Search

Background: Lung cancer remains a critical public health issue, presenting multifaceted challenges in prevention, diagnosis, and treatment. This article aims to review the current landscape of lung cancer research and management, delineate the persistent challenges, and outline pragmatic solutions., Materials and Methods: Global experts from academia, regulatory agencies such as the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), the National Cancer Institute (NCI), professional societies, the pharmaceutical and biotech industries, and patient advocacy groups were gathered by the New York Lung Cancer Foundation to review the state of the art in lung cancer and to formulate calls to action., Results: Improving lung cancer management and research involves promoting tobacco cessation, identifying individuals at risk who could benefit from early detection programs, and addressing treatment-related toxicities. Efforts should focus on conducting well-designed trials to determine the optimal treatment sequence. Research into innovative biomarkers and therapies is crucial for more personalized treatment. Ensuring access to appropriate care for all patients, whether enrolled in clinical trials or not, must remain a priority., Conclusions: Lung cancer is a major health burden worldwide, and its treatment has become increasingly complex over the past two decades. Improvement in lung cancer management and research requires unified messaging and global collaboration, expanded education, and greater access to screening, biomarker testing, treatment, as well as increased representativeness, participation, and diversity in clinical trials., (Copyright © 2024 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Objective: Buprenorphine is the standard of care for treatment of opioid withdrawal. However, when sublingual (SL) administration is not appropriate or practical, parenteral administration by the intravenous (IV) or intramuscular (IM) route may be a reasonable substitute. Although previously used intravenously for the treatment of pain, current practitioners have limited experience with parenteral use of buprenorphine., Methods: This is a case series using retrospective chart review of patients at an urban public hospital who received IV or IM buprenorphine for treatment of opioid withdrawal. A query of the electronic health record (EHR) was performed to identify patients who had received IV or IM buprenorphine from January 2020 to December 2021. Charts were reviewed for patient demographics, medical history, substance use history, urine drug screens, clinical scenario, indication for parenteral buprenorphine, dose of buprenorphine, vital sign trends, and any measure of change in withdrawal., Results: Eight patients were identified. The most frequent initial dose of parenteral buprenorphine was 0.3 mg, and if buprenorphine needed to be re-dosed it was most commonly administered every six hours. The most common indications for use were delirium or intractable nausea and vomiting related to opioid withdrawal. Withdrawal improved in 6 of the 8 cases, and often allowed for subsequent use of SL buprenorphine. There were no adverse effects identified., Conclusion: Parenteral buprenorphine was successfully used to treat opioid withdrawal in a select group of patients. Further studies are needed to identify the optimal use parameters of parenteral buprenorphine.

Introduction: The primary analysis (median follow-up 34.9 mo across all arms) of the phase 3 POSEIDON study revealed a statistically significant overall survival (OS) improvement with first-line tremelimumab plus durvalumab and chemotherapy (T+D+CT) versus CT in patients with EGFR and ALK wild-type metastatic NSCLC (mNSCLC). D+CT had a trend for OS improvement versus CT that did not reach statistical significance. This article reports prespecified OS analyses after long-term follow-up (median >5 y)., Methods: A total of 1013 patients were randomized (1:1:1) to T+D+CT, D+CT, or CT, stratified by tumor cell programmed cell death ligand-1 (PD-L1) expression (≥50% versus <50%), disease stage (IVA versus IVB), and tumor histologic type (squamous versus nonsquamous). Serious adverse events were collected during follow-up., Results: After a median follow-up of 63.4 months across all arms, T+D+CT had sustained OS benefit versus CT (hazard ratio [HR] = 0.76, 95% confidence interval [CI]: 0.64-0.89; 5-y OS: 15.7% versus 6.8%). OS improvement with D+CT versus CT (HR = 0.84, 95% CI: 0.72-1.00; 5-y OS: 13.0%) was consistent with the primary analysis. OS benefit with T+D+CT versus CT remained more pronounced in nonsquamous (HR = 0.69, 95% CI: 0.56-0.85) versus squamous (HR = 0.85, 95% CI: 0.65-1.10) mNSCLC. OS benefit with T+D+CT versus CT was still evident regardless of PD-L1 expression, including patients with PD-L1 tumor cell less than 1%, and remained evident in STK11-mutant (nonsquamous), KEAP1-mutant, and KRAS-mutant (nonsquamous) mNSCLC. No new safety signals were identified., Conclusions: After a median follow-up of more than 5 years, T+D+CT had durable long-term OS benefit versus CT, supporting its use as first-line treatment in mNSCLC, including in patient subgroups with harder-to-treat disease., Competing Interests: Disclosure Peters has received grants (paid to institution) from Amgen, Arcus, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, F. Hoffmann-La Roche/Genentech, GlaxoSmithKline, iTeos, Merck Sharp & Dohme, Merck Serono, Mirati, PharmaMar, Promontory Therapeutics, and Seattle Genetics; has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events (paid to institution) from AiCME, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, ecancer, Eli Lilly, F. Hoffmann-La Roche/Genentech, Foundation Medicine, GlaxoSmithKline, Illumina, Imedex, Ipsen, Medscape, Merck Sharp & Dohme, Mirati, MJH Life Sciences, Novartis, Peerview, Pfizer, RTP, and Takeda; and has participation on a data safety monitoring board or advisory board (payment to institution) for AbbVie, AiCME, Amgen, Arcus, AstraZeneca, Bayer, BeiGene, BerGenBio, Biocartis, Bioinvent, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, F. Hoffmann-La Roche/Genentech, Fishawack, Foundation Medicine, F-Star, Genzyme, Gilead, GlaxoSmithKline, Hutchmed, Illumina, Imedex, Incyte, Ipsen, IQVIA, iTeos, Janssen, Medscape, Medtoday, Merck Sharp & Dohme, Merck Serono, Merrimack, Mirati, MJH Life Sciences, Novartis, Novocure, Nykode Therapeutics, OncologyEducation, Peerview, Pharma Mar, Pfizer, Promontory Therapeutics, Regeneron, RMEI, RTP, Sanofi, Seattle Genetics, and Takeda. Cho reports receiving research funding from MOGAM Institute, LG Chem, Oscotec, Interpark Bio Convergence Corp., GIInnovation, GI-Cell, Abion, AbbVie, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Champions Oncology, CJ Bioscience, CJ Blossom Park, Cyrus, Dizal Pharma, Genexine, Janssen, Lilly, Merck Sharp & Dohme, Novartis, Nuvalent, Oncternal, Ono, Regeneron, Dong-A ST, Bridgebio Therapeutics, Yuhan, ImmuneOncia, Illumina, Kanaph Therapeutics, Therapex, JINTSbio, Hanmi, CHA Bundang Medical Center, and Vertical Bio AG; receiving royalties from Champions Oncology, Crown Bioscience, Imagen, and PearlRiver Bio GmbH; receiving consulting fees from Abion, BeiGene, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, CJ, CureLogen, Cyrus Therapeutics, Ono, Onegene Biotechnology, Yuhan, Pfizer, Eli Lilly, GI-Cell, Guardant, HK Inno-N, Imnewrun Biosciences Inc., Janssen, Takeda, Merck Sharp & Dohme, Janssen, Medpacto, Blueprint Medicines, RandBio, and Hanmi; receiving payment or honoraria for presentations from ASCO, AstraZeneca, Guardant, Roche, ESMO, International Association for the Study of Lung Cancer, Korean Cancer Association, Korean Society of Medical Oncology, Korean Society of Thyroid-Head and Neck Surgery, Korean Cancer Study Group, Novartis, Merck Sharp & Dohme, The Chinese Thoracic Oncology Society, and Pfizer; having scientific advisory board participation for Kanaph Therapeutics Inc., Bridgebio Therapeutics, Cyrus Therapeutics, Guardant Health, Oscotec Inc., J INTS Bio, Therapex Co., Ltd., Gilead, and Amgen; having membership of the board of directors for J INTS BIO; having stock ownership in TheraCanVac Inc., Gencurix Inc., Bridgebio Therapeutics, Kanaph Therapeutics Inc., Cyrus Therapeutics, Interpark Bio Convergence Corp., and J INTS BIO; having employment with Yonsei University Health System; and being a founder of DAAN Biotherapeutics. Alatorre-Alexander has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Amgen, AstraZeneca, Bristol-Myers Squibb, Janssen, Merck Sharp & Dohme, and Roche; received support for attending meetings and/or travel from AstraZeneca, Merck Sharp & Dohme, and Roche; and participated on a data safety monitoring board or advisory board for Amgen, AstraZeneca, Bristol-Myers Squibb, Janssen, Merck Sharp & Dohme, and Roche. Geater has received research funding (paid to institution) from AstraZeneca, Boehringer Ingelheim, Merck Sharp & Dohme, Novartis, and Roche; received honoraria from AstraZeneca and Boehringer Ingelheim; and performed an advisory role for Merck Sharp & Dohme and Pfizer. Laktionov has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events for AstraZeneca, Biocad, Bristol-Myers Squibb, Merck Sharp & Dohme, and Roche AG, and has participated on a data safety monitoring board or advisory board for AstraZeneca, Biocad, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, and Roche AG. Kim has received grants (paid to institution) from Yuhan and support for attending an investigator meeting from AstraZeneca. Hussein has received consulting fees from IntegraConnect, Coherus Biosciences, Athenex, Karyopharm Therapeutics, Bristol-Myers Squibb, AstraZeneca, Mirati Therapeutics, Exelixis, Biopharma, Oncocyte, Aptitude Health, IntrinsiQ, GIntrinsiQ, National Community Oncology Dispensing Association, Integra PrescisionQ, AbbVie, and CTI BioPharma Corp. Araujo has received grants from Lilly, Boehringer, Merck Sharp & Dohme, Bristol-Myers Squibb, Roche, Pfizer, AstraZeneca, Novartis, and Merck; consulting fees from Merck Sharp & Dohme, Roche, AstraZeneca, Bristol-Myers Squibb, Lilly, Illumina, and Sanofi; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Merck Sharp & Dohme, Bristol-Myers Squibb, AstraZeneca, Boehringer, Merck, Roche, Pfizer, and Lilly; and support for attending meetings and/or travel from Daiichi Sankyo, Bristol-Myers Squibb, and AstraZeneca. Saito has received grants from AstraZeneca, Bristol-Myers Squibb, Chugai Pharmaceutical, and ONO Pharmaceutical, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, ONO Pharmaceutical, and Pfizer. Reinmuth has received consulting fees from Amgen, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Hoffmann-La Roche, Janssen, Merck Sharp & Dohme, and Pfizer; received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Hoffmann-La Roche, Janssen, Merck Sharp & Dohme, Pfizer, Sanofi, and Takeda; received support for attending meetings and/or travel from Janssen, Sanofi, and Takeda; and participated on a data safety monitoring board or advisory board for Symphogen. Lowery, Mann, Stewart, and Jiang are employees of, and own stocks in, AstraZeneca. Garon has received grants paid to their institution from ABL-Bio, AstraZeneca, Bristol-Myers Squibb, Daiichi Sanko, Dynavax Technologies, Eli Lilly, EMD Serono, Genentech, Gilead, Iovance Biotherapeutics, Merck, Mirati Therapeutics, Neon, and Novartis; consulting fees paid to their institution from AbbVie, ABL-Bio, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Dracen Pharmaceuticals, EMD Serono, Eisai, Eli Lilly, Gilead, GlaxoSmithKline, Merck, Natera, Novartis, Personalis, Regeneron, Sanofi, Shionogi, Xilio, and Zymeworks; and support for attending meetings and/or travel from A2 Bio and Novartis. Mok reports receiving grants paid to their institution from AstraZeneca, Bristol-Myers Squibb, G1 Therapeutics, Merck Sharp & Dohme, Merck Serono, Novartis, Pfizer, Roche, SFJ, Takeda, and Xcovery; consulting fees from AbbVie Inc., ACEA Pharma, Adagene, Alpha Biopharma Co., Ltd., Amgen, Amoy Diagnostics Co., AVEO Pharmaceuticals, Inc., Bayer Healthcare Pharmaceuticals Ltd., BeiGene, Berry Oncology, Boehringer Ingelheim, Blueprint Medicines Corporation, Bristol-Myers Squibb, Bowtie Life Insurance Company Limited, Bridge Biotherapeutics Inc., Covidien LP, C4 Therapeutics Inc., Cirina Ltd., CStone Pharmaceuticals, Curio Science, D3 Bio Ltd., Da Volterra, Daiichi Sankyo, Eisai, Elevation Oncology, F. Hoffmann-La Roche Ltd./Genentech, Fishawack Facilitate Ltd., G1 Therapeutics Inc., geneDecode Co., Ltd., Gilead Sciences, Inc., GLG’s Healthcare, Gritstone Oncology, Inc., Guardant Health, Hengrui Therapeutics Inc., HutchMed, Ignyta, Inc., Illumina Inc., Incyte Corporation, Inivata, IQVIA, Janssen, Lakeshore Biotech Ltd., Lilly, Lunit USA, Inc., Loxo-Oncology, Lucence Health Inc., Medscape LLC/WebMD, Medtronic, Merck Serono, Merck Sharp & Dohme, Mirati Therapeutics Inc., MiRXES, MoreHealth, Novartis, Novocure GmbH, Omega Therapeutics Inc., OrigiMed, OSE Immunotherapeutics, PeerVoice, Pfizer, PrIME Oncology, Prenetics, Puma Biotechnology Inc., Qiming Development (HK) Ltd., Regeneron Pharmaceuticals Inc., Roche Pharmaceuticals/Diagnostics/Foundation One, Sanofi-Aventis, SFJ Pharmaceutical Ltd., Simcere of America Inc., Synergy Research, Summit Therapeutics Sub, Inc., Takeda Pharmaceuticals HK Ltd., Tigermed, Vertex Pharmaceuticals, Virtus Medical Group, XENCOR, Inc., and Yuhan Corporation; receiving payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from ACEA Pharma, Alpha Biopharma Co. Ltd., Amgen, Amoy Diagnostics Co. Ltd., AstraZeneca (before January 1, 2019), BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Daz Group, Fishawack Facilitate Ltd., InMed Medical Communications, Janssen Pharmaceutica NV, Jiahui Holdings Co. Ltd., LiangYiHui Healthcare, Lilly, Lucence Health Inc., MD Health Brazil, Medscape LLC, Merck Pharmaceuticals HK Ltd., Merck Sharp & Dohme, MiRXES, Novartis, OrigiMed Co. Ltd., P. Permanyer SL, PeerVoice, Physicians’ Education Resource, Pfizer, PrIME Oncology, Research to Practice, Roche Pharmaceuticals/Diagnostics/Foundation One, Sanofi-Aventis, Shanghai BeBirds Translation & Consulting Co. Ltd., Taiho Pharmaceutical Co. Ltd., Takeda Oncology, and Touch Independent Medical Education Ltd.; receiving support for attending meetings and/or travel from Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, Merck Sharp & Dohme (paid to institution), Novartis, Roche (paid to self and institution), AstraZeneca, Daiichi Sankyo, MiRXES, AbbVie, Zai Lab, and Liangyihui (paid to self); having participation on a data safety monitoring board or advisory board for AbbVie Inc., ACEA Pharma, Amgen, AstraZeneca, Berry Oncology, Blueprint Medicines Corporation, Boehringer Ingelheim, Bowtie Life Insurance Co., Ltd., Bristol-Myers Squibb, C4 Therapeutics Inc., Covidien LP, CStone Pharmaceuticals, Curio Science, D3 Bio Ltd., Daiichi Sankyo Inc., Eisai, Fishawack Facilitate Ltd., G1 Therapeutics Inc., Gilead Sciences Inc., Gritstone Oncology Inc., Guardant Health, geneDecode Co. Ltd. (uncompensated), Hengrui Therapeutics Inc., HutchMed, Ignyta Inc., Incyte Corporation, Imagene AI Ltd., Inivata, IQVIA, Janssen, Lakeshore Biotech, Lilly, Loxo-Oncology Inc., Lunit Inc., Merck Serono, Merck Sharp & Dohme, Mirati Therapeutics Inc., MiRXES Group, Novartis, OrigiMed, Pfizer, Puma Biotechnology Inc., Roche/Genentech, Regeneron Pharmaceuticals Inc., Sanofi-Aventis R&D, SFJ Pharmaceutical, Simcere of America Inc., Simcere Zaiming, Inc., Takeda, Vertex Pharmaceuticals, Virtus Medical Group, XENCOR, Inc., and Yuhan Corporation; having leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, with AstraZeneca PLC, HutchMed, and Aurora; and having stock or stock options in AstraZeneca, Aurora Tele-Oncology Ltd., Biolidics Ltd., HutchMed, Prenetics, D3 Bio, Lunit, Bowtie Life Insurance, Lakeshore Biotech Ltd., Loxo-oncology, Virtus Medical Group, and Phanes Therapeutics, Inc. Johnson has received research funding paid to their institution from AbbVie, Acerta, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, AstraZeneca, Atreca, BeiGene, BerGenBio, BioAtla, Black Diamond, Boehringer Ingelheim, Calithera Biosciences, Carisma Therapeutics, Corvus Pharmaceutical, Curis, CytomX, Daiichi Sankyo, Dracen Pharmaceuticals, Dynavax, Lilly, Elicio Therapeutics, EMD Serono, EQRx, Erasca, Exelixis, Fate Therapeutics, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Harpoon, Helsinn Healthcare SA, Hengrui Therapeutics, Hutchison MediPharma, IDEAYA Biosciences, IGM Biosciences, Immunitas Therapeutics, Immunocore, Incyte, Janssen, Kadmon Pharmaceuticals, Kartos Therapeutics, Loxo-Oncology, Lycera, Memorial Sloan-Kettering, Merck, Merus, Mirati Therapeutics, NeoImmune Tech, Neovia Oncology, Novartis, Numab Therapeutics, Nuvalent, OncoMed Pharmaceuticals, Palleon Pharmaceuticals, Pfizer, PMV Pharmaceuticals, Rain Therapeutics, Regeneron Pharmaceuticals, Relay Therapeutics, Revolution Medicines, Ribon Therapeutics, Rubius Therapeutics, Sanofi, Seven and Eight Biopharmaceuticals/Birdie Biopharmaceuticals, Shattuck Labs, Silicon Therapeutics, Stem CentRx, Syndax Pharmaceuticals, Takeda Pharmaceuticals, Tarveda, TCR2 Therapeutics, Tempest Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics, Turning Point Therapeutics, University of Michigan, Vyriad, Y-mAbs Therapeutics, Bristol-Myers Squibb, Checkpoint Therapeutics, City of Hope National Medical Center, Jounce Therapeutics, Mythic Therapeutics, RasCal Therapeutics, WindMIL Therapeutics, ArriVent BioPharma, Bayer, LockBody Therapeutics, and Taiho Oncology; and receiving consulting fees paid to their institution from AbbVie, Amgen, Arrivent, Alentis Therapeutics, AstraZeneca, Bristol-Myers Squibb, D3 Bio Limited, Daiichi Sankyo, Fate Therapeutics, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Hookipa Biotech, Janssen, Merck, Mirati Therapeutics, Molecular Axiom, Novartis, Pyramid Biosciences, Revolution Medicines, Sanofi-Aventis, SeaGen, Takeda Pharmaceuticals, VBL Therapeutics, Arcus Biosciences, Immunocore, Jazz Pharmaceuticals, Synthekine, Boehringer Ingelheim, Gilead Sciences, Normunity, Lilly, Novocure, and Pfizer. The remaining authors delcare no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

