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Background: Tobacco use (smoking) causes adverse clinical outcomes among patients with cancer, including increased cancer-related mortality. In participants in cancer clinical trials, the prevalence of tobacco use and the factors associated with tobacco use are not well described., Methods: Data were examined from participants enrolled in SWOG cancer clinical treatment trials between 2016 and 2022 who reported their smoking status at trial enrollment. Baseline variables (smoking status, insurance type, zip code, and demographic factors) were obtained from patient registration forms. Bivariate and multivariable associations were examined via logistic regression., Results: Among 4326 patients enrolled in 29 trials, 48.1% reported currently/previously smoking, including 12.4% currently, 4.9% recently, and 30.7% formerly. Ever smoking was more commonly reported in males, patients aged ≥65 years, patients with Medicaid or no insurance, patients from areas of high socioeconomic deprivation, and rural patients. Patients of Hispanic ethnicity and Asian and Pacific Islander patients were less likely to have ever smoked. In multivariable regression, patients with lung cancer were most likely to report ever smoking compared to patients with breast cancer (odds ratio, 4.98; p < .001)., Conclusions: In the first comprehensive evaluation of smoking status among trial participants enrolled in National Cancer Institute network group treatment trials, nearly half reported ever smoking and one in six reported current or recent smoking. Smoking was more common among vulnerable population patients defined by demographic and socioeconomic factors. Tobacco use should be routinely assessed and reported in clinical trials to help reduce the negative cancer and overall health effects of persistent tobacco use and to address disparities among patients with cancer., (© 2024 American Cancer Society.)

Purpose: Leptomeningeal disease (LMD) is associated with significant morbidity and mortality for metastatic non-small cell lung cancer (NSCLC). We describe our clinical experience in evaluating the use of cerebrospinal fluid (CSF)-derived circulating tumor cells (CTCs) for the diagnosis of LMD and the detection of genomic alterations in CSF cell-free DNA (cfDNA)., Methods: Patients with NSCLC who had CSF collection as part of routine clinical care for suspected LMD were included in the study. CSF was evaluated for CTCs and cfDNA using a commercial assay (CNSide; Biocept, San Diego, CA), and molecular profiling was performed. Molecular testing results from sequencing of tumor tissue and plasma circulating tumor DNA were collected. cMET and human epidermal growth factor receptor 2 (HER2) expression analysis was performed using fluorescence in situ hybridization (FISH)., Results: Twenty-two patients were included (77% female; median age 60 years). Sixty-four percent had sensitizing EGFR mutations, and 32% had an atypical EGFR mutation. Thirteen of the 22 patients (59%) were diagnosed with LMD using the CSF CTC assay. Five of these 13 patients (38%) had negative CSF cytology for LMD, and two patients (15%) had normal magnetic resonance imaging brain imaging. Seven of the 13 patients (54%) had sufficient CTCs to perform molecular profiling. The concordance with tissue next-generation sequencing was 100%, and the driver mutation was identified in all seven patients with the CSF cfDNA assay. cMET expression and HER2 expression via FISH were noted in 11 patients (50%) and four patients (18%) respectively., Conclusion: We detected higher sensitivity to diagnose LMD using CSF CTC-based assay; 38% of LMD cases identified using this assay were missed by standard CSF cytology. CSF molecular testing using CSF cfDNA demonstrated high concordance with tissue-based molecular testing.

Background: According to WHO, lung cancer is the leading cause of cancer-related death worldwide, but treatment has advanced in the last decade. The widespread use of Next Generation Sequencing has led to the discovery of several pathogenic mutations including RNA binding motif 10 (RBM10), a part of the spliceosome complex that regulates splicing of pre-mRNA., Patients and Methods: Electronic medical records were utilized to create a database of patients (50 patients) seen from 2018-2023 with NSCLC and RBM10 mutations, with appropriate IRB approval. For subgroup analysis, we separated into groups by rapid progression vs stable disease defined as progression-free survival earlier than respective clinical trials., Results: From the analysis of treatment response the mutated RBM10 population had a median PFS was 6.7 months compared to 13.9 in the wild-type RBM10 population controlled for driver mutations TP53 mutation had a higher representation in the RBM10 mutated rapid progression group than the stable disease group. The ZFHX3 mutation had a higher representation in the RBM10 mutated stable disease group., Conclusions: RBM10 mutations were associated with aggressive disease with treatment progression faster than median durations of response. RBM10 mutations with concurrent ZFHX3 and EGFR mutations were associated with more stable disease, while concurrent KRAS and TP53 predicted even more aggressive disease., Competing Interests: Disclosure The authors have no conflicts to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: To bring cultivated beef to the market, a scalable system that can support growth of bovine satellite cells (bSCs) in a serum-free and preferably also animal-free medium is of utmost importance. The use of microcarriers (MCs) is, at the moment, one of the most promising technologies for scaling up. MCs offer a large surface to volume ratio, they can be used in scalable stirred tank bioreactors, where the culture conditions can be tightly controlled to meet the cells' requirements (temperature, pH, dissolved oxygen). The inherent capacity of the cells to migrate from one MC to another, also known as bead-to-bead transfer, facilitates a scale-up strategy involving MCs. Previous studies have shown growth of bSCs on three commercially available MCs in serum containing media. Unfortunately there is currently no information available regarding their growth on MCs in serum-free conditions., Methods: In this study, we aimed to find suitable serum-free media, MCs and attachment promoting compounds (APCs) supporting the growth of bSCs. Initially, six commercial MCs and three serum-free media were evaluated. The effects of three APCs were compared (vitronectin, laminin and fibronectin). Subsequently, the effects of different concentrations and modes of addition of the best performing APC were investigated., Results and Discussion: Our results showed that Cytodex 1, Synthemax II and CellBIND supported bSCs' growth in all serum-free media. Overall, better growth was observed with Cytodex 1 in serum-free proliferation media. We showed that the use of laminin or vitronectin with Cytodex 1 can significantly improve cell growth and purity. Laminin also allowed attachment and growth of bSCs on Plastic MCs which had been previously unsuccessful without APCs. Finally, we optimized the use of vitronectin from a sustainability and process perspective, and showed that it can be used solely as a coating for Cytodex 1 (16-100 ng/cm 2 ) MCs, instead of as a medium supplement, enhancing cell attachment and proliferation., Competing Interests: VB, AK, EM, TV, and MP are employed by Mosa Meat B.V., a company that aims to commercialize cultured meat. MP is co-founder and shareholder of Mosa Meat B.V. Mosa Meat B.V. has patents on serum-free growth medium (WO2021158103), and serum-free differentiation medium (WO2022114955). The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Bodiou, Kumar, Massarelli, van Haaften, Post and Moutsatsou.)

Background: This study characterized the impact of baseline symptom burden on long-term quality-of-life in patients receiving head and neck radiation therapy (RT)., Methods: The Vanderbilt Head and Neck Symptom Survey was collected prior to head and neck RT and at follow-up visits. Responses were divided into symptom clusters of toxicities and scored from 0 (asymptomatic) to 10 (severe). Patients with responses at baseline and 1-year or 2-year follow-up were stratified by scores ≤1 or >1 and compared using the Mann-Whitney U-test., Results: At 1-year follow-up (n = 75), patients with higher baseline scores had greater symptom burden for every cluster except in taste/smell. At 2-year follow-up (n = 47), patients with higher baseline scores had greater symptom burden for every cluster except in nutrition, dry mouth, trismus, neck tightness, and hearing., Conclusion: The Vanderbilt Head and Neck Symptom Survey demonstrated a relationship between baseline symptom burden and long-term quality-of-life and might be useful as a screening tool., (© 2024 The Author(s). Head & Neck published by Wiley Periodicals LLC.)

