Search

Objective: Cancer patients aged ≥80 years present unique characteristics affecting response to immune checkpoint inhibitors (ICIs), with unidentified molecular differences. This study aimed to explore potential biomarkers of response to ICI in patients ≥80 years., Methods and Analysis: We analysed tumour samples (n=24 123) from patients ≥80 (versus<80) with non-small cell lung cancer (NSCLC), melanoma (MEL), and renal cell cancer (RCC). Using gene expression deconvolution, we investigated differences in tumour microenvironment (TIME) composition. Then, using next-generation sequencing and programmed death-ligand 1 (PD-L1) assessment, we evaluated gene expression differences between age groups and across tumour types, with a focus on ageing-related processes such as DNA damage response (DDR), immune checkpoint (IC) and metabolism-related genes. In a subset of patients ≥80 (n=1013), gene clustering and differential gene expression analyses were carried out to identify potential tumour-type specific expression patterns in responders to ICI., Results: Significant differences in TIME composition were seen in patients with NSCLC and MEL. In patients ≥80, tumour mutational burden was lower in patients with NSCLC, higher in MEL and RCC had fewer PD-L1+tumours. DDR, IC and metabolism-related gene enrichments were distinct in patients ≥80. In patients ≥80 treated with ICIs (n=1013), there were no significant differences in survival between gene clusters, but differential gene expression analysis identified potential tumour-type specific expression patterns in responders., Conclusion: Our findings reveal tumour type-specific expression profiles, TIMEs and response signatures to ICIs in patients ≥80, supporting further biomarker investigations in this population., Competing Interests: Anwaar Saeed reports a leadership role with Autem therapeutics, Exelixis, KAHR medical and Bristol Myers Squibb; consulting or advisory board role with AstraZeneca, Bristol Myers Squibb, Merck, Exelixis, Pfizer, Xilio therapeutics, Taiho, Amgen, Autem therapeutics, KAHR medical and Daiichi Sankyo; institutional research funding from AstraZeneca, Bristol Myers Squibb, Merck, Clovis, Exelixis, Actuate therapeutics, Incyte Corporation, Daiichi Sankyo, Five prime therapeutics, Amgen, Innovent biologics, Dragonfly therapeutics, Oxford Biotherapeutics, Arcus therapeutics and KAHR medical; and participation as a data safety monitoring board chair for Arcus therapeutics. AKS reports research funding (to institution) from Ascentage, Bristol Myers Squibb, IDEAYA, Immunocore, Merck, Olatec Therapeutics, Regeneron, Replimune and Seagen and consulting/advisory role for Bristol Myers Squibb, Iovance, Regeneron, Novartis and Pfizer. HM reports research funding (to the institution) from AstraZeneca and U CAN-CER VIVE Foundation and advisory roles for AstraZeneca, Genentech and Daiichi Sankyo. DU reports consulting and advisory roles with Daiichi Sankyo/AstraZeneca, AstraZeneca/Medimmune, Jazz Pharmaceuticals and Sanofi. HB has served as consultant/advisory board member for Janssen, Astellas, Merck, Pfizer, Roche, Harpoon, Amgen, Bayer, Daiichi Sankyo, Sanofi Genzyme, AstraZeneca and has received research funding (to institution) from Bristol Myers Squibb, Circle Pharma, Daiichi Sankyo and Novartis. CK reports research funding (to institution) from AstraZeneca, Novartis, Regeneron, Janssen, Genentech, Lyell, Daiichi Sankyo, Gilead, Macrogenics, Boehringer Ingelheim, Black Diamond Therapeutics and consulting fees from Arcus, AstraZeneca, Daiichi Sankyo, Eisai, Regeneron, Sanofi, Takeda, J&J and Pinetree. ARN reports research funding (to institution) from Loxo@Lilly, Surface Oncology, ADC Therapeutics, IGM Biosciences, EMD Serono, Aravive, Nikang Therapeutics, Inspirna, Exelexis, Revolution Medicine, Jacobio, Pionyr, Jazz