First-generation KRAS G12C inhibitors, such as sotorasib and adagrasib, are limited by the depth and duration of clinical responses. One potential explanation for their modest clinical activity is the dynamic "cycling" of KRAS between its guanosine diphosphate (GDP)- and guanosine triphosphate (GTP)-bound states, raising controversy about whether targeting the GDP-bound form can fully block this oncogenic driver. We herein report that D3S-001, a next-generation GDP-bound G12C inhibitor with faster target engagement (TE) kinetics, depletes cellular active KRAS G12C at nanomolar concentrations. In the presence of growth factors, such as epithelial growth factor and hepatocyte growth factor, the ability of sotorasib and adagrasib to inhibit KRAS was compromised whereas the TE kinetics of D3S-001 was nearly unaffected, a unique feature differentiating D3S-001 from other GDP-bound G12C inhibitors. Furthermore, the high covalent potency and cellular TE efficiency of D3S-001 contributed to robust antitumor activity preclinically and translated into promising clinical efficacy in an ongoing phase 1 trial (NCT05410145). Significance: The kinetic study presented in this work unveils, for the first time, that a GDP-bound conformation-selective KRAS G12C inhibitor can potentially deplete cellular active KRAS in the presence of growth factors and offers new insights into the critical features that drive preclinical and clinical efficacy for this class of drugs., (©2024 The Authors; Published by the American Association for Cancer Research.)

Competing Interests: Financial Disclosure Neil S. Silverman reports receiving payment from Cepheid. The other authors did not report any potential conflicts of interest.

Objective: To assess the effect of gestational age-based dosing of unfractionated heparin (UFH) compared with standard dosing of UFH for thromboprophylaxis on an elevated serum activated partial thromboplastin time (aPTT) during prolonged antepartum hospitalizations., Methods: This was a randomized trial of pregnant persons who were admitted in the antepartum period for at least 72 hours. Participants were randomly allocated to the standard dose of UFH (5,000 units subcutaneously every 12 hours) or the gestational age-based dose of UFH (first trimester [less than 14 weeks]: 5,000 units subcutaneously every 12 hours; second trimester [14-27 6/7 weeks]: 7,500 units subcutaneously every 12 hours; third trimester (28 weeks or more): 10,000 units subcutaneously every 12 hours). The primary outcome was the proportion of antepartum patients who had an elevated serum aPTT value above the normal range (more than 36.2 seconds) 6 hours after an UFH dose. Secondary outcomes included the development of venous thromboembolism (VTE) and reported side effects of heparin administration., Results: Between December 15, 2020, and April 1, 2022, 97 patients with antepartum hospitalizations were screened and 46 were randomized: 22 allocated to standard dosing and 24 allocated to gestational age-based dosing of UFH. A significantly greater proportion of antepartum patients who received gestational age-based dosing had an abnormal elevation in aPTT compared with those who received standard dosing (33.3% vs 4.8%, P =.02). Gestational age-based dosing resulted in higher maximum [interquartile range] aPTT (30.4 [27.4, 37.5] vs 26.6 [23.0, 29.6], P =.01) and anti-Xa levels (0.09 [0.09, 0.11] vs 0.09 [0.09, 0.09], P =.04). There was no significant difference in VTE between groups ( P =.47)., Conclusion: Gestational age-based dosing of UFH for thromboprophylaxis of antepartum hospitalizations was associated with significantly increased rates of elevated coagulation parameters compared with standard fixed dosing. This study suggests a need for close monitoring if higher doses of UFH during pregnancy are used later in gestation. The efficacy of gestational age-based dosing compared with standard dosing for UFH to prevent thromboembolic events remains an area for future investigation., Clinical Trial Registration: ClinicalTrials.gov , NCT04635839., Competing Interests: Financial Disclosure Cristianna Vallera's institution received funding from the Society for Obstetric Anesthesia & Perinatology. The other authors did not report any potential conflicts of interest., (Copyright © 2024 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Although comprehensive biomarker testing is recommended for all patients with advanced/metastatic non-small cell lung cancer (NSCLC) before initiation of first-line treatment, tissue availability can limit testing. Genomic testing in liquid biopsies can be utilized to overcome the inherent limitations of tissue sampling and identify the most appropriate biomarker-informed treatment option for patients. The Blood First Assay Screening Trial is a global, open-label, multicohort trial that evaluates the efficacy and safety of multiple therapies in patients with advanced/metastatic NSCLC and targetable alterations identified by liquid biopsy. We present data from Cohort D (ROS1-positive). Patients ≥18 years of age with stage IIIB/IV, ROS1-positive NSCLC detected by liquid biopsies received entrectinib 600 mg daily. At data cutoff (November 2021), 55 patients were enrolled and 54 had measurable disease. Cohort D met its primary endpoint: the confirmed objective response rate (ORR) by investigator was 81.5%, which was consistent with the ORR from the integrated analysis of entrectinib (investigator-assessed ORR, 73.4%; data cutoff May 2019, ≥12 months of follow-up). The safety profile of entrectinib was consistent with previous reports. These results demonstrate consistency with those from the integrated analysis of entrectinib in patients with ROS1-positive NSCLC identified by tissue-based testing, and support the clinical value of liquid biopsies to inform clinical decision-making. The integration of liquid biopsies into clinical practice provides patients with a less invasive diagnostic method than tissue-based testing and has faster turnaround times that may expedite the reaching of clinical decisions in the advanced/metastatic NSCLC setting. ClinicalTrials.gov registration: NCT03178552 ., (© 2024. The Author(s).)

Objective: The incidence of Crohn's disease (CD) and rheumatoid arthritis (RA) co-morbidity, as well as the number of individuals affected, is on the rise due to their shared molecular and cellular factors. This study aimed to identify potential therapeutic targets and medicines for comorbid CD and RA., Methods: We integrated single-cell RNA sequencing, Mendelian randomization, and colocalization analysis results from public databases to analyse immune cell subgroups in CD and RA patients and identify candidate therapeutic targets. We further screened potential medicines for the identified candidate targets using the Comparative Toxicogenomics Database (CTD) and molecular docking and molecular dynamics simulations., Results: The proportion of CD8 effector memory T cells (Tem) was consistently elevated in the peripheral blood mononuclear cells (PBMCs) of both CD and RA patients. MYBL1 had a causal effect on the onset of both CD (OR = 1.23; 95 % CI, 1.05-1.45; P = 0.046) and RA (OR = 1.45; 95 % CI, 1.14-1.85; P = 0.04). Four potential therapeutic molecules were retrieved from the CTD database, among which tretinoin (docking score: -6.3 kcal/mol) showed the best potential., Conclusion: Our comprehensive analysis suggests that CD8 Tem cells are a key cell group in comorbid RA and CD and that MYBL1 has a causal effect. Tretinoin was identified as a potential targeted therapeutic drug, which is of great clinical research value., Competing Interests: 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., (© 2024 Published by Elsevier Ltd.)

Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are recurrent oncogenic drivers found in a variety of solid tumours, including lung cancer. Several tropomyosin receptor kinase (TRK) inhibitors have been developed to treat tumours with NTRK gene fusions. Larotrectinib and entrectinib are first-generation TRK inhibitors that have demonstrated efficacy in patients with TRK fusion lung cancers. Genomic testing is recommended for all patients with metastatic non-small cell lung cancer for optimal drug therapy selection. Multiple testing methods can be employed to identify NTRK gene fusions in the clinic and each has its own advantages and limitations. Among these assays, RNA-based next-generation sequencing (NGS) can be considered a gold standard for detecting NTRK gene fusions; however, several alternatives with minimally acceptable sensitivity and specificity are also available in areas where widespread access to NGS is unfeasible. This review highlights the importance of testing for NTRK gene fusions in lung cancer, ideally using the gold-standard method of RNA-based NGS, the various assays that are available, and treatment algorithms for patients., Competing Interests: Declaration of competing interest Support for attending meetings and/or travel: Sanofi. Marina Chiara Garassino: Personal financial interests: AstraZeneca, Abion, MSD International GmbH, Bayer, BMS, Boehringer Ingelheim Italia S.p.A, Celgene, Eli Lilly, Incyte, Novartis, Pfizer, Roche, Takeda, Seattle Genetics, Mirati, Daiichi Sankyo, Regeneron, Merck, Blueprint, Jansenn, Sanofi, AbbVie, BeiGenius, Oncohost, Medscape, Gilead, Io Biotech; Institutional financial interests: Eli Lilly, MSD, Pfizer (MISP); AstraZeneca, MSD International GmbH, BMS, Boehringer Ingelheim Italia S.p.A, Celgene, Eli Lilly, Ignyta, Incyte, MedImmune, Novartis, Pfizer, Roche, Takeda, Tiziana, Foundation Medicine, GSK, Spectrum Pharmaceuticals; Others: AIRC, AIFA, Italian Moh, TRANSCAN; Research funding, Horizon 2020. Herbert H. Loong: Advisory: Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Illumina, Novartis, Merck Sereno, Takeda, George Clinical; Speakers’ bureau: AbbVie, Bayer, Daiichi Sankyo, Eisai, Eli Lilly, Guardant Health, Novartis; Travel support: Bayer, Boehringer Ingelheim, MSD, Novartis, Pfizer; Research funding: MSD, Mundipharma, Novartis; Others: Member of Pharmacy and Poisons (Registration of Pharmaceutical Products and Substances: Certification of Clinical Trial/Medicinal Test) Committee, Pharmacy & Poisons Board of Hong Kong. Fernando Lopez-Rios: Honoraria/advisory boards: Abbvie, Astellas, AstraZeneca, Bayer, BMS, Daiichi Sankyo, Janssen, Lilly, MSD, Merck, Pfizer, Roche, Sanofi, Takeda, Thermo Fisher Scientific; Associated research paid to institution: AstraZeneca, Lilly, Pfizer, Roche, Thermo Fisher Scientific. Tony Mok: Grant/research support from (paid to institution): AstraZeneca, BMS, G1 Therapeutics, MSD, Merck Serono, Novartis, Pfizer, Roche, SFJ, Takeda, XCovery; Speaker’s fees received from: ACEA Pharma, Alpha Biopharma Co., Ltd., Amgen, Amoy Diagnostics Co., Ltd., AstraZeneca (before 1/1/19), BeiGene, Boehringer Ingelheim, BMS, Daiichi Sankyo, Daz Group, Fishawack Facilitate Ltd., InMed Medical Communication, Janssen Pharmaceutica NV, Jiahui Holdings Co. Limited, LiangYiHui Healthcare, Lilly, Lucence Health Inc., MD Health Brazil, Medscape LLC, Merck Pharmaceuticals HK Ltd., Merck Sharp & Dohme, MiRXES, Novartis, OrigiMed Co. Ltd., P. Permanyer SL, PeerVoice, Physicians’ Education Resource (PER), Pfizer, PrIME Oncology, Research to Practice, Roche Pharmaceuticals/Diagnostics/Foundation One, Sanofi-Aventis, Shanghai BeBirds Translation & Consulting Co., Ltd., Shanghai Promedican Pharmaceuticals Co., Ltd., Taiho Pharmaceutical Co. Ltd, Takeda Oncology, Touch Independent Medical Education Ltd; Honoraria/honorarium received (for consultation services/as independent consultant) from: Abbvie Inc., ACEA Pharma, Adagene, Alpha Biopharma Co., Ltd., Amgen, Amoy Diagnostics Co., Ltd., AnHeart Therapeutics, AstraZeneca (before 1/1/19), AVEO Pharmaceuticals, Inc., Bayer Healthcare Pharmaceuticals Ltd., BeiGene, BerGenBio ASA, Berry Oncology, Boehringer Ingelheim, Blueprint Medicines Corporation, BMS, Bowtie Life Insurance Company Limited, Bridge Biotherapeutics Inc., Covidien LP, C4 Therapeutics Inc., Cirina Ltd., CStone Pharmaceuticals, Curio Science, D3 Bio Ltd., Da Volterra, Daiichi Sankyo, Eisai, Elevation Oncology, F. Hoffmann-La Roche Ltd., Genentech, GLG’s Healthcare, Fishawack Facilitate Ltd., G1 Therapeutics Inc., geneDecode Co., Ltd, Gilead Sciences, Inc. Gritstone Oncology, Inc., Guardant Health, Hengrui Therapeutics Inc., HutchMed, Ignyta, Inc., Illumina, Inc., Incyte Corporation, Inivata, IQVIA, Janssen, Lakeshore Biotech Ltd, Lilly, Lunit USA, Inc., Loxo Oncology, Lucence Health Inc., Medscape LLC/ WebMD, Medtronic, Merck Serono, MSD, Mirati Therapeutics Inc., MiRXES, MoreHealth, Novartis, Novocure GmbH, Omega Therapeutics Inc., OrigiMed, OSE Immunotherapeutics, PeerVoice, Pfizer, PrIME Oncology, Prenetics, Puma Biotechnology Inc., Qiming Development (HK) Ltd., Regeneron Pharmaceuticals Inc., Roche Pharmaceuticals/Diagnostics/Foundation One, Sanofi-Aventis, SFJ Pharmaceutical Ltd., Simcere of America Inc., Summit Therapeutics Sub, Inc., Synergy Research, Takeda Pharmaceuticals HK Ltd., Tigermed, Vertex Pharmaceuticals, Virtus Medical Group, XENCOR, Inc., Yuhan Corporation; Stock shareholder in: Alentis Therapeutics AG, AstraZeneca, Aurora Tele-Oncology Ltd., Biolidics Ltd., HutchMed, Prenetics, D3 Bio, Lunit Inc.; Stock options: Bowtie Life Insurance Co. Ltd., D3 Bio, Lakeshore Biotech Ltd, Loxo Oncology, Lunit USA, Inc., Virtus Medical Group, Phanes Therapeutics, Inc., Insighta; Advisory board for: AbbVie Inc., ACEA Pharma, Amgen, AstraZeneca, BerGenBio ASA, Berry Oncology, Blueprint Medicines Corporation, Boehringer Ingelheim, Bowtie Life Insurance Co Ltd, BMS, C4 Therapeutics Inc, Covidien LP, CStone Pharmaceuticals, Curio Science, D3 Bio Ltd., Daiichi Sankyo Inc., Eisai, Fishawack Facilitate Ltd., G1 Therapeutics Inc., Gilead Sciences Inc., Gritstone Oncology, Inc., Guardant Health, geneDecode Co. Ltd. (uncompensated), Hengrui Therapeutics Inc., HutchMed, Ignyta Inc., Incyte Corporation, Imagene AI Ltd., Inivata, IQVIA, Janssen, Lakeshore Biotech, Lily, Loxo Oncology Inc., Lunit, Inc., Merck Serono, Merck Sharp & Dohme, Mirati Therapeutics Inc., MiRXES Group, Novartis, OrigiMed, Pfizer, Prenetics, Puma Biotechnology Inc., Roche/Genentech, Regeneron Pharmaceuticals Inc., Sanofi-Aventis R&D, SFJ Pharmaceutical, Simcere of America Inc., Simcere Zaiming, Inc., Takeda, Vertex Pharmaceuticals, Virtus Medical Group, Yuhan Corporation; Board of directors/leadership roles (remunerated): AstraZeneca PLC (from January 2019–Present), HutchMed, Aurora, Insighta (from July 2023–Present); Board of directors/leadership roles (non-remunerated): American Society of Clinical Oncology (2018–2022), Asian Thoracic Oncology Research Group (2016–Present), Chinese Lung Cancer Research Foundation Limited (2005–2012), Chinese Society of Clinical Oncology (2009–2020), Hong Kong Cancer Fund (2011–Present), Hong Kong Cancer Therapy Society (2004–Present), International Association for the Study of Lung Cancer (2007–2019), St. Stephen’s College & Prep. School (2017–Present), Hong Kong Academy of Sciences (2022–Present). Solange Peters: I have Received education grants, provided consultation, attended advisory boards and/or provided lectures for the following organizations, from whom honoraria received (all fees to institution): Consultation/Advisory role: AbbVie, Amgen, Arcus, AstraZeneca, Bayer, Beigene, BerGenBio, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, BMS, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F-Star, Fishawack, Foundation Medicine, Genzyme, Gilead, GSK, Hutchmed, Illumina, Incyte, Ipsen, iTeos, Janssen, Merck Sharp and Dohme, Merck Serono, Merrimack, Mirati, Nykode Therapeutics, Novartis, Novocure, Pharma Mar, Promontory Therapeutics, Pfizer, Regeneron, Roche/Genentech, Sanofi, Seattle Genetics, Takeda; Board of director position: Galenica; Talk in a company’s organized public event: AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, Foundation Medicine, GSK, Illumina, Ipsen, Merck Sharp and Dohme, Mirati, Novartis, Pfizer, Roche/Genentech, Sanofi, Takeda; Receipt of grants/research supports: Principal investigator in trials (institutional financial support for clinical trials) sponsored by: Amgen, Arcus, AstraZeneca, Beigene, BMS, GSK, iTeos, Merck Sharp and Dohme, Mirati, Pharma Mar, Promontory Therapeutics, Roche/Genentech, Seattle Genetics. David Planchard: Consulting, advisory role or lectures: AstraZeneca, Abbvie, BMS, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Janssen, Pfizer, Roche, Pierre-fabre, Takeda, ArriVent, Mirati, Seagen; Clinical trials research as principal or co-investigator (institutional financial interests): AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmune, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo, Abbvie, Janssen, Pierre-Fabre, Takeda, ArriVent, Mirati, Seagen; Travel, accommodations and/or expenses: AstraZeneca, Roche, Novartis, Pfizer. Sanjay Popat: Consulting fees (personal fees): Amgen, AstraZeneca, Bayer, Blueprint, BMS, Boehringer Ingelheim, Daiichi Sankyo, GSK, Guardant Health, Incyte, Janssen, Lilly, Merck Serono, MSD, Novartis, Roche, Takeda, Pfizer, Seattle Genetics, Turning Point Therapeutics, EQRx; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events (personal fees): AstraZeneca, Bayer, Guardant Health, Janssen, Merck Serono, Roche, Takeda; Payment for expert testimony (personal fees): Roche, Merck Serono; Support for attending meetings and/or travel (travel expenses reimbursement): Janssen, Roche; Leadership in fiduciary role in other board, society, committee or advocacy group (unpaid): British Thoracic Oncology Group, ALK Positive UK, Lung Cancer Europe, Ruth Strauss Foundation, Mesothelioma Applied Research Foundation; ETOP-IBCSG Partners Foundation Board. Erin R. Rudzinski: Clinical trials research: ON-TRK study (Bayer). Alexander Drilon: Honoraria/advisory boards: 14ner/Elevation Oncology, Amgen, Abbvie, ArcherDX, AstraZeneca, Beigene, BergenBio, Blueprint Medicines, Chugai Pharmaceutical, EcoR1, EMD Serono, Entos, Exelixis, Helsinn, Hengrui Therapeutics, Ignyta/Genentech/Roche, Janssen, Loxo/Bayer/Lilly, Merus, Monopteros, MonteRosa, Novartis, Nuvalent, Pfizer, Prelude, Repare RX, Takeda/Ariad/Millenium, Treeline Bio, TP Therapeutics, Tyra Biosciences, Verastem; Associated research paid to institution: Pfizer, Exelixis, GSK, Teva, Taiho, PharmaMar; Royalties: Wolters Kluwer; Other (food/beverage): Merck, Puma, Merus, Boehringer Ingelheim; CME honoraria: Answers in CME, Applied Pharmaceutical Science, Inc., AXIS, Clinical Care Options, EPG Health, Harborside Nexus, I3 Health, Imedex, Liberum, Medendi, Medscape, Med Learning, MJH Life Sciences, MORE Health, Ology, OncLive, Paradigm, Peerview Institute, PeerVoice, Physicians Education Resources, Remedica Ltd., Research to Practice, RV More, Targeted Oncology, TouchIME, WebMD. Caicun Zhou: Consulting fees: Innovent Biologics, Hengrui, Qilu, TopAlliance Biosciences; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Lily China, Sanofi, Boehringer Ingelheim, Roche, Merck Sharp & Dohme, Qilu, Hengrui, Innovent Biologics, Alice, C-Stone, LUYE Pharma, TopAlliance Biosciences, Amoy Diagnostics, AnHeart., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

It is unclear if SARS CoV-2 infection during pregnancy is associated with adverse neurodevelopmental repercussions to infants. We assessed pediatric neurodevelopmental outcomes in children born to mothers with laboratory-confirmed SARS CoV-2 infection during pregnancy. Neurodevelopmental outcomes of in-utero exposed children were compared to that of pre-pandemic control children in Los Angeles (LA), CA, USA and Rio de Janeiro, Brazil. Bayley Scales of Infant and Toddler Development, 3rd edition (Bayley-III), the gold standard tool for evaluating neurodevelopment until 36 months of age and Ages and Stages Questionnaires (ASQ-3), a frequently used screening instrument for evaluating neurodevelopment in this same age group were the assessment tools used. Developmental delay (DD) was defined as having a score < - 2 SD below the norm (< 70) in at least one of three Bayley-III domains, (cognitive, motor or language) or a score below the cut-off (dark zone) in at least one of five ASQ-3 domains (communication, gross motor, fine motor, problem solving, personal-social). Exposed children were born between April 2020 and December 2022 while control children were born between January 2016 to December 2019. Neurodevelopmental testing was performed in 300 children total: 172 COVID-19 exposed children between 5-30 months of age and 128 control children between 6-38 months of age. Bayley-III results demonstrated that 12 of 128 exposed children (9.4%) had DD versus 2 of 128 controls (1.6%), p = 0.0007. Eight of 44 additional exposed children had DD on ASQ-3 testing. Fully, 20 of 172 exposed children (11.6%) and 2 of 128 control children (1.6%), p = 0.0006 had DD. In Rio, 12% of exposed children versus 2.6% of controls, p = 0.02 had DD. In LA, 5.7% of exposed children versus 0 controls, p = 0.12 had DD. Severe/critical maternal COVID-19 predicted below average neurodevelopment in the exposed cohort (OR 2.6, 95% CI 1.1-6.4). Children exposed to antenatal COVID-19 have a tenfold higher frequency of DD as compared to controls and should be offered neurodevelopmental follow-up., (© 2024. The Author(s).)

After disease progression on EGFR tyrosine kinase inhibitor (TKI) therapy, patients with EGFR -mutated NSCLC who are then treated with platinum-based chemotherapy (PBC) obtain only limited clinical benefit with transient responses. Therapies with greater efficacy and tolerable safety profiles are needed in this setting. The receptor tyrosine kinase HER3 is widely expressed in NSCLC, and increased expression is associated with poor treatment outcomes. In the U31402-A-U102 phase I trial, HER3-DXd showed promising antitumor activity with manageable safety in heavily pre-treated patients with EGFR -mutated NSCLC across a range of tumor HER3 expression levels and EGFR TKI resistance mechanisms. HERTHENA-Lung02 is the first phase III trial to evaluate the safety and efficacy of HER3-DXd versus PBC in patients with progression on a third-generation EGFR TKI. Clinical Trial Registration: NCT05338970 (clinicaltrials.gov); 2021-005879-40 (EudraCT Number).

