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Background: Lung cancer in Australia contributes 9% of all new cancer diagnoses and is the leading cause of cancer death and burden. Clinical practice guidelines provide evidence-based treatment recommendations for best practice management. We aimed to determine the extent of delivery of guideline-concordant treatment (GCT) and to identify modifiable variables influencing receipt of GCT and survival., Methods: Data was sourced from the Victorian Lung Cancer Registry (VLCR) in Victoria, Australia. Descriptive statistics were used to summarize patient and disease characteristics according to treatment type: GCT versus non-GCT versus no/declined treatment. Statistical analyses included multiple logistic regression, multiple COX regression and Kaplan-Meier survival estimates., Results: 52% of patients were treated with GCT, 32.8% non-GCT and 15.2% declined or received no treatment. GCT treated patients were younger, never smoked, had no comorbidities, had better performance status, had early stage cancer, were discussed at a multidisciplinary meeting or had treatment at a higher volume hospital. Overall, patients that received GCT had a 24% lower risk of mortality compared to patients that received non-GCT., Conclusion: Modifiable variables impacting likelihood of receiving GCT included age, smoking status and treating hospital characteristics. Several modifiable variables were identified with positive impacts on survival including increased treatment of the elderly, smoking cessation, delivery of GCT, and treatment in higher volume hospitals. The measurement and reporting of delivery of GCT has positive impacts on survival and therefore merits consideration as an evidence-based quality indicator in the reporting of lung cancer quality and safety outcomes., Competing Interests: Disclosure All other authors state that they have no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Background and Purpose: To evaluate the impact of a deep learning (DL)-assisted interactive contouring tool on inter-observer variability and the time taken to complete tumour contouring., Materials and Methods: Nine clinicians contoured the gross tumour volume (GTV) using the PET-CT scans of 10 non-small cell lung cancer (NSCLC) patients, either using DL-assisted or manual contouring tools. After contouring a case using one contouring method, the same case was contoured one week later using the other method. The contours and time taken were compared., Results: Use of the DL-assisted tool led to a statistically significant decrease in active contouring time of 23 % relative to the standard manual segmentation method (p < 0.01). The mean observation time for all clinicians and cases made up nearly 60 % of interaction time for both contouring approaches. On average the time spent contouring per case was reduced from 22 min to 19 min when using the DL-assisted tool. Additionally, the DL-assisted tool reduced contour variability in the parts of tumour where clinicians tended to disagree the most, while the consensus contour was similar whichever of the two contouring approaches was used., Conclusions: A DL-assisted interactive contouring approach decreased active contouring time and local inter-observer variability when used to delineate lung cancer GTVs compared to a standard manual method. Integration of this tool into the clinical workflow could assist clinicians in contouring tasks and improve contouring efficiency., 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 © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: Functional lung avoidance (FLA) radiation therapy is an evolving field. The aim of FLA planning is to reduce dose to areas of functioning lung, with comparable target coverage and dose to organs at risk. Multicriteria optimization (MCO) is a planning tool that may assist with FLA planning. This study assessed the feasibility of using MCO to adapt radiation therapy plans to avoid functional regions of lung that were identified using a 68 Ga-4D-V/Q positron emission tomography/computed tomography., Methods and Materials: A prospective clinical trial U1111-1138-4421 was performed in which patients had a 68 Ga-4D-V/Q positron emission tomography/computed tomography before radiation treatment. Of the 72 patients enrolled in this trial, 38 patients had stage III non-small cell lung cancer and were eligible for selection into this planning study. Functional lung target volumes HF lung (highly functioning lung) and F lung (functional lung) were defined using the ventilated and perfused lung. Using knowledge-based planning, a baseline anatomic plan was created, and then a functional adapted plan was generated using multicriteria optimization. The primary aim was to spare dose to HF lung. Using the MCO tools, a clinician selected the final FLA plan. Dose to functional lung, target volumes, organs at risk and measures of plan quality were compared using standard statistical methods., Results: The HF lung volume was successfully spared in all patients. The F lung volume was successfully spared in 36 of the 38 patients. There were no clinically significant differences in dose to anatomically defined organs at risk. There were differences in the planning target volume near maximum and minimum doses. Across the entire population, there was a statistically significant reduction in the functional mean lung dose but not in the functional volume receiving 20 Gy. All trade-off decisions were made by the clinician., Conclusions: Using MCO for FLA was achievable but did result in changes to planning target volume coverage. A distinct advantage in using MCO was that all decisions regarding the cost and benefits of FLA could be made in real time., Competing Interests: Disclosures Michael S. Hofman acknowledges grant support from AAA/Novartis, ANSTO, Bayer, and Isotopia; consulting fees for lectures or advisory boards from Astellas, AstraZeneca, Janssen, Merck/MSD, Mundipharma, and Point Biopharma. Nicholas Hardcastle, Shankar Siva, and Tomas Kron receives research grants from Varian Medical Systems and Reflexion Medical for unrelated work. Shankar Siva receives research grants from Merck-Sharp-Dohme and Bayer Pharmaceuticals. Shankar Siva acknowledges consulting fees for lectures or advisory boards from Astra Zeneca and Reflexion. Nicholas Bucknell acknowledges consulting fees for lectures or advisory boards from Astra Zeneca. The remaining authors declare there are no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Disruption of the class I human leukocyte antigen (HLA) molecules has important implications for immune evasion and tumor evolution. We developed major histocompatibility complex loss of heterozygosity (LOH), allele-specific mutation and measurement of expression and repression (MHC Hammer). We identified extensive variability in HLA allelic expression and pervasive HLA alternative splicing in normal lung and breast tissue. In lung TRACERx and lung and breast TCGA cohorts, 61% of lung adenocarcinoma (LUAD), 76% of lung squamous cell carcinoma (LUSC) and 35% of estrogen receptor-positive (ER+) cancers harbored class I HLA transcriptional repression, while HLA tumor-enriched alternative splicing occurred in 31%, 11% and 15% of LUAD, LUSC and ER+ cancers. Consistent with the importance of HLA dysfunction in tumor evolution, in LUADs, HLA LOH was associated with metastasis and LUAD primary tumor regions seeding a metastasis had a lower effective neoantigen burden than non-seeding regions. These data highlight the extent and importance of HLA transcriptomic disruption, including repression and alternative splicing in cancer evolution., (© 2024. The Author(s).)

Purpose: This phase 1b/2 trial evaluated the efficacy and safety of capmatinib plus nazartinib in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC)., Methods: In phase 1b, patients with progression on first-/second-generation EGFR-TKIs received escalating doses of capmatinib 200-400 mg bid plus nazartinib 50-150 mg qd. Once the MTD/RP2D was declared, phase 2 commenced with patient enrollment into groups according to mutation status and prior lines of treatment: group 1 (fasted; EGFR-TKI resistant; 1-3 prior lines; EGFR L858R/ex19del ; any T790M/MET); group 2 (fasted; EGFR-TKI naïve; 0-2 prior lines; de novo T790M+; any MET); group 3 (fasted; treatment-naïve; EGFR L858R/ex19del ; T790M-; any MET); group 4 (with food; 0-2 prior lines; EGFR L858R/ex19del ; any T790M/MET). Primary endpoints in phase 2 were investigator-assessed overall response rate (ORR) per RECIST v1.1 (groups 1-3), safety, and tolerability of the combination with food (group 4). Efficacy was assessed by T790M and MET status for a subgroup of patients., Results: The RP2D was capmatinib 400 mg bid plus nazartinib 100 mg qd. In phase 2 (n = 144), the ORR was 28.8 %, 33.3 %, 61.7 %, and 42.9 % in groups 1 (n = 52), 2 (n = 3), 3 (n = 47), and 4 (n = 42), respectively. In group 1 +phase 1b RP2D, the ORR was 45.8 %, 26.2 %, 37.9 %, and 32.4 % in MET+ (n = 24), MET- (n = 42), T790M+ (n = 29), and T790M- (n = 34) patients. Most common any-grade treatment-related adverse events (≥25 %; n = 144) were peripheral edema (54.9 %), nausea (41.7 %), diarrhea (34.0 %), and maculopapular rash (25.0 %)., Conclusion: Capmatinib plus nazartinib showed antitumor activity in patients with EGFR-TKI-resistant, EGFR-mutated NSCLC. The overall safety profile was acceptable., Clinical Trial Registration: ClinicalTrials.gov NCT02335944., Competing Interests: Declaration of Competing Interest Enriqueta Felip: Consulting or Advisory Role: AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Lilly, Roche, Gilead Sciences, GlaxoSmithKline, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Peptomyc, Pfizer, Regeneron, Sanofi, Takeda, Turning Point Therapeutics, Daiichi Sankyo. Speakers' Bureau: Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Lilly, Roche, Genentech, Janssen, Medical Trends, Medscape, Merck Serono, Merck Sharp & Dohme, Peervoice, Pfizer, Sanofi, Takeda, Touch Oncology. Travel, Accommodations, Expenses: AstraZeneca, Janssen, Roche. Other Relationship: Grifols. Uncompensated Relationships: Member of the Scientific Advisory Committee Hospital Universitari Parc Taulí , SEOM (Sociedad Española de Oncología Médica), President from 2021–2023, “ETOP IBCSG Partners” Member of the Scientific Committee. Giulio Metro: Consultants fee from Amgen, Pfizer, Takeda, and AstraZeneca. Ross A. Soo: Advisory Board: Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Janssen, Lily, Merck, Merck Serono, Novartis, Pfizer, Puma, Roche, Taiho, Takeda, Thermo Fisher, Yuhan. Research grant: AstraZeneca, Boehringer Ingelheim. Jürgen Wolf: Advisory boards and lecture fees: Amgen, AstraZeneca, Bayer, Blueprint, BMS, Boehringer-Ingelheim, Chugai, Daiichi Sankyo, Janssen, Lilly, Loxo, Merck, MSD, Novartis, Nuvalent, Pfizer, Roche, Seattle Genetics, Takeda; Research Support (to institution): BMS, Janssen Pharmaceutica, Novartis, Pfizer. Benjamin J. Solomon: Honoraria: AstraZeneca, Merck Sharp & Dohme (Inst), Roche/Genentech, Pfizer (Inst), Amgen (Inst). Consulting or Advisory Role: Bristol Myers Squibb (Inst), Merck Sharp & Dohme, AstraZeneca (Inst), Pfizer (Inst), Roche/Genentech (Inst), Amgen, Lilly, BeiGene, Takeda, GlaxoSmithKline (Inst), Janssen (Inst), GlaxoSmithKline. Research Funding: Sanofi (Inst). Daniel SW Tan: Honoraria: Bristol Myers Squibb, Takeda, Novartis, Roche, Pfizer. Consulting or Advisory Role: Novartis, Merck, Loxo, AstraZeneca, Roche, Pfizer, C4 Therapeutics. Research Funding: Novartis (Inst), GlaxoSmithKline (Inst), AstraZeneca (Inst). Travel, Accommodations, Expenses: Pfizer, Boehringer Ingelheim, Roche. Andrea Ardizzoni: Honoraria: AstraZeneca, BMS, Lilly, MSD Oncology, Abbvie, Roche. Consulting or Advisory Role: AstraZeneca, MSD Oncology, BMS, Lilly, Novartis, Takeda, Janssen Oncology, Roche, Sanofi. Dae Ho Lee: Honoraria: Abbvie; AstraZeneca/MedImmune; BC World Pharm; Boehringer Ingelheim; Bristol-Myers Squibb; ChongKeunDang Healthcare; Lilly; Menarini; MSD; Novartis; Ono Pharmaceutical; Pfizer; Roche/Genentech; Samyang; ST Cube; Takeda; Yuhan. Consulting or Advisory Role: ST Cube. Lecia V. Sequist: Consulting or Advisory Role: AstraZeneca; Genentech/Roche; Takeda. Research Funding: AstraZeneca (Inst); Boehringer Ingelheim (Inst); Delfi Diagnostics (Inst); Novartis (Inst). Fabrice Barlesi: Consulting or Advisory Role: Roche/Genentech (Inst), Novartis (Inst), Bristol Myers Squibb (Inst), AstraZeneca/MedImmune (Inst), Boehringer Ingelheim (Inst), Lilly (Inst), Merck Serono (Inst), MSD Oncology (Inst), Takeda (Inst), Bayer (Inst), Amgen (Inst), Eisai Europe (Inst), Sanofi (Inst), Mirati Therapeutics (Inst). Research Funding: Roche/Genentech (Inst), AstraZeneca/MedImmune (Inst), Bristol Myers Squibb (Inst), Pierre Fabre (Inst), AbbVie (Inst), Amgen (Inst), Bayer (Inst), Boehringer Ingelheim (Inst), Eisai (Inst), Lilly (Inst), Ipsen (Inst), Innate Pharma (Inst), Novartis (Inst), Merck Serono (Inst), MSD Oncology (Inst), Pfizer (Inst), Sanofi/Aventis (Inst), Takeda (Inst). Travel, Accommodations, Expenses: Roche/Genentech. Santiago Ponce-Aix: No conflicts of interest. Delvys Rodriguez Abreu: Consulting/advisory role from Roche, Bristol-Myers Squibb, AstraZeneca Spain, Novartis; Speaker fees from Roche, Bristol-Myers Squibb, and MSD; Travel expense from Roche, Bristol-Myers Squibb, MSD, and Novartis. Maria Rosario Garcia Campelo: Consulting or Advisory Role: Roche/Genentech, MSD Oncology, AstraZeneca, Bristol Myers Squibb, Pfizer, Novartis, Takeda, Boehringer Ingelheim, Janssen Oncology. Speakers' Bureau: Roche, AstraZeneca, Bristol Myers Squibb, Pfizer, Novartis, Takeda, Boehringer Ingelheim, MSD Oncology, Sanofi/Aventis, Janssen Oncology, Amgen, Lilly. Travel, Accommodations, Expenses: Roche/Genentech, MSD Oncology, Pfizer. Mette Sprauten: No conflicts of interest. Leslie O’Sullivan Djentuh: Employee of Novartis. Nathalie Smith: Employee of Novartis. Aline Jary: Employee of Novartis. Riccardo Belli: Employee of Novartis. Sabine Glaser: Employee of Novartis and stockholder of Novartis, Alcon, Sandoz. Mike Zou: Employee of Daiichi Sankyo, Inc. Xiaoming Cui: Employee and stockholder - Novartis. Monica Giovannini: Employee of Novartis. James Chih-Hsin Yang: Honoraria: Boehringer Ingelheim, Roche, MSD, AstraZeneca, Novartis, Bristol Myers Squibb, Ono Pharmaceutical, Takeda, Lilly, Pfizer. Consulting or Advisory Role: Boehringer Ingelheim, Novartis, AstraZeneca, Clovis Oncology, Lilly, MSD Oncology, Merck Serono, Celgene, Bayer, Pfizer, Ono Pharmaceutical, Bristol Myers Squibb, Boehringer Ingelheim (Inst), Yuhan, Hansoh, Blueprint Medicines, Daiichi Sankyo, G1 Therapeutics, AbbVie, Takeda, Amgen, Incyte, Merck Serono (Inst), Janssen (Inst), GlaxoSmithKline (Inst), Amgen (Inst), Takeda (Inst), Daiichi Sankyo (Inst), AstraZeneca (Inst), Novartis (Inst), MSD Oncology (Inst). Travel, Accommodations, Expenses: Pfizer., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Following the approval of the first antibody-drug conjugates (ADCs) in the early 2000s, development has increased dramatically, with 14 ADCs now approved and >100 in clinical development. In lung cancer, trastuzumab deruxtecan (T-DXd) is approved in human epidermal growth factor receptor 2 (HER2)-mutated, unresectable or metastatic non-small-cell lung cancer, with ADCs targeting HER3 (patritumab deruxtecan), trophoblast cell-surface antigen 2 [datopotamab deruxtecan and sacituzumab govitecan (SG)] and mesenchymal-epithelial transition factor (telisotuzumab vedotin) in late-stage clinical development. In breast cancer, several agents are already approved and widely used, including trastuzumab emtansine, T-DXd and SG, and multiple late-stage trials are ongoing. Thus, in the coming years, we are likely to see significant changes to treatment algorithms. As the number of available ADCs increases, biomarkers (of response and resistance) to better select patients are urgently needed. Biopsy sample collection at the time of treatment selection and incorporation of translational research into clinical trial designs are therefore critical. Biopsy samples taken peri- and post-ADC treatment combined with functional genomics screens could provide insights into response/resistance mechanisms as well as the impact of ADCs on tumour biology and the tumour microenvironment, which could improve understanding of the mechanisms underlying these complex molecules. Many ADCs are undergoing evaluation as combination therapy, but a high bar should be set to progress clinical evaluation of any ADC-based combination, particularly considering the high cost and potential toxicity implications. Efforts to optimise ADC dosing/duration, sequencing and the potential for ADC rechallenge are also important, especially considering sustainability aspects. The ETOP IBCSG Partners Foundation are driving strong collaborations in this field and promoting the generation/sharing of databases, repositories and registries to enable greater access to data. This will allow the most important research questions to be identified and prioritised, which will ultimately accelerate progress and help to improve patient outcomes., Competing Interests: Disclosure SP reports receipt of institutional educational grants and honoraria (all fees to institution) for consultation, attending advisory boards and/or providing lectures for the following organisations: consultation/advisory role: AbbVie, AiCME, Amgen, Arcus, AstraZeneca, Bayer, Beigene, BerGenBio, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb (BMS), 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 & Dohme (MSD), Merck Serono, Merrimack, Mirati, Novartis, Novocure, OncologyEducation, Pharma Mar, Phosplatin Therapeutics, PER, Peerview, Pfizer, Regeneron, RMEI, Roche/Genentech, RTP, Sanofi, Seattle Genetics, Takeda, Vaccibody; Board of Director role: Galenica SA; presentation at a company-organised public event: AiCME, AstraZeneca, Boehringer Ingelheim, BMS, ecancer, Eli Lilly, Foundation Medicine, GSK, Illumina, Imedex, Ipsen, Medscape, MSD, Mirati, Novartis, PER, Peerview, Pfizer, Roche/Genentech, RTP, Sanofi, Takeda; receipt of grants/research support: principal investigator in trials (institutional financial support for clinical trials) sponsored by Amgen, AstraZeneca, Beigene, BMS, GSK, MSD, Roche/Genentech. SL reports receipt of research funding to institution from Novartis, BMS, Merck Sharp & Dohme (MSD), Puma Biotechnology, Eli Lilly, Nektar Therapeutics, AstraZeneca/Daiichi Sankyo, Seattle Genetics; has acted as consultant (not compensated) to Seattle Genetics, Novartis, BMS, MSD, AstraZeneca/Daiichi Sankyo, Eli Lilly, Pfizer, Gilead Therapeutics, Nektar Therapeutics, PUMA Biotechnologies, Roche-Genentech; has acted as consultant (paid to institution) to Novartis, GSK, Roche-Genentech, AstraZeneca/Daiichi Sankyo, Gilead Sciences, Seattle Genetics, MSD, Eli Lilly, BMS. FA reports research grants (compensated to the hospital) from AstraZeneca, Daiichi Sankyo, Roche, Lilly, Pfizer, Owkin, Novartis, Guardant Health; honoraria (compensated to the hospital) for advisory board participation or speaker activities from AstraZeneca, Daiichi Sankyo, Roche, Lilly, Pfizer, Owkin, Novartis, Guardant Health, N-Power Medicine, SERVIER, Gilead, Boston Pharmaceutics; personal honoraria for advisory board participation from Lilly. SC reports receipt of personal consulting fees from Novartis, AstraZeneca, Nuvalent, Genesis Therapeutics, Effector Therapeutics, SAGA Diagnostics, Prelude Therapeutics, Gerson Lehman Group; stock options from Effector Therapeutics, Odyssey Biosciences; research funding from AstraZeneca, Daiichi Sankyo. EF reports receipt of personal speaker honoraria from Amgen, AstraZeneca, BMS, Daiichi Sankyo, Eli Lilly, F. Hoffmann-La Roche, Genentech, Janssen, Medical Trends, Medscape, Merck Serono, MSD, Peervoice, Pfizer, Sanofi, Takeda, Touch Oncology; personal honoraria for advisory board participation from AbbVie, Amgen, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, BMS, Eli Lilly, F. Hoffmann-La Roche, Gilead, GSK, Janssen, Merck Serono, MSD, Novartis, Peptomyc, Pfizer, Regeneron, Sanofi, Takeda, Turning Point, Daiichi Sankyo; financial support for meeting attendance and/or travel from AstraZeneca, Janssen, Roche. SPF reports receipt of personal honoraria for advisory board participation from Amgen, AstraZeneca, Illumina, Pfizer; honoraria to institution for advisory board participation from Roche; personal speaker honoraria from Takeda; holds personal stocks/shares in Revolution Medicines. PAJ reports receipt of grants and personal fees from AstraZeneca, Boehringer Ingelheim; personal fees from Pfizer, Roche/Genentech, Chugai Pharmaceuticals, Loxo Oncology; grants and personal fees from Eli Lilly; personal fees from SFJ Pharmaceuticals, Voronoi; grants and personal fees from Daiichi Sankyo; personal fees from Biocartis, Novartis, Sanofi, Scorpion Therapeutics, Merus, Frontier Medicines, Hongyun Biotechnology, Duality Biologics, Blueprint Medicines, Phanes Therapeutics; grants and personal fees from Takeda Oncology; personal fees from Mirati Therapeutics, Transcenta, Silicon Therapeutics, Syndax, Nuvalent, Bayer, Eisai, Allorion Therapeutics, Accutar Biotech, AbbVie; grants from Revolution Medicines; grants from PUMA; grants from Astellas, outside the submitted work. In addition, PAJ is a co-inventor on a DFCI patent on EGFR mutations and receives post-marketing royalties from Lab Corp. KMK reports receipt of personal consultancy fees from AbbVie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Daiichi Sankyo, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, Ventana; personal speaker honoraria from AbbVie, AstraZeneca, Amgen, Boehringer Ingelheim, BMS, Janssen, Merck Serono, Merck Sharp & Dohme, Mirati, Novartis, Pfizer, Roche, Sanofi, Ventana, Medscape, Mirati, Prime Oncology, PeerVoice, PER. EM reports receipt of personal honoraria for consulting/advisory roles to Exact Sciences, MSD Oncology, Daiichi Sankyo/AstraZeneca, Pfizer, Seagen, Ipsen; reimbursement of travel, accommodation and expenses from Roche, Pfizer, Lilly, Novartis, Gilead Sciences, AstraZeneca, Pierre Fabre. AP reports receipt of personal honoraria for consulting or an advisory role for AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Daiichi Sankyo, Lilly, GSK, Janssen, MSD, Mundipharma, Novartis, Roche; speakers bureaus for AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, eCancer, Janssen, MSD, Medscape, PeerVoice, touchONCOLOGY. MP reports receipt of personal honoraria for consultancy to Roche, Eli Lilly, Pfizer, Boehringer Ingelheim, MSD, BMS, Novartis, AstraZeneca, Takeda, Gritstone, Sanofi, GSK, Amgen, AbbVie, Ipsen, Esaï, Daiichi Sankyo, Janssen, AnHeart Therapeutics, Novocure; lecture fees from Eli Lilly, Roche, AstraZeneca, Pfizer, Amgen, Boehringer Ingelheim, BMS, Takeda, MSD, Chugai, Illumina, Sanofi, Janssen; research grants (paid to institution) from Roche, AstraZeneca, Takeda, Boehringer Ingelheim. EFS reports consultancy fees (paid to institution) from AstraZeneca, BMS, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Janssen, MSD, Roche Sanofi, Takeda; personal honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Boehringer Ingelheim, Daiichi Sankyo; participation on a Data Safety Monitoring Board for DSI. CS reports grants from AstraZeneca, Boehringer Ingelheim, BMS, Pfizer, Roche-Ventana, Invitae (previously Archer Dx Inc.), Ono Pharmaceutical, Personalis; is Chief Investigator and Steering Committee Chair for the AZ MeRmaiD 1 and 2 clinical trials; is Co-Chief Investigator of the NHS Galleri trial funded by GRAIL and a paid member of GRAIL’s Scientific Advisory Board; has received consultancy fees from Achilles Therapeutics (also SAB member), Bicycle Therapeutics (also SAB member), Genentech, Medicxi, China Innovation Centre of Roche (CICoR) formerly Roche Innovation Centre—Shanghai, Metabomed (until July 2022), Relay Therapeutics SAB member, Saga Diagnostics SAB member, the Sarah Cannon Research Institute; has received honoraria from Amgen, AstraZeneca, BMS, GSK, Illumina, MSD, Novartis, Pfizer, Roche-Ventana; has previously held stock options in Apogen Biotechnologies and GRAIL, currently has stock options in Epic Bioscience and Bicycle Therapeutics, and has stock options and is co-founder of Achilles Therapeutics; declares a patent application (PCT/US2017/028013) for methods to lung cancer, targeting neoantigens (PCT/EP2016/059401), identifying patent response to immune checkpoint blockade (PCT/EP2016/071471), methods for lung cancer detection (US20190106751A1), identifying patients who respond to cancer treatment (PCT/GB2018/051912), determining HLA LOH (PCT/GB2018/052004), predicting survival rates of patients with cancer (PCT/GB2020/050221), methods for systems and tumour monitoring (PCT/EP2022/077987); is an inventor on a European patent application (PCT/GB2017/053289) relating to assay technology to detect tumour recurrence—this patent has been licensed to a commercial entity and under their terms of employment, he is due a share of any revenue generated from such license(s). GV reports receipt of honoraria for consulting and participation in advisory boards from Roche, AstraZeneca, Daiichi Sankyo, Gilead, Pfizer and Agilent. RAS reports receipt of personal speaker honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, Roche; honoraria for advisory board participation from AstraZeneca, Eisai, GSK, Guardant, Janssen, Merck, MSD, Novocure, Pfizer, Pharmamar, Roche; financial compensation for his role as Editor for CTR and Editor in Chief for Lung Cancer; receipt of institutional research grants for ETOP and/or IBCSG studies from Amgen, AstraZeneca, BMS, Celgene, Ipsen, Janssen, Mirati, MSD, Novartis, Pfizer, Pierre Fabre, Roche; is an ETOP IBCSG Partners Foundation Member and President of the Board of Directors (uncompensated)., (Copyright © 2024 European Society for Medical Oncology. All rights reserved.)