Pharmaceuticals, NGM Biopharmaceuticals, Immunophotonics, Selexine, consultant editor compensation from JCO Precision Oncology, travel compensation from SITC/AACR/Conquer Cancer, Foundation/BinayTara Foundation and Foundation Med/Caris Life Sciences, Jazz Pharmaceuticals and grants from SWOG Hope Foundation, FDA Broad Agency Contract, with advisory Board and Speaking Engagement for Foundation Med. AE, MJO and PW are employees of Caris Life Sciences. All other authors declare no potential conflict of interest., (Copyright © Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

GT103 is a first-in-class, fully human, IgG3 monoclonal antibody targeting complement factor H that kills tumor cells and promotes anti-cancer immunity in preclinical models. We conducted a first-in-human phase 1b study dose escalation trial of GT103 in refractory non-small cell lung cancer to assess the safety of GT103 (NCT04314089). Dose escalation was performed using a "3 + 3" schema with primary objectives of determining safety, tolerability, PK profile and maximum tolerated dose (MTD) of GT103. Secondary objectives included describing objective response rate, progression-free survival and overall survival. Dose escalation cohorts included GT103 given intravenously at 0.3, 1, 3, 10, and 15 mg/kg every 3 weeks, and 10 mg/kg every 2 weeks. Thirty one patients were enrolled across 3 institutions. Two dose-limiting adverse events were reported: grade 3 acute kidney injury (0.3 mg/kg) and grade 2 colitis (1 mg/kg). No dose-limiting toxicities were noted at the highest dose levels and the MTD was not reached. No objective responses were seen. Stable disease occurred in 9 patients (29%) and the median overall survival was 25.7 weeks (95% confidence interval [CI], 19.1-30.6). Pharmacokinetic analysis confirmed an estimated half life of 6.5 days. The recommended phase 2 dose of GT103 was 10 mg/kg every 3 weeks, however further dose optimization is needed given the absence of an MTD. The study achieved its primary objective of demonstrating safety and tolerability of GT103 in refractory NSCLC., Competing Interests: Competing interests: This research was supported by Grid Therapeutics. Drs. Patz, Campa, and Gottlin have affiliation with both Grid Therapeutics and Duke University. JMC reports trial funding from Bristol-Myers Squibb, Genentech, Spectrum, Adaptimmune, AbbVie, Moderna, GlaxoSmithKline, Array, AstraZeneca, Grid Therapeutics, Abel Zeta, Pfizer; advisory/consulting from AstraZeneca, Merck, Pfizer, Spectrum, Genentech, Novartis, Turning Point, G1 Therapeutics, Vivacitas, Omega, Amgen, Corbus, Sanofi; speaking and travel from Merck and Amgen; DSMB from BioThera and G1 Therapeutics. GS reports speaking for Astra-Zeneca, consulting for Daiichi Sankyo, board member for Florida chapter of ASCO, and stock Options and consulting compensation for Onc.AI. HM reports advisory board for AstraZeneca, Genentech, and Daiichi Sankyo; and research funding from AstraZeneca. TS reports clinical trial funding from AstraZeneca, Seagen, Mirati Therapeutics, Genentech/Roche, Nuvalent, Inc.; consulting from Takeda, G1 Therapeutics, Spectrum Pharmaceuticals, Gilead Sciences, AstraZeneca, Coherus Biosciences, Blueprint Medicines, Boehringer Ingelheim, Pfizer, Abbvie; travel funding from Pfizer; DSMB participation from Genentech. NR reports advisory compensation from BMS, Merck, Jazz, Genentech, Daiichi, Regeneron, ABBVIE, research funding Merck, Regeneron, and speaking from Jazz. JC reports Scientific Advisor from Actimed, Enzychem, Gen Sci, Pfizer, Tensegrity; DSMB Member of BioAtla, G1 Therapeutics; PI/Institutional Research Funding for AstraZeneca, Helsinn, Pfizer, NCI/NCTN; Publications Committee of Amgen, Frensenius-Kabi, G1, Pfizer. GS reports advisory board from EMD Serono, BMS, Merck, Seattle