEducation, Pharma Mar, Phosplatin Therapeutics, PER, PeerView, Pfizer, PRIME, Regeneron, RMEI, Roche/Genentech, RTP, Sanofi, Seattle Genetics, Takeda, Vaccibody; financial interests, institution, other, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AiCME, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, ecancer, Eli Lilly, Foundation Medicine, Illumina, Imedex, Medscape, Merck Sharp and Dohme, Mirati Therapeutics, Novartis, PeerView, PER, Pfizer, Prime, Roche/Genentech, RTP, Sanofi, Takeda; financial interests, institutional, other, support for attending meetings and/or travel from AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Merck Sharp and Dohme, Novartis, Pfizer, Roche/Genentech, Takeda; financial interests, institutional, other, participation on a data safety monitoring board or advisory board for AbbVie, AiCME, Amgen, Arcus, AstraZeneca, Bayer, BeiGene, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, F-Star, Fishawack, Foundation Medicine, Genzyme, Gilead, GSK, Illumina, Imedex, IQVIA, Incyte, Ipsen, iTeos, Janssen, Medscape, Medtoday, Merck Sharp and Dohme, Merck Serono, Merrimack, Novartis, Novocure, OncologyEducation, Pharma Mar, Phosplatin Therapeutics, PER, PeerView, Pfizer, PRIME, Regeneron, RMEI, Roche/Genentech, RTP, Sanofi, Seattle Genetics, Takeda, Vaccibody. EF reports financial interests, institutional, research grant from Merck Healthcare KGaA (grant for oncology innovation), Fundación Merck Salud; financial interests, institutional, consulting fees from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Daichi Sankyo, Eli Lilly, F. Hoffmann-La Roche, GlaxoSmithKline, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Peptomyc, Pfizer, Sanofi, Takeda, BerGenBio; financial interests, institutional, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Janssen, Medical Trends, Medscape, Merck Serono, Merck Sharp & Dohme, PeerVoice, Pfizer, Sanofi, Takeda, Touch Oncology; other financial/non-financial interests, board member for Grífols. BJS reports financial interests, institutional, funding, institutional funding for conduct of clinical trial from Amgen; financial interests, personal, advisory board/honoraria from Amgen, Roche-Genentech, Novartis, Pfizer, AstraZeneca, Bristol Myers Squibb, Takeda, Eli Lilly, Merck Sharp Dohme, Janssen. SSR reports financial interests, personal, research grant from Amgen, AstraZeneca; financial interests, personal, advisory board for AstraZeneca, Mirati Therapeutics, Merck, BMS, GlaxoSmithKline, Genmab. CD reports no relationships to disclose. CL reports financial interests, personal, advisory board from Amgen; financial interests, personal, educational presentation/workshop from Amgen; financial interests, institutional, advisory board for CBPartners; non-financial interests, institutional, principal investigator, coordinating PI for Amgen, BI, Mirati Therapeutics, Revolution Medicines, Roche; non-financial interests, institutional, principal investigator, local PI Apollomics. CGF reports financial interests, other, consulting fees from AstraZeneca, Janssen; advisory board for IASCL; financial interests, personal, stocks/shares, stock or stock options in Oncoclínicas - Brazil. NB reports financial interests, other, consulting fees/honoraria from Amgen. CCO, YW, BM, TV, GN, BS report financial interests, personal, current or former full-time employment, employee and stockholder/shareholder in Amgen. DW reports financial interests, personal, invited speaker, advisory event, travel for BMS; financial interests, personal, invited speaker, advisory event for AstraZeneca, Janssen, EMD Serono; financial interests, personal, invited speaker, advisory event, consultant for Amgen, Merck; financial interest, personal, advisory event, consultant for Jazz Pharmaceuticals, Fresenius Kbi; financial interests, personal, advisory event for Pfizer, Mirati Therapeutics, Regeneron/Sanofi; financial interests, personal, advisory event for Exelixis, Eisai, Pfizer, Mirati Therapeutics, Regeneron/Sanofi, Lilly, Sanofi, Astellas, Gilead. LPA reports financial interests, research grant from MSD, AstraZeneca, Pfizer, BMS; financial interests, consulting fees from Lilly, MSD, Roche, PharmaMar, Merck, AstraZeneca, Novartis, Servier, Amgen, Pfizer, Sanofi, Bayer, BMS, Mirati Therapeutics, GSK, Janssen, Takeda, Daiichi Sankyo; financial interests, payment/honoraria for lectures, presentations, speakers bureau from AstraZeneca, Janssen, Merck, Mirati Therapeutics. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Osimertinib, a third-generation, irreversible, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), selectively inhibits both EGFR-TKI sensitizing (EGFRm) and EGFR T790M resistance mutations and has demonstrated efficacy in non-small cell lung cancer (NSCLC) CNS metastases. Most patients with EGFRm NSCLC treated with osimertinib will eventually develop resistance. ORCHARD (NCT03944772) is a phase II study aiming to characterize first-line osimertinib resistance and identify post-progression treatments., Methods: Adults aged ≥ 18 years (Japan ≥ 20 years), with EGFRm locally advanced/metastatic NSCLC will be allocated to one of three groups after first-line osimertinib progression, based on molecular profiling from a post-progression tumor biopsy. Group A will evaluate patients with protocol-determined biomarkers of resistance treated with novel osimertinib combination therapies, Group B will evaluate patients without a detectable protocol-determined biomarker treated with non-biomarker selected therapies that are chemotherapy- or EGFR-TKI-based, and Group C (observational) includes patients with histologically transformed disease, and/or a biomarker with an available therapy not investigated in ORCHARD. Group C patients will be treated as per local practice and followed to assess overall survival. The study's platform design allows for adaptability to include emerging treatments related to novel resistance mechanisms. The primary endpoint is confirmed objective response rate (investigator assessed). Other endpoints are progression-free survival, duration of response, overall survival, pharmacokinetics and safety., Conclusions: ORCHARD aims to characterize mechanisms of resistance to first-line osimertinib and explore treatments to overcome acquired resistance. The modular design allows for additional biomarker-directed cohorts and treatment options as understanding of osimertinib resistance mechanisms evolves., Competing Interests: Disclosure H Yu has received research funding to her institution from AstraZeneca, Pfizer, Cullinan, Daiichi, Novartis, Lilly and advisory board fees from AstraZeneca, Blueprint Medicine and Janssen. S Goldberg has received research funding from AstraZeneca and Boehringer Ingelheim, received advisory board/personal fees from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Genentech and Spectrum. Z Piotrowska has received research funding to her institution from Novartis, Takeda, Spectrum, AstraZeneca, Tesaro, Cullinan, Daiichi and AbbVie and has received advisory board fees from AstraZeneca, Blueprint Medicines, Janssen, Takeda, Jazz Pharmaceuticals and C4 Therapeutics. X Le receives consulting/advisory fees from EMD Serono (Merck KGaA), AstraZeneca, Spectrum Pharmaceutics, Eli Lilly, Boehringer Ingelheim, and Research Funding from Eli Lilly and Boehringer Ingelheim. JW Riess has received research funding from AstraZeneca, Merck, Spectrum, Revolution Medicines and Novartis, received advisory board/personal fees from Novartis, Medtronic, Blueprint Medicines, Boehringer Ingelheim and Spectrum. G Patel is an employee of AstraZeneca. H Ambrose, J Chmielecki, G Doughton, S Kraljevic, X Li-Sucholeiki, J Maidment and P Szekeres are employees of AstraZeneca and hold stock/stock options., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: Several treatment modalities are available for patients with stage I non-small cell lung cancer (NSCLC). Over the past decade, these treatment modalities have been further investigated and might have changed current treatment regimens. In this review we present an overview of the treatment options, developments and future perspectives for stage I NSCLC. Furthermore, we describe the current use of these treatment modalities in the Netherlands., Materials and Methods: A bibliographical search was performed in PubMed and the Cochrane Library for publications concerning treatment modalities for stage I NSCLC. In addition, evidence-based guidelines of the European Society for Medical Oncology (ESMO) and the National Comprehensive Cancer Network (NCCN) were studied., Results: The guideline-recommended treatment for operable stage I NSCLC patients is a lobectomy with systematic lymph node dissection. Inoperable patients or those refusing surgery are offered stereotactic ablative radiotherapy (SABR). Percutaneous ablation, such as radiofrequency ablation, is a non-surgical minimally invasive technique offered to those who are ineligible for surgery or SABR. The role of systemic