Lorlatinib is a brain-penetrant, third-generation tyrosine kinase inhibitor (TKI) indicated for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC). In clinical trials, lorlatinib has shown durable efficacy and a manageable safety profile in treatment-naive patients and in those who have experienced progression while receiving first- and/or second-generation ALK TKIs. Lorlatinib has a distinct safety profile from other ALK TKIs, including hyperlipidemia and central nervous system effects. Clinical trial data showed that most adverse events (AEs) can be managed effectively or reversed with dose modifications (such as dose interruptions or reductions) or with concomitant medications without compromising clinical efficacy or quality of life for patients. A pragmatic approach to managing AEs related to lorlatinib is required. We present patient-focused recommendations for the evaluation and management of select AEs associated with lorlatinib developed by clinicians and nurses with extensive lorlatinib expertise in routine clinical practice. The recommendations follow the general framework of "prepare, monitor, manage, reassess" to streamline AE management and assist in practical, actionable, and personalized patient care., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Geoffrey Liu reports grant support from AstraZeneca, Boehringer Ingelheim, Pfizer, Amgen, EMD Serono and Takeda; and participation on an advisory board for AstraZeneca, EMD Serono, Jazz Pharmaceuticals, MSD, Novartis, Pfizer, Roche, BMS, Bayer, Novartis, Amgen, and Takeda. Julien Mazieres reports institutional grant support from AstraZeneca, Pierre Fabre, and Roche; and advisory board fees from AstraZeneca, BMS, Daiichi Sankyo, Merck, MSD, Novartis, Pfizer, and Roche. Jan Stratmann reports personal fees from Roche, Boehringer Ingelheim, AstraZeneca, BMS, Oncopeptides, Amgen, LEO Pharma, Novartis, Takeda, Lilly, MSD/Merck, Sanofi, Pfizer, outside of the submitted work and institutional grants from AstraZeneca outside of the submitted work. Sai-Hong Ignatius Ou reports institutional grant for clinical research from Mirati, J&J/Janssen, Pfizer, Revolution Medicine, Nuvalent, Merck, and BMS; speaker honorarium from Pfizer and J&J/Janssen; advisory honorarium from Pfizer, J&J/Janssen, AnHeart Therapeutics, Lilly, BeiGene, and DAVA Oncology; stock ownership in Turning Point Therapeutics and Elevation Oncology; and ownership (<5%) in MBrace Therapeutics and BlossomHill Therapeutics. Tony Mok reports institutional grants from AstraZeneca, BMS, G1 Therapeutics, Merck, MSD, Novartis, Pfizer, Roche, SFJ Pharmaceuticals, Takeda, and Xcovery; consulting fees from AbbVie, ACEA Pharma, Adagene, Alpha Biopharma, Amgen, Amoy Diagnostics, Bayer, BeiGene, Berry Oncology, Boehringer Ingelheim, Blueprint, BMS, Bridge Biotherapeutics, Covidien, C4 Therapeutics, Cirina, CStone Pharmaceuticals, Curio Science, D3 Bio, Da Volterra, Daiichi Sankyo, Eisai, Elevation Oncology, G1 Therapeutics, geneDecode, Gilead Sciences, Gritstone Oncology, Guardant Health, Hengrui Therapeutics, HutchMed, Ignyta, Incyte, Inivata, IQVIA, Janssen, Lilly, Lunit USA, Loxo Oncology, Lucence Health, Medscape/WebMD, Merck, MSD, Mirati, MiRXES, MoreHealth, Novartis, Omega Therapeutics, OrigiMed, OSE Immunotherapeutics, PeerVoice, Pfizer, prIME Oncology, Puma Biotechnology, Qiming Development, Roche/Genentech, Sanofi, SFJ Pharmaceuticals, Simcere of America, Synergy Research, Takeda, Tigermed, Vertex, Virtus, and Yuhan; honoraria from ACEA Pharma, Alpha Biopharma, Amgen, Amoy Diagnostics, AstraZeneca, BeiGene, Boehringer Ingelheim, BMS, Daiichi Sankyo, Daz Group, Fishawack Facilitate, InMed, Janssen, Jiahui Holdings, LiangYiHui Healthcare, Lilly, Lucence Health, MD Health Brazil, Medscape, Merck Pharmaceuticals HK, MSD, MiRXES, Novartis, OrigiMed, Permanyer, PeerVoice, Physicians’ Education Resource, Pfizer, prIME Oncology, Research to Practice, Roche Pharmaceuticals/Diagnostics/Foundation One, Sanofi-Aventis, Shanghai BeBirds Translation & Consulting, Taiho, Takeda, and Touch Independent Medical Education; travel support from AstraZeneca, BMS, Boehringer Ingelheim, Daiichi Sankyo, MiRXES, MSD, Novartis, Pfizer, and Roche; institutional travel support from BMS, Boehringer Ingelheim, MSD, Novartis, Pfizer, and Roche; participation on advisory boards for AbbVie, ACEA Pharma, Amgen, AstraZeneca, Berry Oncology, Blueprint, Boehringer Ingelheim, Bowtie Life Insurance, BMS, C4 Therapeutics, Covidien, CStone Pharmaceuticals, Curio Science, D3 Bio, Daiichi Sankyo, Eisai, Fishawack Facilitate, G1 Therapeutics, geneDecode, Gilead Sciences, Gritstone Oncology, Guardant Health, Hengrui Therapeutics, HutchMed, Ignyta, Incyte, Inivata, IQVIA, Janssen, Lakeshore Biotech, Lilly, Loxo Oncology, Lunit, Merck, MSD, Mirati, MiRXES, Novartis, OrigiMed, Pfizer, Puma Biotechnology, Roche/Genentech, Sanofi-Aventis, SFJ Pharmaceuticals, Simcere of America, Takeda, Vertex, Virtus, and Yuhan; leadership or fiduciary role at AstraZeneca, HutchMed, Lunit, ACT Genomics-Sanomics Group, and Aurora Tele-Oncology; and stock ownership in AstraZeneca, Aurora Tele-Oncology, Biolidics, HutchMed, and ACT Genomics-Sanomics Group. Mary Grizzard reports no conflicts of interest. Yasushi Goto reports grant support for the clinical trial group from AstraZeneca and Pfizer; institutional grant support from AbbVie, BMS, Daiichi Sankyo, Eli Lilly, Kyorin Pharmaceutical, Novartis, Ono Pharmaceutical, Pfizer, and Preferred Networks; honoraria from BMS, Boehringer Ingelheim, Chugai Pharmaceutical, Eli Lilly, Merck, MSD, Novartis, Ono Pharmaceutical, Pfizer, Taiho, and Thermo Fisher; participation on advisory boards for AstraZeneca, BMS, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Guardant Health, Illumina, MSD, Novartis, Ono Pharmaceutical, Pfizer, and Taiho; and leadership or fiduciary role at Cancer Net Japan and Japanese Association of Medical Technologists. Enriqueta Felip reports institutional funding from Merck and Fundación Merck Salud; consulting fees from Amgen, AstraZeneca, Bayer, BMS, Daiichi Sankyo, Eli Lilly, GSK, Janssen, Merck, MSD, Novartis, Peptomyc, Pfizer, Roche, Sanofi, and Takeda; honoraria from Amgen, AstraZeneca, BMS, Eli Lilly, Janssen, Medical Trends, Medscape, Merck, MSD, PeerVoice, Pfizer, Roche, Sanofi, Takeda, and Touch Oncology; and independent board membership for Grifols. Benjamin J. Solomon reports royalties for contribution to a section from UpToDate; consulting fees for participation on advisory boards from Amgen, AstraZeneca, BMS, Janssen, MSD, Novartis, Pfizer, Sanofi, Takeda, and Roche/Genentech; honoraria from Amgen, AstraZeneca, BMS, Pfizer, Takeda, and Roche/Genentech; and leadership or fiduciary role as a board member of Thoracic Oncology Group of Australia and Cancer Council of Victoria. Todd M. Bauer reports consulting fees from Bayer, Pfizer, and Lilly; honoraria from Bayer, BMS, Guardant Health, Pfizer, and Lilly; travel support from Pfizer; participation on advisory boards for AstraZeneca, Bayer, Illumina, and Pfizer; and institutional support for participation on an advisory board for Blueprint., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: The phase III CheckMate 722 trial (ClinicalTrials.gov identifier: NCT02864251) evaluated nivolumab plus chemotherapy versus chemotherapy in patients with epidermal growth factor receptor ( EGFR )-mutated metastatic non-small-cell lung cancer (NSCLC) after disease progression on EGFR tyrosine kinase inhibitors (TKIs)., Methods: Patients with disease progression after first- or second-generation EGFR TKI therapy (without EGFR T790M mutation) or osimertinib (with/without T790M mutation) were randomly assigned 1:1 to nivolumab (360 mg once every 3 weeks) plus platinum-doublet chemotherapy (once every 3 weeks) or platinum-doublet chemotherapy alone (once every 3 weeks) for four cycles. Primary end point was progression-free survival (PFS). Secondary end points included 9- and 12-month PFS rates, overall survival (OS), objective response rate (ORR), and duration of response (DOR)., Results: Overall, 294 patients were randomly assigned. At final analysis (median follow-up, 38.1 months), PFS was not significantly improved with nivolumab plus chemotherapy versus chemotherapy (median, 5.6 v 5.4 months; hazard ratio [HR], 0.75 [95% CI, 0.56 to 1.00]; P = .0528), with 9- and 12-month PFS rates of 25.9% versus 19.8%, and 21.2% versus 15.9%, respectively. Post hoc PFS subgroup analyses showed a trend favoring nivolumab plus chemotherapy in patients with tumors harboring sensitizing EGFR mutations (HR, 0.72 [95% CI, 0.54 to 0.97]), one line of previous EGFR TKI (0.72 [95% CI, 0.54 to 0.97]), or both (0.64 [95% CI, 0.47 to 0.88]). Median OS was 19.4 months with nivolumab plus chemotherapy versus 15.9 months with chemotherapy, while ORR was 31.3% versus 26.7%, and median DOR was 6.7 versus 5.6 months, respectively. Grade 3/4 treatment-related adverse events occurred in 44.7% and 29.4% of patients treated with nivolumab plus chemotherapy and chemotherapy alone, respectively., Conclusion: Nivolumab plus chemotherapy did not significantly improve PFS versus chemotherapy in patients with EGFR- mutated metastatic NSCLC previously treated with EGFR TKIs. No new safety signals were identified.

Respiratory distress (RD) has been reported in SARS-CoV-2 exposed uninfected (SEU) term neonates. Prior studies suggest that prenatal exposure to Coronavirus Disease 19 (COVID-19) may activate an inflammatory cascade in the newborn airway. In this study, we examine the relationship between maternal COVID-19 vaccination and neonatal RD using a longitudinal cohort of mother-infant pairs in Los Angeles, CA. Two-hundred and twenty-one mothers with laboratory confirmed SARS-CoV-2 during pregnancy and 227 exposed fetuses are enrolled in our study. Maternal disease severity and neonatal RD variables were defined based on current accepted clinical criteria. To explore the multifactorial associations between maternal COVID-19 parameters and infant RD, we utilize a multivariable logistic regression model and a proteomic sub-analysis to propose a pathway for the development of RD following in utero exposure to SARS-CoV-2. Unusually high rates of RD are observed in SEU infants (17%). The odds ratio of RD is 3.06 (95% CI:1.08-10.21) in term neonates born to unvaccinated individuals versus those born to individuals vaccinated prior to maternal infection. Proteomic analysis reveals a robust inflammatory response associated with ciliary dysregulation and enhanced IgE production among SEU neonates with RD. Maternal vaccination against COVID-19 reduces the frequency of neonatal RD., (© 2024. The Author(s).)