Lung cancer is the leading cause of cancer death in the US and globally. The mortality from lung cancer has been declining, due to a reduction in incidence and advances in treatment. Although recent success in developing targeted and immunotherapies for lung cancer has benefitted patients, it has also expanded the complexity of potential treatment options for health care providers. To aid in reducing such complexity, experts in oncology convened a conference (Bridging the Gaps in Lung Cancer) to identify current knowledge gaps and controversies in the diagnosis, treatment, and outcomes of various lung cancer scenarios, as described here. Such scenarios relate to biomarkers and testing in lung cancer, small cell lung cancer, EGFR mutations and targeted therapy in non-small cell lung cancer (NSCLC), early-stage NSCLC, KRAS/BRAF/MET and other genomic alterations in NSCLC, and immunotherapy in advanced NSCLC., (© The Author(s) 2024. Published by Oxford University Press.)

Lung cancer continues to contribute to the highest percentage of cancer-related deaths worldwide. Advancements in the treatment of non-small cell lung cancer like immune checkpoint inhibitors have dramatically improved survival and long-term disease response, even in curative and perioperative settings. Unfortunately, resistance develops either as an initial response to treatment or more commonly as a progression after the initial response. Several modalities have been utilized to combat this. This review will focus on the various combination treatments with immune checkpoint inhibitors including the addition of chemotherapy, various immunotherapies, radiation, antibody-drug conjugates, bispecific antibodies, neoantigen vaccines, and tumor-infiltrating lymphocytes. We discuss the status of these agents when used in combination with immune checkpoint inhibitors with an emphasis on lung cancer. The early toxicity signals, tolerability, and feasibility of implementation are also reviewed. We conclude with a discussion of the next steps in treatment.

Background: This investigator-initiated phase II trial aimed to evaluate the efficacy of cabozantinib in combination with nivolumab and ipilimumab (CaboNivoIpi) in previously treated patients with radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC) (NCT03914300)., Methods: Eligible patients with RAI-refractory DTC who progressed on 1 prior line of VEGFR-targeted therapy received a 2-week run-in of cabozantinib monotherapy followed by CaboNivoIpi for 4 cycles (cycle length = 6 weeks), followed by cabozantinib plus nivolumab (cycle length = 4 weeks) until disease progression. The primary endpoint was objective response rate (ORR) within the first 6 months of treatment. A Simon optimal 2-stage design allowed for an interim analysis after accrual of 10 evaluable patients. At least 5 responses were needed to proceed to stage 2., Results: Among 11 patients enrolled, the median age was 69 years. Prior VEGFR-targeted therapies included lenvatinib, pazopanib, and sorafenib plus everolimus. Median follow-up was 7.9 months. Among 10 evaluable patients, ORR within the first 6 months of treatment was 10% (1 partial response). Median progression-free survival was 9 months [95% CI: 3.0, not reached] and median overall survival was 19.2 months [(95% CI: 4.6, not reached]. Grade 3/4 treatment-related adverse events (AEs) were noted in 55% (6/11) and grade 5 AEs in 18% (2/11) of patients. The most common treatment-related AE was hypertension. The study did not reach its prespecified efficacy threshold., Conclusion: CaboNivoIpi had low ORRs and a high rate of grade ≥3 treatment-related AEs., Clinical Trial Registration: NCT03914300., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Background: The study summarizes the potential use of immunotherapy for BRAF- mutated papillary thyroid cancer (PTC) by analyzing the immune profile of City of Hope PTC patient samples and comparing them to the thyroid dataset available in the TCGA database., Materials and Methods: PTC cases with available formalin-fixed paraffin-embedded archived tumor tissue were identified. RNA was extracted from the tumor tissue and analyzed by NanoString to evaluate their immune gene expression profile. Immunohistochemistry was used to determine the expression of immune suppressive genes and lymphocytic infiltration into the tumor tissue. Thyroid cancer cell lines (MDA-T32, MDA-T68, MDA-T85, and MDA-T120) were used to determine the correlation between the BRAF inhibition and CD274 expression., Results: The study found that PTC cases with BRAF mutations had higher expression of immune checkpoint markers CD274 and CTLA4, as well as higher tumor-infiltrating lymphocytes, particularly CD4+T cells. Additionally, the study identified immunosuppressive markers expressed by tumor cells like CD73, CD276, and CD200 that could be targeted for immunotherapy. Further experiments using PTC cell lines lead to the conclusion that CD274 expression correlates with BRAF activity and that inhibitors of BRAF could potentially be used in combination with immunotherapy to treat PTC., Conclusions: These findings suggest that PTC cases with BRAF mutations or high expression may be correlated with an immune hot signature and could benefit from immunotherapeutic strategies., Competing Interests: Competing interests: No, there are no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We conducted spatial immune tumor microenvironment (iTME) profiling using formalin-fixed paraffin-embedded (FFPE) samples of 25 KRAS-mutated non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs), including 12 responders and 13 non-responders. An eleven-marker panel (CD3, CD4, CD8, FOXP3, CD68, arginase-1, CD33, HLA-DR, pan-keratin (PanCK), PD-1, and PD-L1) was used to study the tumor and immune cell compositions. Spatial features at single cell level with cellular neighborhoods and fractal analysis were determined. Spatial features and different subgroups of CD68 + cells and FOXP3 + cells being associated with response or resistance to ICIs were also identified. In particular, CD68 + cells, CD33 + and FOXP3 + cells were found to be associated with resistance. Interestingly, there was also significant association between non-nuclear expression of FOXP3 being resistant to ICIs. We identified CD68 dim cells in the lung cancer tissues being associated with improved responses, which should be insightful for future studies of tumor immunity., (© 2024. The Author(s).)

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for the treatment of patients with NSCLC, including diagnosis, primary disease management, surveillance for relapse, and subsequent treatment. The panel has updated the list of recommended targeted therapies based on recent FDA approvals and clinical data. This selection from the NCCN Guidelines for NSCLC focuses on treatment recommendations for advanced or metastatic NSCLC with actionable molecular biomarkers.