Understanding the role of the tumor microenvironment (TME) in lung cancer is critical to improving patient outcomes. We identified four histology-independent archetype TMEs in treatment-naïve early-stage lung cancer using imaging mass cytometry in the TRACERx study (n = 81 patients/198 samples/2.3 million cells). In immune-hot adenocarcinomas, spatial niches of T cells and macrophages increased with clonal neoantigen burden, whereas such an increase was observed for niches of plasma and B cells in immune-excluded squamous cell carcinomas (LUSC). Immune-low TMEs were associated with fibroblast barriers to immune infiltration. The fourth archetype, characterized by sparse lymphocytes and high tumor-associated neutrophil (TAN) infiltration, had tumor cells spatially separated from vasculature and exhibited low spatial intratumor heterogeneity. TAN-high LUSC had frequent PIK3CA mutations. TAN-high tumors harbored recently expanded and metastasis-seeding subclones and had a shorter disease-free survival independent of stage. These findings delineate genomic, immune, and physical barriers to immune surveillance and implicate neutrophil-rich TMEs in metastasis., Significance: This study provides novel insights into the spatial organization of the lung cancer TME in the context of tumor immunogenicity, tumor heterogeneity, and cancer evolution. Pairing the tumor evolutionary history with the spatially resolved TME suggests mechanistic hypotheses for tumor progression and metastasis with implications for patient outcome and treatment. This article is featured in Selected Articles from This Issue, p. 897., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: Australia has one of the highest rates of asbestos-associated diseases. Mesothelioma remains an area of unmet need with a 5-year overall survival of 10%. First-line immunotherapy with ipilimumab and nivolumab is now a standard of care for unresectable pleural mesothelioma following the CheckMate 743 trial, with supportive data from the later line single-arm MAPS2 trial. RIOMeso evaluates survival and toxicity of this regimen in real-world practice., Methods: Demographic and clinicopathologic data of Australian patients treated with ipilimumab and nivolumab in first- and subsequent-line settings for pleural mesothelioma were collected retrospectively. Survival was reported using the Kaplan-Meier method and compared between subgroups with the log-rank test. Toxicity was investigator assessed using Common Terminology Criteria for Adverse Events version 5.0., Results: A total of 119 patients were identified from 11 centers. The median age was 72 years, 83% were male, 92% had Eastern Cooperative Oncology Group less than or equal to 1, 50% were past or current smokers, and 78% had known asbestos exposure. In addition, 50% were epithelioid, 19% sarcomatoid, 14% biphasic, and 17% unavailable. Ipilimumab and nivolumab were used first line in 75% of patients. Median overall survival (mOS) was 14.5 months (95% confidence interval [CI]: 13.0-not reached [NR]) for the entire cohort. For patients treated first line, mOS was 14.5 months (95% CI: 12.5-NR) and in second- or later-line patients was 15.4 months (95% CI: 11.2-NR). There was no statistically significant difference in mOS for epithelioid patients compared with nonepithelioid (19.1 mo [95% CI: 15.4-NR] versus 13.0 mo [95% CI: 9.7-NR], respectively, p = 0.064). Furthermore, 24% of the patients had a Common Terminology Criteria for Adverse Events grade greater than or equal to 3 adverse events, including three treatment-related deaths. Colitis was the most frequent adverse event., Conclusions: Combination immunotherapy in real-world practice has poorer survival outcomes and seems more toxic compared with clinical trial data. This is the first detailed report of real-world survival and toxicity outcomes using ipilimumab and nivolumab treatment of pleural mesothelioma., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: Smoking is a risk factor for the development of lung cancer and reduces life expectancy within the general population. Retrospective studies suggest that non-smokers have better outcomes after treatment for lung cancer. We used a prospective database to investigate relationships between pre-treatment smoking status and survival for a cohort of patients with stage III non-small-cell lung cancer (NSCLC) treated with curative-intent concurrent chemoradiotherapy (CRT)., Methods: All patients treated with CRT for stage III NSCLC at a major metropolitan cancer centre were prospectively registered to a database. A detailed smoking history was routinely obtained at baseline. Kaplan-Meier statistics were used to assess overall survival and progression-free survival in never versus former versus current smokers., Results: Median overall survival for 265 eligible patients was 2.21 years (95 % Confidence Interval 1.78, 2.84). It was 5.5 years (95 % CI 2.1, not reached) for 25 never-smokers versus 1.9 years (95 % CI 1.5, 2.7) for 182 former smokers and 2.2 years (95 % CI 1.3, 2.7) for 58 current smokers. Hazard ratio for death was 2.43 (95 % CI 1.32-4.50) for former smokers and 2.75 (95 % CI 1.40, 5.40) for current smokers, p = 0.006. Actionable tumour mutations (EGFR, ALK, ROS1) were present in more never smokers (14/25) than former (9/182) or current (3/58) smokers. TKI use was also higher in never smokers but this was not significantly associated with superior survival (Hazard ratio 0.71, 95 % CI 0.41, 1.26)., Conclusions: Never smokers have substantially better overall survival than former or current smokers after undergoing CRT for 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 © 2024 Elsevier B.V. All rights reserved.)

Epidermal growth factor receptor (EGFR) mutations are detected in up to one third of patients with unresectable stage III non-small cell lung cancer (NSCLC). The current standard of care for unresectable stage III NSCLC is consolidation durvalumab for patients who have not progressed following concurrent chemoradiotherapy (the 'PACIFIC regimen'). However, the benefit of immunotherapy, specifically in patients with EGFR mutation-positive (EGFRm) tumors, is not well characterized, and this treatment approach is not recommended in these patients, based on a recent ESMO consensus statement. EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have demonstrated significant improvements in patient outcomes in EGFRm metastatic NSCLC. The benefits of these agents have also translated to patients with EGFRm early-stage resectable disease as adjuvant therapy. The role of EGFR-TKIs has yet to be prospectively characterized in the unresectable setting. Preliminary efficacy signals for EGFR-TKIs in unresectable EGFRm stage III NSCLC have been reported from a limited number of subgroup and retrospective studies. Several clinical trials are ongoing assessing the safety and efficacy of EGFR-TKIs in this patient population. Here, we review the current management of unresectable EGFRm stage III NSCLC. We outline the rationale for investigating EGFR-TKI strategies in this setting and discuss ongoing studies. Finally, we discuss the evidence gaps and future challenges for treating patients with unresectable EGFRm stage III NSCLC., Competing Interests: Declaration of competing interest Terufumi Kato reports consulting/advisory roles: AstraZeneca, BeiGene, Daiichi-Sankyo, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer; honoraria: Amgen Inc., AstraZeneca, BeiGene, Boehringer Ingelheim, Chugai Pharmaceuticals Co., Ltd., Daiichi-Sankyo, Eli Lilly and Company, GlaxoSmithKline, Janssen, Merck KGaA, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical Co., Ltd., Pfizer, Taiho Pharmaceutical, Takeda; employment (spouse): Eli Lilly and company; research support (to institution): AbbVie Inc., Amgen Inc., AstraZeneca, BeiGene, Blueprint Medicines, Chugai Pharmaceutical Co., Ltd., Daiichi-Sankyo, Eli Lilly and Company, HaiHe Biopharma, Merck KGaA, Merck Sharp & Dohme, Novartis, Pfizer, Regeneron Pharmaceuticals Inc., Takeda, Turning Point Therapeutics Inc. Ignacio Casarini reports local principal investigator role: AstraZeneca, Bristol-Myers Squibb, Exelixis, Lilly, Merck Sharp & Dohme, Novartis, Roche (non-financial and for institution); principal investigator role for multiple clinical studies: AstraZeneca, Bristol-Myers Squibb, Exelixis, Lilly, Merck Sharp & Dohme, Novartis; principal investigator role for one clinical study: Roche. Corinne Faivre-Finn reports research funding: AstraZeneca, and Elekta; travel expenses: AstraZeneca, Elekta, Peter MacCallum Cancer Centre, and CF-F’s institution; and uncompensated relationships: AstraZeneca, Elekta, and Merck Sharpe & Dohme. CF-F is supported by a grant from the National Institute for Health Research (NIHR) Manchester Biomedical Research Centre. Fiona Hegi-Johnson reports research funding: AstraZeneca; honoraria: AstraZeneca; payment or honoraria for lectures and presentations: BeiGene, Merck Sharpe & Dohme. Participation on an advisory board: AstraZeneca. FH-J is supported by the Victorian Cancer Agency. Shun Lu reports consulting/advisory roles: AstraZeneca, Boehringer Ingelheim, GenomiCare Biotechnology, Hutchison MediPharma Ltd., Pfizer, prIME Oncology, Roche, Simcere Pharmaceutical Group, Yuhan, Zai Lab; speaker’s bureau: AstraZeneca, Hansoh Pharmaceutical Group Co. Ltd., Hengrui Pharmaceuticals Company Ltd., Roche; research funding (to institution): AstraZeneca, BeiGene, Bristol-Myers Squibb, Hansoh Pharmaceutical Group Co. Ltd., Hengrui Pharmaceuticals Company Ltd., Hutchison MediPharma Ltd., Lilly Suzhou Pharmaceutical Co. Ltd., Roche. Mustafa Özgüroğlu reports consulting/advisory roles: Astellas (to self and institution), Janssen, Sanofi; honoraria: Astellas (to self and institution), Janssen, Novartis, Roche, Sanofi. Suresh S. Ramalingam reports consulting/advisory roles: Amgen Inc., AstraZeneca, Bristol-Myers Squibb, Genentech, Merck & Co. Inc., Takeda Inc., Tesaro; research funding: Amgen Inc., Advaxis Inc., AstraZeneca, Bristol-Myers Squibb, Genmab, Merck & Co. Inc., Takeda, Tesaro Inc. Manuel Cobo declares no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objectives: In the Phase I/III IMpower133 study, first-line atezolizumab plus carboplatin and etoposide (CP/ET) treatment for extensive-stage small cell lung cancer (ES-SCLC) significantly improved overall survival (OS) and progression-free survival versus placebo plus CP/ET. We explored patient and disease characteristics associated with long-term survival in IMpower133, and associations of differential gene expression and SCLC-A (ASCL1-driven), SCLC-N (NEUROD1-driven), SCLC-P (POU2F3-driven), and SCLC-inflamed (SCLC-I) transcriptional subtypes with long-term survival., Materials and Methods: Patients with previously untreated ES-SCLC were randomized 1:1 to four 21-day cycles of CP/ET with atezolizumab or placebo. Long-term survivors (LTS) were defined as patients who lived ≥ 18 months post randomization. A generalized linear model was used to evaluate the odds of living ≥ 18 months. Differential gene expression was analyzed using RNA-sequencing data in LTS and non-LTS. OS was assessed by T-effector and B-cell gene signature expression. Distribution of SCLC transcriptional subtypes was assessed in LTS and non-LTS., Results: More LTS were in the atezolizumab arm (34%) than in the placebo arm (20%). The odds ratio for living ≥ 18 months in the atezolizumab arm versus the placebo arm was 2.1 (P < 0.03). Enhanced immune-related signaling was seen in LTS in both arms. Exploratory OS analyses showed atezolizumab treatment benefit versus placebo across T-effector and B-cell gene signature expression subgroups. A higher proportion of LTS than non-LTS in both arms had the SCLC-I subtype; this difference was particularly pronounced in the atezolizumab arm., Conclusion: These exploratory analyses suggest that long-term survival is more likely with atezolizumab than placebo in ES-SCLC, confirming the treatment benefit of the IMpower133 regimen., Clinicaltrial: gov Identifier: NCT02763579., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: S.V.L. declares grants or contracts from Alkermes, Bayer, Blueprint, Bristol Myers Squibb, Elevation Oncology, Genentech, Lilly, Merck, Merus, Pfizer, Rain Therapeutics, RAPT, Turning Point Therapeutics; consulting fees from Amgen, AstraZeneca, Bayer, BeiGene, Blueprint, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Elevation Oncology, Genentech/Roche, Gilead, Guardant Health, Janssen, Jazz Pharmaceuticals, Lilly, Merck/Merck Sharpe & Dohme, Novartis, Regeneron, Sanofi, Takeda, Turning Point Therapeutics; and participation on a Data Safety Monitoring or Advisory Board for Candel Therapeutics. T.S.K.M. declares consulting and advisory personal fees from AbbVie, Inc., ACEA Pharma, Alpha Biopharma Co. Ltd., Amgen, Amoy Diagnostics Co. Ltd., AstraZeneca, BeiGene, Boehringer-Ingelheim, Bristol Myers Squibb, Blueprint Medicines Corporation, CStone Pharmaceuticals, Daiichi Sankyo, Eisai, Fishawack Facilitate Ltd., geneDecode (uncompensated), Gritstone Oncology Inc., Guardant Health, Hengrui Therapeutics, Ignyta Inc., IQVIA, Incyte Corporation, Janssen, Lilly, Loxo-Oncology, Lunit USA, Inc., Merck Serono, Merck Sharp & Dohme, Mirati Therapeutics Inc., Novartis, OrigiMed, Pfizer, Inc., Puma Biotechnology Inc., Roche, Sanofi-Aventis R&D, Takeda, Yuhan Corporation, SFJ Pharmaceuticals, Curio Science, Inivata, Berry Oncology, Qiming Development (HK) Ltd., Gilead Sciences, Inc., Vertex Pharmaceuticals, and Covidien LP; lecture personal fees from ACEA Pharmaceuticals, Alpha Biopharma Co. Ltd., Amgen, Amoy Diagnostics Co. Ltd., AstraZeneca, BeiGene, Boehringer-Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Fishawack Facilitate Ltd., geneDecode, (uncompensated), InMed Medical Communication, Janssen, Lilly, Lunit USA, Inc., MD Health (Brazil), Medscape/WebMD, Merck Serono, Merck Sharpe & Dohme, Novartis, OrigiMed, PeerVoice, Physicians’ Education Resource, P. Permanyer SL, Pfizer, Inc., PrIME Oncology, Research to Practice, Roche, Sanofi-Aventis R&D, Takeda, Touch Medical Media, Daz Group, Lucence Health Inc., Merck Pharmaceuticals HK Ltd., Shanghai BeBirds Translation & Consulting Co. Ltd., Liangyihui Network Technology Co. Ltd., and Taiho; grants from AstraZeneca, Bristol Myers Squibb, Merck Serono, Merck Sharpe & Dohme, Novartis, Pfizer, Inc., Roche, Takeda, Clovis Oncology, SFJ Pharmaceuticals, XCovery, and G1 Therapeutics Inc.; personal fees for supporting an advisory board for Inivata, Berry Therapeutics Inc., and G1 Therapeutics Inc.; shareholding for Aurora, Sanomics Ltd., Hutchison ChiMed; and a role on the Board of Directors for Lunit USA, Inc., AstraZeneca PLC, Hutchison ChiMed, Sanomics Ltd., Aurora. B.Y.N declares employment by Genentech and stockholding in Roche. A.S.M declares grants or contracts from NIH/NCI, Verily, Novartis, Department of Defense, and Mark Foundation; payment or honoraria to institution for lecture, presentations, speakers bureaus, manuscript writing or education events from AbbVie, AstraZeneca, BeiGene, Bristol Myers Squibb, Genentech; support for attending meetings and/or travel from Shanghai Roche Pharmaceuticals; patents planned, issues, or pending for patents submitted unrelated to this work; and other financial or non-financial interests from non-remunerated director of the Mesothelioma Applied Research Foundation. R. De Boer declares payment of honoraria from Novartis, AstraZeneca, and Gilead; and support for attending meetings and/or travel from Amgen, Novartis, and Roche. S.S. declares payment or honoraria for lectures, presentation, speakers bureaus, manuscript writing, or educations events from Chugai Pharma, AstraZeneca, Ono Pharmaceutical, Bristol Myers Squibb, Merck Sharpe & Dohme, Nippon Boehringer-Ingelheim, Pfizer, Taiho Pharmaceutical, Eli Lilly, and Company, Novartis, Kyowa Kirin, Yakult Honsha, and Towa Pharmaceutical. R. Dziadziuszko declares consulting fees from Roche, Boehringer-Ingelheim, AstraZeneca, Takeda, Pfizer, Foundation Medicine, Novartis, and Karyopharm; and payment or honoraria from Roche, Novartis, AstraZeneca, and Pfizer. A.S. declares payment or honoraria from AstraZeneca, Bristol Myers Squibb, Roche, Merck Sharpe & Dohme, Novartis, and Pfizer; support for attending meetings and/or travel from Bristol Myers Squibb, Roche, Boehringer-Ingelheim, and AstraZeneca; and participation on data safety monitoring or advisory boards for Bristol Myers Squibb, Roche, Takeda, AstraZeneca, BIOCAD, and Boehringer-Ingelheim. M.J.H declares payment or honoraria from Boehringer-Ingelheim, AstraZeneca, Takeda, Pfizer, Merck Sharpe & Dohme, and Roche; and participation on data safety monitoring or advisory boards for Boehringer-Ingelheim, AstraZeneca, Takeda, Pfizer, Merck Sharpe & Dohme, and Roche. M.C.G. declares grants from AstraZeneca, Bayer, Bristol Myers Squibb, Janssen, Merck Serono, Merck Sharpe & Dohme, Novartis, Pfizer, Roche, Amgen, GSK, Sanofi; consulting fees from AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer-Ingelheim, Janssen, Lilly, Yuhan, Merck Serono, Merck Sharpe & Dohme, Novartis, Pfizer, Roche, Amgen, Libbs, and Sanofi; payment of honoraria from Boehringer-Ingelheim, Pfizer, Bayer, Roche, Merck Sharpe & Dohme, Bristol Myers Squibb, AstraZeneca, Novartis, Merck Serono, Janssen, and Amgen; support for attending meetings and/or travel from Boehringer-Ingelheim, Pfizer, Bayer, Roche, Merck Sharpe & Dohme, Bristol Myers Squibb, AstraZeneca, Novartis, and Merck Serono; participation on data safety monitoring or advisory boards for TEVA, Boehringer-Ingelheim, Bayer, Pfizer, Roche, Merck Sharpe & Dohme, Bristol Myers Squibb, AstraZeneca, Yuhan, Janssen, Merck Serono, Novartis, Amgen; and payment of honoraria for promotional activities from Boehringer-Ingelheim, Pfizer, Roche, Merck Sharpe & Dohme, Bristol Myers Squibb, AstraZeneca, Novartis, TEVA, Amgen, and Janssen. C.M.G. declares research grants/funding to self from AstraZeneca; advisory/consultancy to AstraZeneca, Kisoji Biotechnology, Jazz Pharmaceuticals, and Bristol Myers Squibb; and speaker bureau/expert testimony for AstraZeneca and BeiGene. J.V.H declares advisory/consultancy for Bristol Myers Squibb, BrightPath Biotherapeutics, Janssen Global Services, Nexus Health Systems Pneuma Respiratory, Kairos Venture Investments, Roche, Leads Biolabs, AstraZeneca, Boehringer-Ingelheim, Catalyst, Genentech, GlaxoSmithKline, Guardant Health, Foundation Medicine, Hengrui Therapeutics, Eli Lilly, Novartis, Spectrum, EMD Serono, Sanofi, Takeda, and Mirati Therapeutics; research support to AstraZeneca, GlaxoSmithKline, and Spectrum; and royalties/licensing fees from Spectrum. L.A.B. declares an advisory role/consultancy for AstraZeneca, AbbVie, Bristol Myers Squibb, and Merck; and research funding from AstraZeneca and AbbVie. S.L. declares employment by Genentech and stockholding in Roche. A.C. declares employment by Roche and stockholding in Roche. S.M. declares employment by Roche and stockholding in Roche. L.A. declares employment by Roche and stockholding in Roche. D.S.S. declares employment by Genentech and stockholding in Roche. M.R. declares consulting fees from Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Lilly, Merck, Merck Sharpe & Dohme, Mirati, Novartis, Pfizer, Sanofi, and Roche; payment of honoraria from Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Lilly, Merck, Merck Sharpe & Dohme, Mirati, Novartis, Pfizer, Sanofi, and Roche; support for attending meetings and/or travel from Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Lilly, Merck, Merck Sharpe & Dohme, Mirati, Novartis, Pfizer, Sanofi, and Roche; and participation on data safety monitoring or advisory boards for DSMB Sanofi. G.L. and M.K. declare no conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