Objectives: Optimal management of placenta accreta spectrum (PAS) requires antenatal diagnosis. We sought to evaluate the sensitivity of ultrasound findings suggestive of PAS in detecting posterior PAS., Methods: Cohort study of patients with posterior placentation and pathology-confirmed PAS from 2011 to 2020 at a tertiary center. Patients were excluded if ultrasound images were unavailable. Ultrasounds were reviewed for presence of lacunae, hypervascularity, myometrial thinning, loss of the hypoechoic zone, bridging vessels, abnormal uterine serosa-bladder interface, placental bulge, placental extension into/beyond the myometrium, and an exophytic mass. Risk factors, postpartum outcomes, and ultrasound findings were compared by antepartum suspicion for PAS. Sensitivity was calculated for each ultrasound finding., Results: Thirty-three patients were included. PAS was not suspected antenatally in 70 % (23/33). Patients with unsuspected PAS were more likely to be non-Hispanic, have in vitro fertilization, no prior Cesarean deliveries, no placenta previa, and delivered later in gestation. Depth of invasion and estimated blood loss were less for unsuspected PAS, but there was no difference in hysterectomy between groups. Ultrasound findings were less frequently seen in those who were not suspected antenatally: lacunae 17.4 vs. 100 % (p<0.001), hypervascularity 8.7 vs. 80 % (p<0.001), myometrial thinning 4.4 vs. 70 % (p<0.001), and placental bridging vessels 0 vs. 60 % (p<0.001). There was poor sensitivity (0-42.4 %) for all findings., Conclusions: Posterior PAS is less likely to be detected antenatally due to a lower sensitivity of typical ultrasound findings in the setting of a posterior placenta. Further studies are needed to better identify reliable markers of posterior PAS., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Background: The combination of platinum-based chemotherapy with immune-checkpoint inhibitors (ICIs) is a standard of care option in the front-line treatment of advanced non-small cell lung cancer (NSCLC). Positive efficacy and safety results have been demonstrated with different chemo-ICI combinations in the corresponding clinical trials, however no randomized prospective comparison is available and there is no evidence on how to choose among the available regimens., Methods: A virtual International Expert Panel took place in July 2023 to review data on chemo-ICI regimens available in the first-line setting in patients with NSCLC, and reach common considerations both in clinical practice and in research setting., Results: Overall, all panelists agreed that safety of the chemo-immunotherapy combination regimens is supported by reviewed data, showing no additional toxicity concerns over those of the individual components of each regimen and highlighting differences in toxicity profile based on ICI component (single anti-PD-1 versus double anti-PD-1 and anti-CTLA-4). Among disease characteristics, PD-L1 value (<1%) but not histology was considered a potential selection factor in favor of the combination with dual ICI. With regards to clinical features, the panelists agreed that chemotherapy, whichever the ICI combination regimen, remains the backbone to counteract disease-related symptoms included those conditioning worse performance status. The panelists defined high, medium, and low priorities in clinical research. High priority was attributed to prospectively evaluating the impact of the addition of anti-CTLA-4 on brain metastasis, biomarker subgroups, and the optimal duration and schedule of combination regimens., Conclusions: Based on the available evidence, the panelists reached common considerations on strengths and differences between chemotherapy plus single agent ICI and chemotherapy plus double agent ICIs in patients with advanced NSCLC. In the absence of direct comparison, different toxicity profile and subgroup analysis by PD-L1 are considered as the main potential features to select among the two regimens, however to be confirmed by recommended prospective randomized clinical research., Competing Interests: Declaration of competing interest C. Gridelli received honoraria as speaker bureau or advisory board member or as consultant from MSD, BMS, Roche, Astra Zeneca, Novartis, Pfizer, Menarini, Boehringer, Karyopharm, Eli Lilly, Amgen, Sanofi, GSK, Boehringer Ingelheim. S. Peters received education grants, provided consultation, attended advisory boards and/or provided lectures for the following organizations: AbbVie, AiCME, Amgen, Arcus, AstraZeneca, Bayer, Beigene, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, F-Star, Fishawack, Foundation Medicine, Genzyme, Gilead, GSK, Illumina, Imedex, IQVIA, Incyte, iTeos, Janssen, Medscape, Medtoday, Merck Sharp and Dohme, Merck Serono, Merrimack, Mirati, Novartis, Novocure, OncologyEducation, Pharma Mar, Phosplatin Therapeutics, PER, Peerview, Pfizer, PRIME, Regeneron, RMEI, Roche/Genentech, RTP, Sanofi, Seattle Genetics, Takeda, Vaccibody. T. Mok received education grants, honoraria, provided consultation, attended advisory boards and/or provided lectures for the following organizations: AstraZeneca, Aurora Tele-Oncology Platform, Lunit, ACT Genomics-Sanomics Group, HUTCHMED, Alpha Biopharma, ACEA Pharmaceutical Research, Amgen, Amoy Diagnostics, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo/UCB Japan, Fishawack Facilitate, InMed, Lilly, Merck Sharp & Dohme, Novartis, Origimed, Pfizer, Prime Oncology, Roche, Sanofi Aventis GmbH, Taiho Pharmaceutical, Takeda, Lucence, Medscape, Permanyer Publications, PeerVoice, Physicans' Education Resource, Research to Practice, Shanghai BeBirds Translation & Consulting, Liangyihui Network Technology Co, Ltd, AbbVie, Berry Oncology, Blueprint Medicines, C4 Therapeutics, CStone Pharmaceuticals, Curio Science, D3, Eisai, Gilead Sciences, Gritstone Bio, Guardant Health, touchIME, Hengrui Therapeutics, Ignyta, Incyte, Inivata, IQvia, Lilly, Loxo, Lunit, Merck Serono, Mirati Therapeutics, Puma Biotechnology, SFJ Pharmaceuticals Group, Vertex, Yuhan, Qiming Development (HK) Ltd, G1 Therapeutics, Janssen, geneDecode. Stock and Other Ownership Interests: Aurora Tele-Oncology Platform, HUTCHMED, ACT Genomics-Sanomics Group. MC Garassino received education grants, honoraria, provided consultation, attended advisory boards and/or provided lectures for the following organizations: MSD Oncology, AstraZeneca/MedImmune, GlaxoSmithKline, Takeda, Roche, Bristol Myers Squibb, Novartis, Tiziana Life Sciences, Sanofi, Celgene, Daiiki Sankyo, Inivata, Incyte, Pfizer, Seattle Genetics, Lilly, GlaxoSmithKline, Bayer, Blueprint Medicines, Janssen, Regeneron, Otsuka, AstraZeneca, Roche/Genentech, Spectrum Pharmaceuticals, Ipsen, Exelixis, Amgen. Luis Paz-Ares reports institutional research support from AstraZeneca, Bayer, Bristol-Myers Squibb, Merck Sharpe & Dohme, and Laboratorios Pfizer Ltda.; personal fees (self/family) from Altum Secuency, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Eli Lilly and Company, Genomica, Ipsen Biopharmaceuticals Inc., Janssen Biotech, Merck Sharpe & Dohme, Mirati, Novartis, Laboratorios Pfizer Ltda., PharmaMar, Roche, Servier Pharmaceuticals, and Takeda Oncology; and serves as a board member at Genómica and Altum all outside the submitted work. F. de Marinis received honoraria or consulting fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, Novartis, Takeda, Xcovery, and Roche. Dr. Attili reports no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objectives: In the phase 3 POSEIDON study, first-line tremelimumab plus durvalumab and chemotherapy significantly improved overall survival and progression-free survival versus chemotherapy in metastatic non-small-cell lung cancer (NSCLC). We present patient-reported outcomes (PROs)., Patients and Methods: Treatment-naïve patients were randomized 1:1:1 to tremelimumab plus durvalumab and chemotherapy, durvalumab plus chemotherapy, or chemotherapy. PROs (prespecified secondary endpoints) were assessed using the European Organisation for Research and Treatment of Cancer 30-item core quality of life questionnaire version 3 (QLQ-C30) and its 13-item lung cancer module (QLQ-LC13). We analyzed time to deterioration (TTD) of symptoms, functioning, and global health status/quality of life (QoL) from randomization by log-rank test and improvement rates by logistic regression., Results: 972/1013 (96 %) patients randomized completed baseline QLQ-C30 and QLQ-LC13 questionnaires, with scores comparable between treatment arms. Patients receiving tremelimumab plus durvalumab and chemotherapy versus chemotherapy had longer median TTD for all PRO items. Hazard ratios for TTD favored tremelimumab plus durvalumab and chemotherapy for all items except diarrhea; 95 % confidence intervals did not cross 1.0 for global health status/QoL, physical functioning, cognitive functioning, pain, nausea/vomiting, insomnia, constipation, hemoptysis, dyspnea, and pain in other parts. For durvalumab plus chemotherapy, median TTD was longer versus chemotherapy for all items except nausea/vomiting and diarrhea. Hazard ratios favored durvalumab plus chemotherapy for all items except appetite loss; 95 % confidence intervals did not cross 1.0 for global health status/QoL, physical functioning, role functioning, dyspnea, and pain in other parts. For both immunotherapy plus chemotherapy arms, improvement rates in all PRO items were numerically higher versus chemotherapy, with odds ratios > 1., Conclusions: Tremelimumab plus durvalumab and chemotherapy delayed deterioration in symptoms, functioning, and global health status/QoL compared with chemotherapy. Together with significant improvements in survival, these results support tremelimumab plus durvalumab and chemotherapy as a first-line treatment option in metastatic NSCLC., Competing Interests: Declaration of Competing Interest Edward B. Garon reports grants or contracts from ABL Bio, AstraZeneca, Bristol-Myers Squibb, Daiichi-Sankyo, Dynavax Technologies, Eli Lilly, EMD Serono, Genentech, Gilead, Iovance Biotherapeutics, Merck, Mirati Therapeutics, Neon, and Novartis; consulting fees from AbbVie, ABL Bio, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Dracen Pharmaceuticals, EMD Serono, Eisai, Eli Lilly, Gilead, GlaxoSmithKline, Merck, Natera, Novartis, Personalis, Regeneron, Sanofi, Shionogi, Xilio, and Zymeworks; and travel support from A2 Bio and Novartis. Byoung Chul Cho reports consulting fees from Abion, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Bridgebio Therapeutics, Bristol-Myers Squibb, CJ, CureLogen, Cyrus Therapeutics, Eli Lilly, GI-Cell, Hanmi, HK Inno-N, Imnewrun Biosciences, Janssen, KANAPH Therapeutic, Medpacto, MSD, Novartis, Ono Pharmaceutical, Onegene Biotechnology, Oscotec, Pfizer, RandBio, Roche, Takeda, and Yuhan; advisory board participation for Bridgebio Therapeutics, Cyrus Therapeutics, Guardant Health, Kanaph Therapeutics, and Oscotec; honoraria from ASCO, AstraZeneca, ESMO, Guardant Health, IASLC, Korean Cancer Association, Korean Cancer Study Group, Korean Society of Medical Oncology, Korean Society of Thyroid-Head and Neck Surgery, MSD, Novartis, Pfizer, Roche, and The Chinese Thoracic Oncology Society; research funding from AbbVie, Abion, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bridgebio Therapeutics, CHA Bundang Medical Center, Champions Oncology, CJ Bioscience, CJ Blossom Park, Cyrus Therapeutics, Dizal Pharma, Dong-A ST, Eli Lilly, Genexine, GI-Cell, GIInnovation, Hanmi, Illumina, ImmuneOncia, Interpark Bio, Janssen, J Ints Bio, Kanaph Therapeutics, LG Chem, Medpacto, MOGAM Institute, MSD, Novartis, Nuvalent, Oncternal, Ono Pharmaceutical, Oscotec, Regeneron, Therapex, and Yuhan; royalties from Champions Oncology, Crown Bioscience, and Imagen; board membership for Interpark Bio and J Ints Bio; stock ownership in Bridgebio Therapeutics, Cyrus Therapeutics, Gencurix, Interpark Bio, Kanaph Therapeutics, J Ints Bio, and TheraCanVac; and other relationships for DAAN Biotherapeutics (Founder) and Korean University Health System (Employment). Alexander Luft has nothing to disclose. Jorge Alatorre-Alexander reports advisory board participation for Amgen, AstraZeneca, Bristol-Myers Squibb, Janssen, MSD, and Roche; travel support from AstraZeneca, MSD, and Roche; and honoraria from Amgen, AstraZeneca, Bristol-Myers Squibb, Janssen, MSD, and Roche. Sarayut Lucien Geater reports research funding (to institution) from AstraZeneca, Boehringer Ingelheim, MSD, Novartis and Roche; honoraria from AstraZeneca, and Boehringer Ingelheim; and advisory board participation for Pfizer. Sang-We Kim reports research funding (to institution) from Yuhan; and travel support from AstraZeneca. Grygorii Ursol has nothing to disclose. Maen Hussein reports consulting fees from AbbVie, Aptitude Health, AstraZeneca, Athenex, Biopharma, Bristol-Myers Squibb, Coherus Biosciences, CTI BioPharma, Exelixis, GIntrinsiQ, IntegraConnect, Integra PrecisionQ, IntrinsiQ, Karyopharm Therapeutics, Mirati Therapeutics, National Community Oncology Dispensing Association, and Oncocyte. Farah Louise Lim has nothing to disclose. Cheng-Ta Yang has nothing to disclose. Luiz Henrique Araujo reports consulting fees from AstraZeneca, Bristol-Myers Squibb, Illumina, Lilly, MSD, Roche, and Sanofi; honoraria from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Lilly, Merck, MSD, Pfizer, and Roche; travel support from AstraZeneca, Bristol-Myers Squibb, and Daiichi-Sankyo; and grants or contracts from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Lilly, Merck, MSD, Novartis, Pfizer, and Roche. Haruhiro Saito reports honoraria from AstraZeneca and ONO Pharmaceutical; and grants or contracts from AstraZeneca, Bristol-Myers Squibb, Chugai Pharmaceutical, and ONO Pharmaceutical. Niels Reinmuth reports honoraria from AstraZeneca, Bristol-Myers Squibb, Lilly, MSD, and Roche; and consulting fees from AstraZeneca, Bristol-Myers Squibb, MSD, and Roche. Nenad Medic, Helen Mann and Xiaojin Shi are full time employees of and own stock in AstraZeneca. Solange Peters reports honoraria (to institution) from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, ecancer, Eli Lilly, Fishawack, Imedex, IQVIA, Medscape, MSD, Novartis, Oncology Education, PER, Pfizer, Prime Oncology, RMEI Medical Education, Research to Practice, Roche/Genentech, and Takeda; advisory board participation for AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Biocartis, Bioinvent, Bristol-Myers Squibb, Clovis Oncology, Daiichi-Sankyo, Debiopharm Group, Eli Lilly, Foundation Medicine, Illumina, Incyte, Janssen, Merck Serono, MSD, Merrimack, Novartis, Pfizer, PharmaMar, Phosplatin Therapeutics, Regeneron, Roche/Genentech, Sanofi, Seattle Genetics, and Takeda; and research funding (to institution) from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Illumina, Iovance Biotherapeutics, Lilly, Merck Serono, MSD, Novartis, Pharma Mar, Pfizer, Phosplatin Therapeutics, Takeda, Sanofi, Seattle Genetics, and Roche/Genentech. Tony Mok reports honoraria from ACEA Pharma, Alpha Biopharma, Amgen, Amoy Diagnostics, AstraZeneca (before 1/1/19), BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Daz, Fishawack Facilitate, InMed Medical Communication, Janssen, Jiahui Holdings, LiangYiHui Healthcare, Lilly, Lucence Health, MD Health Brazil, Medscape, Merck, MiRXES, MSD, Novartis, OrigiMed, P. Permanyer SL, PeerVoice, PER, Pfizer, Prime Oncology, Research to Practice, Roche Pharmaceuticals/Diagnostics/Foundation One, Sanofi-Aventis, Shanghai BeBirds Translation & Consulting, Taiho Pharmaceutical, Takeda, and Touch Independent Medical Education; consulting fees from for AbbVie, ACEA Pharma, Adagene, Alpha Biopharma, Amgen, Amoy Diagnostics, Bayer, BeiGene, Berry Oncology, Boehringer Ingelheim, Blueprint Medicines, Bristol-Myers Squibb, Covidien, C4 Therapeutics, Cirina, CStone Pharmaceuticals, Curio Science, D3 Bio, Da Volterra, Daiichi-Sankyo, Eisai, Elevation Oncology, G1 Therapeutics, geneDecode, Gilead, Gritstone Oncology, Guardant Health, Hengrui Therapeutics, HutchMed, Ignyta, Inivata, IQVIA, Janssen, Lilly, Lunit USA, Loxo Oncology, Lucence Health, Medscape/WebMD, Merck Serono, MSD, Mirati Therapeutics, MiRXES, MoreHealth, Novartis, Omega Therapeutics, OrigiMed, OSE Immunotherapeutics, PeerVoice, Pfizer, Prime Oncology, Puma Biotechnology, Qiming Development, Roche/Genetech, Roche Pharmaceuticals/Diagnostics/Foundation One, Sanofi-Aventis, SFJ Pharmaceutical, Simcere of America, Synergy Research, Takeda, Tigermed, Vertex Pharmaceuticals, Virtus Medical Group, and Yuhan; advisory board participation for AbbVie, ACEA Pharma, Amgen, AstraZeneca, Berry Oncology, Blueprint Medicines, Boehringer Ingelheim, Bowtie Life Insurance, Bristol-Myers Squibb, C4 Therapeutics, Covidien, CStone Pharmaceuticals, Curio Science, D3 Bio, Daiichi-Sankyo, Eisai, Fishawack Facilitate, G1 Therapeutics, Gilead, Gritstone Oncology, Guardant Health, geneDecode (uncompensated), Hengrui Therapeutics, HutchMed, Ignyta, Incyte, Inivata, IQVIA, Janssen, Lakeshore Biotech, Lilly, Loxo Oncology, Lunit, Merck Serono, Mirati Therapeutics, MiRXES, MSD, Novartis, OrigiMed, Pfizer, Puma Biotechnology, Roche/Genentech, Sanofi-Aventis, SFJ Pharmaceutical, Simcere of America, Takeda, Vertex Pharmaceuticals, Virtus Medical Group, Yuhan; leadership roles for ACT Genomics-Sanomics, AstraZeneca, Aurora Tele-Oncology, HutchMed, and Lunit USA; stock/stock options in Act Genomics-Sanomics, AstraZeneca, Aurora Tele-Oncology, Biolidics, and HutchMed; research funding (to institution) from AstraZeneca, Bristol-Myers Squibb, G1 Therapeutics, MSD, Merck Serono, Novartis, Pfizer, Roche, SFJ, Takeda, and XCovery; and travel support (some to institution) from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, MiRXES, MSD, Novartis, Pfizer, Roche. Melissa Johnson reports research funding (paid to institution) from AbbVie, Acerta, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, AstraZeneca, Atreca, BeiGene, BerGenBio, BioAtla, Black Diamond, Boehringer Ingelheim, Bristol-Myers Squibb, Calithera Biosciences, Carisma Therapeutics, Checkpoint Therapeutics, City of Hope National Medical Center, Corvus Pharmaceuticals, Curis, CytomX, Daiichi-Sankyo, Dracen Pharmaceuticals, Dynavax, Lilly, Elicio Therapeutics, EMD Serono, Erasca, EQRx, Exelixis, Fate Therapeutics, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Harpoon, Helsinn Healthcare, Hengrui Therapeutics, Hutchison MediPharma, IDEAYA Biosciences, IGM Biosciences, Immunitas Therapeutics, Immunocore, Incyte, Janssen, Jounce Therapeutics, Kadmon Pharmaceuticals, Kartos Therapeutics, Loxo Oncology, Lycera, Memorial-Sloan Kettering, Merck, Merus, Mirati Therapeutics, Mythic Therapeutics, NeoImmune Tech, Neovia Oncology, Novartis, Numab Therapeutics, OncoMed Pharmaceuticals, Palleon Pharmaceuticals, Pfizer, PMV Pharmaceuticals, Rain Therapeutics, RasCal Therapeutics, Regeneron Pharmaceuticals, Relay Therapeutics, Revolution Medicines, Ribon Therapeutics, Rubius Therapeutics, Sanofi, Seven and Eight Biopharmaceuticals/Birdie Biopharmaceuticals, Shattuck Labs, Silicon Therapeutics, StemCentRx, Syndax Pharmaceuticals, Takeda, Tarveda, TCR2 Therapeutics, Tempest, Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics, Turning Point Therapeutics, University of Michigan, Vyriad, WindMIL, and Y-mAbs Therapeutics; and consulting fees (paid to institution) from AbbVie, Arcus Biosciences, Amgen, Arrivent, Astellas, AstraZeneca, Axelia Oncology, Black Diamond, Calithera, Daiichi-Sankyo, EcoR1, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Ideaya Biosciences, Immunocore, iTeos, Janssen, Jazz Pharmaceuticals, Merck, Mirati Therapeutics, Molecular Axiom, Novartis, Oncorus, Pyramid Biosciences, Regeneron Pharmaceuticals, Revolution Medicines, SeaGen, Sanofi-Aventis, Takeda, Turning Point Therapeutics, Synethekine, and VBL Therapeutics., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: On the basis of available data, at least 1 ultrasound assessment of pregnancies recovering from SARS-CoV-2 infection is recommended. However, reports on prenatal imaging findings and potential associations with neonatal outcomes following SARS-CoV-2 infection in pregnancy have been inconclusive., Objective: This study aimed to describe the sonographic characteristics of pregnancies after confirmed SARS-CoV-2 infection and assess the association of prenatal ultrasound findings with adverse neonatal outcomes., Study Design: This was an observational prospective cohort study of pregnancies diagnosed with SARS-CoV-2 by reverse transcription polymerase chain reaction between March 2020 and May 2021. Prenatal ultrasound evaluation was performed at least once after diagnosis of infection, with the following parameters measured: standard fetal biometric measurements, umbilical and middle cerebral artery Dopplers, placental thickness, amniotic fluid volume, and anatomic survey for infection-associated findings. The primary outcome was the composite adverse neonatal outcome, defined as ≥1 of the following: preterm birth, neonatal intensive care unit admission, small for gestational age, respiratory distress, intrauterine fetal demise, neonatal demise, or other neonatal complications. Secondary outcomes were sonographic findings stratified by trimester of infection and severity of SARS-CoV-2 infection. Prenatal ultrasound findings were compared with neonatal outcomes, severity of infection, and trimester of infection., Results: A total of 103 SARS-CoV-2-affected mother-infant pairs with prenatal ultrasound evaluation were identified; 3 cases were excluded because of known major fetal anomalies. Of the 100 included cases, neonatal outcomes were available in 92 pregnancies (97 infants); of these, 28 (29%) had the composite adverse neonatal outcome, and 23 (23%) had at least 1 abnormal prenatal ultrasound finding. The most common abnormalities seen on ultrasound were placentomegaly (11/23; 47.8%) and fetal growth restriction (8/23; 34.8%). The latter was associated with a higher rate of the composite adverse neonatal outcome (25% vs 1.5%; adjusted odds ratio, 22.67; 95% confidence interval, 2.63-194.91; P<.001), even when small for gestational age was removed from this composite outcome. The Cochran Mantel-Haenszel test controlling for possible fetal growth restriction confounders continued to show this association (relative risk, 3.7; 95% confidence interval, 2.6-5.9; P<.001). Median estimated fetal weight and birthweight were lower in patients with the composite adverse neonatal outcome (P<.001). Infection in the third trimester was associated with lower median percentile of estimated fetal weight (P=.019). An association between placentomegaly and third-trimester SARS-CoV-2 infection was noted (P=.045)., Conclusion: In our study of SARS-CoV-2-affected maternal-infant pairs, rates of fetal growth restriction were comparable to those found in the general population. However, composite adverse neonatal outcome rates were high. Pregnancies with fetal growth restriction after SARS-CoV-2 infection were associated with an increased risk for the adverse neonatal outcome and may require close surveillance., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Biomarker tests in lung cancer have been traditionally ordered by the treating oncologist upon confirmation of an appropriate pathological diagnosis. The delay this introduces prolongs yet further what is already a complex, multi-stage, pre-treatment pathway and delays the start of first-line systemic treatment, which is crucially informed by the results of such analysis. Reflex testing, in which the responsibility for testing for an agreed range of biomarkers lies with the pathologist, has been shown to standardise and expedite the process. Twelve experts discussed the rationale and considerations for implementing reflex testing as standard clinical practice., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: The LUX-Lung 3 study investigated the efficacy of chemotherapy compared with afatinib, a selective, orally bioavailable ErbB family blocker that irreversibly blocks signaling from epidermal growth factor receptor (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), and ErbB4 and has wide-spectrum preclinical activity against EGFR mutations. A phase II study of afatinib in EGFR mutation-positive lung adenocarcinoma demonstrated high response rates and progression-free survival (PFS)., Patients and Methods: In this phase III study, eligible patients with stage IIIB/IV lung adenocarcinoma were screened for EGFR mutations. Mutation-positive patients were stratified by mutation type (exon 19 deletion, L858R, or other) and race (Asian or non-Asian) before two-to-one random assignment to 40 mg afatinib per day or up to six cycles of cisplatin plus pemetrexed chemotherapy at standard doses every 21 days. The primary end point was PFS by independent review. Secondary end points included tumor response, overall survival, adverse events, and patient-reported outcomes (PROs)., Results: A total of 1,269 patients were screened, and 345 were randomly assigned to treatment. Median PFS was 11.1 months for afatinib and 6.9 months for chemotherapy (hazard ratio [HR], 0.58; 95% CI, 0.43 to 0.78; P = .001). Median PFS among those with exon 19 deletions and L858R EGFR mutations (n = 308) was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = .001). The most common treatment-related adverse events were diarrhea, rash/acne, and stomatitis for afatinib and nausea, fatigue, and decreased appetite for chemotherapy. PROs favored afatinib, with better control of cough, dyspnea, and pain., Conclusion: Afatinib is associated with prolongation of PFS when compared with standard doublet chemotherapy in patients with advanced lung adenocarcinoma and EGFR mutations.