Genetics, Astellas, Janssen, Bicycle Therapeutics, Pfizer, Gilead, Scholar Rock, Eli Lilly, Loxo Oncology, Vial, Aktis, Daiichi-Sankyo; Consultant/Scientific Advisory Board (SAB)/trial steering committee: Syapse, Merck, Servier, Syncorp, Ellipses; Research Support to institution from EMD Serono, Jazz Therapeutics, Bayer, Sumitomo Pharma, Blue Earth Diagnostics; Speaker from Seagen, Gilead, Natera, Exelixis, Janssen, Astellas, Bayer, Aveo, Pfizer, Merck; Data safety monitoring committee (honorarium) from Mereo; Employment: Spouse employed by Myriad, Exact Sciences; and Travel: BMS, Astellas. SB receives support from the National Institutes of Health, the Childhood Arthritis and Rheumatology Research Alliance (CARRA), serves on an NIH DSMB, and consults for UCB (Morrisville, NC, USA), CARRA, and Rutgers University. Stephen Balevic is a member of the American College of Rheumatology, the Childhood Arthritis and Rheumatology Research Alliance (CARRA), Alpha Omega Alpha, the American Society of Clinical Investigators, and the Society for Pediatric Research, and served as the Assistant Scientific Director for CARRAAN reports funding from Genentech, Genmab, MedImmune/AstraZeneca, Seattle Genetics; consulting from Sanofi, Promega; SAB from Leap Therapeutics; NCI Chair, Core Correlatives Sciences Committee (NCTN-CCSC); and patents of No 925592 and No. 62/337,633. MC is a founder of Grid Therapeutics, LLC and is on the advisory board. EBG is a founder of Grid Therapeutics, LLC. SA reports being member of scientific advisory boards for Cellepus Therapeutics (and Co-founder), Leap Therapeutics, Guardian Bio, Immutep, Shoreline Therapeutics, Tubulis, Xilis, Glympse Bio, Achilles Therapeutics, Memgen, RAPT Biotherapeutics. EFP is a founder, CEO and on the BOD of Grid Therapeutics, LLC. All other authors report no competing interests., (© 2024. The Author(s).)

Background: Cannabis (CAN) use has risen significantly over the last few decades. CAN has potent immunosuppressive properties, which could antagonize the effect of immunotherapy (IO). The impact of CAN use on clinical cancer outcomes remains unclear., Objectives: In this study, we evaluated the clinical effect of CAN use on clinical outcomes among patients with solid malignancies receiving IO., Design: This is a retrospective cohort study of all patients with solid malignancies receiving IO between August 2014 and August 2018., Methods: Patients were stratified based on CAN use to CAN users and CAN non-users. The primary outcome was overall survival (OS), and the secondary outcomes were progression-free survival (PFS) and disease control rate (DCR). Univariable and multivariable logistic and Cox regression analyses were performed to compare the outcomes between the two groups, adjusting for covariates., Results: The records of 106 patients were reviewed, 28 (26%) of whom were CAN users and 78 (74%) were CAN non-users. One patient was excluded. Most CAN users consumed dronabinol (82%). The median follow-up for OS and PFS was 29.2 months. Median OS in the CAN users was 6.7 months compared to 17.3 months in the CAN non-users (HR, 1.78; 95% CI, 1.06-2.97; p  = 0.029). The median PFS was 4.8 months in the CAN users compared to 9.7 months in the CAN non-users (HR, 1.74; 95% CI, 1.09-2.79; p  = 0.021). DCR was 11% among CAN users and 38% among CAN non-users (OR, 0.23; 95% CI; 0.06-0.68; p  = 0.007). An exploratory racial disparity analysis showed that this negative impact of CAN was primarily seen in White patients., Conclusion: In this single institutional experience, CAN use was associated with worse OS, PFS, and DCR among cancer patients receiving IO. Prospective trials are needed to further study this potential antagonistic interaction between CAN and IO and explore the racial disparities related to CAN exposure., (© The Author(s), 2024.)