Background: Horizon scanning (HS) is the systematic identification of emerging therapies to inform policy and decision-makers. We developed an agile and tailored HS methodology that combined multi-criteria decision analysis weighting and Delphi rounds. As secondary objectives, we aimed to identify new medicines in melanoma, non-small cell lung cancer and colorectal cancer most likely to impact the Australian government's pharmaceutical budget by 2025 and to compare clinician and consumer priorities in cancer medicine reimbursement., Method: Three cancer-specific clinician panels (total n = 27) and a consumer panel (n = 7) were formed. Six prioritisation criteria were developed with consumer input. Criteria weightings were elicited using the Analytic Hierarchy Process (AHP). Candidate medicines were identified and filtered from a primary database and validated against secondary and tertiary sources. Clinician panels participated in a three-round Delphi survey to identify and score the top five medicines in each cancer type., Results: The AHP and Delphi process was completed in eight weeks. Prioritisation criteria focused on toxicity, quality of life (QoL), cost savings, strength of evidence, survival, and unmet need. In both curative and non-curative settings, consumers prioritised toxicity and QoL over survival gains, whereas clinicians prioritised survival. HS results project the ongoing prevalence of high-cost medicines. Since completion in October 2021, the HS has identified 70 % of relevant medicines submitted for Pharmaceutical Benefit Advisory Committee assessment and 60% of the medicines that received a positive recommendation., Conclusion: Tested in the Australian context, our method appears to be an efficient and flexible approach to HS that can be tailored to address specific disease types by using elicited weights to prioritise according to incremental value from both a consumer and clinical perspective., Policy Summary: Since HS is of global interest, our example provides a reproducible blueprint for adaptation to other healthcare settings that integrates consumer input and priorities., Competing Interests: Declaration of Competing Interest MA has received financial support to attend conferences and meetings by AstraZeneca and serves on the advisory board for Pfizer and Bristol Myers Squibb. PAA has/had a consultant/advisory role for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, AstraZeneca, Sun Pharma, Canofi, Idera, Sandoz, Immunocore, 4SC, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, Seagen, iTeos, Medicenna, Bio-Al Health, ValoTX, Replimmune. He has received research funding grants from Bristol Myers Squibb, Roche-Genentech, Pfizer, Sanofi. He has received travel support from Pfizer. SA has served uncompensated on the boards of Health Issues Centre, Australia, Victorian Agency for Health Information, and Safer Care Victoria. MPB has received honoraria from BNS Australia, USD Oncology, and Novartis. He holds an advisory role for Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, and Cartherics for which his institution receives reimbursements. His institution has also received reimbursement for research support from Bristol Myers Squibb, Merck Sharp & Dohme, Pharmaust, Zucero Therapeutics, and CStone Pharmaceuticals. MB has received compensation and research support as an advisor and consultant to Pierre Fabre, MSD, GSK, Servier, and AstraZeneca. MI is on the advisory boards of Pfizer, Roche, Takeda, BeiGene, Amgen, Merck, and MSD and has received honoraria from Pfizer, Roche, Takeda, Novartis, as well as research funding from Pfizer. TJ reports consulting fees from AstraZeneca and MSD, and advisory boards and committees for AstraZeneca, Amgen, Bristol Myers Squibb, Merck & Co., MSD, Gilead, Puma, Pfizer Inc., Roche AG, Specialised Therapeutics, and Takeda Pharmaceutical, outside the submitted work. SK reports honoraria to institution from Astra Zeneca, Roche, Pfizer, Bristol Myers Squibb, MSD and Takeda; consulting fees from AstraZeneca, Pfizer, MSD, Novartis, Roche, Takeda, Amgen; and research funding to institution from Astra Zeneca. MK reports institutional grants from Nordic Farma, Merck-Serono, Pierre Fabre, Servier, Bayer, Bristol Myers Squibb, Merck, and Roche; and consulting fees and honoraria paid to institution from Pierre Fabre and Servier. BTL has served as an uncompensated advisor and consultant to Amgen, AstraZeneca, Boehringer Ingelheim, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, and Lilly. He has received research grants to his institution from Amgen, AstraZeneca, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, Hengrui USA, and Lilly. He has received academic travel support from Amgen, Jiangsu Hengrui Medicine and MORE Health. He is an inventor on two institutional patents at MSK (US62/685,057, US62/514,661) and has intellectual property rights as a book author at Karger Publishers and Shanghai Jiao Tong University Press. BTL is supported by the Memorial Sloan Kettering Cancer Centre Support Grant P30 CA008748 and Research Project Grant R01CA249666 from the National Institutes of Health. GVL is consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Innovent Biologics USA, Merck Sharpe & Dohme, Novartis, OncoSec, PHMR Ltd, Pierre Fabre, Provectus, Qbiotics, Regeneron. JML receives research support from Ipsen Pharmaceuticals, Novartis and Amgen, and reports consulting fees and/or honoraria from Amgen, Ipsen, Taiho, Novartis, SAGA Diagnostics and Natera. BM is on the advisory boards of Amgen, MSD, Bristol Myers Squibb, Beigene and AstraZeneca. GAM has received research support from Bristol Myers Squibb and as Principal Investigator his institution has received reimbursement of trial costs from Roche-Genentech. TMM reports consulting fees and participation on advisory boards for Bristol Myers Squibb, MSD, Merck, AstraZeneca, Novartis, GSK, Eisai, and honoraria from AstraZeneca. TMM has received support to attend meetings from Bristol Myers Squibb and AstraZeneca. LN has received institutional consulting fees from Bristol Myers Squibb, Pfizer, and Merck Sharp & Dohme, and reports support to attend a research meeting from AstraZeneca. NP has served on advisory boards or received personal honoraria from Boehringer Ingelheim, MSD, Merck, Bristol-Myers Squib, Astra Zeneca, Takeda, Pfizer, Roche, Novartis, Ipsen and Bayer and has received research funding to his institution from Bayer, Pfizer and Roche. TMP has received research support from Roche and Pfizer, and holds a consulting or advisory role for Merck, Bristol Myers Squibb, Novartis, Sanofi/Regeneron, and Pfizer. SP is compensated consultant to Amgen, AstraZeneca, Bayer, Blueprint, BMS, Boehringer Ingelheim, Daiichi Sankyo, EQRx, GSK, Guardant Health, Incyte, Janssen, Lilly, Merck Serono, MSD, Novartis, Roche, Takeda, Pfizer, Seattle Genetics, Turning Point Therapeutics, declares expert testimony to Roche and Merck Serono, and travel support from Janssen and Roche.BJS is on the Advisory Boards/Honoraria for Pfizer, Novartis, Roche, AstraZeneca, Merck, Bristol Myers Squibb, Eli Lilly, Amgen, BeiGene, Janssen, Takeda. JAS has received support for conference attendance from MSD (virtual registration ASCO). JT has received consulting fees or honoraria from Haystack Oncology, Servier, Pierre Fabre, MSD, Merck Serono, Amgen, Novartis, Seres and AstraZeneca. JT is on the advisory boards of Beigene, Daiichi Sankyo, Gilead, Illumina, Novartis, BMS, and MSD. WX has received research support from Merck, honoraria from MSD, Merck and AstraZeneca, and support for attending meetings from MSD (virtual registration ASCO) and Eli Lilly (virtual registration SABCS). WX is on the advisory boards of MSD, Merck and Novartis, and holds unpaid positions as Chair of the Melanoma and Skin Cancer trials group and Australasian Merkel Cell Carcinoma interest group.DY has received institutional payments for his role on advisory boards for AstraZeneca, Servier, Specialised Therapeutics, MSD and BayerJZ serves in an advisory/consultancy role for Merck Sharp & Dohme, Specialised Therapeutics, CEND, Deciphera, Revolution Medicine, FivePHusion, Genorbio, 1Global, Novotech, Alloplex Biotherapeutics, NOUS Consulting, and Oncology Republic; owns stock in Biomarin, Ophthea, Amarin, Concert Pharmaceuticals, Frequency Therapeutics, Gilead, Madrigal Pharmaceuticals, UniQure, Zogenix, Orphazyme, Moderna Therapeutics, TWST, Novavax, and Teladoc; has received honoraria from Gilead Sciences, MSD Oncology, and Viatris; and his institution has received research funding from Bristol-Myers Squibb, AstraZeneca, Pfizer, IQvia, Mylan, Ipsen, Eisai, Medtronic, MSD Oncology and Servier; and has received travel, accommodations, expenses from ICON Group, MSD Oncology, and PRAXIS., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: In ADAURA, adjuvant osimertinib significantly improved disease-free survival versus placebo in resected stage IB to IIIA EGFR-mutated NSCLC. We report in-depth analyses of three-year safety, tolerability, and health-related quality of life (HRQoL) from ADAURA., Methods: Patients were randomized 1:1 to osimertinib 80 mg or placebo once daily for up to 3 years. Safety assessments were performed at baseline, week 2, week 4, week 12, and every 12 weeks until treatment completion or discontinuation, and 28 days after treatment was stopped. The SF-36 survey measured HRQoL at baseline, week 12, week 24, and every 24 weeks until recurrence, treatment completion or discontinuation. Data cutoff: April 11, 2022., Results: Safety and HRQoL analysis sets: osimertinib, n = 337 and n = 339; placebo, n = 343 each. Median (range) total exposure duration was longer with osimertinib versus placebo: 35.8 (0-38) versus 25.1 (0-39) months. Most adverse events (AEs) were first reported within 12 months of starting treatment (osimertinib 97%, placebo 86%). AEs leading to dose reduction, interruption or discontinuation were reported in 12%, 27% and 13% respectively of patients with osimertinib; 1%, 13% and 3% with placebo. Stomatitis and diarrhea were the most common AEs leading to osimertinib dose reduction or interruption; interstitial lung disease was the most common leading to osimertinib discontinuation (per protocol). There were no differences in time to deterioration for SF-36 physical, mental component summaries between osimertinib and placebo., Conclusions: No new safety signals were reported and HRQoL was maintained with 3 years of adjuvant osimertinib treatment. Combined with significant efficacy benefit, these data further support adjuvant osimertinib in stage IB to IIIA EGFR-mutated NSCLC., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. In a randomized phase II clinical trial, the Trans Tasman Radiation Oncology Group compared single- versus multifraction stereotactic ablative body radiotherapy (SABR) in 90 patients with 133 oligometastases to the lung. The study found no differences in safety, efficacy, systemic immunogenicity, or survival between arms, with single-fraction SABR picked as the winner on the basis of cost-effectiveness. In this article, we report the final updated survival outcome analysis. The protocol mandated no concurrent or post-therapy systemic therapy until progression. Modified disease-free survival (mDFS) was defined as any progression not addressable by local therapy, or death. At a median follow-up of 5.4 years, the 3- and 5-year estimates for overall survival (OS) were 70% (95% CI, 59 to 78) and 51% (95% CI, 39 to 61). There were no significant differences between the multi- and single-fraction arms for OS (hazard ratio [HR], 1.1 [95% CI, 0.6 to 2.0]; P = .81). The 3- and 5-year estimates for disease-free survival were 24% (95% CI, 16 to 33) and 20% (95% CI, 13 to 29), with no differences between arms (HR, 1.0 [95% CI, 0.6 to 1.6]; P = .92). The 3- and 5-year estimates for mDFS were 39% (95% CI, 29 to 49) and 34% (95% CI, 24 to 44), with no differences between arms (HR, 1.0 [95% CI, 0.6 to 1.8]; P = .90). In this patient population, where patients receive SABR in lieu of systemic therapy, one-in-three patients are alive without disease in the long term. There were no differences in outcomes by fractionation schedule.