Objectives: The phase 3 NEPTUNE study (NCT02542293) evaluated first-line durvalumab plus tremelimumab (DT) versus chemotherapy for metastatic NSCLC. Prespecified exploratory analyses were conducted in an extended cohort enrolled in China., Materials and Methods: Patients were randomized (1:1) to DT or standard chemotherapy, stratified by PD-L1 tumor cell (TC) expression (≥25 % vs < 25 %), histology, and smoking history. The primary analysis for this cohort was overall survival (OS) in patients with PD-L1 TC < 1 %. Secondary analyses included OS and progression-free survival (PFS) in the ITT population and PD-L1 subgroups, and safety. No alpha was allocated to these cohort analyses (data cut-off, 21-September-2020)., Results: 78 and 82 patients were randomized to DT and chemotherapy, respectively; 26 and 29 had PD-L1 TC < 1 % (median follow-up, 31.2 and 29.7 months [censored patients]). Among patients with PD-L1 TC < 1 %, OS favored DT versus chemotherapy (HR 0.60; 95 % CI, 0.32-1.11), with medians of 15.0 months (95 % CI, 10.5-27.4) and 11.7 months (95 % CI, 8.6-20.5), respectively; 24-month rates were 36.0 % (95 % CI, 18.2-54.2) and 17.9 % (95 % CI, 6.5-33.7). In the ITT population, OS was prolonged with DT versus chemotherapy (HR 0.70; 95 % CI, 0.48-1.02); medians were 20.0 and 14.1 months and 24-month rates were 44.2 % and 30.4 %. PFS was similar in the PD-L1 TC < 1 % (HR 1.13; 95 % CI, 0.59-2.14) and ITT (HR 0.95; 95 % CI, 0.66-1.36) populations; 12-month rates were 15.6 % versus 11.3 % and 23.9 % versus 16.6 %. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 31.2 % with DT and 52.6 % with chemotherapy; 3.9 % versus 10.3 % discontinued due to TRAEs., Conclusions: In exploratory analyses, first-line DT showed a trend towards improved OS versus chemotherapy among Chinese patients in the PD-L1 TC < 1 % population and ITT population, with 24-month OS and 12-month PFS rates indicating benefit in survival curve tails. DT was well tolerated with no new safety signals., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Zhou reports receiving personal fees from AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, MSD, Pfizer, Roche, and Sanofi. Ms. Mann and Dr. Shire are full-time employees of AstraZeneca. Ms. Mann owns stock in AstraZeneca. Dr. Naicker was a full-time employee of AstraZeneca with stock ownership at the time of the study and when the reported analyses were conducted. Dr. Mok became a nonexecutive director on the AstraZeneca Board in January 2019 and stepped down as the principal investigator on the NEPTUNE study, is an independent nonexecutive director of and shareholder in HutchMed, is Board Chairman of and shareholder in the Act Genomics-Sanomics Group, serves on the Board of Directors of and is a shareholder in Aurora, and serves on the Board of Directors (NEID) of and has stock options in Lunit USA Inc., and has stock options in Biolidics Ltd. In addition, he reports receiving personal fees from AbbVie, ACEA Pharma, Adagene, Alpha Biopharma, Amgen, Amoy Diagnostics, Bayer Healthcare Pharmaceuticals Ltd, BeiGene, Berry Oncology, Blueprint Medicines Corporation, Boehringer Ingelheim, Bowtie Life Insurance Co Ltd, C4 Therapeutics Inc., Covidien LP, CStone Pharmaceuticals, Curio Science, D3 Bio Ltd, Da Volterra, Daiichi Sankyo Inc., Daz Group, Eisai, Elevation Oncology, F. Hoffmann-La Roche Ltd/Genentech, Fishawack Facilitate Ltd, Gilead Sciences Inc., Gritstone Oncology Inc., Guardant Health, Hengrui Therapeutics Inc., Ignyta Inc., Incyte Corporation, Inivata, InMed Medical Communication, IQVIA, Janssen, Jiahui Holdings Co. Ltd, Lakeshore Biotech, Liangyihui Healthcare, Lilly, Loxo-Oncology Inc., Lucence Health Inc., MD Health Brazil, Medscape/WebMD, Merck Pharmaceuticals HK Ltd, Mirati Therapeutics Inc., MiRXES Group, MoreHealth, Omega Therapeutics Inc., OrigiMed Co. Ltd, OSE Immunotherapeutics, PeerVoice, Physicians' Education Resource, P. Permanyer SL, PrIME Oncology, Puma Biotechnology Inc., Qiming Development (HK), Research to Practice, Sanofi Aventis R&D, Shanghai BeBirds Translation & Consulting Co. Ltd, Simcere of America Inc., Synergy Research, Taiho Pharmaceutical Co. Ltd, Takeda Pharmaceuticals HK Ltd, Tigermed, Touch Independent Medical Education Ltd, Vertex Pharmaceuticals, Virtus Medical Group, and Yuhan Corporation; grants and personal fees from AstraZeneca, Bristol-Myers Squibb, G1 Therapeutics, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche, SFJ Pharmaceuticals, Takeda, and XCovery; and has undertaken consultancy (uncompensated) for geneDecode Co. Ltd. Dr. de Castro Jr reports receiving personal fees from Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Janssen, Libbs, Lilly, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Sanofi. The remaining authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

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.

Introduction: Most published guidelines for genomic biomarker testing in NSCLC reflect the disease epidemiology and treatments readily available in Europe and North America. Nevertheless, 60% of annual global NSCLC cases occur in Asia, where patient characteristics, tumor molecular profiles, and treatments vary greatly from the Western world. For example, mutations in the EGFR occur at a higher prevalence in Asia than in other world regions. Although medical associations such as the International Association for the Study of Lung Cancer, European Society for Medical Oncology, and American Society of Clinical Oncology have described principles for tumor genomic biomarker testing in NSCLC, there is a need for recommendations specific for Asia., Methods: This report provides consensus recommendations for NSCLC biomarker testing from Asian lung cancer experts for clinicians working in Asia to improve patient care. Biomarker testing approaches for actionable genetic alterations in EGFR, ALK, ROS1, and others are discussed., Results: These recommendations are divided into nonmetastatic and metastatic forms of adenocarcinoma and squamous cell carcinoma. Owing to the higher prevalence of EGFR mutations in Asia, the experts emphasized the need for EGFR testing to include not just common mutations (exon 19 deletions and L858R substitutions) but also other uncommon EGFR mutations. In addition to the assessment of biomarkers in the tumor tissue, the role of assessing tumor biomarkers by liquid biopsy is discussed., Conclusion: This consensus provides practical recommendations for biomarker testing in nonmetastatic and metastatic Asian NSCLC patients., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: We evaluated whether tissue tumor mutational burden (tTMB) and STK11, KEAP1, and KRAS mutations have clinical utility as biomarkers for pembrolizumab monotherapy versus platinum-based chemotherapy in patients with programmed death ligand 1 (PD-L1)-positive (tumor proportion score ≥1%) advanced/metastatic non-small-cell lung cancer (NSCLC) without EGFR/ALK alterations in the phase III KEYNOTE-042 trial., Patients and Methods: This retrospective exploratory analysis assessed prevalence of tTMB and STK11, KEAP1, and KRAS mutations determined by whole-exome sequencing of tumor tissue and matched normal DNA and their associations with outcomes in KEYNOTE-042. Clinical utility of tTMB was assessed using a prespecified cut point of 175 mutations/exome., Results: Of 793 patients, 345 (43.5%) had tTMB ≥175 mutations/exome and 448 (56.5%) had tTMB <175 mutations/exome. No association was observed between PD-L1 expression and tTMB. Continuous tTMB score was associated with improved overall survival (OS) and progression-free survival among patients receiving pembrolizumab (Wald test, one-sided P < 0.001) but not those receiving chemotherapy (Wald test, two-sided P > 0.05). tTMB ≥175 mutations/exome was associated with improved outcomes for pembrolizumab versus chemotherapy, whereas tTMB <175 mutations/exome was not {OS: hazard ratio, 0.62 [95% confidence interval (CI) 0.48-0.80] and 1.09 (95% CI 0.88-1.36); progression-free survival: 0.75 (0.59-0.95) and 1.27 (1.04-1.55), respectively}. Improved OS [hazard ratio (95% CI)] for pembrolizumab versus chemotherapy was observed regardless of STK11 [STK11 mutant (n = 33): 0.37 (0.16-0.86), STK11 wild-type (n = 396): 0.83 (0.65-1.05)]; KEAP1 [KEAP1 mutant (n = 64): 0.75 (0.42-1.35), KEAP1 wild-type (n = 365): 0.78 (0.61-0.99)], or KRAS [KRAS mutant (n = 69): 0.42 (0.22-0.81); KRAS wild-type (n = 232): 0.86 (0.63-1.18)] mutation status., Conclusion: tTMB with a cut point of ≥175 mutations/exome is a potential predictive biomarker for pembrolizumab monotherapy for advanced/metastatic PD-L1 tumor proportion score ≥1% NSCLC. Pembrolizumab is a standard first-line treatment in this setting regardless of STK11, KEAP1, or KRAS mutation status., (Copyright © 2023 Merck Sharp & Dohme LLC., a subsidiary Merck & Co., Inc., The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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.

Introduction: Lorlatinib is a potent, third-generation inhibitor of ALK. In the planned interim analysis of the ongoing, phase 3, randomized, global CROWN trial (NCT03052608), lorlatinib resulted in significantly longer progression-free survival than crizotinib in patients with previously untreated, advanced, ALK -positive NSCLC. Here, we present a subgroup analysis of Asian patients in the CROWN study., Methods: Patients received lorlatinib 100 mg once daily or crizotinib 250 mg twice daily. The primary end point was progression-free survival assessed by blinded independent central review. Objective response rate (ORR), intracranial ORR, safety, and select biomarkers were secondary end points., Results: At data cutoff (September 20, 2021), 120 patients were included in the Asian intention-to-treat subgroup (lorlatinib n = 59; crizotinib n = 61). At 36 months, 61% (95% confidence interval [CI]: 47-72) and 25% (95% CI: 12-41) of patients in the lorlatinib and crizotinib groups, respectively, were alive without disease progression (hazard ratio for disease progression by blinded independent central review or death: 0.40; 95% CI: 0.23-0.71). ORR was 78% (95% CI: 65-88) versus 57% (95% CI: 44-70) for patients treated with lorlatinib and crizotinib, respectively. In patients with measurable, nonmeasurable, or both measurable and nonmeasurable brain metastases at baseline, intracranial ORR was 73% (95% CI: 39-94) versus 20% (95% CI: 4-48) for patients treated with lorlatinib and crizotinib, respectively. The definition of nonmeasurable brain metastases is: a brain lesion less than 10 mm in MRI scan is defined as nonmeasurable brain metastasi based on RECIST criteria (Clinical trial evaluation criteria). Hypercholesterolemia, hypertriglyceridemia, and edema were the most frequently reported adverse events with lorlatinib., Conclusions: Lorlatinib efficacy and safety in the Asian subgroup of CROWN were consistent with those in the overall population., (© 2023 The Authors.)

Osimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), potently and selectively inhibits EGFR-TKI-sensitizing and EGFR T790M resistance mutations. This analysis evaluates acquired resistance mechanisms to second-line osimertinib (n = 78) in patients with EGFR T790M advanced non-small cell lung cancer (NSCLC) from AURA3 (NCT02151981), a randomized phase 3 study comparing osimertinib with chemotherapy. Plasma samples collected at baseline and disease progression/treatment discontinuation are analyzed using next-generation sequencing. Half (50%) of patients have undetectable plasma EGFR T790M at disease progression and/or treatment discontinuation. Fifteen patients (19%) have >1 resistance-related genomic alteration; MET amplification (14/78, 18%) and EGFR C797X mutation (14/78, 18%)., (© 2023. The Author(s).)

Purpose: The open-label, phase III POSEIDON study evaluated tremelimumab plus durvalumab and chemotherapy (T + D + CT) and durvalumab plus chemotherapy (D + CT) versus chemotherapy alone (CT) in first-line metastatic non-small-cell lung cancer (mNSCLC)., Methods: Patients (n = 1,013) with EGFR / ALK wild-type mNSCLC were randomly assigned (1:1:1) to tremelimumab 75 mg plus durvalumab 1,500 mg and platinum-based chemotherapy for up to four 21-day cycles, followed by durvalumab once every 4 weeks until progression and one additional tremelimumab dose; durvalumab plus chemotherapy for up to four 21-day cycles, followed by durvalumab once every 4 weeks until progression; or chemotherapy for up to six 21-day cycles (with or without maintenance pemetrexed; all arms). Primary end points were progression-free survival (PFS) and overall survival (OS) for D + CT versus CT. Key alpha-controlled secondary end points were PFS and OS for T + D + CT versus CT., Results: PFS was significantly improved with D + CT versus CT (hazard ratio [HR], 0.74; 95% CI, 0.62 to 0.89; P = .0009; median, 5.5 v 4.8 months); a trend for improved OS did not reach statistical significance (HR, 0.86; 95% CI, 0.72 to 1.02; P = .0758; median, 13.3 v 11.7 months; 24-month OS, 29.6% v 22.1%). PFS (HR, 0.72; 95% CI, 0.60 to 0.86; P = .0003; median, 6.2 v 4.8 months) and OS (HR, 0.77; 95% CI, 0.65 to 0.92; P = .0030; median, 14.0 v 11.7 months; 24-month OS, 32.9% v 22.1%) were significantly improved with T + D + CT versus CT. Treatment-related adverse events were maximum grade 3/4 in 51.8%, 44.6%, and 44.4% of patients receiving T + D + CT, D + CT, and CT, respectively; 15.5%, 14.1%, and 9.9%, respectively, discontinued treatment because of treatment-related adverse events., Conclusion: D + CT significantly improved PFS versus CT. A limited course of tremelimumab added to durvalumab and chemotherapy significantly improved OS and PFS versus CT, without meaningful additional tolerability burden, representing a potential new option in first-line mNSCLC.

Congenital heart disease (CHD) in pregnancy is associated with an increased risk of adverse maternal, obstetric, and neonatal outcomes, plausibly through mechanisms involving abnormal placental development and function. This retrospective study aims to elucidate how maternal CHD influences placental health. Demographic and clinical information were collected via electronic medical record review, and placentas underwent histopathological evaluation. Fifty-three singleton pregnancies were included: 35 participants (66%) were classified as lower cardiovascular risk (modified World Health Organization Classification (mWHO) I, II, II-III), and 18 (34%) were classified as higher cardiovascular risk (mWHO III, IV). 12 participants (23%) had a fetus with small for gestational age (SGA). Maternal vascular malperfusion (53%) and placental abruption (11.6%) were common in this cohort, with prevalence above baseline risk. Participants at higher cardiovascular risk had higher rates of SGA (p = 0.04), subchorionic hematomas (p = 0.01) and birth weight:placental weight < 10th percentile (p = 0.04), but did not differ in rates of maternal vascular malperfusion (p = 0.15) compared to those at lower cardiovascular risk. In pregnancies with maternal CHD, SGA and histologic evidence of maternal vascular malperfusion and placental abruption were common, though patients at higher cardiovascular risk did not show evidence of worsened placental health compared to those at lower risk., (© 2023. The Author(s).)