Background: Immunotherapy has been widely incorporated into the treatment of patients with non-small-cell lung cancer (NSCLC). Many of these patients will experience immune-related adverse events (irAEs) without decreased efficacy. We report a retrospective analysis of the association between irAEs and efficacy outcomes from the BTCRC LUN 16-081 randomized phase 2 trial of consolidation nivolumab (N) plus ipilimumab (IPI) vs N alone following chemoradiotherapy in unresectable Stage IIIA/IIIB NSCLC., Results: A total of 105 patients enrolled from 9/2017 to 4/2021. In arm A (N alone), 65 % of patients developed irAEs with no difference in PFS or OS in patients with and without irAEs. In arm B (IPI+N), 84 % of patients developed irAE with no difference in OS in patients with and without irAEs, but longer PFS in those who experienced irAEs (30.9 vs. 6.8mo, P = .010). Patients in Arm A that discontinued treatment due to irAE (n = 8) had shorter PFS (8.2 vs. 31.9mo, P ≤ .0001) and OS (12.3mo vs. NE, P < .0001). Patients in Arm B that discontinued treatment due to irAEs (n = 18) had no difference in either PFS or OS., Conclusions: The development of irAEs after chemoradiotherapy due to the use of Nivolumab alone or in combination with Ipilimumab did not result in reduced efficacy outcomes, with an observed improvement in PFS in the combination arm. If the irAEs resulted in discontinuation of treatment, this was associated with decreased efficacy outcomes in the N alone arm but not in the IPI + N arm., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Esophageal adenocarcinoma (EAC) remains a devastating disease and second line treatment options in the metastatic space are limited. Homologous recombination (HR) defects have been described in EAC in up to 40% of patients. Poly (ADP-ribose) polymerase (PARP)1 and PARP2 inhibitors have shown efficacy in HR defective prostate and ovarian cancers. Here, we describe the activity of the PARP inhibitor niraparib in metastatic EAC with HR defects., Methods: In this single arm Simon two-stage Phase II study, we assessed the safety and efficacy of niraparib in patients with metastatic EAC previously treated with platinum containing chemotherapy harboring defective HR. Defective HR was defined as deleterious alterations in the following HR genes: BRCA1/2, PALB2, ATM, BARD1, BRIP1, CDK12, CHEK2, FANCA, RAD51, RAD51B, RAD51C, RAD51D, RAD54L, NBN, ARID1A and GEN1., Results: 14 patients were enrolled in this study. The trial was stopped early due to slow accrual. 3 patients did not have post-treatment scans because of rapid clinical decline. The overall response rate (ORR) (95% exact CI) was 0/11 = 0% (0%, 28.49%). The disease control rate (DCR) (95% exact CI) was 2/11 = 18.2% (2.3%, 51.8%). The median PFS was 1.8 months (95% CI = 1.0-3.7). The median OS for evaluable patients was 6.6 months (95% CI =2.7-11.4) and 5.7 months for all patients (95% CI =2.7-10.1). The most common adverse events seen were anemia, fatigue, and thrombocytopenia., Conclusion: In patients with metastatic EAC, single agent niraparib as second line therapy is not an effective option., 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 © 2024 Khalid, Fountzilas, Burney, Mamdani, Schneider, Fausel, Perkins and Jalal.)