Competing Interests: Disclosure LEH reports personal fees as an invited speaker from Benecke, Medtalks and VJOncology; personal fees for participation in mentorship programme funded by AstraZeneca; personal fees for travel support from Roche; personal fees as member of the committee that revised the Dutch guidelines on NSCLC, brain metastases and leptomeningeal metastases; fees paid to her institution for an educational webinar from Janssen; fees paid to her institution for advisory board membership from Amgen, Bristol Myers Squibb (BMS), Boehringer Ingelheim, Janssen, Lilly, Merck, Merck Sharp & Dohme (MSD), Novartis, Pfizer, Roche and Takeda; fees paid to her institution as an invited speaker from AstraZeneca, Bayer, high5oncology, Lilly and MSD; fees paid to her institution for interview sessions from Roche; fees paid to her institution for podcast appearance from Takeda; institutional research grants from AstraZeneca, Boehringer Ingelheim, Roche, Takeda, Pfizer and Merck; institutional funding as a local principal investigator (PI) from AbbVie, AstraZeneca, Blueprint Medicines, Gilead, GlaxoSmithKline (GSK), Merck Serono, Mirati, MSD, Novartis, Roche and Takeda; non-remunerated roles as chair for metastatic NSCLC of the lung cancer group for European Organisation for Research and Treatment of Cancer (EORTC) and as the secretary of the studies foundation for NVALT (Nederlandse Vereniging van Artsen voor Longziekten en Tuberculose). KMK reports personal fees as an invited speaker from Amgen, AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, Medscape, Merck Serono, MSD, Novartis, Pfizer, Prime Oncology, Roche and Roche Diagnostics/Ventana; personal fees for consultancy and advisory board membership from AbbVie, Amgen, AstraZeneca, Bayer, Debiopharm, Diaceutics, Janssen, Merck Serono, MSD, Novartis, Pfizer, Regeneron, Roche and Roche Diagnostics/Ventana; non-remunerated roles as the past Pathology Committee Chair for IASLC (International Association for the Study of Lung Cancer) and member of the UK Lung Cancer Consortium. JM reports fees paid to her institution as an invited speaker from AstraZeneca, Boehringer Ingelheim, BMS, MSD and Roche; fees paid to her institution for expert testimony from AstraZeneca, Boehringer Ingelheim and MSD; fees paid to her institution for travel expenses from Ipsen. TSM reports personal fees as an invited speaker from AbbVie, ACEA Pharma, Alpha Biopharma, Amgen, Amoy Diagnostics, BeiGene, Boehringer Ingelheim, BMS, Daiichi Sankyo, Daz Group, Eli Lilly, Fishawack Facilitate, InMed Medical Communication, Janssen, Jiahui Holdings Co., LiangYiHui Healthcare, Lucene Health Inc., Lunit USA, Inc., MD Health, Medscape/WebMD, Merck Serono, MSD, MiRXES, Novartis, OrigiMed, PeerVoice, PER, Permanyer SL, Pfizer, Prime Oncology, Research to Practice, Roche, Sanofi-Aventis, Shanghai BeBirds Translation & Consulting Co., Taiho Pharmaceutical Co., Takeda and Touch Medical Media; personal fees for advisory board membership from AbbVie, ACEA Pharma, Alpha Biopharma, Amgen, Amoy Diagnostics, BeiGene, Berry Oncology, Blueprint Medicines, Boehringer Ingelheim, BMS, C4 Therapeutics, Cirina Ltd., Covidien LP, CStone Pharma, Curio Science, D3 Bio Ltd., Da Volterra, Daiichi Sankyo, Eisai, Eli Lilly, Fishawack Facilitate, G1 Therapeutics, Gilead Sciences, Gritstone Oncology, Guardant Health, Hengrui, Ignyta, Incyte, Inivata, IQVIA, Janssen, Lakeshore Biotech, Loxo Oncology, Lucene Health Inc., Lunit USA, Inc., Medscape/WebMD, Merck Serono, Mirati Therapeutics, MiRXES, MoreHealth, MSD, Novartis, OrigiMed, OSE Immunotherapeutics, Pfizer, Puma Tech, Qiming Development, Roche, Roche/Genentech, Sanofi-Aventis, SFJ Pharmaceutical Ltd., Synergy Research, Takeda, Tigermed, Vertex Pharmaceuticals, Virtus Medical and Yuhan; personal fees as the Chairman for ACT Genomics-Sanomics Group; personal fees as a member of the board of directors from AstraZeneca and HutchMed; holds stocks/shares from AstraZeneca, Aurora Tele-Oncology, Biolidics Ltd., HutchMed and Sanomics Ltd.; institutional funding from AstraZeneca, BMS, Clovis Oncology, G1 Therapeutics, Merck Serono, MSD, Novartis, Pfizer, Roche, SFJ Pharmaceuticals, Takeda and XCovery; non-remunerated roles as an invited speaker with AstraZeneca, Aurora Tele-Oncology, Lunit USA, Inc. and Sanomics Ltd. and for an advisory role with geneDecode; non-remunerated leadership roles with ASCO (American Society of Clinical Oncology), ATORG (Asian Thoracic Oncology Research Group), CLCRF (Chinese Lung Cancer Research Foundation Limited), CSCO (Chinese Society of Clinical Oncology), HKCF (Hong Kong Cancer Fund), HKCTS (Hong Kong Cancer Therapy Society), IASLC and St. Stephen’s College & Prep School (Hong Kong). UN reports fees paid to her institution as an invited speaker from MSD; fees paid to her institution for advisory board membership and a writing engagement from AstraZeneca; institutional funding as a coordinating PI for Bayer; non-remunerated roles as a PI for clinical trials funded by Deutsche Krebshilfe and as a member of the board of directors and vice-chair of ‘Strahlenschutzkommission’ from the German Commission on Radiological Protection. AP reports personal fees as an invited speaker from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Mundipharma and Takeda; personal fees for advisory board membership from AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, Janssen, MSD, Pfizer and Roche; non-remunerated activities with AIOM (Italian Association of Medical Oncology) as member of the Scientific Committee for lung cancer guidelines. SP reports personal fees for an editorial role as an Associate Editor for Annals of Oncology; fees paid to her institution as an invited speaker from AstraZeneca, BMS, Boehringer Ingelheim, e-cancer, Eli Lilly, Fishawack, Illumina, Imedex, Medscape, Mirati, MSD, Novartis, OncologyEducation, PER, Pfizer, PRIME, RMEI, Roche/Genentech, RTP, Sanofi and Takeda; fees paid to her institution for advisory board membership from AbbVie, Amgen, Arcus, AstraZeneca, Bayer, BeiGene, Bio Invent, Biocartis, Blueprint Medicines, BMS, Boehringer Ingelheim, Daiichi Sankyo, Debiopharm, Eli Lilly, F-Star, Foundation Medicine, Genzyme, Gilead, GSK, Illumina, Incyte, IQVIA, iTeos, Janssen, Merck Serono, Mirati, MSD, Novartis, Novocure, Pfizer, PharmaMar, Phosplatin Therapeutics, Regeneron, Roche/Genentech, Sanofi, Seattle Genetics, Takeda and Vaccibody; institutional funding as a steering committee member from AstraZeneca, BeiGene, BMS, iTeos, Mirati, MSD, PharmaMar, Phosplatin Therapeutics and Roche/Genentech; institutional funding as a coordinating PI from AstraZeneca; institutional funding as a trial chair from GSK and Roche/Genentech; non-remunerated role as President and Council Member for the Ballet Béjart Lausanne Foundation; non-remunerated leadership roles as President of ESMO (2020-2022), Vice-President of SAMO (Swiss Academy of Multidisciplinary Oncology), Vice-President of Lung Group for SAKK (Swiss Group for Clinical Cancer Research); non-remunerated role as PI involved in academic trials for ETOP (European Thoracic Oncology Platform)/EORTC/SAKK; non-remunerated role as Council Member and Scientific Committee Chair for ETOP/IBCSG Partners (International Breast Cancer Study Group); member of AACR (American Association for Cancer Research), ASCO, ASMAC/VSAO (Association of Swiss Interns and Residents), FMH (Association of Swiss Physicians) and IASLC. DP reports personal fees as an invited speaker from AbbVie, AstraZeneca, Janssen, Novartis, Peer CME, Pfizer, priME Oncology and Samsung; personal fees for advisory board membership from AbbVie, AstraZeneca, BMS, Celgene, Daiichi Sankyo, Janssen, Merck, Novartis, Pfizer, Roche and Samsung; institutional funding as a PI from AbbVie, AstraZeneca, BMS, Daiichi Sankyo, Janssen, Merck, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi and Sanofi-Aventis. EFS reports personal fees as an invited speaker from Boehringer Ingelheim and Daiichi Sankyo; personal fees for advisory board membership from Merck Serono; fees paid to his institution for advisory board membership from AstraZeneca, BMS, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Janssen, MSD, Roche, Sanofi and Takeda; institutional funding as a local PI from AstraZeneca, Genmab, Gilead and Pfizer. BJS reports personal fees as an invited speaker from AstraZeneca, Pfizer and Roche/Genentech; personal fees for advisory board membership from Amgen and Roche/Genentech; fees paid to his institution for advisory board membership from AstraZeneca, BMS, Merck and Novartis; fees paid to his institution for steering committee membership from Novartis, Pfizer and Roche/Genentech; personal fees as a member of the board of directors from Cancer Council Victoria and Thoracic Oncology Group of Australasia; personal fees as a consultant from Peter MacCallum Cancer Centre; royalties from UpToDate. GV reports personal fees as an invited speaker and for advisory board membership from Roche; personal fees as a consultant from Ab Medica; institutional funding as a PI from AIRC (Fondazione AIRC per la ricerca sul cancro ETS) and the Italian Ministry of Health. MR reports personal fees as an invited speaker from Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Lilly, Merck, MSD, Novartis, Roche and Sanofi; personal fees for advisory board membership from Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Mirati, MSD, Pfizer, Roche and Sanofi.

Cancer-associated cachexia (CAC) is a major contributor to morbidity and mortality in individuals with non-small cell lung cancer. Key features of CAC include alterations in body composition and body weight. Here, we explore the association between body composition and body weight with survival and delineate potential biological processes and mediators that contribute to the development of CAC. Computed tomography-based body composition analysis of 651 individuals in the TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy (Rx)) study suggested that individuals in the bottom 20th percentile of the distribution of skeletal muscle or adipose tissue area at the time of lung cancer diagnosis, had significantly shorter lung cancer-specific survival and overall survival. This finding was validated in 420 individuals in the independent Boston Lung Cancer Study. Individuals classified as having developed CAC according to one or more features at relapse encompassing loss of adipose or muscle tissue, or body mass index-adjusted weight loss were found to have distinct tumor genomic and transcriptomic profiles compared with individuals who did not develop such features. Primary non-small cell lung cancers from individuals who developed CAC were characterized by enrichment of inflammatory signaling and epithelial-mesenchymal transitional pathways, and differentially expressed genes upregulated in these tumors included cancer-testis antigen MAGEA6 and matrix metalloproteinases, such as ADAMTS3. In an exploratory proteomic analysis of circulating putative mediators of cachexia performed in a subset of 110 individuals from TRACERx, a significant association between circulating GDF15 and loss of body weight, skeletal muscle and adipose tissue was identified at relapse, supporting the potential therapeutic relevance of targeting GDF15 in the management of CAC., (© 2023. The Author(s) under exclusive license to Springer Nature America, Inc.)

Competing Interests: Disclosure LEH reports personal fees as an invited speaker from Benecke, Medtalks and VJOncology; personal fees for participation in mentorship programme funded by AstraZeneca; personal fees for travel support from Roche; personal fees as member of the committee that revised the Dutch guidelines on NSCLC, brain metastases and leptomeningeal metastases; fees paid to her institution for an educational webinar from Janssen; fees paid to her institution for advisory board membership from Amgen, Bristol-Myers Squibb (BMS), Boehringer Ingelheim, Janssen, Lilly, Merck, Merck Sharp & Dohme (MSD), Novartis, Pfizer, Roche and Takeda; fees paid to her institution as an invited speaker from AstraZeneca, Bayer, high5oncology, Lilly and MSD; fees paid to her institution for interview sessions from Roche; fees paid to her institution for podcast appearance from Takeda; institutional research grants from AstraZeneca, Boehringer Ingelheim, Roche, Takeda, Pfizer and Merck; institutional funding as a local principal investigator (PI) from AbbVie, AstraZeneca, Blueprint Medicines, Gilead, GlaxoSmithKline (GSK), Merck Serono, Mirati, MSD, Novartis, Roche and Takeda; non-remunerated roles as chair for metastatic NSCLC of the lung cancer group for European Organisation for Research and Treatment of Cancer (EORTC) and as the secretary of the studies foundation for Nederlandse Vereniging van Artsen voor Longziekten en Tuberculose (NVALT). KK reports personal fees as an invited speaker from Amgen, AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, Medscape, Merck Serono, MSD, Novartis, Pfizer, Prime Oncology, Roche and Roche Diagnostics/Ventana; personal fees for consultancy and advisory board membership from AbbVie, Amgen, AstraZeneca, Bayer, Debiopharm, Diaceutics, Janssen, Merck Serono, MSD, Novartis, Pfizer, Regeneron, Roche and Roche Diagnostics/Ventana; non-remunerated roles as the past Pathology Committee Chair for International Association for the Study of Lung Cancer (IASLC) and member of the UK Lung Cancer Consortium. JM reports fees paid to her institution as an invited speaker from AstraZeneca, Boehringer Ingelheim, BMS, MSD and Roche; fees paid to her institution for expert testimony from AstraZeneca, Boehringer Ingelheim and MSD; fees paid to her institution for travel expenses from Ipsen. TSM reports personal fees as an invited speaker from AbbVie, ACEA Pharma, Alpha Biopharma, Amgen, Amoy Diagnostics, BeiGene, Boehringer Ingelheim, BMS, Daiichi Sankyo, Daz Group, Eli Lilly, Fishawack Facilitate, InMed Medical Communication, Janssen, Jiahui Holdings Co., LiangYiHui Healthcare, Lucene Health Inc., Lunit USA, Inc., MD Health, Medscape/WebMD, Merck Serono, MIRXES, MSD, Novartis, OrigiMed, PeerVoice, PER, Permanyer SL, Pfizer, Prime Oncology, Research to Practice, Roche, Sanofi-Aventis, Shanghai BeBirds Translation & Consulting Co., Taiho Pharmaceutical Co., Takeda and Touch Medical Media; personal fees for advisory board membership from AbbVie, ACEA Pharma, Alpha Biopharma, Amgen, Amoy Diagnostics, BeiGene, Berry Oncology, Blueprint Medicines, Boehringer Ingelheim, BMS, C4 Therapeutics, Cirina Ltd, Covidien LP, CStone Pharma, Curio Science, D3 Bio Ltd, Da Volterra, Daiichi Sankyo, Eisai, Eli Lilly, Fishawack Facilitate, G1 Therapeutics, Gilead Sciences, Gritstone Oncology, Guardant Health, Hengrui, Ignyta, Incyte, Inivata, IQVIA, Janssen, Lakeshore Biotech, Loxo Oncology, Lucene Health Inc., Lunit USA, Inc., Medscape/WebMD, Merck Serono, Mirati Therapeutics, MiRXES, MoreHealth, MSD, Novartis, OrigiMed, OSE Immunotherapeutics, Pfizer, Puma Tech, Qiming Development, Roche, Roche/Genentech, Sanofi-Aventis, SFJ Pharmaceutical Ltd, Synergy Research, Takeda, Tigermed, Vertex Pharmaceuticals, Virtus Medical and Yuhan; personal fees as the Chairman for ACT Genomics-Sanomics Group; personal fees as a member of the board of directors from AstraZeneca and HutchMed; holds stocks/shares from AstraZeneca, Aurora Tele-Oncology, Biolidics Ltd, HutchMed and Sanomics Ltd.; institutional funding from AstraZeneca, BMS, Clovis Oncology, G1 Therapeutics, Merck Serono, MSD, Novartis, Pfizer, Roche, SFJ Pharmaceuticals, Takeda and XCovery; non-remunerated roles as an invited speaker with AstraZeneca, Aurora Tele-Oncology, Lunit USA, Inc. and Sanomics Ltd and for an advisory role with geneDecode; non-remunerated leadership roles with American Society of Clinical Oncology (ASCO), Asian Thoracic Oncology Research Group (ATORG), Chinese Lung Cancer Research Foundation Limited (CLCRF), Chinese Society of Clinical Oncology (CSCO), Hong Kong Cancer Fund (HKCF), Hong Kong Cancer Therapy Society (HKCTS), IASLC and St. Stephen’s College & Prep School (Hong Kong). UN reports fees paid to her institution as an invited speaker from MSD; fees paid to her institution for advisory board membership and a writing engagement from AstraZeneca; institutional funding as a coordinating PI for Bayer; non-remunerated roles as a PI for clinical trials funded by Deutsche Krebshilfe and as a member of the board of directors and vice-chair of ‘Strahlenschutzkommission’ from the German Commission on Radiological Protection. AP reports personal fees as an invited speaker from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Mundipharma and Takeda; personal fees for advisory board membership from AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, Janssen, MSD, Pfizer and Roche; non-remunerated activities with Italian Association of Medical Oncology (AIOM) as member of the Scientific Committee for lung cancer guidelines. SP reports personal fees for an editorial role as an Associate Editor for Annals of Oncology; fees paid to her institution as an invited speaker from AstraZeneca, BMS, Boehringer Ingelheim, ecancer, Eli Lilly, Fishawack, Illumina, Imedex, Medscape, Mirati, MSD, Novartis, OncologyEducation, Physician’s Education Resource (PER), Pfizer, Partnerships in International Medical Education (PRIME), RMEI Medical Education, LLC (RMEI), Roche/Genentech, Research To Practice (RTP), Sanofi and Takeda; fees paid to her institution for advisory board membership from AbbVie, Amgen, Arcus, AstraZeneca, Bayer, BeiGene, Bio Invent, Biocartis, Blueprint Medicines, BMS, Boehringer Ingelheim, Daiichi Sankyo, Debiopharm, Eli Lilly, F-Star, Foundation Medicine, Genzyme, Gilead, GSK, Illumina, Incyte, IQVIA, iTeos, Janssen, Merck Serono, Mirati, MSD, Novartis, Novocure, Pfizer, PharmaMar, Phosplatin Therapeutics, Regeneron, Roche/Genentech, Sanofi, Seattle Genetics, Takeda and Vaccibody; institutional funding as a steering committee member from AstraZeneca, BeiGene, BMS, iTeos, Mirati, MSD, PharmaMar, Phosplatin Therapeutics and Roche/Genentech; institutional funding as a coordinating PI from AstraZeneca; institutional funding as a trial chair from GSK and Roche/Genentech; non-remunerated role as President and Council Member for the Ballet Béjart Lausanne Foundation; non-remunerated leadership roles as President of ESMO (2020-2022), Vice- President of Swiss Academy of Multidisciplinary Oncology (SAMO), Vice-President of Lung Group for Swiss Group for Clinical Cancer Research (SAKK); non-remunerated role as PI involved in academic trials for European Thoracic Oncology Platform (ETOP)/EORTC/SAKK; non-remunerated role as Council Member and Scientific Committee Chair for ETOP/International Breast Cancer Study Group (IBCSG) Partners member of American Association of Cancer Research (AACR), ASCO, Association Suisse des médecines-assistant(e)s et chef(fe)s de Clinique (ASMAC)/Verband Schweizerischer Assistenz- und Oberärztinnen und- ärzte (VSAO), Fédération des médecins suisses (FMH) and IASLC. DP reports personal fees as an invited speaker from AbbVie, AstraZeneca, Janssen, Novartis, Peer CME, Pfizer, priME Oncology and Samsung; personal fees for advisory board membership from AbbVie, AstraZeneca, BMS, Celgene, Daiichi Sankyo, Janssen, Merck, Novartis, Pfizer, Roche and Samsung; institutional funding as a PI from AbbVie, AstraZeneca, BMS, Daiichi Sankyo, Janssen, Merck, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi and Sanofi-Aventis. ES reports personal fees as an invited speaker from Boehringer Ingelheim and Daiichi Sankyo; personal fees for advisory board membership from Merck Serono; fees paid to his institution for advisory board membership from AstraZeneca, BMS, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Janssen, MSD, Roche, Sanofi and Takeda; institutional funding as a local PI from AstraZeneca, Genmab, Gilead and Pfizer. BJS reports personal fees as an invited speaker from AstraZeneca, Pfizer and Roche/Genentech; personal fees for advisory board membership from Amgen and Roche/Genentech; fees paid to his institution for advisory board membership from AstraZeneca, BMS, Merck and Novartis; fees paid to his institution for steering committee membership from Novartis, Pfizer and Roche/Genentech; personal fees as a member of the board of directors from Cancer Council Victoria and Thoracic Oncology Group of Australasia; personal fees as a consultant from Peter MacCallum Cancer Centre; royalties from UpToDate. GV reports personal fees as an invited speaker and for advisory board membership from Roche; personal fees as a consultant from Ab Medica; institutional funding as a PI from Fondazione AIRC per la ricerca sul cancro ETS (AIRC) and the Italian Ministry of Health. MR reports personal fees as an invited speaker from Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Lilly, Merck, MSD, Novartis, Roche and Sanofi; personal fees for advisory board membership from Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Mirati, MSD, Pfizer, Roche and Sanofi.