Objective: To evaluate neuromotor repertoires and developmental milestones in infants exposed to antenatal COVID-19., Design: Longitudinal cohort study., Setting: Hospital-based study in Los Angeles, USA and Rio de Janeiro, Brazil between March 2020 and December 2021., Participants: Infants born to mothers with COVID-19 during pregnancy and prepandemic control infants from the Graz University Database., Interventions: General movement assessment (GMA) videos between 3 and 5 months post-term age were collected and clinical assessments/developmental milestones evaluated at 6-8 months of age. Cases were matched by gestational age, gender and post-term age to prepandemic neurotypical unexposed controls from the database., Main Outcome Measures: Motor Optimality Scores Revised (MOS-R) at 3-5 months. Presence of developmental delay (DD) at 6-8 months., Results: 239 infants were enrolled; 124 cases (83 in the USA/41 in Brazil) and 115 controls. GMA was assessed in 115 cases and 115 controls; 25% were preterm. Median MOS-R in cases was 23 (IQR 21-24, range 9-28) vs 25 (IQR 24-26, range 20-28) in controls, p<0.001. Sixteen infants (14%) had MOS-R scores <20 vs zero controls, p<0.001. At 6-8 months, 13 of 109 case infants (12%) failed to attain developmental milestones; all 115 control infants had normal development. The timing of maternal infection in pregnancy (first, second or third trimester) or COVID-19 disease severity (NIH categories asymptomatic, mild/moderate or severe/critical) was not associated with suboptimal MOS-R or DD. Maternal fever in pregnancy was associated with DD (OR 3.7; 95% CI 1.12 to 12.60) but not suboptimal MOS-R (OR 0.25; 95% CI 0.04 to 0.96)., Conclusions: Compared with prepandemic controls, infants exposed to antenatal COVID-19 more frequently had suboptimal neuromotor development., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: There are limited data on how coronavirus disease 2019 (COVID-19) severity, timing of infection, and subsequent vaccination impact transplacental transfer and persistence of maternal and infant antibodies., Methods: In a longitudinal cohort of pregnant women with polymerase chain reaction-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, maternal/infant sera were collected at enrollment, delivery/birth, and 6 months. Anti-SARS-CoV-2 spike immunoglobulin (Ig)G, IgM, and IgA were measured by enzyme-linked immunosorbent assay., Results: Two-hundred fifty-six pregnant women and 135 infants were enrolled; 148 maternal and 122 neonatal specimens were collected at delivery/birth; 45 maternal and 48 infant specimens were collected at 6 months. Sixty-eight percent of women produced all anti-SARS-CoV-2 isotypes at delivery (IgG, IgM, IgA); 96% had at least 1 isotype. Symptomatic disease and vaccination before delivery were associated with higher maternal IgG at labor and delivery. Detectable IgG in infants dropped from 78% at birth to 52% at 6 months. In the multivariate analysis evaluating factors associated with detectable IgG in infants at delivery, significant predictors were 3rd trimester infection (odds ratio [OR] = 4.0), mild/moderate disease (OR = 4.8), severe/critical disease (OR = 6.3), and maternal vaccination before delivery (OR = 18.8). No factors were significant in the multivariate analysis at 6 months postpartum., Conclusions: Vaccination in pregnancy post-COVID-19 recovery is a strategy for boosting antibodies in mother-infant dyads., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: NEPTUNE, a phase 3, open-label study, evaluated first-line durvalumab plus tremelimumab versus chemotherapy in metastatic NSCLC (mNSCLC)., Methods: Eligible patients with EGFR and ALK wild-type mNSCLC were randomized (1:1) to first-line durvalumab (20 mg/kg every 4 weeks until progression) plus tremelimumab (1 mg/kg every 4 weeks for up to four doses) or standard chemotherapy. Randomization was stratified by tumor programmed death-ligand 1 expression (≥25% versus <25%), tumor histologic type, and smoking history. The amended primary end point was overall survival (OS) in patients with blood tumor mutational burden (bTMB) greater than or equal to 20 mutations per megabase (mut/Mb). Secondary end points included progression-free survival (PFS) in patients with bTMB greater than or equal to 20 mut/Mb and safety and tolerability in all treated patients., Results: As of June 24, 2019, 823 patients were randomized (intention-to-treat [ITT]); 512 (62%) were bTMB-evaluable, with 129 of 512 (25%) having bTMB greater than or equal to 20 mut/Mb (durvalumab plus tremelimumab [n = 69]; chemotherapy [n = 60]). Baseline characteristics were balanced in the intention-to-treat. Among patients with bTMB greater than or equal to 20 mut/Mb, OS improvement with durvalumab plus tremelimumab versus chemotherapy did not reach statistical significance (hazard ratio 0.71 [95% confidence interval: 0.49-1.05; p = 0.081]; median OS, 11.7 versus 9.1 months); the hazard ratio for PFS was 0.77 (95% confidence interval, 0.51-1.15; median PFS, 4.2 versus 5.1 months). In the overall safety population, incidence of grade 3 or 4 treatment-related adverse events was 20.7% (durvalumab plus tremelimumab) and 33.6% (chemotherapy)., Conclusions: NEPTUNE did not meet its primary end point of improved OS with durvalumab plus tremelimumab versus chemotherapy in patients with mNSCLC and bTMB greater than or equal to 20 mut/Mb. Despite the amended study design, with a resultant small primary analysis population, therapeutic activity was aligned with expectations based on mechanistic biology and previous studies., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Objectives: Quality of life (QoL) for patients with non-small cell lung cancer (NSCLC) is negatively impacted by their disease and treatment side effects. We present detailed patient-reported outcome (PRO) data from the phase 3 CROWN study, which compared lorlatinib with crizotinib in patients with previously untreated ALK-positive advanced NSCLC., Materials and Methods: PROs were assessed using the European Organisation for Research and Treatment of Cancer QoL Questionnaire with Lung Cancer module. A longitudinal, random-intercept, random-slope, mixed-effect model assessed score changes from baseline up to (not including) end of treatment. Mean changes of absolute scores from baseline at each cycle were calculated and presented up to cycle 18 (≥ 10-point change considered clinically meaningful)., Results: In both lorlatinib (n = 148) and crizotinib (n = 140) arms, there were longitudinal improvements across multiple functioning and symptom scores during treatment compared with pre-treatment. Numerical improvements for most longitudinal functioning scores (physical, role, emotional, social) favored lorlatinib; cognitive functioning favored crizotinib. Numerical improvements favored lorlatinib for several symptoms (fatigue, nausea and vomiting, insomnia, appetite loss, constipation, diarrhea [clinically meaningful improvement], and cough); peripheral neuropathy favored crizotinib. Subgroup analyses showed PROs did not differ by presence/absence of baseline brain metastases., Conclusions: Patients receiving first-line lorlatinib or crizotinib showed improvements and delayed deterioration in QoL, functioning, and several symptoms. Alongside the previously reported significantly longer progression-free survival and higher intracranial response rates for lorlatinib versus crizotinib, these data further support the use of lorlatinib over crizotinib in patients with advanced ALK-positive NSCLC with/without baseline brain metastases and provide evidence of several QoL improvements with lorlatinib when used in the first-line setting., Competing Interests: Declaration of Competing Interest ICMJE form COIs Dr Mazieres reports receiving personal consulting fees or honorarium from Pfizer, and personal consultancy fees from F. Hoffman La-Roche Ltd, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Hengrui Therapeutics, and Amgen. Dr Iadeluca, Ms Reisman, Dr Thurm, Ms Polli are employees of Pfizer and hold Pfizer stock/stock options. Dr Shaw reports receiving personal honoraria, advisory board or consultancy fees, and institutional research support from Pfizer, and is currently an employee of Novartis and holds Novartis stock/stock options. Dr Solomon reports receiving personal honoraria or advisory board fees from Pfizer, Novartis, F. Hoffman La-Roche Ltd, Amgen, AstraZeneca, Merck Sharp & Dohme, Bristol Myers Squibb, BeiGene, Takeda, Janssen, and Lilly. Dr Bauer reports receiving personal consultancy and speakers’ bureau fees from AstraZeneca, Lilly, Bayer; personal consultancy fees from Bristol Myers Squibb, Foundation Medicine, Pfizer, Loxo Oncology, Guardant Health, Exelixis, Blueprint Medicines; payment/reimbursement of exact expenses from Lilly, Bristol Myers Squibb, Foundation Medicine, Ignyta, Moderna Therapeutics, Loxo Oncology, Bayer, Guardant Health; institutional consultancy fees from Leap Therapeutics, Ignyta, Moderna Therapeutics, Pfizer; and institutional grant support from Pfizer, Daiichi Sankyo, Medpacto, Incyte, Mirati Therapeutics, MedImmune, AbbVie, AstraZeneca, MabVax, Stemline Therapeutics, Merck, Lilly, GlaxoSmithKline, Novartis, Genentech, Deciphera, Merrimack, Immunogen, Millennium, Phosplatin Therapeutics, Calithera Biosciences, Kolltan Pharmaceuticals, Principia Biopharma, Peleton, Immunocore, F. Hoffman La-Roche Ltd, Aileron Therapeutics, Bristol Myers Squibb, Amgen, Onyx, Sanofi, Boehringer Ingelheim, Astellas Pharma, Five Prime Therapeutics, Jacobio, Top Alliance BioScience, Janssen, Clovis Oncology, Takeda, Karyopharm Therapeutics, Foundation Medicine, ARMO BioSciences, Leap Therapeutics, Ignyta, Moderna Therapeutics, Pfizer, Loxo Oncology, and Bayer. Dr de Marinis reports receiving personal advisory fees from AstraZeneca, Bristol Myers Squibb, Novartis, F. Hoffman La-Roche Ltd, and Merck Sharp & Dohme. Dr Felip reports receiving personal speakers’ bureau fees from Medscape, Peervoice, Springer, Touch Independent Medical Education, prIME Oncology, CME Outfitters; personal advisory board fees from AbbVie, Amgen, Bayer, Blueprint Medicines, Lilly, GlaxoSmithKline, Janssen, Merck, Puma Biotechnology, F. Hoffman La-Roche Ltd, Sanofi Genzyme, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pfizer, Takeda, Daichii Sankyo; personal advisory or board member fees from Grifols; grant support from Fundación Merck Salud. Dr Goto reports receiving grant support or contracts from Pfizer, AZK; institutional grant support or contracts from AbbVie, Lilly, Pfizer, Bristol Myers Squibb, ONO Pharmaceutical, Novartis, Kyorin Pharmaceutical, Daiichi Sankyo, Preferred Networks Inc.; personal honoraria for lectures, presentations, speakers’ bureau, manuscript writing or educational events from Lilly, Chugai Pharmaceutical, Taiho Pharmaceutical, Boehringer Ingelheim, ONO Pharmaceutical, Bristol Myers Squibb, Pfizer, Merck Sharp & Dohme, Novartis, Merck, and Thermo Fisher; personal advisory board or data safety monitoring board fees from AstraZeneca, Chugai Pharmaceutical, Boehringer Ingelheim, Lilly, Taiho Pharmaceutical, Pfizer, Novartis, Guardant Health, Illumina, Daiichi Sankyo, ONO Pharmaceutical, Bristol Myers Squibb, and Merck Sharp & Dohme; and reports a leadership, fiduciary or board role with Cancer Net Japan, and JAMT. Dr Kim reports receiving medical writing support from Pfizer; institutional grant support from Pfizer, Alpha Biopharma, Amgen, AstraZeneca, Boehringer Ingelheim, Bridge BioTherapeutics, Chong Keun Dang, Daiichi Sankyo, GlaxoSmithKline, Hanmi, Janssen, Merck, Merus, Mirati Therapeutics, Merck Sharp & Dohme, Novartis, ONO Pharmaceutical, F. Hoffman La-Roche Ltd, Takeda, TP Therapeutics, Xcovery, and Yuhan; and travel support from Amgen, and Daiichi Sankyo. Dr Mok reports receiving grant support from AstraZeneca, Bristol-Myers Squibb, Merck Serono, Merck Sharpe & Dohme, Novartis, Pfizer, Roche, Takeda, Clovis Oncology, SFJ Pharmaceuticals, XCovery, G1 Therapeutics Inc.; personal consultancy, advisory or lecture fees from Abbvie, ACEA Pharmaceuticals, Alpha Biopharma, Amgen, Amoy Diagnostics, 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, InMed Medical Communication, Janssen, Lilly, Loxo-Oncology, Lunit USA, Inc., MD Health (Brazil), Medscape/WebMD, Merck Serono, Merck Sharp & Dohme, Mirati Therapeutics Inc., MoreHealth, Novartis, OrigiMed, PeerVoice, Physicians' Education Resource, P. Permanyer SL, Pfizer, Inc, PrIME Oncology, Puma Biotechnology Inc, Research to Practice, Roche, Sanofi-Aventis R&D, Takeda, Touch Medical Media, Virtus Medical Group (stock option), Yuhan Corporation, HutchMed (shareholder), SFJ Pharmaceuticals, Curio Science, Inivata, Berry Oncology, G1 Therapeutics Inc., Aurora (shareholder), 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, Gilead Sciences, Inc, Vertex Pharmaceuticals, Covidien LP, Elevation Oncology, C4 Therapeutics, Inc, D3 Bio Ltd.; shareholder or stock options from Loxo-Oncology, Lunit USA, Inc., Act Genomics-Sanomics Group; Board of Director at AstraZeneca PLC (Jan 2019 onwards), HutchMed (Oct 2018 onwards), Act Genomics-Sanomics Group (Board Chairman 2015 onwards), Lunit USA, Inc. (Mar 2021 onwards), Aurora (Sep 2020 onwards). Dr Liu reports receiving grants or contracts from institutions - NCI (US), CIHR (Canada), CCSRI (Canada), AstraZeneca, Takeda, Boehringer Ingelheim; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events (personal) from AstraZeneca, Pfizer, EMD Serono, Takeda, Jazz; Participation on a Data Safety Monitoring Board or Advisory Board (personal) from AstraZeneca, Pfizer, EMD Serono, Merck, Abbvie, Jazz, Takeda, Roche, BMS, Novartis., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Brigatinib is a potent next-generation ALK tyrosine kinase inhibitor approved for treatment-naive and crizotinib-refractory advanced ALK-positive (ALK+) NSCLC. We evaluated brigatinib after other next-generation ALK tyrosine kinase inhibitors., Methods: In this single-arm, phase 2, ALK in Lung Cancer Trial of brigAtinib-2 (NCT03535740), patients with advanced ALK+ NSCLC whose disease progressed on alectinib or ceritinib received brigatinib 180 mg once daily (after 7-d 90-mg lead-in). Primary end point was independent review committee (IRC)-assessed overall response rate (ORR). Circulating tumor DNA (ctDNA) was analyzed., Results: Among 103 patients (data cutoff: September 30, 2020; median follow-up [range]: 10.8 [0.5-17.7] mo), confirmed IRC-ORR was 26.2% (95% confidence interval [CI]: 18.0-35.8), median duration of response, 6.3 months (95% CI: 5.6-not reached), and median progression-free survival (mPFS), 3.8 months (95% CI: 3.5-5.8). mPFS was 1.9 months (95% CI: 1.8-3.7) in patients with ctDNA-detectable baseline ALK fusion (n = 64). Among 86 patients who progressed on alectinib, IRC-ORR was 29.1% (95% CI: 19.8-39.9); mPFS was 3.8 months (95% CI: 1.9-5.4). Resistance mutations were present in 33.3% (26 of 78) of baseline ctDNA; 54% (14 of 26) of mutations were G1202R; 52% (33 of 64) of patients with detectable ALK fusion had EML4-ALK variant 3. Most common all-grade treatment-related adverse events were increased creatine phosphokinase (32%) and diarrhea (27%). The mean dose intensity of brigatinib (180 mg once daily) was 85.9%., Conclusions: In ALK in Lung Cancer Trial of brigAtinib-2, brigatinib was found to have a limited activity in patients with ALK+ NSCLC post-ceritinib or post-alectinib therapy. mPFS was longer with brigatinib in patients without baseline detectable plasma ALK fusion., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Pregnancies complicated by Coronavirus Disease 2019 (COVID-19) are at an increased risk of severe morbidity due to physiologic changes in immunologic, cardiovascular, and respiratory function. There is little is known about how severity of COVID-19 changes protein and metabolite expression in pregnancy., Objective: This study aims to investigate the pathophysiology behind various clinical trajectories in pregnant patients diagnosed with COVID-19 using multi-omics profiling., Study Design: This is a prospective cohort study of 30 pregnant patients at a single tertiary care center. Participants were categorized by severity of COVID-19 disease (control, asymptomatic, mild/moderate, or severe). Maternal serum samples underwent LC-MS-based multiomics analysis for profiling of proteins, lipids, electrolytes, and metabolites. Linear regression models were used to assess how disease severity related to analyte levels. Reactome pathway enrichment analysis was conducted on differential analytes., Results: Of 30 participants, 25 had confirmed diagnosis of COVID-19 (6 asymptomatic (one post-infection), 13 mild/moderate (all post-infection), 6 severe), and 5 participants were controls. Severe COVID-19 was associated with distinct profiles demonstrating significant proteomic and lipidomic signatures which were enriched for annotations related to complement and antibody activity. (FDR < 0.05). Downregulated analytes were not significantly enriched but consisted of annotation terms related to lipoprotein activity (FDR > 0.2). Post-infection mild/moderate COVID-19 did not have significantly altered serum protein, metabolite, or lipid metabolite levels compared to controls., Conclusions: Pregnancies with severe COVID-19 demonstrate greater inflammation and complement activation and dysregulation of serum lipids. This altered multiomic expression provides insight into the pathophysiology of severe COVID-19 in pregnancy and may serve as potential indicators for adverse pregnancy outcomes., Competing Interests: The study was approved by the Institutional Review Board (UCLA IRB# 20-000579). After patient was identified, participants underwent screening and eligible participants were contacted by a study coordinator by phone or email. Verbal or email consented was obtained. All co-authors have read and approved the manuscript in its current submitted form. Authors AQ and SY are co-founders of, are employed by, and own stock in Dalton Bioanalytics Inc. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All other authors report no conflict of interest., (Copyright: © 2022 Altendahl et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: Lorlatinib significantly improved progression-free survival (PFS) versus crizotinib and showed robust intracranial activity in patients with previously untreated advanced ALK -positive non-small-cell lung cancer (NSCLC) in the phase III CROWN trial. Here, we report post hoc efficacy outcomes in patients with and without brain metastases at baseline, and present data on the incidence and management of CNS adverse events (AEs) in CROWN., Methods: Eligible patients were randomly assigned 1:1 to first-line lorlatinib (100 mg once daily) or crizotinib (250 mg twice a day); no crossover between treatment arms was permitted. Tumor assessments, including CNS magnetic resonance imaging, were performed at screening and then at 8-week intervals. Regular assessments of patient-reported outcomes were conducted., Results: PFS by blinded independent central review was improved with lorlatinib versus crizotinib in patients with and without brain metastases at baseline (12-month PFS rates: 78% v 22% and 78% v 45%, respectively). Lorlatinib was associated with lower 12-month cumulative incidence of CNS progression versus crizotinib in patients with (7% v 72%) and without (1% v 18%) brain metastases at baseline. In total, 35% of patients had CNS AEs with lorlatinib, most of grade 1 severity. Occurrence of CNS AEs did not result in a clinically meaningful difference in patient-reported quality of life. At analysis, 56% of CNS AEs had resolved (33% without intervention; 17% with lorlatinib dose modification), and 38% were unresolved; most required no intervention. Lorlatinib dose modification did not notably influence PFS., Conclusion: First-line lorlatinib improved PFS outcomes and reduced CNS progression versus crizotinib in patients with advanced ALK -positive non-small-cell lung cancer with or without brain metastases at baseline. Half of all CNS AEs resolved without intervention or with lorlatinib dose modification.