Introduction: Activating RET alterations have been reported in a variety of solid tumors, including pheochromocytoma where they occur both sporadically and as part of familial multiple endocrine neoplasia type 2 (MEN2) syndromes. Selpercatinib is a first-in-class, highly selective, and potent small molecule RET kinase inhibitor that has demonstrated marked and durable anti-tumor activity in diverse RET-activated solid tumors in the LIBRETTO-001 study (NCT03157128)., Methods: We describe the first six pheochromocytoma cases treated with selpercatinib in the LIBRETTO-001 study., Results: Of the six patients (one sporadic and five reported as part of MEN2 syndromes) in this case report, four had a partial response/complete response and two had stable disease per independent review committee. Treatment duration ranged from 9.2 months to more than 56.4 months. The safety profile of treatment was consistent with selpercatinib in other indications., Conclusion: These data support selpercatinib as an effective therapy against RET-mutant pheochromocytoma, adding to the diversity of RET-activated tumor types that may benefit from targeted RET inhibition., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Introduction: We evaluated efficacy and safety of cabozantinib plus atezolizumab or cabozantinib alone in advanced NSCLC previously treated with an immune checkpoint inhibitor (ICI)., Methods: COSMIC-021 (NCT03170960) is a phase 1b, multicenter study in advanced solid tumors. This analysis included patients with stage IV non-squamous NSCLC without actionable genomic aberrations in EGFR, ALK, ROS1 , or BRAF - V600E who progressed on one prior ICI and less than or equal to two prior lines of systemic anticancer therapy. Patients received cabozantinib 40 mg orally/day plus atezolizumab 1200 mg intravenously every three weeks (combination cohort) or cabozantinib 60 mg orally/day (single-agent cabozantinib cohort). Primary end point of the combination cohort was objective response rate per Response Evaluation Criteria in Solid Tumors v1.1 by investigator. Outcomes in the single-agent cabozantinib cohort were exploratory., Results: Eighty-one patients assigned to combination therapy and 31 assigned to single-agent cabozantinib received greater than or equal to one dose of study treatment. Median (range) follow-up was 26.1 months (12.1-44.2) and 22.4 months (1.5-29.0), respectively. Objective response rate was 20% (95% confidence interval: 11.7%-30.1%) in combination cohort and 6% (95% confidence interval: 0.8%-21.4%) in single-agent cabozantinib cohort. Treatment-related adverse events (TRAEs) occurred in 86% of patients in the combination cohort and 90% in the single-agent cabozantinib cohort; grade 3/4 TRAEs were 44% and 48%, respectively. There were two grade 5 TRAEs: pneumonitis (n = 1, combination) and gastric ulcer hemorrhage (n = 1, single-agent). Neither PD-L1 expression in tumor cells nor tumor mutation burden correlated with outcomes., Conclusions: Cabozantinib plus atezolizumab demonstrated modest clinical activity and manageable toxicity in advanced NSCLC after progression on prior ICI., Competing Interests: Dr. Neal reported receiving honoraria from Biomedical Learning Institute CME, Clinical Care Options, CME Matter, Medscape CME, MJH Life Sciences CME, MLI Peerview CME, Prime Oncology CME, Projects in Knowledge CME, Research to Practice CME, Rockpointe CME, Medical Educator Consortium, HMP Education, a consulting or advisory role with AstraZeneca, Blueprint Pharmaceuticals, Calithera Biosciences, D2G Oncology, Exelixis, Genentech, Roche, Jounce Therapeutics, Eli Lilly and Company, Natera, Regeneron, Sanofi, Surface Oncology, Takeda Pharmaceuticals, Turning Point Therapeutics, and receiving institutional research funding from 10.13039/100006483AbbVie, Adaptimmune, Boehringer Ingelheim, 10.13039/100010544Exelixis, 10.13039/100004328Genentech, 10.13039/100004337Roche, GSK, 10.13039/100005565Janssen, 10.13039/100004334Merck, Nektar Therapeutics, 10.13039/100004336Novartis, Takeda Pharmaceuticals. Dr. Armando Santoro reported having a consulting or advisory role with Sanofi, Incyte, receiving honoraria from AbbVie, Amgen, ArQule, AstraZeneca, Bayer, BMS, Celgene, Eisai, Gilead Sciences, Lilly, MSD, Novartis, Pfizer, Roche, Sandoz, Servier, Takeda, and participating in a data safety or advisory board with BMS, Servier, Gilead, Pfizer, Eisai, Bayer, MSD. Dr. Maria Gonzalez-Cao reported receiving grants or contracts from Roche, AstraZeneca, and Novartis, honoraria from Bristol Myers Squibb, MSD, AstraZeneca, Novartis, and Pierre Fabre, support for travel, accommodations, and expenses from MSD, AstraZeneca, and Pierre Fabre, and having a leadership or fiduciary role with the Spanish Melanoma Group. Dr. Ryan D. Gentzler reported receiving honoraria from Targeted Oncology, OncLive, Clinical Care Options, Society for Immunotherapy of Cancer, American Society of Clinical Oncology, MedStar Health, Aptitude Health, support for attending meetings from International Association for the Study of Lung Cancer, American Society of Clinical Oncology, Dava Oncology, Tempus, having a consulting or advisory role with AstraZeneca, Daiichi Sankyo, Gilead, Janssen, Jazz Pharmaceuticals, Mirati Therapeutics, OncoCyte, Sanofi, Takeda, Merus, Regeneron, receiving institutional research funding from 10.13039/100002429Amgen, Alliance Foundation, 10.13039/100004325AstraZeneca, Big Ten Research Consortium, 10.13039/100002491Bristol Myers Squibb, 10.13039/100010795Chugai, 10.13039/501100022274Daiichi Sankyo, 10.13039/100008130Helsinn Therapeutics, Hoosier Cancer Research Network, 10.13039/100005565Janssen, 10.13039/100016765Jounce Therapeutics, Merck, 10.13039/100016957Mirati Therapeutics, 10.13039/100004319Pfizer, 10.13039/100008199RTI International, Takeda, Dizal, Puma, and having leadership or committee roles with Hoosier Cancer Research Network, ASCO, Journal of Clinical Oncology, NCI Investigational Drug Steering Committee, and International Association for the Study of Lung Cancer. Dr. Jerome Goldschmidt reported receiving honoraria from G1 Therapeutics, and support for travel, accommodations, and expenses from Sara Cannon Research Institute. Dr. Claudia Proto reports receiving honoraria from AstraZeneca, Bristol Myers Squibb, MSD, Roche, Sanofi, having a consulting or advisory role with AstraZeneca, MSD and Roche, institutional research funding from MSD, Lilly, Pfizer, support for travel, accommodations, expenses from AstraZeneca, MSD, and Roche, and is the principal investigator in clinical trials for Janssen, Pfizer, Lilly, Spectrum Pharmaceuticals, Roche, MSD, BMS, and AstraZeneca. Dr. Shiven Patel reported receiving a consulting or advisory role with AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Regeneron, Sanofi, TerSera Therapeutics LLC, Total Health Conferencing, Natera, Takeda, Merck, BMS, and receiving institutional research funding from AstraZeneca, Janssen, Merck, and Takeda. Dr. Sonam Puri reported having an institutional consulting or advisory role with Jazz Pharma, receiving consulting fees from G1 Therapeutics, Pfizer, Bristol-Myers Squibb, receiving honoraria from Aptitude Health, and support for travel, accommodations, and expenses from Dava Oncology. Dr. Stephen V. Liu reported having a consulting or advisory role with AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Catalyst, Daiichi Sankyo, Eisai, Elevation Oncology, Genentech, Roche, Gilead Sciences, Guardant Health, Janssen Oncology, Jazz Pharmaceuticals, Merck, Merus, Mirati, Novartis, Regeneron, Sanofi, Takeda, and Turning Point Therapeutics, receiving institutional research funding from AbbVie, 10.13039/100018529Alkermes, Elevation Oncology, Ellipses, Genentech, Roche, 10.13039/100005564Gilead Sciences, Merck, Merus, Nuvalent, Inc., RAPT Therapeutics, and Turning Point Therapeutics, and participation in a data safety monitoring board or advisory board with Candel Therapeutics. Dr. Erminia Massarelli reported receiving honoraria from AstraZeneca, Merck, Eli Lilly and Company, Takeda Pharmaceuticals, Mirati, and having a consulting or advisory role with Bristol Myers Squibb, Daiichi Sankyo Co., Fusion Therapeutics, Janssen, Eli Lilly and Company, Sanofi, AbbVie, Iovance Therapeutics, and Mirati. Ms. Denise Williamson, Drs. Martin Schwickart, Christian Scheffold, and Svetlana Adrianova are employees of and reported having stock with Exelixis. In addition, Dr. Christian Scheffold reported a patent: Combinations of Cabozantinib and Atezolizumab to Treat Cancer; patent number 11198731. Dr. Enriqueta Felip reported having a consulting or advisory role with AbbVie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Gilead, GlaxoSmithKline, Janssen, Merck Serono, MSD, Novartis, Peptomyc, Pfizer, Regeneron, Sanofi, Takeda, Turning Point, Daiichi Sankyo, honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, F. Hoffmann-La Roche, Genentech, Janssen, Medical Trends, Medscape, Merck Serono, MSD, Peervoice, Pfizer, Sanofi, Takeda, Touch Oncology, and receiving support for travel, accommodations, and expenses from AstraZeneca, Janssen, Roche. The remaining authors declare no conflict of interest., (© 2024 The Authors.)

Mesothelioma is a rare cancer that originates from the mesothelial surfaces of the pleura and other sites, and is estimated to occur in approximately 3,500 people in the United States annually. Pleural mesothelioma is the most common type and represents approximately 85% of these cases. The NCCN Guidelines for Mesothelioma: Pleural provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with pleural mesothelioma. These NCCN Guidelines Insights highlight significant updates to the NCCN Guidelines for Mesothelioma: Pleural, including revised guidance on disease classification and systemic therapy options.