Central nervous system (CNS) metastases are common in non-small-cell lung cancer (NSCLC) and associated with poor prognosis and high disease burden. Effective options are needed to treat CNS metastases, and delay or prevent their formation. For epidermal growth factor receptor mutation-positive (EGFRm) advanced NSCLC and brain metastases, upfront EGFR-tyrosine kinase inhibitors (TKIs) are recommended by the joint European Association of Neuro-Oncology-European Society for Medical Oncology and experts. While early-generation EGFR-TKIs have limited CNS efficacy, the third-generation, irreversible, EGFR-TKI osimertinib has potent efficacy in NSCLC CNS metastases. This review discusses the CNS data of osimertinib in the context of therapeutic strategies and future prospects based on expert review of published literature and relevant clinical, real-world, and ongoing studies in this setting. Osimertinib penetrates the blood-brain barrier and achieves greater exposure in the brain compared with other EGFR-TKIs. Osimertinib has demonstrated CNS efficacy, including in leptomeningeal metastases, in EGFRm advanced disease. In EGFRm stage IB-IIIA NSCLC, adjuvant osimertinib reduced CNS disease recurrence versus placebo. The burden and poor prognosis of CNS metastases necessitate more therapeutic options for their management and reduced risk of recurrence in patients with EGFRm NSCLC. Clinical studies are ongoing in advanced disease to investigate osimertinib combinations with chemotherapy/radiation therapy and optimal treatment post-CNS progression with osimertinib. Further prospective research evaluating treatments using CNS-specific endpoints and evaluating CNS resistance is needed to improve outcomes for patients with CNS metastases., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Up to 70% of people with lung cancer may be affected by cancer-related malnutrition or muscle loss, depending on treatment modality and disease stage. This narrative review explores recent studies on malnutrition and muscle loss as well as nutritional and multimodal interventions to treat these conditions in the context of the changing treatment landscape in lung cancer. Various types of interventions, including individualized counseling, protein and other specific nutrient supplementation, as well as multimodal interventions to treat malnutrition and muscle loss, have been investigated. Overall, individualized dietary counseling, increasing protein intake, and supplementation with omega-3 (n-3) fatty acids appear to be beneficial for some, albeit varying, patient outcomes. Multimodal interventions, generally including a nutrition and exercise component, show promising results; however, the impact on patient outcomes is mixed. A key finding of this review is a lack of large, randomized trials to guide nutrition intervention specifically in people with lung cancer. Despite the high prevalence of malnutrition and muscle loss in people with lung cancer and the known adverse outcomes, current evidence for nutrition intervention is limited. A targeted effort is required to improve the quality of evidence for nutrition intervention in this population to provide support for clinicians to deliver effective nutrition care., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Unmanaged consequences of cancer and its treatment are high among patients with lung cancer and their informal carers, resulting in avoidable healthcare use and financial burden. Provision of cancer supportive care addressing the impacts of cancer and its treatment has demonstrated efficacy in mitigating these consequences; however, globally, there is a lack of investment in these services. Paucity of robust economic evidence regarding benefit of cancer supportive care has limited policy impact and allocation of resources. This study therefore utilised a Social Return on Investment (SROI) methodology to conduct a forecast evaluation of lung cancer supportive care services, to ascertain potential social value and return on investment., Methods: An SROI economic evaluation model was developed using qualitative stakeholder consultations synthesised with published evidence to develop the inputs, outcomes and financial value associated with the delivery of a hypothetical model of quality lung cancer supportive care services over a one and five year period. SROI ratios were generated to determine the social value and cost savings associated per every $1AUD invested in cancer supportive care for both the healthcare system and patients. Deadweight, drop off and attribution were calculated, and sensitivity analysis was performed to confirm the stability of the model., Results: The value generated from modelled supportive care service investments in a one-year period resulted in an SROI ratio of 1:9; that is, for every dollar invested in supportive care, AUD$9.00 social return is obtained when savings to the healthcare system and benefits to the patients are combined. At five-years, these same investments resulted in greater cumulative value generated for both the patient and the healthcare system, with a SROI ratio of 1:11., Conclusion: Our study provides strong evidence for policy makers, clinicians and consumers to advocate for further investment in cancer supportive care, as demonstrated cost savings could be achieved through implementation of the proposed supportive care service model, with these accruing over a five-year period. The SROI model provides a comprehensive framework detailing supportive care services and the health workforce necessary to achieve value-based outcomes for patients and the healthcare system., (© 2022. The Author(s).)

Background: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is established as the preferred method of mediastinal lymph node (LN) staging in non-small cell lung cancer (NSCLC). Selective (targeted) LN sampling is most commonly performed however studies in early stage NSCLC and locally advanced NSCLC confirm systematic EBUS-TBNA evaluation improves accuracy of mediastinal staging. This study aims to establish the rate of detection of positron emission tomography (PET)-occult LN metastases following systematic LN staging by EBUS-TBNA, and to determine the utility of systematic mediastinal staging for accurate delineation of radiation treatment fields in patients with locally advanced NSCLC., Methods: Consecutive patients undergoing EBUS-TBNA for diagnosis/staging of locally advanced NSCLC will be enrolled in this international multi-centre single arm study. Systematic mediastinal LN evaluation will be performed, with all LN exceeding 6 mm to be sampled by TBNA. Where feasible, endoscopic ultrasound staging (EUS-B) may also be performed. Results of minimally invasive staging will be compared to FDG-PET. The primary end-point is proportion of patients in whom systematic LN staging identified PET-occult NSCLC metastases. Secondary outcome measures include (i) rate of nodal upstaging, (ii) false positive rate of PET for mediastinal LN assessment, (iii) analysis of clinicoradiologic risk factors for presence of PET-occult LN metastases, (iv) impact of systematic LN staging in patients with discrepant findings on PET and EBUS-TBNA on target coverage and dose to organs at risk (OAR) in patients undergoing radiotherapy., Discussion: With specificity of PET of 90%, guidelines recommend tissue confirmation of positive mediastinal LN to ensure potentially early stage patients are not erroneously denied potentially curative resection. However, while confirmation of pathologic LN is routinely sought, the exact extent of mediastinal LN involvement in NSCLC in patient with Stage III NSCLC is rarely established. Studies examining systematic LN staging in early stage NSCLC report a significant discordance between PET and EBUS-TBNA. In patients with locally advanced disease this has significant implications for radiation field planning, with risk of geographic miss in the event of PET-occult mediastinal LN metastases. The SEISMIC study will examine both diagnostic outcomes following systematic LN staging with EBUS-TBNA, and impact on radiation treatment planning., Trial Registration: ACTRN12617000333314, ANZCTR, Registered on 3 March 2017., (© 2022. The Author(s).)

Introduction: In the phase 1/3 IMpower133 study, atezolizumab plus carboplatin and etoposide (CP/ET) followed by maintenance atezolizumab for first-line treatment of extensive-stage SCLC (ES-SCLC) led to improvement in both overall survival (OS) and progression-free survival (PFS) versus placebo plus CP/ET followed by maintenance placebo. We explored the benefit of atezolizumab versus placebo in the subset of patients who reached the IMpower133 maintenance phase and the safety profile of maintenance therapy., Methods: Patients with untreated ES-SCLC were randomized 1:1 to four 21-day cycles of CP/ET with atezolizumab or placebo, followed by maintenance atezolizumab or placebo. The primary end points were OS and investigator-assessed PFS. A multivariate Cox model from the start of maintenance treatment was used to evaluate the treatment effect and account for lead-time bias; a generalized linear model was used to identify prognostic or predictive characteristics for reaching the maintenance phase., Results: A similar proportion of patients in each arm received at least the first dose of maintenance therapy (atezolizumab: 77%, n = 154 of 201; placebo: 81%, n = 164 of 202) and were included in the maintenance analysis population. An Eastern Cooperative Oncology Group performance status of 0 and absence of liver metastases at baseline were identified as prognostic factors for reaching the maintenance phase. The positive treatment effect with atezolizumab remained after adjusting for baseline characteristics. Median OS and PFS from the start of maintenance therapy in the atezolizumab versus placebo arm were 12.5 versus 8.4 months (hazard ratio = 0.59, 95% confidence interval: 0.43-0.80) and 2.6 versus 1.8 months (hazard ratio = 0.63 [95% confidence interval: 0.49-0.80]), respectively. Treatment-related adverse events from the start of maintenance therapy occurred in 41% (n = 64 of 155) and 25% (n = 41 of 163) of safety-evaluable patients in the atezolizumab and placebo arms, respectively, and were grade 3 or 4 in 28% (n = 43 of 155) and 23% (n = 37 of 163) of the respective populations; no patient in the atezolizumab arm and one patient in the placebo arm had a grade 5 treatment-related adverse event., Conclusions: These data in the context of other immunotherapy trials in ES-SCLC suggest that induction with atezolizumab plus CP/ET and maintenance treatment with atezolizumab are important components that contributed to the OS benefit observed in IMpower133. Safety results from randomization and from the start of maintenance therapy were similar between the treatment arms despite the continuation of atezolizumab in the maintenance phase., (Copyright © 2022. Published by Elsevier Inc.)

Background: Mucosal melanoma (MM) is a rare melanoma subtype with distinct biology and poor prognosis. Data on the efficacy of immune checkpoint inhibitors (ICIs) are limited. We determined the efficacy of ICIs in MM, analyzed by primary site and ethnicity/race., Patients and Methods: A retrospective cohort study from 25 cancer centers in Australia, Europe, USA and Asia was carried out. Patients with histologically confirmed MM were treated with anti-programmed cell death protein 1 (PD-1) ± ipilimumab. Primary endpoints were response rate (RR), progression-free survival (PFS), overall survival (OS) by primary site (naso-oral, urogenital, anorectal, other), ethnicity/race (Caucasian, Asian, Other) and treatment. Univariate and multivariate Cox proportional hazards model analyses were conducted., Results: In total, 545 patients were included: 331 (63%) Caucasian, 176 (33%) Asian and 20 (4%) Other. Primary sites included 113 (21%) anorectal, 178 (32%) urogenital, 206 (38%) naso-oral and 45 (8%) other. Three hundred and forty-eight (64%) patients received anti-PD-1 and 197 (36%) anti-PD-1/ipilimumab. RR, PFS and OS did not differ by primary site, ethnicity/race or treatment. RR for naso-oral was numerically higher for anti-PD-1/ipilimumab [40%, 95% confidence interval (CI) 29% to 54%] compared with anti-PD-1 (29%, 95% CI 21% to 37%). Thirty-five percent of patients who initially responded progressed. The median duration of response (mDoR) was 26 months (95% CI 18 months-not reached). Factors associated with short PFS were Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥3 (P < 0.01), lactate dehydrogenase (LDH) more than the upper limit of normal (ULN) (P = 0.01), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). Factors associated with short OS were ECOG PS ≥1 (P < 0.01), LDH >ULN (P = 0.03), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01)., Conclusions: MM has poor prognosis. Treatment efficacy of anti-PD-1 ± ipilimumab was similar and did not differ by ethnicity/race. Naso-oral primaries had numerically higher response to anti-PD-1/ipilimumab, without difference in survival. The addition of ipilimumab did not show greater benefit over anti-PD-1 for other primary sites. In responders, mDoR was short and acquired resistance was common. Other factors, including site and number of metastases, were associated with survival., Competing Interests: Disclosure FD: receives/received honoraria and travel support from Merck Sharp & Dohme Bristol-Myers Squibb and Sun Pharma. KN: honoraria from Ono Pharmaceutical, Novartis Pharma, Bristol-Myers Squibb and MSD. EIB: has received consulting fees from BMS and Novartis; has research funding paid to the institution from BMS, Merck, Novartis and Genentech. JAS: conference support from MSD. AZ: received travel support from Novartis, Sanofi Grenzyme and Bristol-Myers Squibb, outside the submitted work. MJM: served as a consultant for AstraZeneca, immunai, nektar therapeutics, catalyst pharmaceuticals and istari oncology. YN: consultant/advisory board—MSD, Novartis. Institutional research funding—Kaken, Ono pharma, Pola Pharma, Torii. Honoraria—BMS, Maruho, MSD, Novartis, Ono Pharma, Taisho Toyama, Taiho Pharma. XB: merit award supported by BMS.CA: Travel accommodations—meetings: Roche, BMS, AMGEN. AI: advisory board: Novartis. Honoraria for lectures: BMS, MSD, Novartis, Sanofi, Pierre-Fabre. MF: advisory board—Bayer. KCK: has served as consultant and/or has received honoraria from Amgen, Roche, Bristol Myers Squibb, Merck Sharp and Dohme, Pierre Fabre and Novartis, and received travel support from Amgen, Merck Sharp and Dohme, Bristol Myers Squibb, Amgen, Pierre Fabre, Medac and Novartis. VA: personal fees: Bristol Myers Squibb, Merck Serono, MSD, Novartis, Pierre Fabre, Roche, Oncosec. OK: personal fees from Bristol Myers Squibb and Merck Sharp & Dohme, outside the submitted work. AH: has served on advisory boards for BMS, MSD, Novartis, Pierre Fabre and Q Biotic. RDC: consultant/advisory board—Alkermes, Aura Biosciences, Bristol Myers Squibb, Castle Biosciences, Chimeron, Ideaya, Immunocore, InxMed, Iovance, Merck, Novartis, Oncosec, Pierre Fabre, PureTech Health, Regeneron, Rgenix, Sanofi Genzyme, Sorrento Therapeutics, Trisalus. OH: speaker’s bureau honoraria from BMS, Novartis, Pfizer and Sanofi Regeneron, and is an advisory board member/consultant for Aduro, Akeso Bio, Amgen, Beigene, Bioatla, BMS, Roche Genentech, GSK, Immunocore, Incyte, Janssen, Merck, Nextcure, Novartis, Pfizer, Sanofi Regeneron, Seagen, Tempus and Zelluna. AH: received grants and personal fees from Amgen, BMS, Immunocore, Novartis, MerckSerono, MSD/Merck, Philogen, Pierre Fabre, Regeneron, Replimune, Roche, Sanofi-Genzyme and Sun Pharma, outside the submitted work. MSC: consultant advisor for Amgen, BMS, Eisai, Ideaya, MSD, Nektar, Novartis, Oncosec, Pierre-Fabre, Qbiotics, Regeneron, Roche, Merck and Sanofi, and received honoraria from BMS, MSD and Novartis. MM: received honoraria for participation at advisory boards from Novartis, BMS, MSD, Pierre Fabre, Sanofi, reports lecture from Novartis, BMS, MSD, Pierre Fabre, Sanofi and reports grants from Roche, Novartis. CR: advisor for Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, Merck, Roche, AstraZeneca and is scientific founder of Aglaia therapeutics. CL: BMS: research grant, honoraria, consultancy, speaker’s bureau, travel accommodations—meetings, advisory role, serving on an advisory board; MSD: honoraria, consultancy, advisory role, serving on an advisory board, travel accommodations—meetings; Novartis: honoraria, consultancy, speaker’s bureau, advisory role, serving on an advisory board; Amgen: honoraria, consultancy, speaker’s bureau, serving on an advisory board; Roche: research grant, honoraria, consultancy, speaker’s bureau, advisory role, serving on an advisory board; Avantis Medical Systems: board; Pierre-Fabre/Pfizer/Incyte: honoraria. JG: consultant/advisory boards for MSD, Roche, Pfizer, Bayer, Novartis, Simcere Pharmaceutical Group, Shanghai Junshi Biosciences and Oriengene. DBJ: advisory boards for Array Biopharma, Bristol Myers Squibb, Catalyst Biopharma, Iovance Biotherapeutics, Janssen, Merck, Novartis and OncoSec. Research support from Bristol Myers Squibb and Incyte. PAA: has/had a consultant/advisory role for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, AstraZeneca, Sun Pharma, Sanofi, Idera, Sandoz, Immunocore, 4SC, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, Seagen, iTeos. He also received research funding from Bristol Myers Squibb, Roche-Genentech, Pfizer, Sanofi. ANS: advisory board/personal fees: Bristol-Myers Squibb, Immunocore, Novartis, Castle Biosciences. Institutional trial support: Bristol-Myers Squibb, Immunocore, Novartis, Xcovery, Polaris, Pfizer, Checkmate Pharmaceuticals, Forghorn Therapeutics. RJS: advisory board—BMS, Merck, Novartis, Pfizer; research support from Merck. LZ: served as consultant and/or has received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, Sunpharma and travel support from Amgen, Merck Sharp & Dohme, Bristol-Myers Squibb, Pierre Fabre, Sanofi, Sunpharma and Novartis. SS: grants from Novartis, AstraZeneca, Merck Sharp & Dohme and Genentech; and personal fees from AstraZeneca, Merck Sharp & Dohme and Bristol Myers Squibb, outside the submitted work. CUB: personal fees from BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre, Third Rock Ventures, grants from BMS, Novartis, NanoString, other from Uniti Cars, Forty Seven, Neon Therapeutics, Verastem, other from Immagene B.V. RD: intermittent, project-focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dohme (MSD), Bristol-Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA and touchIME outside the submitted work. BCS: speaker’s bureau honoraria and personal fees from BMS, Novartis, MDS, Pierre Fabre. AMM: advisory board—BMS, MSD, Novartis, Roche, Pierre-Fabre, QBiotics. GVL: consultant advisor for Aduro Biotech Inc, Amgen Inc, Array Biopharma inc, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Highlight Therapeutics S.L., Merck Sharpe & Dohme, Novartis Pharma AG, Pierre Fabre, QBiotics Group Limited, Regeneron Pharmaceuticals Inc. All other authors have declared no conflicts of interest. Data sharing Availability of data and material: patients’ medical records. All data were anonymized immediately after collection., (Copyright © 2022 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Background: Lung cancer is the most common cause of cancer-related death in the world, however lung cancer screening has not been implemented in most countries at a population level. A previous Cochrane Review found limited evidence for the effectiveness of lung cancer screening with chest radiography (CXR) or sputum cytology in reducing lung cancer-related mortality, however there has been increasing evidence supporting screening with low-dose computed tomography (LDCT).  OBJECTIVES: To determine whether screening for lung cancer using LDCT of the chest reduces lung cancer-related mortality and to evaluate the possible harms of LDCT screening., Search Methods: We performed the search in collaboration with the Information Specialist of the Cochrane Lung Cancer Group and included the Cochrane Lung Cancer Group Trial Register, Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library, current issue), MEDLINE (accessed via PubMed) and Embase in our search. We also searched the clinical trial registries to identify unpublished and ongoing trials. We did not impose any restriction on language of publication. The search was performed up to 31 July 2021.  SELECTION CRITERIA: Randomised controlled trials (RCTs) of lung cancer screening using LDCT and reporting mortality or harm outcomes.  DATA COLLECTION AND ANALYSIS: Two review authors were involved in independently assessing trials for eligibility, extraction of trial data and characteristics, and assessing risk of bias of the included trials using the Cochrane RoB 1 tool. We assessed the certainty of evidence using GRADE. Primary outcomes were lung cancer-related mortality and harms of screening. We performed a meta-analysis, where appropriate, for all outcomes using a random-effects model. We only included trials in the analysis of mortality outcomes if they had at least 5 years of follow-up. We reported risk ratios (RRs) and hazard ratios (HRs), with 95% confidence intervals (CIs) and used the I 2 statistic to investigate heterogeneity.  MAIN RESULTS: We included 11 trials in this review with a total of 94,445 participants. Trials were conducted in Europe and the USA in people aged 40 years or older, with most trials having an entry requirement of ≥ 20 pack-year smoking history (e.g. 1 pack of cigarettes/day for 20 years or 2 packs/day for 10 years etc.). One trial included male participants only. Eight trials were phase three RCTs, with two feasibility RCTs and one pilot RCT. Seven of the included trials had no screening as a comparison, and four trials had CXR screening as a comparator. Screening frequency included annual, biennial and incrementing intervals. The duration of screening ranged from 1 year to 10 years. Mortality follow-up was from 5 years to approximately 12 years.  None of the included trials were at low risk of bias across all domains. The certainty of evidence was moderate to low across different outcomes, as assessed by GRADE. In the meta-analysis of trials assessing lung cancer-related mortality, we included eight trials (91,122 participants), and there was a reduction in mortality of 21% with LDCT screening compared to control groups of no screening or CXR screening (RR 0.79, 95% CI 0.72 to 0.87; 8 trials, 91,122 participants; moderate-certainty evidence). There were probably no differences in subgroups for analyses by control type, sex, geographical region, and nodule management algorithm. Females appeared to have a larger lung cancer-related mortality benefit compared to males with LDCT screening. There was also a reduction in all-cause mortality (including lung cancer-related) of 5% (RR 0.95, 95% CI 0.91 to 0.99; 8 trials, 91,107 participants; moderate-certainty evidence).  Invasive tests occurred more frequently in the LDCT group (RR 2.60, 95% CI 2.41 to 2.80; 3 trials, 60,003 participants; moderate-certainty evidence). However, analysis of 60-day postoperative mortality was not significant between groups (RR 0.68, 95% CI 0.24 to 1.94; 2 trials, 409 participants; moderate-certainty evidence).  False-positive results and recall rates were higher with LDCT screening compared to screening with CXR, however there was low-certainty evidence in the meta-analyses due to heterogeneity and risk of bias concerns. Estimated overdiagnosis with LDCT screening was 18%, however the 95% CI was 0 to 36% (risk difference (RD) 0.18, 95% CI -0.00 to 0.36; 5 trials, 28,656 participants; low-certainty evidence). Four trials compared different aspects of health-related quality of life (HRQoL) using various measures. Anxiety was pooled from three trials, with participants in LDCT screening reporting lower anxiety scores than in the control group (standardised mean difference (SMD) -0.43, 95% CI -0.59 to -0.27; 3 trials, 8153 participants; low-certainty evidence). There were insufficient data to comment on the impact of LDCT screening on smoking behaviour.  AUTHORS' CONCLUSIONS: The current evidence supports a reduction in lung cancer-related mortality with the use of LDCT for lung cancer screening in high-risk populations (those over the age of 40 with a significant smoking exposure). However, there are limited data on harms and further trials are required to determine participant selection and optimal frequency and duration of screening, with potential for significant overdiagnosis of lung cancer. Trials are ongoing for lung cancer screening in non-smokers., (Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Toxicity concerns from thoracic radiation therapy in the treatment of lung cancers have changed substantially over the past few decades. Survival in the treatment of lung cancer has markedly improved and the introduction of advanced radiation and imaging techniques to treatment planning and delivery has made reducing toxicity possible. Phase 3 dose-escalation trials have revealed that excess dose to critical organs within the thorax can negatively impact overall survival. We summarize the existing literature on the known toxicities of thoracic radiation therapy, summarize the technological advances that have made toxicity reduction possible, and provide an overview of emerging technologies and biomarkers that are being evaluated to assess future toxicity reductions., (Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.)