therapy is currently limited. However, the efficacy of immunotherapy is being investigated in clinical trials. In the Netherlands, an increasing use of SABR and a relative decrease in resection rates have been observed., Conclusion: Surgery and SABR are currently the prevailing treatment modalities for stage I NSCLC patients. Despite optimization of treatment regimens, survival of patients with stage I NSCLC remains to be improved. Future studies are required to optimize treatment strategies, but also to investigate factors influencing treatment decision-making for patients with stage I NSCLC., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Since several years targeted therapy has been part of treatment in NSCLC in subsets of patients with specific genetic alterations. One of these alterations involves HER2, a member of the ERBB family of tyrosine kinase receptors. Despite that HER2 alterations in NSCLC have been studied for years, there is still no consensus about subgroup definitions. In this review HER2 alterations in NSCLC are discussed, including diagnostic challenges and treatment strategies. Three principal mechanisms of HER2 alterations can be identified: HER2 protein overexpression, HER2 gene amplification and HER2 gene mutations. There are several methods for the detection of HER2 "positivity" in NSCLC, but no gold standard has been established. Laboratory methods for assessment of HER2 positivity in NSCLC include immunohistochemistry (IHC) for protein overexpression and fluorescent in situ hybridization (FISH) and next generation sequencing (NGS) for genetic alterations. Many trials testing HER2 targeted therapy in HER2 altered NSCLC has not lead to a renewed standard of care for this group of patients. Therefore, today the (re)search on how to analyse, define and treat HER2 alterations in NSCLC continues. Still there is no consensus about HER2 subgroup definitions and results of the many trials studying possible treatment strategies are inconclusive. Future research should focus on the most important missing link, whether all HER2 alterations are relevant oncogenic drivers and whether it should be considered as a therapeutic target in NSCLC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: The objective was to study outcomes in patients in a population registry who were surgically staged as having pT3N0 NSCLC according to the seventh and eighth editions of the TNM staging classification., Methods: Details of patients who underwent surgery for NSCLC staged as pT3N0M0 from 2010 to 2013 on the basis of the seventh edition of the TNM classification were retrieved from the Netherlands Comprehensive Cancer Organization. These data were next matched with corresponding pathology data from a nationwide registry. Patients were categorized into four major pT3 subgroups as follows: those with a tumor diameter more than 7 cm, those with separate tumor nodules in the same lobe (two or more nodules), those with parietal pleural invasion, and a mixed group (consisting mainly of those with a tumor diameter larger than 7 cm combined with parietal pleural invasion)., Results: A total of 683 patients were eligible for analysis. The 3- and 5-year overall survival (OS) rates for the subtype tumor diameter larger than 7 cm were 59.9% and 47.2%, respectively, and were comparable to the rates for the subtype with pleural invasion (50.4% and 45.3%), respectively. The mixed group had worse 3- and 5-year OS rates (37.5% and 28.7%, respectively), which were comparable to the outcomes for TNM eighth edition-staged IIIB and pT4 cases in the International Association for the Study of Lung Cancer database. For the subtype two or more nodules, the 3- and 5-year OS rates were 70.6% and 62.8%, respectively, with patients with adenocarcinoma showing a significantly better OS than did patients with squamous cell carcinoma: a 5-year OS rate of 65.1% versus 47.2%, respectively (p < 0.001), suggesting that the prognosis for the adenocarcinoma subgroup may be comparable to that for the pT2 category, whereas squamous cell carcinoma nodules can remain pT3., Conclusion: This population analysis of overall survival rate by pT3N0 subcategory for NSCLC suggests that histologic type is a relevant descriptor in the category two or more nodules. The findings do not support migration of the group with a tumor diameter larger than 7 cm to the category pT4in the eighth edition of the TNM classification, and they suggest that a combination of two pT3 descriptors (the mixed