Objectives: NTRK fusions result in constitutively active oncogenic TRK proteins responsible for ∼ 0.2 % of non-small cell lung cancer (NSCLC) cases. Approximately 40 % of patients with advanced NSCLC develop CNS metastases; therefore, treatments with intracranial (IC) efficacy are needed. In an integrated analysis of three phase I/II studies (ALKA-372-001: EudraCT 2012-000148-88; STARTRK-1: NCT02097810; STARTRK-2: NCT02568267), entrectinib, a potent, CNS-active, TRK inhibitor, demonstrated efficacy in patients with NTRK fusion-positive (fp) NSCLC (objective response rate [ORR]: 64.5 %; 2 August 2021 data cut-off). We present updated data for this cohort., Materials and Methods: Eligible patients were ≥ 18 years with locally advanced/metastatic, NTRK-fp NSCLC with ≥ 12 months of follow-up. Tumor responses were assessed by blinded independent central review (BICR) per RECIST v1.1 at Week 4 and every eight weeks thereafter. Co-primary endpoints: ORR; duration of response (DoR). Secondary endpoints included progression-free survival (PFS); overall survival (OS); IC efficacy; safety. Enrolment cut-off: 2 July 2021; data cut-off: 2 August 2022., Results: The efficacy-evaluable population included 51 patients with NTRK-fp NSCLC. Median age was 60.0 years (range 22-88); 20 patients (39.2 %) had investigator-assessed baseline CNS metastases. Median survival follow-up was 26.3 months (95 % CI 21.0-34.1). ORR was 62.7 % (95 % CI 48.1-75.9), with six complete and 26 partial responses. Median DoR and PFS were 27.3 months (95 % CI 19.9-30.9) and 28.0 months (95 % CI 15.7-30.4), respectively. Median OS was 41.5 months. In patients with BICR-assessed baseline CNS metastases, IC-ORR was 64.3 % (n = 9/14; 95 % CI 35.1-87.2), including seven complete responders, and IC-DoR was 55.7 months. In the safety-evaluable population (n = 55), most treatment-related adverse events were grade 1/2; no treatment-related deaths were reported., Conclusion: Entrectinib has continued to demonstrate deep and durable systemic and IC responses in patients with NTRK-fp NSCLC., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Byoung Chul Cho: Received research funding from MOGAM, LG Chem, Oscotec, Interpark Bio Convergence Corp, GI Innovation, GI Cell, Abion, AbbVie, AstraZeneca, Bayer, Blueprint Medicines, Boehringer-Ingelheim, Champions Oncology, CJ Bioscience, CJ Blossom Park, Cyrus, Dizal Pharma, Genexine, Janssen, Eli Lilly, MSD, Novartis, Nuvalent, Oncternal Therapeutics, Ono Pharmaceutical, Dong-A ST, Bridge Biotherapeutics, Yuhan, ImmuneOncia, Illumina, Kanaph Therapeutics, Therapex, J INTS Bio, Hanmi Pharm, and CHA Bundang Medical Center. Royalties from Champions Oncology, Crown Bioscience, and Imagen. Consulting role for Abion, BeiGene, Novartis, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, CJ, Celogen, Cyrus, Ono Pharmaceutical, Onegene Biotechnology, Yuhan, Pfizer, Eli Lilly, GI Cell, Guardant Health, HK inno.N, Imnewrun, Janssen, Takeda, MSD, Medpacto, Blueprint Medicines, RandBio, and Hanmi Pharm. Invited speaker for ASCO, AstraZeneca, Guardant Health, F. Hoffmann-La Roche Ltd, ESMO, IASLC, Korean Cancer Association, Korean Society of Medical Oncology, Korean Society of Thyroid-Head and Neck Surgery, Korean Cancer Study Group, Novartis, MSD, The Chinese Thoracic Oncology Society, and Pfizer. Advisory role for Kanaph Therapeutics, Bridge Biotherapeutics, Cyrus, Guardant Health, and Oscotec. Member of the board of directors for Interpark Bio Convergence Corp and J INTS Bio. Stock ownership for TheraCanVac, Gencurix, Bridge Biotherapeutics, Kanaph Therapeutics, Cyrus, Interpark Bio Convergence Corp, and J INTS Bio. Employment with Yonsei University Health System. Founder of DAAN Biotherapeutics. Chao-Hua Chiu: Received honoraria from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Janssen, Merck KGaA, MSD, Novartis, Ono Pharmaceutical, Pfizer, F. Hoffmann-La Roche Ltd, and Takeda. Erminia Massarelli: Advisory board for Janssen, Eli Lilly, Bristol Myers Squibb, Sanofi, and Merck. Speaker’s bureau for Eli Lilly, Merck, and AstraZeneca. Gary L. Buchschacher Jr: Institutional research support from F. Hoffmann-La Roche Ltd/Genentech. Koichi Goto: Received research grants from Amgen, Astellas, AstraZeneca, Bayer Yakuhin Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Craif, Daiichi Sankyo, Eisai, Eli Lilly, Haihe Biopharma, Ignyta, Janssen Pharmaceutical, Kissei Pharmaceutical, Kyowa Kirin, Life Technologies, Loxo Oncology, LSI Medience Corporation, Medical & Biological Laboratories, Merck, Merus, MSD, Novartis, Ono Pharmaceutical Co, Pfizer, Precision Medicine, Riken Genesis Co, Sumitomo Pharma, Spectrum Pharmaceuticals, Sysmex Corporation, Taiho Pharmaceutical, Takeda, Xcoo, and Turning Point Therapeutics. Invited speaker for Amgen, Amoy Diagnostics, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Bayer Yakuhin, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Eli Lilly, Guardant Health, Janssen, Novartis, Ono Pharmaceutical, Otsuka Pharmaceutical, Riken Genesis Co, Taiho Pharmaceutical, and Takeda. Advisory board for Amgen, Daiichi Sankyo, Eli Lilly, Haihe Biopharma, Janssen, and Syneos Health. Tobias R. Overbeck: Received payment or honoraria for lectures/presentations, speakers bureau, manuscript writing, or educational events from AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Roche Pharma, Merck Sharp and Dohme, Novartis, and Takeda Oncology; support for attending meetings and/or travel from AstraZeneca and Janssen-Cilag; participation on Data Safety Monitoring Board or Advisory Board for AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Roche Pharma, Merck Sharp and Dohme, Novartis, and Takeda Oncology. Herbert H.F. Loong: Received research grants from MSD, Mundipharma, and Novartis. Invited speaker for AbbVie, Bayer, Eisai, Eli Lilly, Guardant Health, and Novartis. Travel support from Bayer and Boehringer Ingelheim. Advisory role for Boehringer Ingelheim, Celgene, Eli Lilly, Illumina, Novartis, Merck, EMD Serono, Takeda, and George Clinical. Member, Pharmacy and Poisons (Registration of Pharmaceutical products and substances: Certification of clinical trial/medicinal test) Committee, Pharmacy & Poisons Board of Hong Kong. Cheng E. Chee: Received honoraria fees from AstraZeneca and has participated on a Data Safety Monitoring Board or Advisory Board for Guardant Health AMEA, Merck, and Roche/Genentech. Pilar Garrido: Invited speaker for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, MSD, Medscape, Novartis, Pfizer, F. Hoffmann-La Roche Ltd, Takeda, and TouchIME. Advisory role for AbbVie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, GSK, Janssen, Eli Lilly, MSD, Novartis, Pfizer, F. Hoffmann-La Roche Ltd, and Takeda. Xiaorong Dong: no disclosures. Yun Fan: no disclosures. Shun Lu: Research grants from AstraZeneca, Hutchinson, Bristol Myers Squibb, Hengrui Medicine, BeiGene, F. Hoffmann-La Roche Ltd, and Hansoh Pharmaceutical. Speaker fees from AstraZeneca, F. Hoffmann-La Roche Ltd, and Hansoh Pharmaceutical. Advisory and consulting fees from AstraZeneca, Pfizer, Hutchinson, Zai Lab, GenomiCare, Novartis, Yuhan, Menarini, Mirati Therapeutics, Inc, Daiichi Sankyo, D3 Bio, Simcere, Takeda, and F. Hoffmann-La Roche Ltd. Sven Schwemmers: Full-time/part-time employment with F. Hoffmann-La Roche Ltd. Owns stocks/share with F. Hoffmann-La Roche Ltd. Walter Bordogna: Full-time/part-time employment with F. Hoffmann-La Roche Ltd. Owns stocks/share with F. Hoffmann-La Roche Ltd. Harald Zeuner: Full-time/part-time employment with F. Hoffmann-La Roche Ltd. Stuart Osborne: Full-time/part-time employment with F. Hoffmann-La Roche Ltd. Owns stocks/share with F. Hoffmann-La Roche Ltd. Thomas John: Invited speaker for F. Hoffmann-La Roche Ltd and AstraZeneca. Advisory role for Bristol Myers Squibb, AstraZeneca, Amgen, F. Hoffmann-La Roche Ltd, Pfizer, Takeda, Boehringer Ingelheim, MSD, Merck, Puma, Specialised Therapeutics, Gilead, and Seagen., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