Background: Prion diseases cause a range of movement disorders involving the cortical, extrapyramidal, and cerebellar systems, and yet there are no large systematic studies of their prevalence, features, associations, and responses to commonly used treatments., Objectives: We sought to describe the natural history and pharmacological management of movement disorders in prion diseases., Methods: We studied the serial examination findings, investigation results, and symptomatic treatment recorded for 700 patients with prion diseases and 51 mimics who had been enrolled onto the prospective longitudinal National Prion Monitoring Cohort study between 2008 and 2020. We performed an analysis to identify whether there were patterns of movement disorders associated with disease aetiology, PRNP codon 129 polymorphism, disease severity rating scales, magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) findings., Results: Gait disturbances, myoclonus, and increased tone are the most frequently observed movement disorders in patients with prion diseases. The typical pattern of early motor dysfunction involves gait disturbance, limb ataxia, impaired smooth pursuit, myoclonus, tremor, and increased limb tone. Disturbances of gait, increased tone, and myoclonus become more prevalent and severe as the disease progresses. Chorea, alien limb phenomenon, and nystagmus were the least frequently observed movement disorders, with these symptoms showing spontaneous resolution in approximately half of symptomatic patients. Disease severity and PRNP codon 129 polymorphism were associated with different movement disorder phenotypes. Antiepileptics and benzodiazepines were found to be effective in treating myoclonus., Conclusions: We describe the prevalence, severity, evolution, treatment, and associated features of movement disorders in prion diseases based on a prospective cohort study. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Tumor mutational burden (TMB) is being explored as a predictive biomarker for cancer immunotherapy outcomes in non-small cell lung cancer. BFAST (NCT03178552)-an open-label, global, multicohort trial-evaluated the safety and efficacy of first-line targeted therapies or immunotherapy in patients with unresectable Stage IIIB or IV advanced or metastatic non-small cell lung cancer who were selected for biomarker status using blood-based targeted next-generation sequencing. In the Phase 3 cohort C evaluating blood-based (b)TMB as a biomarker of atezolizumab efficacy, patients with bTMB of ≥10 (N = 471) were randomized 1:1 to receive atezolizumab or platinum-based chemotherapy per local standard of care. Cohort C did not meet its primary endpoint of investigator-assessed progression-free survival in the population with bTMB of ≥16 (hazard ratio, 0.77; 95% confidence interval: 0.59, 1.00; P = 0.053). Adverse events leading to treatment withdrawal occurred in 10% of patients in the atezolizumab arm and 20% in the chemotherapy arm. Adverse events of special interest occurred in 42% of patients in the atezolizumab arm and 26% in the chemotherapy arm. A prespecified exploratory analysis compared the bTMB clinical trial assay with the FoundationOne Liquid Companion Diagnostic assay and showed high concordance between assays. Additional exploration of bTMB to identify optimal cutoffs, confounding factors, assay improvements or cooperative biomarkers is warranted., (© 2022. The Author(s).)

Background Current recommendations for delivery timing of pregnant persons with congenital heart disease (CHD) are based on expert opinion. Justification for early-term birth is based on the theoretical concern of increased cardiovascular stress. The objective was to evaluate whether early-term birth with maternal CHD is associated with lower adverse maternal or neonatal outcomes. Methods and Results This is a retrospective cohort study of pregnant persons with CHD who delivered a singleton after 37 0/7 weeks gestation at a quaternary care center with a multidisciplinary cardio-obstetrics care team between 2013 and 2021. Patients were categorized as early-term (37 0/7 to 38 6/7 weeks) or full-term (≥39 0/7) births and compared. Multivariable logistic regression was conducted to calculate the adjusted odds ratio for the primary outcomes. The primary outcomes were composite adverse cardiovascular, maternal obstetric, and adverse neonatal outcome. Of 110 pregnancies delivering at term, 55 delivered early-term and 55 delivered full-term. Development of adverse cardiovascular and maternal obstetric outcome was not significantly different by delivery timing. The rate of composite adverse neonatal outcomes was significantly higher in early-term births (36% versus 5%, P <0.01). After adjusting for confounding variables, early-term birth remained associated with a significantly increased risk of adverse neonatal outcomes (adjusted odds ratio 11.55 [95% CI, 2.59-51.58]). Conclusions Early-term birth for pregnancies with maternal CHD was associated with an increased risk of adverse neonatal outcomes, without an accompanying decreased rate in adverse cardiovascular or obstetric outcomes. In the absence of maternal or fetal indications for early birth, induction of labor before 39 weeks for pregnancies with maternal CHD should be reserved for routine obstetrical indications.

Sporadic Creutzfeldt-Jakob disease, the most common human prion disease, typically presents as a rapidly progressive dementia and has a highly variable prognosis. Despite this heterogeneity, clinicians need to give timely advice on likely prognosis and care needs. No prognostic models have been developed that predict survival or time to increased care status from the point of diagnosis. We aimed to develop clinically useful prognostic models with data from a large prospective observational cohort study. Five hundred and thirty-seven patients were visited by mobile teams of doctors and nurses from the National Health Service National Prion Clinic within 5 days of notification of a suspected diagnosis of sporadic Creutzfeldt-Jakob disease, enrolled to the study between October 2008 and March 2020, and followed up until November 2020. Prediction of survival over 10-, 30- and 100-day periods was the main outcome. Escalation of care status over the same time periods was a secondary outcome for a subsample of 113 patients with low care status at initial assessment. Two hundred and eighty (52.1%) patients were female and the median age was 67.2 (interquartile range 10.5) years. Median survival from initial assessment was 24 days (range 0-1633); 414 patients died within 100 days (77%). Ten variables were included in the final prediction models: sex; days since symptom onset; baseline care status; PRNP codon 129 genotype; Medical Research Council Prion Disease Rating Scale, Motor and Cognitive Examination Scales; count of MRI abnormalities; Mini-Mental State Examination score and categorical disease phenotype. The strongest predictor was PRNP codon 129 genotype (odds ratio 6.65 for methionine homozygous compared with methionine-valine heterozygous; 95% confidence interval 3.02-14.68 for 30-day mortality). Of 113 patients with lower care status at initial assessment, 88 (78%) had escalated care status within 100 days, with a median of 35 days. Area under the curve for models predicting outcomes within 10, 30 and 100 days was 0.94, 0.92 and 0.91 for survival, and 0.87, 0.87 and 0.95 for care status escalation, respectively. Models without PRNP codon 129 genotype, which is not immediately available at initial assessment, were also highly accurate. We have developed a model that can accurately predict survival and care status escalation in sporadic Creutzfeldt-Jakob disease patients using clinical, imaging and genetic data routinely available in a specialist national referral service. The utility and generalizability of these models to other settings could be prospectively evaluated when recruiting to clinical trials and providing clinical care., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Tyrosine kinase inhibitors (TKIs) are the standard of care for patients with non-small cell lung cancer (NSCLC) that harbor mutations of the epidermal growth factor receptor (EGFR) gene. First-line therapy for these patients is often osimertinib, a third-generation EGFR TKI. Erlotinib, gefitinib, afatinib, and dacomitinib are first- and second-generation TKIs that are also available. However, almost all patients eventually develop disease progression due to TKI-acquired resistance. The mechanisms of resistance after TKI exposure often involve EGFR or its downstream pathways. While a frequently utilized strategy for combating acquired resistance to EGFR TKIs remains standard platinum-based chemotherapy, clinical investigation of promising novel agents targeting common resistance mechanisms such as MET, HER2, and HER3 is of increased interest. In this review, we discuss the mechanisms of resistance to TKIs in EGFR-mutant NSCLC, examine current treatment standards, and discuss novel developing therapies. Both EGFR-dependent (involving secondary mutations in EGFR) and EGFR-independent (mutations that bypass EGFR signaling and histologic transformation) resistance mechanisms are considered. Several novel treatment strategies are emerging to overcome these resistance mechanisms, as the understanding and identification of specific EGFR-TKI resistance mechanisms continues to improve. The treatments in development aim to target or bypass the mechanisms of resistance, including MET-, HER2-, and HER3-directed therapies. In patients with acquired TKI resistance, molecular profiling at the time of initial progression may help identify relevant mechanisms of resistance. Clinical trial participation is vital to continued investigation for EGFR-mutant NSCLC., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Stage I non-small cell lung cancer (NSCLC) presents diverse outcomes. To identify molecular features leading to tumor recurrence in early-stage NSCLC, we perform multiregional whole-exome sequencing (WES), RNA sequencing, and plasma-targeted circulating tumor DNA (ctDNA) detection analysis between recurrent and recurrent-free stage I NSCLC patients (CHN-P cohort) who had undergone R0 resection with a median 5-year follow-up time. Integrated analysis indicates that the multidimensional clinical and genomic model can stratify the prognosis of stage I NSCLC in both CHN-P and EUR-T cohorts and correlates with positive pre-surgical deep next generation sequencing (NGS) ctDNA detection. Increased genomic instability related to DNA interstrand crosslinks and double-strand break repair processes is significantly associated with early tumor relapse. This study reveals important molecular insights into stage I NSCLC and may inform clinical postoperative treatment and follow-up strategies., Competing Interests: Declaration of interests M.J.-H. is a Cancer Research UK Fellow and has received funding from CRUK, National Institute for Health Research, Rosetrees Trust, UKI NETs, and NIHR University College London Hospitals Biomedical Research Center. M.J.-H. is a member of the Scientific Advisory Board and Steering Committee for Achilles Therapeutics. A.Y., K.L., R.W., J.B., L.W., H.L., Y.S., and S.W. are employees of Berry Oncology Corporation., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: We retrospectively assessed prognostic value of circulating cell-free DNA (cfDNA) using data from the phase III ALEX study in treatment-naïve, advanced ALK+ non-small cell lung cancer (NSCLC)., Patients and Methods: Patients were randomized to receive twice-daily alectinib 600 mg (n = 152) or crizotinib 250 mg (n = 151). cfDNA was quantified from baseline plasma samples, with patients stratified into ≤median and >median cfDNA biomarker-evaluable populations (BEP). Effect of cfDNA concentration on outcomes was analyzed using a Cox regression model with treatment group as covariate, and in multivariate analyses., Results: Median cfDNA concentration in the BEP was 11.53 ng/mL (n = 276). A positive correlation was found between cfDNA concentration and number of lesions, organ lesion sites, and tumor size (sum of longest diameter; all P < 0.0001). In both treatment arms, patients in the >median BEP were more likely to experience disease progression than the ≤median BEP [alectinib adjusted HR = 2.04; 95% confidence interval (CI), 1.07-3.89; P = 0.0305 and crizotinib adjusted HR = 1.83; 95% CI, 1.11-3.00, P = 0.0169]. Median progression-free survival was longer with alectinib than crizotinib in both ≤median and >median BEPs (P < 0.0001). Overall survival data remain immature; survival probability was lower in the >median versus ≤median BEP in both treatment arms (alectinib HR = 2.52; 95% CI, 1.08-5.88; P = 0.0333 and crizotinib HR = 2.63; 95% CI, 1.27-5.47; P = 0.0096)., Conclusions: These data suggest that plasma cfDNA concentration may have prognostic value in advanced ALK+ NSCLC. Prospectively designed studies are warranted to investigate this finding., (©2022 The Authors; Published by the American Association for Cancer Research.)

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.)