group) merits migration to pT4., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: EGFR exon 20 insertions comprise 4% to 9% of EGFR mutated NSCLC. Despite being an oncogenic driver, they are associated with primary resistance to EGFR tyrosine kinase inhibitors (TKIs). We hypothesized that dual EGFR blockade with afatinib, an irreversible EGFR TKI, and cetuximab, a monoclonal antibody against EGFR, could induce tumor responses., Methods: Four patients with EGFR exon 20 insertion-positive NSCLC were treated with afatinib 40 mg once daily and cetuximab 250 mg/m 2 to 500 mg/m 2 every 2 weeks., Results: All patients had stage IV adenocarcinoma of the lung harboring an EGFR exon 20 insertion mutation. Previous lines of treatment consisted of platinum doublet chemotherapy (n = 4) and EGFR TKI (n = 2). Three of four patients showed a partial response according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Median progression-free survival was 5.4 months (95% confidence interval: 0.0 - 14.2 months; range 2.7 months - 17.6 months). Toxicity was manageable with appropriate skin management and dose reduction being required in two patients., Conclusions: Dual EGFR blockade with afatinib and cetuximab may induce tumor responses in patients with EGFR exon 20 insertion-positive NSCLC., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: [ 18 F]-fluorothymidine ([ 18 F]-FLT) is a PET-tracer enabling in-vivo visualization and quantification of tumor cell proliferation. For qualitative and quantitative analysis, adequate knowledge of normal tissue uptake is indispensable. This study aimed to quantitatively investigate baseline tracer uptake of blood pool, lung, liver and bone marrow and their precision, and to assess the longitudinal effect of systemic treatment on biodistribution., Methods: 18 F-FLT-PET(/CT) scans (dynamic or static) of 90 treatment-naïve oncological patients were retrospectively evaluated. Twenty-three patients received double baseline scans, and another 39 patients were also scanned early and late during systemic treatment with a tyrosine kinase inhibitor. Reproducible volume of interest were placed in blood pool, lung, liver, and bone marrow. For semi-quantitative analysis, SUVmean, SUVmax, and SUVpeak with several normalizations were derived., Results: SUVs of basal lung, liver, and bone marrow were not significantly different between averaged dynamic and static images, in contrast with blood pool and apical lung. Highest repeatability was seen for liver and bone marrow, with repeatability coefficients of 18.6% and 20.4% when using SUVpeak. Systemic treatment with TKIs both increased and decreased normal tissue tracer uptake at early and late time points during treatment., Conclusion: Simultaneous evaluation of liver and bone marrow uptake in longitudinal response studies may be used to assess image quality, where changes in uptake outside repeatability limits should trigger investigators to perform additional quality control on individual PET images., Advances in Knowledge: For [ 18 F]-FLT PET images, liver and bone marrow have low intra-patient variability when quantified with SUVpeak, but may be affected by systemic treatment., Implications for Patient Care: In [ 18 F]-FLT-PET response monitoring trials, liver and bone marrow uptake may be used for quality control of [ 18 F]-FLT PET images., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: We defined "ultracentral" lung tumors as centrally located non-small cell lung cancers with planning target volumes overlapping the trachea or main bronchi. Increased toxicity has been reported after both conventional and stereotactic radiotherapy for such lesions. We studied outcomes after 12 fractions of 5 Gy (BED10 = 90 Gy, heterogeneous dose distribution) to ultracentral tumors in patients unfit for surgery or conventional chemoradiotherapy., Methods: Clinical outcomes and dosimetric details were analyzed in 47 consecutive patients with single primary or recurrent ultracentral non-small cell lung cancer treated between 2010 and 2015. Those irradiated previously or with metastasis to sites other than the brain and adrenal glands were excluded. Treatments were delivered using volumetric modulated arc therapy., Results: The median age was 77.5 years, 49% of patients had a World Health Organization performance score of 2 or higher, and the median planning target volume was 104.5cm(3) (range 17.7-508.5). At a median follow-up of 29.3 months, median overall survival was 15.9 months, and 