KRAS G12C mutation is prevalent in ~4% of colorectal cancer (CRC) and is associated with poor prognosis. Divarasib, a KRAS G12C inhibitor, has shown modest activity as a single agent in KRAS G12C-positive CRC at 400 mg. Epidermal growth factor receptor has been recognized as a major upstream activator of RAS-MAPK signaling, a proposed key mechanism of resistance to KRAS G12C inhibition in CRC. Here, we report on divarasib plus cetuximab (epidermal growth factor receptor inhibitor) in patients with KRAS G12C-positive CRC (n = 29) from arm C of an ongoing phase 1b trial. The primary objective was to evaluate safety. Secondary objectives included preliminary antitumor activity. The safety profile of this combination was consistent with those of single-agent divarasib and cetuximab. Treatment-related adverse events led to divarasib dose reductions in four patients (13.8%); there were no treatment withdrawals. The objective response rate was 62.5% (95% confidence interval: 40.6%, 81.2%) in KRAS G12C inhibitor-naive patients (n = 24). The median duration of response was 6.9 months. The median progression-free survival was 8.1 months (95% confidence interval: 5.5, 12.3). As an exploratory objective, we observed a decline in KRAS G12C variant allele frequency associated with response and identified acquired genomic alterations at disease progression that may be associated with resistance. The manageable safety profile and encouraging antitumor activity of divarasib plus cetuximab support the further investigation of this combination in KRAS G12C-positive CRC.ClinicalTrials.gov identifier: NCT04449874., (© 2023. Crown.)

Purpose: Patritumab deruxtecan, or HER3-DXd, is an antibody-drug conjugate consisting of a fully human monoclonal antibody to human epidermal growth factor receptor 3 (HER3) attached to a topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. We assessed the efficacy and safety of HER3-DXd in patients with epidermal growth factor receptor ( EGFR )-mutated non-small-cell lung cancer (NSCLC)., Methods: This phase II study (ClinicalTrials.gov identifier: NCT04619004) was designed to evaluate HER3-DXd in patients with advanced EGFR- mutated NSCLC previously treated with EGFR tyrosine kinase inhibitor (TKI) therapy and platinum-based chemotherapy (PBC). Patients received HER3-DXd 5.6 mg/kg intravenously once every 3 weeks or an uptitration regimen (3.2 → 4.8 → 6.4 mg/kg). The primary end point was confirmed objective response rate (ORR; RECIST 1.1) by blinded independent central review (BICR), with a null hypothesis of 26.4% on the basis of historical data., Results: Enrollment into the uptitration arm closed early on the basis of a prespecified benefit-risk assessment of data from the phase I U31402-A-U102 trial. In total, 225 patients received HER3-DXd 5.6 mg/kg once every 3 weeks. As of May 18, 2023, median study duration was 18.9 (range, 14.9-27.5) months. Confirmed ORR by BICR was 29.8% (95% CI, 23.9 to 36.2); median duration of response, 6.4 months; median progression-free survival, 5.5 months; and median overall survival, 11.9 months. The subgroup of patients with previous osimertinib and PBC had similar outcomes. Efficacy was observed across a broad range of pretreatment tumor HER3 membrane expression levels and across diverse mechanisms of EGFR TKI resistance. In patients with nonirradiated brain metastases at baseline (n = 30), the confirmed CNS ORR by BICR per CNS RECIST was 33.3% (95% CI, 17.3 to 52.8). The safety profile (National Cancer Institute Common Terminology Criteria for Adverse Events v5.0) was manageable and tolerable, consistent with previous observations., Conclusion: After tumor progression with EGFR TKI therapy and PBC in patients with EGFR -mutated NSCLC, HER3-DXd once every 3 weeks demonstrated clinically meaningful efficacy with durable responses, including in CNS metastases. A phase III trial in EGFR- mutated NSCLC after progression on an EGFR TKI is ongoing (HERTHENA-Lung02; ClinicalTrials.gov identifier: NCT05338970).

Background and Purpose: The role of stereotactic body radiation therapy (SBRT) in oligoprogressive non-small-cell lung cancer (NSCLC) is controversial. We evaluated whether SBRT in a subset of patients with oligoprogressive or oligorecurrent NSCLC offers a durable response, obviating the need to change systemic therapy., Methods: A retrospective analysis of 168 NSCLC patients who underwent SBRT for oligoprogressive or oligorecurrent disease was performed. Oligoprogression was defined as progression in ≤5 lesions during or after systemic therapy following an initial complete or partial response. Oligorecurrence was defined as progression while off systemic therapy. Progression-free survival (PFS), overall survival (OS) and time to next treatment or death (TNT-D) were estimated., Results: Median age was 68 years. Sixty-seven percent of patients were on systemic therapy at the time of progression. Progression at the primary site was present in 31% of the patients. The number of sites of metastatic progression was 0 to 2 in 76% and 3 to 5 in 24% of the patients. Two-year OS and PFS were 56% (95%CI 46%-64%) and 14% (95%CI 8%-21%), respectively. Median TNT-D was 9 months (95%CI 6-11). No grade 4 or 5 toxicity was seen. In multivariable analysis, patients with 3 to 5 sites of metastatic progression had worse OS (HR 2.6, 95%CI 1.5-4.3, P < .001) and shorter TNT-D (HR 1.7, 95%CI 1.1-2.5, P = .01) than those with 0 to 2 sites., Conclusion: SBRT is a safe and viable treatment option for oligoprogressive and oligorecurrent NSCLC. Patients with 0 to 2 sites had better OS and longer TNT-D compared to those with 3 to 5 lesions., Competing Interests: Disclosure The authors have no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Inherent or acquired resistance to sotorasib poses a substantialt challenge for NSCLC treatment. Here, we demonstrate that acquired resistance to sotorasib in isogenic cells correlated with increased expression of integrin β4 (ITGB4), a component of the focal adhesion complex. Silencing ITGB4 in tolerant cells improved sotorasib sensitivity, while overexpressing ITGB4 enhanced tolerance to sotorasib by supporting AKT-mTOR bypass signaling. Chronic treatment with sotorasib induced WNT expression and activated the WNT/β-catenin signaling pathway. Thus, silencing both ITGB4 and β-catenin significantly improved sotorasib sensitivity in tolerant, acquired, and inherently resistant cells. In addition, the proteasome inhibitor carfilzomib (CFZ) exhibited synergism with sotorasib by down-regulating ITGB4 and β-catenin expression. Furthermore, adagrasib phenocopies the combination effect of sotorasib and CFZ by suppressing KRAS activity and inhibiting cell cycle progression in inherently resistant cells. Overall, our findings unveil previously unrecognized nongenetic mechanisms underlying resistance to sotorasib and propose a promising treatment strategy to overcome resistance.