Competing Interests: Disclosure JN Bodor reports speaker honoraria from MJH Life Sciences and Association of Community Cancer Centers (ACCC), advisory roles with Bayer and National Association for Continuing Education (NACE). J Xiu reports employment with Caris Life Sciences. V Ernani reports advisory roles with Astra Zeneca, Daiichi Sankyo, Pfizer, Bayer, Jazz Pharmaceuticals, Novocure, BioAtla. S Kaur reports speaker honoraria from Eli Lilly. H Mamdani reports advisory roles with AstraZeneca, Genentech, Zentalis, Daiichi Sankyo, institution research support from AstraZeneca. SI Ou reports consulting roles with AnHeart Therapeutics, Pfizer, Janssen, Daiichi Sankyo, BMS, Merus; speaker honoraria from Pfizer, Janssen, DAVA Oncology LLP, OncLive, Caris Life Science; advisory roles with Elevation Oncology, AnHeart Therapeutics; stock/stock options with MBrace Therapeutics, Blossom Hill Therapeutics, Elevation Oncology, Turning Point Therapeutics; research funding to institution from Pfizer, Janssen, Nuvalent, Mirati, Revolution Medicine, Merus, Daiichi Sankyo, Erasca, Merck. H. Borghaei reports research support from BMS, Lilly, Amgen; consultant roles with BMS, Lilly, Genentech, Pfizer, Merck, EMD-Serono, Boehringer Ingelheim, Astra Zeneca, Novartis, Genmab, Regeneron, BioNTech, Amgen, Axiom, PharmaMar, Takeda, Mirati, Daiichi, Guardant, Natera, Oncocyte, Beigene, iTEO , Jazz, Janssen, Puma, BerGenBio, Bayer, Iobiotech, Grid Therapeutics, RAPT; Data and Safety Monitoring Board: University of Pennsylvania CAR T Program, Takeda, Incyte, Novartis, Springworks Employment; Fox Chase Cancer Center Scientific Advisory Board; Sonnetbio (Stock Options); Inspirna (formerly Rgenix, stock options); Nucleai (stock options); honoraria from Amgen, Pfizer, Daiichi, Regeneron; Travel support from Amgen, BMS, Merck, Lilly, EMDSerono, Genentech, Regeneron, Mirati. A Vanderwadle reports employment with Caris Life Sciences. The remaining authors have no conflicts of interest.

Background: Immune checkpoint inhibitors have profoundly impacted survival among patients with metastatic non-small cell lung cancer. However, population-based studies evaluating this impact on survival by race and socioeconomic factors are lacking., Methods: We used the Surveillance, Epidemiology, and End Results Program-Medicare database to identify patients with metastatic non-small cell lung cancer diagnosed between 2015 and 2019. The primary study outcomes were the receipt of an immune checkpoint inhibitor and overall survival. χ2 tests and logistic regression were used to identify demographic factors associated with receipt of immune checkpoint inhibitors. The Kaplan-Meier method was used to calculate 2-year overall survival rates, and log-rank tests were used to compare survival by race and ethnicity., Results: Of 17 134 patients, approximately 39% received an immune checkpoint inhibitor. Those diagnosed with cancer recently (in 2019); who are relatively younger (aged younger than 85 years); non-Hispanic White, non-Hispanic Asian, or Hispanic; living in high socioeconomic status or metropolitan areas; not Medicaid eligible; and with adenocarcinoma histology were more likely to receive immune checkpoint inhibitors. The 2-year overall survival rate from diagnosis was 21% for the overall population. The 2-year overall survival rate from immune checkpoint inhibitor initiation was 30%, among those who received at least 1 cycle and 11% among those who did not receive immune checkpoint inhibitors. The 2-year overall survival rates were higher among non-Hispanic White (22%) and non-Hispanic Asian (23%) patients compared with non-Hispanic Black (15%) and Hispanic (17%) patients. There was no statistically significant racial differences in survival for those who received immune checkpoint inhibitors., Conclusion: Immune checkpoint inhibitor utilization rates and the resulting outcomes were inferior for certain vulnerable groups, mandating the need for strategies to improve access to care., (© The Author(s) 2024. Published by Oxford University Press.)