Objectives: To analyze the efficacy and safety of lorlatinib in Asian and non-Asian patients with pretreated anaplastic lymphoma kinase (ALK)-positive, advanced non-small cell lung cancer (NSCLC) from a phase 1/2 study., Materials and Methods: In this ongoing phase 2 part of the trial, patients with ALK- or ROS1-positive, advanced NSCLC enrolled into six expansion cohorts (EXP1-6), based on ALK and ROS1 status and previous therapy, and received lorlatinib 100 mg once daily. The primary endpoint was objective tumor response and intracranial response. Post hoc analyses of activity were conducted in Asian and non-Asian (based on race) ALK-positive patients who received either previous crizotinib with or without chemotherapy (EXP2-3A) or at least one second-generation ALK tyrosine kinase inhibitor with any number of chemotherapy regimens (EXP3B-5). Analysis of safety (adverse events [AEs]) was in the phase 1 and 2 study population who started lorlatinib 100 mg once daily., Results: 17 Asian patients were enrolled in EXP2-3A and 53 in EXP3B-5; 33 non-Asian patients were enrolled in EXP2-3A and 73 in EXP3B-5. Objective response rates in the Asian and non-Asian subgroups were 82.4% (95% confidence interval [CI]: 56.6-96.2) and 63.6% (95% CI: 45.1-79.6) in EXP2-3A, and 47.2% (95% CI: 33.3-61.4) and 30.1% (95% CI: 19.9-42.0) in EXP3B-5, and median progression-free survival was 13.6 and 12.5 months (EXP2-3A) and 6.9 and 5.5 months (EXP3B-5). Lorlatinib exhibited antitumor activity across ALK resistance mutations, while no differences according to the EML4-ALK variant could be detected. The most common treatment-related AEs were hypercholesterolemia, hypertriglyceridemia, edema, and peripheral neuropathy in both Asian and non-Asian subgroups., Conclusion: Lorlatinib showed substantial overall and intracranial activity in pretreated patients with ALK-positive NSCLC in both Asian and non-Asian patients. AE profiles were similar between Asian and non-Asian patients., Clinicaltrials: gov NCT01970865., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The European Society for Medical Oncology (ESMO) held a virtual consensus-building process on epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer in 2021. The consensus included a multidisciplinary panel of 34 leading experts in the management of lung cancer. The aim of the consensus was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where the available evidence is either limited or conflicting. The main topics identified for discussion were: (i) tissue and biomarkers analyses; (ii) early and locally advanced disease; (iii) metastatic disease and (iv) clinical trial design, patient's perspective and miscellaneous. The expert panel was divided into four working groups to address questions relating to one of the four topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the recommendations developed, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation., Competing Interests: Disclosure AP received education grants, provided consultation, attended advisory board meetings and/or provided lectures for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb (BMS), Daiichi Sankyo, eCancer, Eli Lilly, Janssen, Medscape, Merck Sharp & Dohme (MSD), Merck KGaA, Novartis, Pfizer, Roche/Genentech, Takeda, outside the submitted work. NL reports unrelated institutional research funding received from Amgen, Array, AstraZeneca, Bayer, BMS, Lilly, EMD Serono, Guardant Health, MSD, Pfizer, Roche, Takeda and unrelated personal fees (CME lectures, consulting) received from Bayer, Boehringer Ingelheim, BMS, Canadian Agency for Drugs and Technologies in Health, EMD Serono, MSD, Novartis, Sanofi Genzyme. SPo reports personal fees from Amgen, AstraZeneca, Bayer, BeiGene, Blueprint Medicines, BMS, Boehringer Ingelheim, Daiichi Sankyo, Guardant Health, Janssen, Lilly, Merck KGaA, Novartis, Roche, Takeda, Seattle Genetics, Turning Point Therapeutics, GlaxoSmithKline, outside the submitted work. KK reports personal fees from AstraZeneca, Roche, during the conduct of the study. MJA reports personal fees from AstraZeneca, Takeda, Roche, Alpha Pharmaceutical, Amgen, Lilly, ONO, MSD, Merck, outside the submitted work. MEA reports personal fees from Biocartis, Invivoscribe, Janssen Global Services, BMS, AstraZeneca, Roche, Merck, RMEI Medical Education, Clinical Care Options, PeerView Institute for medical education, outside the submitted work. OA reports personal fees from Pfizer, grants and personal fees from AstraZeneca, Boehringer Ingelheim, personal fees from Lilly, Merck, BMS, grants and personal fees from Roche, outside the submitted work. DP reports personal fees from AstraZeneca, BMS, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche, Samsung, AbbVie, Janssen, outside the submitted work; and clinical trials research (as principal investigator or co-investigator): AstraZeneca, AbbVie, BMS, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, MedImmune, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo, Janssen. FdM reports grants and personal fees from AstraZeneca, grants from Boehringer, personal fees from Roche, BMS, Novartis, MSD, Pfizer, Takeda, outside the submitted work. AMD reports personal fees from Roche, Eli Lilly, Pfizer, Pharmamar, Takeda, Boehringer Ingelheim, grants and personal fees from AstraZeneca, personal fees from Jansen, Chiesi, grants and personal fees from Amgen, personal fees from Bayer, Sanofi, outside the submitted work. RD reports personal fees from Pfizer, personal fees and non-financial support from Roche, non-financial support from AstraZeneca, personal fees from Novartis, Boehringer Ingelheim, Foundation Medicine, Karyopharm, outside the submitted work. CFF reports grants and other from AstraZeneca, other from MSD, grants and other from Elekta, during the conduct of the study. JF reports personal fees from Blueprint Medicines, Novartis, Janssen, AstraZeneca, outside the submitted work. EF reports personal fees from AbbVie, Amgen, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, BMS, Eli Lilly, GlaxoSmithKline, Janssen, Medscape, Merck KGaA, MSD, Novartis, PeerVoice, Pfizer, prIME Oncology, Puma Biotechnology, Roche, Sanofi Genzyme, Springer, Takeda, Touch Medical, grants from Grant for Oncology Innovation (GOI), grants from Fundación Merck Salud, personal fees from CME Outfitters, BeiGene, Medical Trends, Peptomyc, Regeneron, from Syneos Health, outside the submitted work; and Grifols: independent member of the board. GC reports consultation fees from Pfizer, Roche, AstraZeneca, BMS, Daichii Sankyo, Seagen, Gilead, Novartis, Lilly, Ellipsis, Merck. RH reports consultation fees from AbbVie Pharmaceuticals, ARMO Biosciences, AstraZeneca, Bayer HealthCare Pharmaceuticals Inc., Bolt Biotherapeutics, BMS, Candel Therapeutics, Inc., Checkpoint Therapeutics, Cybrexa Therapeutics, DynamiCure Biotechnology, LLC, eFFECTOR Therapeutics, Inc., Eli Lilly and Company, EMD Serono, Foundation Medicine, Inc., Genentech/Roche, Genmab, Gilead, Halozyme Therapeutics, Heat Biologics, HiberCell, Inc., I-Mab Biopharma, Immune-Onc Therapeutics, Immunocore, Infinity Pharmaceuticals, Johnson & Johnson, Loxo Oncology, Merck and Company, Mirati Therapeutics, Nektar, Neon Therapeutics, NextCure, Novartis, Ocean Biomedical, Inc., Oncocyte Corp., Oncternal Therapeutics, Pfizer, Refactor Health, Inc., Ribbon Therapeutics, Sanofi, Seattle Genetics, Shire PLC, Spectrum Pharmaceuticals, STCube Pharmaceuticals, Inc., Symphogen, Takeda, Tesaro, Tocagen, Ventana Medical Systems, Inc., WindMIL Therapeutics, Xencor, Inc., research support from AstraZeneca, Eli Lilly and Company, Genentech/Roche, Merck and Company, and participation on board of Immunocore Holdings Limited, Junshi Pharmaceuticals. PAJ reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, personal fees from Pfizer, Roche/Genentech, Chugai Pharmaceuticals, Loxo Oncology, grants and personal fees from Eli Lilly, personal fees from SFJ Pharmaceuticals, Voronoi, grants and personal fees from Daiichi Sankyo, personal fees from Biocartis, Novartis, Sanofi, grants and personal fees from Takeda Oncology, personal fees from Mirati Therapeutics, Transcenta, Silicon Therapeutics, Syndax, Nuvalent, Bayer, Eisai, Allorion Therapeutics, Accutar Biotech, AbbVie, grants from Revolution Medicines, grants from PUMA, grants from Astellas, outside the submitted work. In addition, PAJ is a co-inventor on a DFCI patent on EGFR mutations and receives postmarketing royalties from Lab Corp. TJ reports personal fees from Pfizer, AstraZeneca, BMS, Merck, MSD, Takeda, Boehringer Ingelheim, Roche, Ignyta, Novartis, Bayer, Amgen, Gilead, Puma Pharmaceuticals, outside the submitted work. TM reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Chugai, personal fees from Pfizer, during the conduct of the study; personal fees from BMS, grants and personal fees from Ono, MSD, personal fees from Novartis, grants and personal fees from Taiho, personal fees from Takeda, Amgen, Invitae, Merck Biopharma, Thermo Fisher, grants from Bridge Biotherapeutics, grants and personal fees from Ethicon, outside the submitted work. TM reports personal fees and other from AbbVie, Inc., ACEA Pharma, Alpha Biopharma Co. Ltd, Amgen, Amoy Diagnostics Co. Ltd, grants, personal fees and other from AstraZeneca, personal fees and other from BeiGene, Boehringer Ingelheim, grants, personal fees and other from BMS, personal fees and other from Blueprint Medicines Corporation, CStone Pharmaceuticals, Daiichi Sankyo, Eisai, Fishawack Facilitate Ltd, other from geneDecode, personal fees and other from Gritstone Oncology Inc., Guardant Health, Hengrui Therapeutics, Ignyta Inc., Incyte Corporation, personal fees from InMed Medical Communication, personal fees and other from Janssen, Lilly, Loxo Oncology, Lunit USA, Inc., personal fees from MD Health (Brazil), Medscape/WebMD, grants, personal fees and other from Merck Serono, MSD, personal fees and other from Mirati Therapeutics Inc., personal fees from MoreHealth, grants, personal fees and other from Novartis, personal fees and other from OrigiMed, personal fees from PeerVoice, Physicians' Education Resource, P. Permanyer SL, grants, personal fees and other from Pfizer, Inc., personal fees from PrIME Oncology, personal fees and other from Puma Biotechnology Inc., personal fees from Research to Practice, grants, personal fees and other from Roche, personal fees and other from Sanofi-Aventis R&D, grants, personal fees and other from Takeda, personal fees from Touch Medical Media, other from Virtus Medical Group, personal fees and other from Yuhan Corporation, other from AstraZeneca PLC, Hutchison Chi-Med, Sanomics Ltd, grants from Clovis Oncology, grants, personal fees and other from SFJ Pharmaceuticals, grants from Xcovery, personal fees and other from Curio Science, personal fees from Inivata, Berry Oncology, grants and personal fees from G1 Therapeutics Inc., other from Aurora, personal fees from Qiming Development (HK) Ltd, Daz Group, Lucence Health Inc., Merck Pharmaceuticals HK Ltd, Shanghai BeBirds Translation & Consulting Co., Ltd, Liangyihui Network Technology Co., Ltd, Taiho, personal fees and other from Gilead Sciences, Inc, Vertex Pharmaceuticals, personal fees from Covidien LP, outside the submitted work. NN reports personal fees from MSD, grants and personal fees from Qiagen, Biocartis, Incyte, Roche, BMS, Merck, Thermo Fisher, AstraZeneca, personal fees from Sanofi, Eli Lilly, Bayer, ArcherDx, grants and personal fees from Illumina, personal fees from Amgen, outside the submitted work. LPA reports grants from MSD, AstraZeneca, Pfizer, BMS, personal fees from Lilly, MSD, Roche, Pharmamar, Merck, AstraZeneca, Novartis, Servier, Amgen, Pfizer, Ipsen, Sanofi, Bayer, Blueprint, BMS, Mirati, Janssen, other from Genomica, Altum sequencing, outside the submitted work. SR reports personal fees from AstraZeneca, BMS, Amgen, GlaxoSmithKline, Merck, Takeda, Eisai, Lilly, outside the submitted work. LS reports grants and personal fees from AstraZeneca, grants from Novartis, personal fees from Janssen, grants and personal fees from Genentech, personal fees from Takeda, Pfizer, grants from Boehringer Ingelheim, outside the submitted work. JV reports honoraria for invited speaker from AstraZeneca, BMS, MSD, and Novartis; participation on advisory board of AstraZeneca, BMS, Boehringer Ingelheim, Daichi Sankyo, MSD, Pfizer, and Roche; grant from MSD. IIW reports grants and personal fees from Genentech/Roche, Bayer, BMS, AstraZeneca, Pfizer, HTG Molecular, personal fees from Asuragen, grants and personal fees from Merck, GlaxoSmithKline, Guardant Health, personal fees from Flame, grants and personal fees from Novartis, Sanofi, personal fees from Daiichi Sankyo, grants and personal fees from Amgen, personal fees from Oncocyte, MSD, Platform Health, grants from Adaptive, Adaptimmune, EMD Serono, Takeda, Karus, Johnson & Johnson, 4D, Iovance, Akoya, outside the submitted work. JW reports personal fees from Amgen, AstraZeneca, Bayer, Blueprint, grants and personal fees from BMS, personal fees from Boehringer Ingelheim, Chugai, Daiichi Sankyo, Ignyta, grants and personal fees from Janssen, personal fees from Lilly, Loxo, MSD, grants and personal fees from Novartis, Pfizer, personal fees from Roche, Seattle Genetics, Takeda, outside the submitted work. YLW reports personal fees from AstraZeneca, BeiGene, Boehringer Ingelheim, BMS, Eli Lilly, MSD, Pfizer, Roche, Sanofi, Novartis, Takeda; grants from AstraZeneca, Boehringer Ingelheim, BMS, Hengrui and Roche, outside the submitted work. JCHY reports personal fees and other from Amgen, grants, personal fees and other from AstraZeneca, personal fees and other from Bayer, Boehringer Ingelheim, BMS, Daiichi Sankyo, other from Eli Lilly, personal fees and other from Merck KGaA, Darmstadt, Germany, MSD, Novartis, personal fees from Ono Pharmaceuticals, Pfizer, personal fees and other from Roche/Genentech, Takeda Oncology, Yuhan Pharmaceuticals, other from Johnson & Johnson, Glaxo, Puma Technology, outside the submitted work. YY reports and contracted studies with ArcherDx, Chugai Pharma and Thermo Fisher Science; honoraria for lectures from MSD, Chugai Pharma, AstraZeneca, Pfizer, Roche/Ventana, Agilent/Dako, Thermo Fisher Science, ArcherDx, Novartis, Eli Lilly, Amgen and Sysmex; participation on advisory board of MSD, Chugai Pharma, AstraZeneca, Novartis, Amgen, Takeda and Daiichi-Sankyo. GP reports grants from Amgen, grants, personal fees and non-financial support from Merck, grants and non-financial support from AstraZeneca, grants and personal fees from Roche, BMS, grants from Lilly, grants and personal fees from MSD, Novartis, outside the submitted work. SPe received education grants, provided consultation, attended advisory board meetings and/or provided lectures for AbbVie, Amgen, AstraZeneca, Bayer, Biocartis, BioInvent, Blueprint Medicines Corporation, Boehringer Ingelheim, BMS, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffmann-La Roche, Foundation Medicine, Illumina, Janssen, MSD, Merck Serono, Merrimack, Novartis, PharmaMar, Pfizer, Regeneron, Sanofi, Seattle Genetics, Takeda and Vaccibody, from whom she received honoraria (all fees to institution). All other authors have declared no conflicts of interest., (Copyright © 2022 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

This overview summarises the current evidence on efficacy and safety of single-fraction stereotactic ablative body radiotherapy (SABR) for primary lung cancers and lung metastases, in comparison with the more widely adapted multi-fraction SABR regimens. A literature search using the Medline database through PubMed was carried out using the following key words: ('stereotactic' or 'sabr' or 'sbrt'), ('radiotherapy' or 'radiation therapy'), ('lung' or 'thorax' or 'thoracic' or 'chest'), ('cancer' or 'metasta-' or 'oligometasta-'), alongside: (i) ('single-fraction' or 'single-dose') to identify trials and cohort studies with single-fraction SABR to lung malignant tumours and (ii) ('fraction' or 'schedule') limiting the search to 'clinical trial' and 'randomized controlled trial' to ensure thorough capture of lung SABR trials comparing different fractionations. The review discusses the radiobiological, technical and organ at risk considerations of single-fraction SABR to the lung., (Copyright © 2022 The Royal College of Radiologists. All rights reserved.)