We have developed and validated a novel LC-MS/MS method for the simultaneous quantification of LB-100 and its active metabolite, endothall, in human plasma following solid-phase extraction. LB-105 and endothall-D6 were used as internal standards. Chromatographic separation was achieved on a Hypercarb™ column using 5 mM (NH 4 ) 2 CO 3 and 30:70 (v/v) 100 mM (NH 4 ) 2 CO 3 :acetonitrile as mobile phases. Detection was performed via positive electrospray ionization mode with multiple reaction monitoring. The assay exhibited linearity in the concentration range of 2.5-500 ng/ml for both analytes. Intra- and inter-assay precision and accuracy were within ±11%. LB-100 and endothall recoveries were 78.7 and 86.7%, respectively. The validated LC-MS/MS method enabled the accurate measurement of LB-100 and endothall in patient samples from an ongoing clinical trial (NCT04560972).

Purpose: With increased adoption of next-generation sequencing, tailored therapy on the basis of molecular status is being delivered for patients with early-stage resectable non-small-cell lung cancer (NSCLC). The purpose of this narrative review was to focus on recent developments of targeted therapies in the adjuvant and neoadjuvant/adjuvant setting for early-stage disease., Methods: A systematic search of the MEDLINE/PubMed database was performed, focusing on studies published within the past 10 years. Our search queried "early-stage NSCLC (AND) tyrosine kinase inhibitor (TKI; OR) epidermal growth factor receptor (EGFR; OR) anaplastic lymphoma kinase ( ALK )" and was limited only to prospective and ongoing studies., Results: Most studies examining the benefit of targeted therapies in early-stage resectable NSCLC have been for EGFR-TKIs in the adjuvant setting. Currently, only one study, the ADAURA trial of adjuvant osimertinib, has demonstrated an overall survival benefit with the use of an EGFR-TKI in the adjuvant setting. Future work to build on the success of the ADAURA trial is focused on determining the optimal duration of targeted therapies and using biomarkers, such as circulating tumor DNA, to risk-stratify patients and guide maintenance targeted therapy duration., Conclusion: The results of several ongoing studies are eagerly awaited regarding the use of targeted therapies in the neoadjuvant/adjuvant setting and for more uncommon or rare mutations such as ALK , ROS proto-oncogene 1, rearranged during transfection, mesenchymal-epithelial transition factor, and B-Raf proto-oncogene V600E. The treatment landscape for early-stage NSCLC harboring actionable mutations is likely to shift dramatically in the upcoming decade.

Opinion Statement: Nasopharyngeal carcinoma (NPC) is distinct in its anatomic location and biology from other epithelial head and neck cancer (HNC). There are 3 WHO subtypes, which considers the presence of Epstein-Barr virus (EBV) and other histopathology features. Despite the survival benefit obtained from modern treatment modalities and techniques specifically in the local and locally advanced setting, a number of patients with this disease will recur and subsequently die of distant metastasis, locoregional relapse, or both. In the recurrent setting, the ideal therapy approach continues to be a topic of discussion and current recommendations are platinum-based combination chemotherapy. Phase III clinical trials which led to the approval of pembrolizumab or nivolumab for head and neck squamous cell carcinoma (HNSCC) specifically excluded NPC. No immune checkpoint inhibitor therapy, to date, has been approved by the FDA to treat NPC although the National Comprehensive Cancer Network (NCCN) recommendations do include use of these agents. Hence, this remains the major challenge for treatment options. Nasopharyngeal carcinoma is challenging as it is really 3 different diseases, and much research is required to determine best options and sequencing of those options. This article is going to address the data to date and discuss ongoing research in EBV + and EBV - inoperable recurrent/metastatic NPC patients., (© 2023. The Author(s).)

Mesothelioma is a rare cancer originating in mesothelial surfaces of the peritoneum, pleura, and other sites. These NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) focus on peritoneal mesothelioma (PeM). The NCCN Guidelines for PeM provide recommendations for workup, diagnosis, and treatment of primary as well as previously treated PeM. The diagnosis of PeM may be delayed because PeM mimics other diseases and conditions and because the disease is so rare. The pathology section was recently updated to include new information about markers used to identify mesothelioma, which is difficult to diagnose. The term "malignant" is no longer used to classify mesotheliomas, because all mesotheliomas are now defined as malignant.

Background: Divarasib (GDC-6036) is a covalent KRAS G12C inhibitor that was designed to have high potency and selectivity., Methods: In a phase 1 study, we evaluated divarasib administered orally once daily (at doses ranging from 50 to 400 mg) in patients who had advanced or metastatic solid tumors that harbor a KRAS G12C mutation. The primary objective was an assessment of safety; pharmacokinetics, investigator-evaluated antitumor activity, and biomarkers of response and resistance were also assessed., Results: A total of 137 patients (60 with non-small-cell lung cancer [NSCLC], 55 with colorectal cancer, and 22 with other solid tumors) received divarasib. No dose-limiting toxic effects or treatment-related deaths were reported. Treatment-related adverse events occurred in 127 patients (93%); grade 3 events occurred in 15 patients (11%) and a grade 4 event in 1 patient (1%). Treatment-related adverse events resulted in a dose reduction in 19 patients (14%) and discontinuation of treatment in 4 patients (3%). Among patients with NSCLC, a confirmed response was observed in 53.4% of patients (95% confidence interval [CI], 39.9 to 66.7), and the median progression-free survival was 13.1 months (95% CI, 8.8 to could not be estimated). Among patients with colorectal cancer, a confirmed response was observed in 29.1% of patients (95% CI, 17.6 to 42.9), and the median progression-free survival was 5.6 months (95% CI, 4.1 to 8.2). Responses were also observed in patients with other solid tumors. Serial assessment of circulating tumor DNA showed declines in KRAS G12C variant allele frequency associated with response and identified genomic alterations that may confer resistance to divarasib., Conclusions: Treatment with divarasib resulted in durable clinical responses across KRAS G12C-positive tumors, with mostly low-grade adverse events. (Funded by Genentech; ClinicalTrials.gov number, NCT04449874.)., (Copyright © 2023 Massachusetts Medical Society.)

This study investigates the role of integrin β4 (ITGB4) and stemness-associated factor SOX2 in platinum resistance in lung squamous cell carcinoma (LUSC). The expression of SOX2 and ITGB4 is found to be high in all LUSC subtypes, but the impact of ITGB4 expression on overall patient survival varies by subtype. Cancer stem cells (CSCs) isolated from LUSC patients were found to be resistant to cisplatin, but knocking down ITGB4 or SOX2 sensitized them to cisplatin. Carfilzomib (CFZ) synergized with cisplatin and suppressed CSC growth by inhibiting ITGB4 and SOX2 expression. Additionally, CFZ was found to inhibit SOX2 expression epigenetically by inhibiting histone acetylation at the SOX2 promoter site. CFZ also suppressed the growth of SOX2-dependent small cell lung cancer cells in vitro and in vivo . The study highlights the unique function of CFZ as a transcriptional suppressor of SOX2, independent of its proteasome inhibitory function., Competing Interests: The authors declare no potential conflicts of interest., (© 2023 The Authors.)

Lung cancer is one of the most common cancers with the highest mortality. Non-small cell lung cancer (NSCLC) contributes to around 85% of lung cancer diagnoses (vs. 15% for small cell lung cancer). The treatment of NSCLC has vastly changed in the last two decades since the development of immunotherapy and targeted therapy against driver mutations. As is the nature of malignancy, cancer cells have acquired resistance to these treatments prompting an investigation into novel treatments and new targets. Bispecific antibodies, capable of targeting multiple substrates at once, and antibody-drug conjugates that can preferentially deliver chemotherapy to tumor cells are examples of this innovation. From our initial evaluation, both treatment modalities appear promising.