Health disparities present a barrier to successful oncology treatment. The potential for precision oncology to reduce health disparities has not previously been analyzed. We performed a retrospective analysis of 12,627 patients from six major cancer centers whose tumors underwent molecular testing at Caris Life Sciences between 2010 and 2020. Kaplan-Meier and Cox regression were used to describe and analyze overall survival. The molecular and demographic features of the cohort were analyzed by χ2 and ANOVA tests. Black patients composed 25% of the cohort and White patients 63%. Among this molecularly-tested cohort, there were minimal outcome differences based on race, geographic location, or poverty level. When analyzing the interaction of age, race, and sex, racial-based disparities were noted primarily for young non-White women in the study cohort but were more pronounced for men and women of all ages in the broader patient population within the Surveillance, Epidemiology, and End Results database. Mutations in five genes-APC, EGFR, STK11, TP53, and KRAS-were found to affect overall survival among our cohort, and their prevalence varied by race in specific tumor types. Real-world outcomes data in mutation-defined cohorts also provided additional context to previously reported therapeutic response trends. Our study shows that patients who undergo molecular testing display reduced racial health disparities compared with the general population, whereas persistent racial disparities are influenced by age and sex. Genomic-driven racial disparities should be examined at a tumor lineage-specific level. Increased access to molecular testing for all eligible patients may play a role in improving health equity. Significance: This study is the largest of its kind to analyze health disparities and genomic features among a diverse multiinstitutional cohort of patients who underwent molecular testing. Continuing to increase awareness of and access to molecular testing approaches may help to reduce cancer health disparities and improve outcomes for all patients., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: African Americans have higher incidence and mortality from lung cancer than non-Hispanic Whites, but investigations into differences in immune response have been minimal. Therefore, we compared components of the tumor microenvironment among African Americans and non-Hispanic Whites diagnosed with non-small cell lung cancer based on PDL1 or tertiary lymphoid structure (TLS) status to identify differences of translational relevance., Methods: Using a cohort of 280 patients with non-small cell lung cancer from the Inflammation, Health, Ancestry, and Lung Epidemiology study (non-Hispanic White: n = 155; African American: n = 125), we evaluated PDL1 tumor proportion score (<1% vs. ≥1%) and TLS status (presence/absence), comparing differences within the tumor microenvironment based on immune cell distribution and differential expression of genes., Results: Tumors from African Americans had a higher proportion of plasma cell signatures within the tumor microenvironment than non-Hispanic Whites. In addition, gene expression patterns in African American PDL1-positive samples suggest that these tumors contained greater numbers of γδ T cells and resting dendritic cells, along with fewer CD8+ T cells after adjusting for age, sex, pack-years, stage, and histology. Investigation of differential expression of B cell/plasma cell-related genes between the two patient populations revealed that two immunoglobulin genes (IGKV2-29 and IGLL5) were associated with decreased mortality risk in African Americans., Conclusions: In the first known race-stratified analysis of tumor microenvironment components in lung cancer based on PDL1 expression or TLS status, differences within the immune cell composition and transcriptomic signature were identified that may have therapeutic implications., Impact: Future investigation of racial variation within the tumor microenvironment may help direct the use of immunotherapy., (©2024 American Association for Cancer Research.)