Background: Postoperative stereotactic radiosurgery after resection of brain metastases is currently the standard of care. However, rates of leptomeningeal disease (LMD) after postoperative stereotactic radiosurgery have been reported to be >30%. Neoadjuvant stereotactic radiosurgery (NaSRS) has been proposed as an alternative treatment approach to decrease this risk., Objective: To report the local control (LC) and LMD rates in patients undergoing NaSRS., Methods: Our retrospective multicenter case series included consecutive patients planned for SRS followed by resection of intracranial lesions with a confirmed primary malignancy. Concurrent SRS alone to other intracranial lesions was permitted. Exclusion criteria included previous local treatment to that particular lesion and Eastern Cooperative Oncology Group performance status ≥3. Outcomes reported included LC, distant intracranial control (DC), overall survival, LMD, and radionecrosis (RN) rates., Results: Overall, 28 patients with 29 lesions were eligible for analysis. The median follow-up was 12.8 months. The mean age was 62.5 (range 43-80) years, and 55% were Eastern Cooperative Oncology Group performance status 0 to 1. The most common primary malignancies included non-small cell lung cancer (43%) and melanoma (32%). Hypofractionated SRS was used in 62.1%. The 12-month LC and LMD rates were 91.3% and 4.0%, respectively. The 12-month RN, DC, and overall survival rates were 5.0%, 51.5%, and 60.1%, respectively., Conclusion: Compared with postoperative SRS, our study suggests that NaSRS leads to comparable local control with a decreased risk of LMD and RN. This is the first NaSRS series with a majority of patients treated with fractionated SRS. NaSRS is a promising approach for appropriate patients where surgical resection is a component of local therapy., (Copyright © Congress of Neurological Surgeons 2021. All rights reserved.)

Introduction: Lorlatinib, a potent, selective third-generation ALK tyrosine kinase inhibitor (TKI), exhibited overall and intracranial antitumor activity in patients with ALK-positive NSCLC., Methods: Retrospective analyses in the ongoing phase 2 trial (NCT01970865) investigated the clinical benefit of continuing lorlatinib beyond progressive disease (LBPD). Patients with previous crizotinib treatment as the only ALK TKI were group A (n = 28); those with at least one previous second-generation ALK TKIs were group B (n = 74). LBPD was defined as greater than 3 weeks of lorlatinib treatment after investigator-assessed progressive disease. Only patients with the best overall response of complete or partial response or stable disease were included., Results: There were no major differences in baseline characteristics between groups. The median duration of treatment for patients who continued LBPD was 32.4 months (group A) and 16.4 months (group B) versus 12.5 months (group A) and 7.7 months (group B) for patients who did not continue LBPD. The median overall survival in group A was not reached (NR) in patients who continued LBPD versus 24.4 months (95% confidence interval [CI]: 12.1-NR); group B's median was 26.5 months (95% CI: 18.7-35.5) in patients who continued LBPD versus 14.7 months (95% CI: 9.3-38.5) in patients who did not continue LBPD. The median overall survival postprogression for groups A and B was NR (95% CI: 21.4-NR) and 14.6 months (95% CI: 11.2-19.2) in patients who continued LBPD and 8.0 months (95% CI: 1.5-NR) versus 5.3 months (95% CI: 2.8-14.3) in patients who did not continue LBPD., Conclusions: Continuing LBPD is a viable treatment strategy for select patients with ALK-positive NSCLC who progressed on lorlatinib., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: Promising single-agent activity from sotorasib and adagrasib in KRAS G12C -mutant tumors has provided clinical evidence of effective KRAS signaling inhibition. However, comprehensive analysis of KRAS -variant prevalence, genomic alterations, and the relationship between KRAS and immuno-oncology biomarkers is lacking., Materials and Methods: Retrospective analysis of deidentified records from 79,004 patients with various cancers who underwent next-generation sequencing was performed. Fisher's exact test evaluated the association between cancer subtypes and KRAS variants. Logistic regression assessed KRAS G12C comutations with other oncogenes and the association between KRAS variants and immuno-oncology biomarkers., Results: Of the 79,004 samples assessed, 13,758 (17.4%) harbored KRAS mutations, with 1,632 (11.9%) harboring KRAS G12C and 12,126 (88.1%) harboring other KRAS variants ( KRAS non-G12C ). Compared with KRAS non-G12C across all tumor subtypes, KRAS G12C was more prevalent in females (56% v 51%, false discovery rate-adjusted P value [FDR- P ] = .0006), current or prior smokers (85% v 56%, FDR- P was most prevalent in patients with non-small-cell lung cancer (9%), appendiceal (3.9%), colorectal (3.2%), tumor of unknown origin (1.6%), small bowel (1.43%), and pancreatic (1.3%) cancers. Compared with v 63%, FDR- P ≤ .0001). The most frequent KRAS variants across all subtypes were G12D (29.5%), G12V (23.0%), G12C (11.9%), G13D (6.5%), and G12R (6.2%). KRAS G12C was most prevalent in patients with non-small-cell lung cancer (9%), appendiceal (3.9%), colorectal (3.2%), tumor of unknown origin (1.6%), small bowel (1.43%), and pancreatic (1.3%) cancers. Compared with KRAS non-G12C -mutated, KRAS G12C -mutated tumors were significantly associated with tumor mutational burden-high status (17.9% v 8.4%, odds ratio [OR] = 2.38; FDR- P < .0001). KRAS G12C -mutated tumors exhibited a distinct comutation profile from KRAS non-G12C -mutated tumors, including higher comutations of STK11 (20.59% v 5.95%, OR = 4.10; FDR- P < .01) and KEAP1 (15.38% v 4.61%, OR = 3.76; FDR- P < .01)., Conclusion: This study presents the first large-scale, pan-cancer genomic characterization of KRAS G12C . The KRAS G12C mutation was more prevalent in females and older patients and appeared to be associated with smoking status. KRAS G12C tumors exhibited a distinct comutation profile and were associated with tumor mutational burden-high status., Competing Interests: Mohamed E. SalemConsulting or Advisory Role: Taiho Pharmaceutical, Exelixis, Bristol Myers Squibb, Exelixis, QED Therapeutics, Novartis, PfizerSpeakers' Bureau: Taiho Pharmaceutical, Daiichi Sankyo/Astra Zeneca, BMS, Merck Sherif M. El-RefaiEmployment: TempusStock and Other Ownership Interests: Tempus Axel GrotheyHonoraria: Elsevier, Aptitude Health, IMEDEXConsulting or Advisory Role: Genentech/Roche, Bayer (Inst), Bristol Myers Squibb (Inst), Lilly (Inst), Boston Biomedical (Inst), Amgen (Inst), Array BioPharma (Inst), Daiichi Sankyo (Inst), OBI PharmaResearch Funding: Genentech/Roche (Inst), Bayer (Inst), Pfizer (Inst), Eisai (Inst), Lilly (Inst), Boston Biomedical (Inst), Daiichi Sankyo (Inst), Array BioPharma (Inst)Travel, Accommodations, Expenses: Genentech/Roche, Bayer Thomas J. GeorgeConsulting or Advisory Role: Tempus, PfizerResearch Funding: Bristol Myers Squibb (Inst), Merck (Inst), AstraZeneca/MedImmune (Inst), Lilly (Inst), Bayer (Inst), Incyte (Inst), Ipsen (Inst), Seattle Genetics (Inst), Genentech (Inst), Astellas Pharma (Inst), BioMed Valley Discoveries (Inst), GlaxoSmithKline (Inst),Open Payments Link: https://openpaymentsdata.cms.gov/physician/321938 Jimmy J. HwangConsulting or Advisory Role: Bristol Myers Squibb, Boehringer Ingelheim, Caris Centers of Excellence, Pfizer, QED Therapeutics, Deciphera, IncyteSpeakers' Bureau: Bristol Myers Squibb, Deciphera, IncyteResearch Funding: Caris Centers of Excellence (Inst), Boehringer Ingelheim (Inst). Bert O'NeilEmployment: Lilly, TempusHonoraria: AstraZeneca Alexander S. BarrettEmployment: TempusStock and Other Ownership Interests: Tempus Derek RaghavanConsulting or Advisory Role: Gerson Lehrman Group, Caris Life Sciences (Inst). Eric Van CutsemConsulting or Advisory Role: Bayer, Lilly, Roche, SERVIER, Bristol Myers Squibb, Celgene, Merck Sharp & Dohme, Merck KGaA, Novartis, AstraZeneca, Halozyme, Array BioPharma, Biocartis, GlaxoSmithKline, Daiichi Sankyo, Pierre Fabre, Sirtex Medical, Taiho Pharmaceutical, Incyte, Astellas PharmaResearch Funding: amgen (Inst), Bayer (Inst), Boehringer Ingelheim (Inst), Lilly (Inst), Novartis (Inst), Roche (Inst), Celgene (Inst), Ipsen (Inst), Merck (Inst), Merck KGaA (Inst), SERVIER (Inst), Bristol Myers Squibb (Inst). Josep TaberneroConsulting or Advisory Role: Bayer, Boehringer Ingelheim, Lilly, MSD, Merck Serono, Novartis, Sanofi, Taiho Pharmaceutical, Peptomyc, Chugai Pharma, Pfizer, Seattle Genetics, Array BioPharma, AstraZeneca, Genentech, Menarini, Servier, HalioDx, F. Hoffmann LaRoche, Mirati Therapeutics, Pierre Fabre, Tessa Therapeutics, TheraMyc, Daiichi Sankyo, Samsung Bioepis, IQvia, Ikena Oncology, Merus, Neophore, Orion Biotechnology, Hutchison MediPharma, Avvinity, Scandion Oncology, Ona Therapeutics, Sotio Biotech, Inspirna IncOther Relationship: Imedex, Medscape, MJH Life Sciences, Peerview, Physicans' Education Resource Jeanne TieHonoraria: SERVIER, InivataConsulting or Advisory Role: AstraZeneca/MedImmune, Bristol Myers Squibb, Pierre Fabre, MSD Oncology, Inivata, Haystack OncologyNo other potential conflicts of interest were reported.

Background: Targeted therapies directed at specific driver oncogenes have improved outcomes for individuals with advanced non-small cell lung cancer (NSCLC). Approximately 5% of lung adenocarcinomas, the most common histologic subtype of NSCLC, harbour rearrangements in the anaplastic lymphoma kinase (ALK) gene leading to constitutive activity of the ALK kinase. Crizotinib was the first tyrosine kinase inhibitor (TKI) demonstrated to be effective in advanced NSCLC. Next-generation ALK TKIs have since been developed including ceritinib, alectinib, brigatinib, ensartinib, and lorlatinib, and have been compared with crizotinib or chemotherapy in randomised controlled trials (RCTs). These ALK-targeted therapies are currently used in clinical practice and are endorsed in multiple clinical oncology guidelines., Objectives: To evaluate the safety and efficacy of ALK inhibitors given as monotherapy to treat advanced ALK-rearranged NSCLC., Search Methods: We conducted electronic searches in the Cochrane Lung Cancer Group Specialised Register, Cochrane Central Register of Controlled Trials, MEDLINE, and Embase. We also searched conference proceedings from the American Society for Clinical Oncology (ASCO), European Society of Medical Oncology (ESMO), and International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer, as well as the reference lists of retrieved articles. All searches were conducted from 2007 until 7 January 2021., Selection Criteria: We included RCTs comparing ALK inhibitors with cytotoxic chemotherapy or another ALK inhibitor in individuals with incurable locally advanced or metastatic pathologically confirmed ALK-rearranged NSCLC., Data Collection and Analysis: Two review authors independently assessed studies for eligibility, extracted study characteristics and outcome data, and assessed risk of bias using the Cochrane risk of bias tool for each included study. We assessed the certainty of evidence using GRADE. Primary outcomes were progression-free survival (PFS) and adverse events (AE); secondary outcomes were overall survival (OS), OS at one year, overall response rate (ORR) by RECIST (Response Evaluation Criteria in Solid Tumours) criteria, and health-related quality of life (HRQoL). We performed a meta-analysis for all outcomes, where appropriate, using the fixed-effect model. We reported hazard ratios (HR) for PFS, OS, and a composite HRQoL of life outcome (time to deterioration), and risk ratios (RR) for AE, ORR, and one-year OS. We presented 95% confidence intervals (95% CIs) and used the I² statistic to investigate heterogeneity. We planned comparisons of 'ALK inhibitor versus chemotherapy' and 'next-generation ALK inhibitor versus crizotinib' with subgroup analysis by type of ALK inhibitor, line of treatment, and baseline central nervous system involvement., Main Results: Eleven studies (2874 participants) met our inclusion criteria: six studies compared an ALK inhibitor (crizotinib, ceritinib, and alectinib) to chemotherapy, and five studies compared a next-generation ALK inhibitor (alectinib, brigatinib, and lorlatinib) to crizotinib. We assessed the evidence for most outcomes as of moderate to high certainty. Most studies were at low risk for selection, attrition, and reporting bias; however, no RCTs were blinded, resulting in a high risk of performance and detection bias for outcomes reliant on subjective measurement. ALK inhibitor versus chemotherapy Treatment with ALK inhibitors resulted in a large increase in PFS compared to chemotherapy (HR 0.45, 95% CI 0.40 to 0.52, 6 RCTs, 1611 participants, high-certainty evidence). This was found regardless of line of treatment. ALK inhibitors may result in no difference in overall AE rate when compared to chemotherapy (RR 1.01, 95% CI 1.00 to 1.03, 5 RCTs, 1404 participants, low-certainty evidence). ALK inhibitors slightly improved OS (HR 0.84, 95% CI 0.72 to 0.97, 6 RCTs, 1611 participants, high-certainty evidence), despite most included studies having a significant number of participants crossing over from chemotherapy to receive an ALK inhibitor after the study period. ALK inhibitors likely increase ORR (RR 2.43, 95% CI 2.16 to 2.75, 6 RCTs, 1611 participants, moderate-certainty evidence) including in measurable baseline brain metastases (RR 4.88, 95% CI 2.18 to 10.95, 3 RCTs, 108 participants) when compared to chemotherapy. ALK inhibitors result in a large increase in the HRQoL measure, time to deterioration (HR 0.52, 95% CI 0.44 to 0.60, 5 RCTs, 1504 participants, high-certainty evidence) when compared to chemotherapy. Next-generation ALK inhibitor versus crizotinib Next-generation ALK inhibitors resulted in a large increase in PFS (HR 0.39, 95% CI 0.33 to 0.46, 5 RCTs, 1263 participants, high-certainty evidence), particularly in participants with baseline brain metastases. Next-generation ALK inhibitors likely result in no difference in overall AE (RR 1.00, 95% CI 0.98 to 1.01, 5 RCTs, 1263 participants, moderate-certainty evidence) when compared to crizotinib. Next-generation ALK inhibitors likely increase OS (HR 0.71, 95% CI 0.56 to 0.90, 5 RCTs, 1263 participants, moderate-certainty evidence) and slightly increase ORR (RR 1.18, 95% CI 1.10 to 1.25, 5 RCTs, 1229 participants, moderate-certainty evidence) including a response in measurable brain metastases (RR 2.45, 95% CI 1.7 to 3.54, 4 RCTs, 138 participants) when compared to crizotinib. Studies comparing ALK inhibitors were conducted exclusively or partly in the first-line setting., Authors' Conclusions: Next-generation ALK inhibitors including alectinib, brigatinib, and lorlatinib are the preferred first systemic treatment for individuals with advanced ALK-rearranged NSCLC. Further trials are ongoing including investigation of first-line ensartinib. Next-generation inhibitors have not been compared to each other, and it is unknown which should be used first and what subsequent treatment sequence is optimal., (Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Introduction: Multidisciplinary Meetings (MDM) are recommended in routine lung cancer care, however its broader impacts demand further evaluation. We assessed the drivers and impacts of MDM presentation in the Victorian Lung Cancer Registry (VLCR)., Methods: We examined the effect of MDM presentation on receipt of treatment and survival in VLCR patients diagnosed between 2011 and 2020. We compared patient characteristics, drivers of MDM discussion and survival between the two groups., Results: Of 9,628 patients, 5,900 (61.3%) were discussed at MDM, 3,728 (38.7%) were not. In the non-MDM group, a lower proportion received surgery (22.1% vs. 31.2%), radiotherapy (34.2% vs. 44.4%) and chemotherapy (44.7% vs. 49.0%). Patients were less likely to be discussed if ≥80 years (OR 0.73, p < 0.001), of ECOG performance status (PS) 4 (OR 0.23, p < 0.001), clinical stage IV (OR 0.34, p < 0.001) or referred from regional (OR 0.52, p < 0.001) or private hospital (OR 0.18, p < 0.001). MDM-presented patients had better median survival (1.70 vs 0.75 years, p < 0.001) and lower adjusted mortality risk (HR 0.75; 0.71-0.80, p < 0.001), a protective effect consistent across all hospital types. Undocumented PS, histopathology and clinical stage were associated with lower likelihood of MDM discussion and worse mortality., Conclusions: In the VLCR, being male, ≥80 years, of poorer PS, advanced clinical stage and poor clinical characterisation significantly disadvantaged patients in relation to MDM discussion. MDM-discussed patients were more likely to undergo treatment and had a 25% lower risk of mortality. This study supports the use of MDMs in lung cancer and identifies areas of inequity to be addressed., (Copyright © 2021. Published by Elsevier B.V.)

Purpose: Response Evaluation Criteria in Solid Tumors (RECIST) has limitations but remains the conventional approach for tumor assessments. We explored whether circulating tumor DNA (ctDNA) can be incorporated into RECIST to provide a more robust measure of tumor response in advanced EGFR-mutant NSCLC., Patients and Methods: In FASTACT-2, patients with advanced NSCLC received platinum/gemcitabine intercalated with erlotinib or placebo. EGFR mutation (tumor and plasma ctDNA) was detected using cobas v2. Patients selected for this hypothesis-generating analysis had EGFR mutations (on either tumor or plasma) at baseline and evaluable week 8 plasma EGFR. Week 8 ctDNA and radiologic response status were correlated with survival using landmark cox regression analyses., Results: Of the original 451 patients, 86 (19.1%) were eligible for this analysis. 73% (n = 63) had detectable ctDNA at baseline. At week 8, 40% (n = 34) had radiologic partial response (PR), 60% (n = 52) had stable disease (SD); 80% (n = 69) had a ctDNA response (undetectable ctDNA). In patients who had initial PR and undetectable ctDNA, 93% (28/30) had ongoing PR subsequently at week 16. The median duration of response was 14.9 months. In patients with SD and undetectable ctDNA at week 8, 28% had radiological PR at week 16. Amongst those with PR at week 8, survival outcomes for those with undetectable vs detectable ctDNA were not statistically significant (PFS HR 0.49, 95%CI 0.16-1.48, p = 0.21; OS HR 0.39, 95%CI 0.13-1.19, p = 0.10). Amongst those with SD at week 8, there was significantly longer survival for those with undetectable vs detectable ctDNA (PFS HR 0.27, 95% CI 0.13-0.57, p < 0.0001; OS HR 0.40, 95% CI 0.20-0.80, p = 0.009)., Conclusion: In patients with SD, undetectable ctDNA at week 8 correlated with survival improvement. Both radiologic and ctDNA responses are prognostic of PFS. Incorporation of ctDNA with RECIST may improve tumor response assessment in EGFR-mutant NSCLC., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: In the past 3 decades, synchrotron microbeam radiation therapy (S-MRT) has been shown to achieve both good tumor control and normal tissue sparing in a range of preclinical animal models. However, the use of S-MRT for the treatment of lung tumors has not yet been investigated. This study is the first to evaluate the therapeutic efficacy of S-MRT for the treatment of lung carcinoma, using a new syngeneic and orthotopic mouse model., Methods and Materials: Lewis Lung carcinoma-bearing mice were irradiated with 2 cross-fired arrays of S-MRT or synchrotron broad-beam (S-BB) radiation therapy. S-MRT consisted of 17 microbeams with a width of 50 µm and center-to-center spacing of 400 µm. Each microbeam delivered a peak entrance dose of 400 Gy whereas S-BB delivered a homogeneous entrance dose of 5.16 Gy (corresponding to the S-MRT valley dose)., Results: Both treatments prolonged the survival of mice relative to the untreated controls. However, mice in the S-MRT group developed severe pulmonary edema around the irradiated carcinomas and did not have improved survival relative to the S-BB group. Subsequent postmortem examination of tumor size revealed that the mice in the S-MRT group had notably smaller tumor volume compared with the S-BB group, despite the presence of edema. Mice that were sham-implanted did not display any decline in health after S-MRT, experiencing only mild and transient edema between 4 days and 3 months postirradiation which disappeared after 4 months. Finally, a parallel study investigating the lungs of healthy mice showed the complete absence of radiation-induced pulmonary fibrosis 6 months after S-MRT., Conclusions: S-MRT is a promising tool for the treatment of lung carcinoma, reducing tumor size compared with mice treated with S-BB and sparing healthy lungs from pulmonary fibrosis. Future experiments should focus on optimizing S-MRT parameters to minimize pulmonary edema and maximize the therapeutic ratio., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Disclosure KHJL has received speaker honorarium from Janssen, outside the submitted work and is currently funded by the Wellcome Imperial 4i Clinical Research Fellowship. BJS has received advisory board/honoraria from Roche/Genentech, AstraZeneca, Pfizer, Novartis, Bristol-Myers-Squibb, Merck, Amgen, and Loxo oncology, outside the submitted work.