Background: Number of metastatic sites can identify patient populations with non-small cell lung cancer (NSCLC) that benefit from aggressive therapy. Total volume of disease is also relevant. We evaluated the prognostic impact of biologically active volume of disease (BaVD) on patients with metastatic lung adenocarcinoma., Materials and Methods: Positron emission tomography/computerized tomography (PET/CT) scans from patients with newly diagnosed lung adenocarcinoma prior to starting any therapy were identified. SUV thresholds of 3 and 4 were used to auto-contour all FDG avid areas. Kaplan-Meier analysis and Cox regression were performed to examine influence on OS., Results: One hundred forty-eight patients were included in the analysis. The median BaVD when using an SUV threshold of 3 was 122.8 mL. The median BaVD when using an SUV threshold of 4 was 46.2 mL When stratified by median BaVD using an SUV of 3, median OS was higher for patients with <=122.8 mL (2.12 years) compared to patients with >122.8 mL (1.46 years) (log-rank P = .001). Similarly, when stratified by median BaVD using an SUV of 4, median OS was higher for patients with <=46.2 mL (1.91 years; 95% CI: 1.65-3.22 years) compared to patients with >46.2 mL (1.48 years; 95% CI: 1.07-1.80 years) (log-rank P = .007). On multivariable analysis, BaVD was significantly associated with OS when using an SUV threshold of 3 (HR: 20.169, P < .001) and 4 (HR: 4.117, P < .001)., Conclusion: BaVD is an important prognostic factor in metastatic lung adenocarcinoma and may aid identification of patients with limited disease who may be candidates for more aggressive therapies., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for management of disease in patients with NSCLC. These NCCN Guidelines Insights focus on neoadjuvant and adjuvant (also known as perioperative) systemic therapy options for eligible patients with resectable NSCLC.

Background: We performed an integrated biomarker evaluation in pembrolizumab-treated patients with R/M HNSCC enrolled in KEYNOTE-012 or KEYNOTE-055. The relationship between biomarkers and HPV status was explored., Methods: We evaluated PD-L1 (combined positive score [CPS]), TMB, T-cell-inflamed gene expression profile (Tcell inf GEP), and HPV status. Associations between biomarkers were evaluated by logistic regression (ORR) and Cox regression (PFS, OS)., Results: Two hundred and fifty-seven patients (KEYNOTE-012, n = 106; KEYNOTE-055, n = 151) had TMB data available; of these, 254 had PD-L1 and 236 had Tcell inf GEP. TMB, PD-L1, and Tcell inf GEP were each significantly associated with ORR (p < 0.01). Kaplan-Meier curves at prespecified cutoffs generally showed PFS and OS separation in the anticipated direction for these biomarkers, except for OS and TMB. TMB did not correlate with PD-L1 or Tcell inf GEP (Spearman ρ = -0.03 and ρ = -0.13, respectively); PD-L1 and Tcell inf GEP were moderately correlated (Spearman ρ = 0.47). In multivariate models, TMB, PD-L1, and Tcell inf GEP were each independently predictive for ORR (p < 0.001). ORR was higher in patients with high versus low levels of biomarkers when dichotomized using prespecified cutoffs; patients with higher versus lower levels of TMB and PD-L1 or TMB and Tcell inf GEP had the highest ORRs. Within HPV subgroups, higher versus lower distributions of biomarkers (PD-L1, TMB, and Tcell inf GEP) were associated with response. HPV detection by p16-immunohistochemistry and WES showed good concordance (81%); results were generally similar by HPV status, regardless of the detection method., Conclusions: TMB and the inflammatory biomarkers PD-L1 and Tcell inf GEP, assessed alone or together, may be useful for characterizing clinical response to pembrolizumab in R/M HNSCC., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

The goal of oncology is to provide the longest possible survival outcomes with the therapeutics that are currently available without sacrificing patients' quality of life. In lung cancer, several data points over a patient's diagnostic and treatment course are relevant to optimizing outcomes in the form of precision medicine, and artificial intelligence (AI) provides the opportunity to use available data from molecular information to radiomics, in combination with patient and tumor characteristics, to help clinicians provide individualized care. In doing so, AI can help create models to identify cancer early in diagnosis and deliver tailored therapy on the basis of available information, both at the time of diagnosis and in real time as they are undergoing treatment. The purpose of this review is to summarize the current literature in AI specific to lung cancer and how it applies to the multidisciplinary team taking care of these complex patients., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Immune checkpoint inhibitors (ICIs) produce a broad spectrum of immune-related adverse events (irAEs) affecting various organ systems. While ICIs are established as a therapeutic option in non-small cell lung cancer (NSCLC) treatment, most patients receiving ICI relapse. Additionally, the role of ICIs on survival in patients receiving prior targeted tyrosine kinase inhibitor (TKI) therapy has not been well-defined., Objective: To investigate the impact of irAEs, the relative time of occurrence, and prior TKI therapy to predict clinical outcomes in NSCLC patients treated with ICIs., Methods: A single center retrospective cohort study identified 354 adult patients with NSCLC receiving ICI therapy between 2014 and 2018. Survival analysis utilized overall survival (OS) and real-world progression free survival (rwPFS) outcomes. Model performance matrices for predicting 1-year OS and 6-month rwPFS using linear regression baseline, optimal, and machine learning modeling approaches., Results: Patients experiencing an irAE were found to have a significantly longer OS and rwPFS compared to patients who did not (median OS 25.1 vs. 11.1 months; hazard ratio [HR] 0.51, confidence interval [CI] 0.39- 0.68, P-value <0.001, median rwPFS 5.7 months vs. 2.3; HR 0.52, CI 0.41- 0.66, P-value <0.001, respectively). Patients who received TKI therapy before initiation of ICI experienced significantly shorter OS than patients without prior TKI therapy (median OS 7.6 months vs. 18.5 months; P-value < 0.01). After adjusting for other variables, irAEs and prior TKI therapy significantly impacted OS and rwPFS. Lastly, the performances of models implementing logistic regression and machine learning approaches were comparable in predicting 1-year OS and 6-month rwPFS., Conclusion: The occurrence of irAEs, the timing of the events, and prior TKI therapy were significant predictors of survival in NSCLC patients on ICI therapy. Therefore, our study supports future prospective studies to investigate the impact of irAEs, and sequence of therapy on the survival of NSCLC patients taking ICIs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sayer, Mambetsariev, Lu, Wong, Duche, Beuttler, Fricke, Pharoan, Arvanitis, Eftekhari, Amini, Koczywas, Massarelli, Roosan and Salgia.)

Translational research in medicine, defined as the transfer of knowledge and discovery from the basic sciences to the clinic, is typically achieved through interactions between members across scientific disciplines to overcome the traditional silos within the community. Thus, translational medicine underscores 'Team Medicine', the partnership between basic science researchers and clinicians focused on addressing a specific goal in medicine. Here, we highlight this concept from a City of Hope perspective. Using cisplatin resistance in non-small cell lung cancer (NSCLC) as a paradigm, we describe how basic research scientists, clinical research scientists, and medical oncologists, in true 'Team Science' spirit, addressed cisplatin resistance in NSCLC and identified a previously approved compound that is able to alleviate cisplatin resistance in NSCLC. Furthermore, we discuss how a 'Team Medicine' approach can help to elucidate the mechanisms of innate and acquired resistance in NSCLC and develop alternative strategies to overcome drug resistance.

Autoimmunity and cancer rates have both been on the rise in Western civilization prompting many to investigate the link between the two entities. This review will investigate the complex interactions between the activation and deactivation of the immune system and the development of malignancy. Additional focus will be placed on the main classes of immune inhibitor therapy utilized in transplant patients and in autoimmune disease including TNF-alpha, Calcineurin, mTOR, purine synthesis antagonists and IMPDH inhibitors.