3-year survival was 20.1%. No isolated local recurrences were observed. Grade 3 or higher toxicity was recorded in 38% of patients, with 21% scored as having a "possible" (n = 2) or "likely" (n = 8) treatment-related death between 5.2 and 18.2 months after treatment. Fatal pulmonary hemorrhage was observed in 15% of patients., Conclusions: Unfit patients with ultracentral tumors who were treated using this scheme had a high local control and a median survival of 15.9 months. Despite manifestation of rates of a fatal lung bleeding comparable to those seen with conventional radiotherapy for endobronchial tumors, the overall rate of G5 toxicity is of potential concern. Additional work is needed to identify tumor and treatment factors related to hemorrhage., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: Current guidelines include both induction therapy plus an operation and chemoradiotherapy (CRT) as options for clinical stage IIIA (cIIIA) non-small cell lung cancer (NSCLC) after multidisciplinary evaluation. We explored the use of operations for cIIIA NSCLC in the Netherlands., Methods: Data about the primary treatment of patients with cIIIA NSCLC (according to the seventh edition of the Tumour, Node, and Metastasis Classification of Malignant Tumours) between 2010 and 2013 were extracted from the Netherlands Cancer Registry. Mortality information was obtained from the automated civil registry., Results: A total of 4816 patients with cIIIA NSCLC (stage cN2, 3240 [67%]; stage T4, 1252 [26%]) were identified. CRT was used in 45% of patients and an operation was a component of treatment in 15%, with 28% of the latter having induction therapy. The 4-year survival rate was highest with induction therapy plus an operation (51%), followed by an operation plus adjuvant therapy (39%) and CRT (27%). Patients receiving induction therapy plus an operation were younger than those receiving CRT (median age 60 versus 66 years). The 30- and 90-day postoperative mortality rates after induction therapy plus lobectomy were 0.6% and 3.7% compared with 4.2% and 12.5% after induction therapy plus bilobectomy or pneumonectomy. Factors associated with poorer survival after induction therapy plus an operation were age older than 69 years, histological findings of nonsquamous cell carcinoma, and bilobectomy or pneumonectomy. Pathological stage IIIA NSCLC was present in only 51% of patients with cIIIA NSCLC who underwent an operation with or without adjuvant therapy, and the disease was of a lower stage in most of the remaining patients., Conclusions: In the Netherlands between 2010 and 2013, 15% of patients with cIIIA NSCLC received an operation, with the minority of these patients receiving induction therapy. In those receiving induction therapy, 90-day mortality after bilobectomy or pneumonectomy was more than three times higher than that for lobectomy. The discrepancy between clinical and pathological stage in patients receiving an upfront operation merits further investigation., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Both bevacizumab and erlotinib have clinical activity in non-small-cell lung cancer (NSCLC). Preclinical data suggest synergistic activity., Patients and Methods: Chemonaive patients with stage IIIb or IV non-squamous NSCLC were treated with bevacizumab 15 mg/kg every 3 weeks and erlotinib 150 mg daily until progression. Primary end point was non-progression rate (NPR) at 6 weeks. Tumor response was measured with computed tomography, 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG-PET) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). KRAS and EGFR mutations were assessed in tumor samples., Results: Forty-seven patients were included. Median follow-up was 15.2 months. NPR at 6 weeks was 75%. Median progression-free survival (PFS) was 3.8 [95% confidence interval (CI) 2.3-5.4] months and median overall survival (OS) was 6.9 (95% CI 5.5-8.4) months. Toxicity was mainly mild. The presence of KRAS (n = 10) or EGFR mutations (n = 5) did not influence outcome. After 3 weeks of treatment, >20% decrease in standard uptake value as measured with positron emission tomography predicted for longer PFS (9.7 versus 2.8 months; P = 0.01) and >40% decrease in K(trans) as assessed by DCE-MRI did not predict for longer PFS., Conclusions: First-line treatment with bevacizumab and erlotinib in stage IIIb/IV NSCLC resulted in an NPR of 75%. OS was however disappointing. Early response evaluation with FDG-PET is the best predictive test for PFS.