Aim: Decreased cancer incidence and reported changes to clinical management indicate that the COVID-19 pandemic has delayed cancer diagnosis and treatment. This study aimed to develop and apply a flexible model to estimate the impact of delayed diagnosis and treatment on survival outcomes and healthcare costs based on a shift in the disease stage at treatment initiation., Methods: A model was developed and made publicly available to estimate population-level health economic outcomes by extrapolating and weighing stage-specific outcomes by the distribution of stages at treatment initiation. It was applied to estimate the impact of 3- and 6-month delays based on Australian data for stage I breast cancer, colorectal cancer, and lung cancer patients, and for T1 melanoma. Two approaches were explored to estimate stage shifts following a delay: (a) based on the relation between time to treatment initiation and overall survival (breast, colorectal, and lung cancer), and (b) based on the tumor growth rate (melanoma)., Results: Using a conservative once-off 3-month delay and considering only shifts from stage I/T1 to stage II/T2, 88 excess deaths and $12 million excess healthcare costs were predicted in Australia over 5 years for all patients diagnosed in 2020. For a 6-month delay, excess mortality and healthcare costs were 349 deaths and $46 million over 5 years., Conclusions: The health and economic impacts of delays in treatment initiation cause an imminent policy concern. More accurate individual patient data on shifts in stage of disease during and after the COVID-19 pandemic are critical for further analyses., (© 2021 John Wiley & Sons Australia, Ltd.)

Purpose: Immunotherapy (IT) and targeted therapy (TT) have improved survival for some patients with metastatic non-small cell lung cancer (NSCLC). Their lived experience is under-studied. We conducted a single centre, qualitative study to understand concerns and unmet needs amongst this novel survivor population., Methods: Eligible participants had metastatic NSCLC, aged >18, English-speaking and >6 months post initiation of IT/TT without progressive disease. Semi-structured interviews focused on physical, psychological, social and functional impacts of diagnosis, therapy and prognosis. Interviews were recorded and transcribed. Data were analysed via qualitative thematic analysis., Results: Between May and December 2019, 20 participants were interviewed: median age 62 (range 34-83), 13 (65%) female; median time since diagnosis of metastatic NSCLC 27 months (range 10-108). Twelve out of 20 (60%) participants had a targetable mutation (EGFR/ALK/BRAF); 6 were receiving IT, 11 TT, 2 IT + chemotherapy and 1 IT + TT. Four main themes were identified: living long-term on IT and TT (chronic toxicities), psychological concerns (living with uncertainty, fear of cancer progression, scan-related anxiety), support with practical issues (finances, employment amidst prognostic uncertainty, challenges with trial participation) and wanting information pertinent to NSCLC subtype., Conclusions: Longer-term survivors of metastatic NSCLC experience significant physical, psychological and functional concerns and unmet needs. Results will inform a broader cross-sectional survey and resources to address the needs of this growing survivor group., Implications for Cancer Survivors: A 'one-size-fits-all' approach to NSCLC survivorship is no longer appropriate. Survivors of metastatic NSCLC treated with novel therapies may benefit from specific information regarding long-term toxicities and psychological supports.

Introduction: Patients with non-small cell lung cancer (NSCLC) can experience rapid disease progression between initial staging FDG-PET scans and commencement of curative-intent radiotherapy (RT). Previous studies that estimated stage migration rates by comparing staging PET/CT and treatment-planning PET/CT images were limited by small sample sizes., Methods: This multicenter, international study combined prospective data from five institutions for PET-staged patients with NSCLC who were intended to receive curative-intent RT. TNM status was compared for staging and RT planning scans and the probability of TNM status and overall stage migration was analyzed as a function of the interval between PET/CT scans. The impacts of N classification, overall stage, and pathology were also studied., Results: Pooled data from 181 patients were analyzed. The median interval between PET/CT scans was 42 days (range, 2-208). Upstaging occurred in 32 % of patients. The overall rate of stage migration was higher for patients presenting with initial stage IIIB/IIIC disease (p = 0.006) and patients with N2-3 nodal disease (p = 0.019). Upstaging to M1 disease was significantly associated with initial stage IIIB/IIIC disease (HR = 15.2) and adenocarcinoma (HR = 10) histology., Conclusion: Longer intervals between imaging and treatment in patients with NSCLC were associated with high rates disease progression with consequent risks of geographic miss in RT planning and futile treatment in patients with M1 disease. Patients with more extensive initial nodal involvement and those with adenocarcinoma had the highest rates of stage migration. Dedicated RT planning PET/CT imaging is recommended, especially if >3 weeks have elapsed after initial staging., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Lorlatinib, a potent, brain-penetrant, third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), has substantial activity against ALK-positive non-small-cell lung cancer (NSCLC). This study assessed the overall, intracranial, and extracranial efficacy of lorlatinib in ALK-positive NSCLC that progressed on second-generation ALK TKIs., Patients and Methods: In the ongoing phase II study (NCT01970865), patients with ALK-positive advanced NSCLC treated with ≥1 prior second-generation ALK TKI ± chemotherapy were enrolled in expansion cohorts (EXP) based on treatment history. Overall, intracranial and extracranial antitumor activity were assessed independently per modified Response Evaluation Criteria in Solid Tumors (RECIST) v1.1., Results: Of the 139 patients with ≥1 prior second-generation ALK TKI (EXP3B-5), 28 received one prior second-generation ALK TKI (EXP3B), 65 two prior ALK TKIs (EXP4), and 46 three prior ALK TKIs (EXP5). In EXP3B-5, the objective response rate (ORR) [95% confidence intervals] was 39.6% (31.4-48.2), intracranial ORR (IC-ORR) was 56.1% (42.4-69.3), extracranial ORR (EC-ORR) was 36.7% (28.7-45.3), median duration of response (DOR) was 9.6 months [5.6-16.7; IC-DOR, 12.4 (6.0-37.1); EC-DOR, 9.7 (6.1-33.3)], median progression-free survival was 6.6 (5.4-7.4) months, and median overall survival was 20.7 months (16.1-30.3). In EXP3B, the ORR was 42.9% (24.5-62.8), the IC-ORR was 66.7% (29.9-92.5), and the EC-ORR was 32.1% (15.9-52.4). In EXP4 and EXP5, the ORR was 38.7% (29.6-48.5), the IC-ORR was 54.2% (39.2-68.6), and the EC-ORR was 37.8% (28.8-47.5)., Conclusions: Lorlatinib had clinically meaningful intracranial and extracranial antitumor activity in the post-second-generation ALK TKI setting, with elevated intracranial versus extracranial ORR, particularly in patients with fewer lines of therapy., Competing Interests: Disclosure EF has served on advisory boards for AbbVie, Bayer, Blueprint Medicines, GlaxoSmithKline, Guardant Health, Janssen, Merck KGaA, and Samsung; speakers' bureaus for Medscape, prIME Oncology, and TouchIME; advisory boards and speakers' bureaus for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Takeda; and received research funding from Fundación Merck Salud and Grant for Oncology Innovation; independent member of the board for Grifols. ATS has served as a compensated consultant or received honoraria from Achilles, Archer, Ariad/Takeda, Bayer, Blueprint Medicines, Chugai, Daiichi-Sankyo, EMD Serono, Foundation Medicine, Guardant, Ignyta, KSQ Therapeutics, Loxo Oncology, Natera, Novartis, Pfizer, Roche-Genentech, Servier, Syros, Taiho Pharmaceutical, and TP Therapeutics; received institutional research funding from Ariad, Ignyta, Novartis, Pfizer, Roche-Genentech, and TP Therapeutics; received travel support from Genentech and Pfizer; and is currently an employee of Novartis. AB has received honoraria from AstraZeneca, Boehringer Ingelheim, Janssen, Novartis, Pfizer, Roche, and Takeda. DRC has received honoraria from AbbVie, Achilles Therapeutics, Apollomics, Archer, Arrys/Kyn, AstraZeneca, BeyondSpring Pharmaceuticals, Biothera, Blueprint Medicines, Bristol-Myers Squibb, CBT Pharmaceuticals, Daiichi-Sankyo, Elevation, EMD Serono, G1 Therapeutics, Hansoh, Helsinn Therapeutics, Hengrui Pharmaceutical, Inivata, Lilly, Medtronic, Regeneron, Ribon Therapeutics, Roche, and Takeda; and received research funding from Takeda. BJS has served as a consultant or on advisory boards for Amgen, AstraZeneca, Bristol-Myers Squibb, Merck, Novartis, Pfizer, and Roche-Genentech. JRB has served as a consultant for Astra Zeneca and Pfizer; has served on advisory boards for Bayer and Kura; and received institutional research funding from Bristol-Myers Squibb, unrelated to this work. TMB reports employment by Tennessee Oncology; has served as a consultant/advisor for Bayer, Blueprint Medicines, Exelixis, Foundation Medicine, Guardant Health, Ignyta, Loxo Oncology, Moderna Therapeutics, and Pfizer; has served on speakers' bureaus for Bayer, Bristol-Myers Squibb, and Lilly; received research funding from AbbVie, Aileron Therapeutics, Amgen, ARMO BioSciences, Astellas Pharma, Astra Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Calithera Biosciences, Clovis Oncology, Daiichi-Sankyo, Deciphera, Five Prime Therapeutics, Foundation Medicine, Genentech/Roche, GlaxoSmithKline, Ignyta, Immunocore, Immunogen, Incyte, Jacobio, Janssen, Karyopharm Therapeutics, Kolltan Pharmaceuticals, Leap Therapeutics, Lilly, Loxo Oncology, MabVax, MedImmune, Medpacto, Inc., Merck, Merrimack, Millennium, Mirati Therapeutics, Moderna Therapeutics, Novartis, Onyx, Peleton, Pfizer, Phosplatin Therapeutics, Principia Biopharma, Roche, Sanofi, Stemline Therapeutics, Takeda, and Top Alliance BioSciences; and compensation for travel, accommodations, and expenses from Astellas Pharma, AstraZeneca, Celgene, Clovis Oncology, EMD Serono, Genentech, Lilly, Merck, Novartis, Pfizer, Pharmacyclics, and Sysmex. SP has received education grants, provided consultation, attended advisory boards, and/or provided lectures for AbbVie, Amgen, AstraZeneca, Bayer, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi-Sankyo, Debiopharm, Eli Lilly, F. Hoffmann-La Roche, Foundation Medicine, Illumina, Janssen, Merck Sharp and Dohme, Merck Serono, Merrimack, Novartis, Pharma Mar, Pfizer, Regeneron, Sanofi, Seattle Genetics, Takeda, and Vaccibody, from whom she has received honoraria (all fees to institution). FT, AA report employment by Pfizer. HT, GP, RW report employment by Pfizer and are Pfizer shareholders. BB reports sponsored research at Gustave Roussy Cancer Center, AbbVie, Amgen, AstraZeneca, BeiGene, Blueprint Medicines, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Cristal Therapeutics, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Ignyta, IPSEN, Inivata, Janssen, Merck KGaA, MSD, Nektar, Onxeo, OSE immunotherapeutics, Pfizer, Pharma Mar, Roche-Genentech, Sanofi, Servier, Spectrum Pharmaceuticals, Takeda, Tiziana Pharma, and Tolero Pharmaceuticals. Data sharing Upon request, and subject to certain criteria, conditions and exceptions (see https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information), Pfizer will provide access to individual de-identified participant data from Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines, and medical devices (1) for indications that have been approved in the US and/or EU or (2) in programs that have been terminated (i.e. development for all indications has been discontinued). Pfizer will also consider requests for the protocol, data dictionary, and statistical analysis plan. Data may be requested from Pfizer trials 24 months after study completion. The de-identified participant data will be made available to researchers whose proposals meet the research criteria and other conditions, and for which an exception does not apply, via a secure portal. To gain access, data requestors must enter into a data access agreement with Pfizer., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: To assess the clinical utility of quantitative PCR (qPCR) assays, a routinely used test for detection of epidermal growth factor receptor (EGFR) mutation in circulating tumour DNA (ctDNA) in treatment-naive advanced lung cancer patients., Materials and Methods: We performed a meta-analysis of randomized controlled trials (RCTs) with individual patient data. Eligible RCTs compared EGFR-tyrosine kinase inhibitor (EGFR-TKI) and chemotherapy in first line setting for advanced lung cancer, and included tumour EGFR+ (tEGFR+) with paired ctDNA results using real-time (quantitative) PCR. We assessed the proportion of tEGFR + detected by ctDNA, and compared the effectiveness of EGFR-TKI versus chemotherapy in ctDNA + and ctDNA- subgroups., Results: Six randomized clinical trials included 1058 tEGFR + patients with paired baseline EGFR ctDNA testing. Of these, 460 (43 %) tested ctDNA- (ctDNA+ 57 %). Progression-free survival was longer for EGFR-TKI versus chemotherapy for both ctDNA+ (HR 0.28; 95 % CI 0.22-0.36, p < 0.00001) and ctDNA- subgroups (HR 0.37; 95 % CI 0.28-0.49, p < 0.00001; p-interaction = 0.14). Objective response rate (odds ratio 6.21; 95 % CI 4.25-9.07, p < 0.00001 vs 6.44; 95 % CI 4.21-9.87, p < 0.00001) and overall survival (HR 0.82; 95 % CI 0.70-1.04 vs HR 0.77; 95CI% 0.59-1.00) similarly favoured EGFR-TKI in both ctDNA + and ctDNA- subgroups respectively., Conclusion: Our findings indicate that approximately two in five tissue EGFR mutation-positive patients will not be detected using a qPCR assay, but would still potentially benefit from highly effective EGFR-TKI treatment. A negative EGFR ctDNA result via qPCR testing is therefore insufficient to exclude benefit from EGFR-TKI. Attempts should be made to repeat EGFR testing with a tissue biopsy in this patient group. As newer ctDNA assays with better sensitivity become available, the clinical impact for any false negatives will remain an important consideration., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The continued introduction of biomarkers and innovative testing methods makes already complex diagnosis in patients with stage IV non-small-cell lung cancer (NSCLC) even more complex. This study primarily analyzed variations in biomarker testing in clinical practice in patients referred to a comprehensive cancer center in the Netherlands. The secondary aim was to compare the cost of biomarker testing with the cost of whole-genome sequencing. The cohort included 102 stage IV NSCLC patients who received biomarker testing in 2017 or 2018 at the comprehensive cancer center. The complete biomarker testing history of the cohort was identified using linked data from the comprehensive cancer center and the nationwide network and registry of histopathology and cytopathology in the Netherlands. Unique biomarker-test combinations, costs, turnaround times, and test utilization were examined. The results indicate substantial variation in test utilization and sequences. The mean cost per patient of biomarker testing was 2259.92 ± 1217.10 USD, or 1881.23 ± 1013.15 EUR. Targeted gene panels were most frequently conducted, followed by IHC analysis for programmed cell death protein ligand 1. Typically, the most common biomarkers were assessed within the first tests, and emerging biomarkers were tested further down the test sequence. At the cost of current biomarker testing, replacing current testing with whole-genome sequencing would have led to cost-savings in only two patients (2%)., (Copyright © 2021 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Radiomics allows extraction of quantifiable features from imaging. This study performs a systematic review and meta-analysis of the performance of radiomics based prognostic models in non-small cell lung cancer (NSCLC)., Materials and Methods: A literature review was performed following PRISMA guidelines. Medline, EMBASE and Cochrane databases were searched for articles investigating radiomics features predictive of overall survival (OS) in NSCLC treated with curative intent radiotherapy. A random-effects meta-analysis of Harrell's Concordance Index (C-index) was performed on the performance of radiomics models., Results: Of the 2746 articles retrieved, 40 studies of 55 datasets and 6223 patients were eligible for inclusion in the systematic review. There was significant heterogeneity in the methodology for feature selection and model development. Twelve datasets reported the C-index of radiomics based models in predicting OS and were included in the meta-analysis. The C-index random effects estimate was 0.57 (95% CI 0.53-0.62). There was significant heterogeneity (I 2  = 70.3%)., Conclusions: Based on this review, radiomics based models for lung cancer have to date demonstrated modest prognostic capabilities. Future research should consider using standardised radiomics features, robust feature selection and model development, and deep learning techniques, absolving the need for pre-defined features, to improve imaging-based models., 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 B.V. All rights reserved.)

Stereotactic ablative radiotherapy offers a radical treatment approach for early stage lung cancers and an aggressive local therapy for pulmonary oligometastases from other tumour sites. Chest wall toxicity is one of the key dose-limiting toxicities for intrathoracic stereotactic treatments. The description of stereotactic radiotherapy chest wall toxicity using functional imaging has not been reported previously. A 56-year-old male received 60 Gy in 8 fractions delivered by volumetric modulated arc therapy for a T1bN0M0 clinical left upper lobe lung cancer. The past medical history included poorly controlled type 1 diabetes mellitus, severe peripheral vascular disease and obesity. The patient attended 9 months later with left-sided, slowly progressive chest pain. An 18 FDG PET/CT performed in order to investigate contralateral pulmonary lesions revealed FDG-avid focal thickening at the left superio-lateral thoracic wall with overlying inflammatory stranding in keeping with an indolent inflammatory process. Chest wall toxicity may present as pain, swelling, fracture and skin changes, and has the 18 FDG PET/CT chjmirocteristics of an inflammatory process. Patients with risk factors for chest wall toxicity, such as obesity, diabetes and smoking should be informed of their higher propensity for this clinically significant treatment side effect. For patients developing chest wall toxicity as demonstrated in this case with associated functional imaging findings, anti-inflammatory treatment should be promptly commenced., (© 2020 The Authors. Journal of Medical Imaging and Radiation Oncology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian and New Zealand College of Radiologists.)

Background and Purpose: The purpose of this work is to present the clinical experience from the first-in-human trial of real-time tumor targeting via MLC tracking for stereotactic ablative body radiotherapy (SABR) of lung lesions., Methods and Materials: Seventeen patients with stage 1 non-small cell lung cancer (NSCLC) or lung metastases were included in a study of electromagnetic transponder-guided MLC tracking for SABR (NCT02514512). Patients had electromagnetic transponders inserted near the tumor. An MLC tracking SABR plan was generated with planning target volume (PTV) expanded 5 mm from the end-exhale gross tumor volume (GTV). A clinically approved comparator plan was generated with PTV expanded 5 mm from a 4DCT-derived internal target volume (ITV). Treatment was delivered using a standard linear accelerator to continuously adapt the MLC based on transponder motion. Treated volumes and reconstructed delivered dose were compared between MLC tracking and comparator ITV-based treatment., Results: All seventeen patients were successfully treated with MLC tracking (70 successful fractions). MLC tracking treatment delivery time averaged 8 minutes. The time from the start of CBCT to the end of treatment averaged 22 minutes. The MLC tracking PTV for 16/17 patients was smaller than the ITV-based PTV (range -1.6% to 44% reduction, or -0.6 to 18 cc). Reductions in mean lung dose (27 cGy) and V20Gy (50 cc) were statistically significant (p < 0.02). Reconstruction of treatment doses confirmed a statistically significant improvement in delivered GTV D98% (p < 0.05) from planned dose compared with the ITV-based plans., Conclusion: The first treatments with lung MLC tracking have been successfully performed in seventeen SABR patients. MLC tracking for lung SABR is feasible, efficient and delivers high-precision target dose and lower normal tissue dose., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)