This narrative review aims to summarize the currently available evidence for the role of radiation in the treatment of thymus cancers. Thymus cancers are rare, heterogeneous tumors with limited evidence to guide their clinical management. There remains some controversy over the role of radiation in the adjuvant and induction/definitive setting. We performed a systematic search of the MEDLINE/PubMed database, focusing on studies published within the last 30 years. Our search queried "thymoma [OR] thymic carcinoma [AND] radiation" and was limited only to prospective and retrospective studies and metanalyses, omitting books, documents, and reviews. Our search resulted in 174 total references, of which only 31 references were within the scope of interest ranging from 1988 to 2021. For resectable disease, there is prospective evidence to support the avoidance of postoperative radiation (PORT) in completely resected Masaoka stage I thymoma, but there is a lack of prospective evidence guiding the use of PORT in other situations. Several retrospective studies and metanalyses have suggested a benefit with PORT for positive margins and advanced stage disease, although it remains controversial whether PORT is beneficial for all completely resected Masaoka stage II thymoma. For unresectable disease, induction chemotherapy followed by reassessment of resectability is the preferred management. Prospective evidence exists to support the use of induction chemoradiation for patients unable to tolerate anthracycline-based chemotherapy and the use of definitive chemoradiation for those unable to undergo surgery. An effective multidisciplinary approach is the optimal strategy for achieving the best outcomes in patients with thymus cancers., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Vidutolimod, a CpG-A TLR9 agonist, was investigated in a phase 1b study (CMP-001-003; ClinicalTrials.gov, NCT03438318) in combination with atezolizumab with and without radiation therapy (RT) in patients with advanced NSCLC., Methods: Patients with progressive disease after anti-programmed cell death protein 1 or programmed death-ligand 1 therapy received either vidutolimod and atezolizumab (part A) or vidutolimod, atezolizumab, and RT (part B). The primary objective was to evaluate the safety of vidutolimod and atezolizumab with and without RT. Key secondary end point was best objective response rate per Response Evaluation Criteria in Solid Tumors, version 1.1., Results: Between March 28, 2018, and July 25, 2019, a total of 29 patients were enrolled and received at least one dose of vidutolimod (part A, n = 13; part B, n = 16). Intratumoral injections of vidutolimod were administered successfully, including injection of visceral lesions. The most common treatment-related adverse events (≥30%) were flu-like symptoms and hypotension. No objective responses were observed; 23.1% and 50.0% of the patients in parts A and B, respectively, had stable disease as best response. In parts A and B, 15.4% and 25.0% of the patients, respectively, had tumor shrinkage (<30% decrease in tumor size, nonirradiated). Enrollment was stopped owing to lack of objective responses. In the two patients with initial tumor shrinkage in part A, a strong serum induction of C-X-C motif chemokine ligand 10 was observed., Conclusions: Vidutolimod and atezolizumab with and without RT had a manageable safety profile, with minimal clinical activity in heavily pretreated patients with programmed cell death protein 1 or programmed death-ligand 1 blockade-resistant NSCLC., (© 2022 The Authors.)

Background: The molecular and clinical features of KRAS-mutated lung cancer patients treated with immunotherapy have yet to be characterized, which could guide the development of therapeutics targeting KRAS with potential immuno-oncology treatment combinations. Research Question: Do KRAS-mutated patients with different subtypes and comutations have different clinical responses and overall survival (OS) to checkpoint inhibitors? Study Design and Methods: 87 patients with NSCLC at the City of Hope who received immune checkpoint inhibitors were identified and analyzed retrospectively. Tumor genomic alterations were extracted from the clinical data with next-generation sequencing using various platforms. Demographic, clinical, molecular, and pathological information was collected with the approval of the institutional review board of the City of Hope. OS was calculated if it was available at the study time point, and responses were determined according to the RECIST v1.1. Results: Among 87 patients, 32 had a KRAS G12C mutation (36.8%), 19 had G12V (21.9%), 18 had G12D (20.7%), 6 had G12A (6.9%), 3 had G12R (3.45%), and 10 had amplification (11.49%) and other uncommon mutations. G12D had a statistically significant Odds Ratio (OR) between patients who had responses and progression of the disease (OR (95% CI) = 0.31 (0.09−0.95), p < 0.05), with 5 G12D-mutated patients having responses and 11 G12D-mutated patients having progression of the disease. In the univariate analysis with OS, there was a trend of better OS in the G12D-mutated patients, with no statistically significant difference in terms of OS between the patients who had G12D mutation and the patients who had other KRAS mutations (HR (95% CI) = 0.53 (0.21−1.36), p = 0.185). The median OS was significantly worse with KRAS comutation CDKN2A/B loss (4.2 vs. 16.9 months, HR = 3.07 (1.09−8.69), p < 0.05) and MET (3.4 vs. 17 months, HR = 3.80 (1.44−10.05), p < 0.01), which were included for the multivariate analysis. The OS with other KRAS comutations was not statistically significant, including STK11 and KEAP1. Conclusion: KRAS mutation subtypes such as G12D and comutations such as CDKN2/A and MET may modulate the immunotherapy responses and outcomes in lung cancer.

Tyrosine kinase inhibitor (TKI) therapy is the recommended first-line treatment for metastatic non-small-cell lung cancer (NSCLC) positive for epidermal growth factor receptor (EGFR) gene mutation. However, most individuals treated with TKI therapy for EGFR-mutant NSCLC will develop tumor resistance to TKI therapy. Therapeutic strategies to overcome TKI resistance are the topic of several ongoing clinical trials. One potential strategy, which has been explored in numerous trials, is the treatment of progressive sites of disease with stereotactic body radiation treatment (SBRT) or stereotactic radiosurgery (SRS). We sought to review the literature pertaining to the use of local ablative radiation therapy in the setting of acquired resistance to TKI therapy and to discuss stereotactic radiation therapy as a strategy to overcome TKI resistance.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) provide recommended management for patients with NSCLC, including diagnosis, primary treatment, surveillance for relapse, and subsequent treatment. Patients with metastatic lung cancer who are eligible for targeted therapies or immunotherapies are now surviving longer. This selection from the NCCN Guidelines for NSCLC focuses on targeted therapies for patients with metastatic NSCLC and actionable mutations.

Introduction: Entrectinib is an approved tyrosine kinase inhibitor (TKI) for ROS1 fusion-positive NSCLC. An updated integrated analysis of entrectinib from the ALKA-372-001, STARTRK-1, and STARTRK-2 trials is presented, with substantially longer follow-up, more patients, and the first description of the median overall survival (OS). An exploratory analysis of entrectinib in ROS1 fusion-positive NSCLC with the central nervous system (CNS)-only progression post-crizotinib is reported., Methods: Adults with ROS1 fusion-positive, locally advanced or metastatic NSCLC who received at least one dose of entrectinib and had 12 months or longer of follow-up were included in the analysis. Co-primary end points were confirmed objective response rate (ORR) and duration of response (DoR) by blinded independent central review. The data cutoff was on August 31, 2020., Results: The efficacy-assessable population comprised 168 ROS1 TKI-naïve patients. The median survival follow-up was 29.1 months (interquartile range, 21.8-35.9). The ORR was 68% (95% confidence interval [CI]: 60.2-74.8); the median DoR was 20.5 months. The median progression-free survival (PFS) was 15.7 months and the median OS was 47.8 months. In the 25 patients with measurable baseline CNS metastases, the intracranial ORR was 80% (95% CI: 59.3-93.2), median intracranial DoR was 12.9 months, and median intracranial PFS was 8.8 months. Among 18 patients with CNS-only progression on previous crizotinib treatment, two achieved a partial response (11%) and four had stable disease (22%). In seven patients with measurable CNS disease from this cohort, the intracranial ORR was 14% (1 partial response)., Conclusions: Entrectinib is active and achieves prolonged survival in ROS1 TKI-naïve patients with ROS1 fusion-positive NSCLC. Modest activity is seen in patients with CNS-only progression post-crizotinib., (© 2022 The Authors.)