Background and Objective: Lorlatinib is a tyrosine kinase inhibitor approved for the treatment of advanced anaplastic lymphoma kinase-positive non-small cell lung cancer. This study assessed the effect of steady-state lorlatinib on the metabolic enzymes cytochrome P450 (CYP) 2B6, CYP2C9, and uridine 5'-diphospho-glucuronosyltransferase (UGT) and the P-glycoprotein (P-gp) transporter., Methods: Thirty-two patients received a single oral dose of a probe drug on Day - 2 to determine the pharmacokinetics of the probe drug alone. Starting on Day 1, patients received 100 mg oral lorlatinib daily. On Day 15, a single oral dose of the probe drug was administered concurrently with lorlatinib. Pharmacokinetic parameters for these probe substrates were assessed., Results: Plasma exposures of all probe substrates were reduced by lorlatinib compared with the probe alone. The greatest reduction in area under the plasma concentration-time curve from time zero to infinity (AUC ∞ ) and maximum (peak) plasma drug concentration (C max ) (67% and 63% decrease, respectively) was observed with the P-gp probe substrate fexofenadine. Lorlatinib coadministration also decreased the AUC ∞ and C max of bupropion (CYP2B6 probe substrate) by 25% and 27%, tolbutamide (CYP2C9 probe substrate) by 43% and 15%, and acetaminophen (UGT probe substrate) by 45% and 28%, respectively., Conclusions: Lorlatinib is a net moderate inducer of P-gp and a weak inducer of CYP2B6, CYP2C9, and UGT after steady state is achieved with daily dosing. Medications that are P-gp substrates with a narrow therapeutic window should be avoided in patients taking lorlatinib; no dose modifications are needed with substrates of CYP2B6, CYP2C9, or UGT., Clinicaltrials: gov: NCT01970865., (© 2023. The Author(s).)

Purpose: Non-small-cell lung cancer (NSCLC) with STK11 mut has inferior outcomes to immune checkpoint inhibitors (ICIs). Using multiomics, we evaluated whether a subtype of STK11 mut NSCLC with a uniquely inflamed tumor immune microenvironment (TIME) harboring TP53 comutations could have favorable outcomes to ICIs., Patients and Methods: NSCLC tumors (N = 16,896) were analyzed by next-generation sequencing (DNA-Seq/592 genes). A subset (n = 5,034) underwent gene expression profiling (RNA-Seq/whole transcriptome). Exome-level neoantigen load for STK11 mut NSCLC was obtained from published pan-immune analysis. Tumor immune cell content was obtained from transcriptome profiles using the microenvironment cell population (MCP) counter. ICI data from POPLAR/OAK (n = 34) and the study by Rizvi et al (n = 49) were used to model progression-free survival (PFS), and a separate ICI-treated cohort (n = 53) from Dana-Farber Cancer Institute (DFCI) was used to assess time to treatment failure (TTF) and tumor RECIST response for STK11 mut TP53 mut versus STK11 mut TP53 wt NSCLC., Results: Overall, 12.6% of NSCLC tumors had a STK11 mut with the proportions of tumor mutational burden (TMB)-high (≥10 mut/Mb), PD-L1 ≥50%, and microsatellite instability-high being 38.3%, 11.8%, and 0.72%, respectively. Unsupervised hierarchical clustering of STK11 mut (n = 463) for stimulator of interferon-gamma (STING) pathway genes identified a STING-high cluster, which was significantly enriched in TP53 mut NSCLC ( P < .01). Compared with STK11 mut TP53 wt , tumors with STK11 mut TP53 mut had higher CD8+T cells and natural killer cells ( P < .01), higher TMB ( P < .001) and neoantigen load ( P < .001), and increased expression of MYC and HIF-1A ( P < .01), along with higher expression ( P < .01) of glycolysis/glutamine metabolism genes. Meta-analysis of data from OAK/POPLAR and the study by Rizvi et al showed a trend toward improved PFS in patients with STK11 mut TP53 mut . In the DFCI cohort, compared with the STK11 mut TP53 wt cohort, the STK11 mut TP53 mut tumors had higher objective response rates (42.9% v 16.7%; P = .04) and also had longer TTF (14.5 v 4.5 months, P adj = .054) with ICI., Conclusion: STK11 mut NSCLC with TP53 comutation is a distinct subgroup with an immunologically active TIME and metabolic reprogramming. These properties should be exploited to guide patient selection for novel ICI-based combination approaches.

Background: Patients with thoracic malignancies who develop COVID-19 infection have a higher hospitalization rate compared to the general population and to those with other cancer types, but how this outcome differs by race and ethnicity is relatively understudied., Methods: The TERAVOLT database is an international, multi-center repository of cross-sectional and longitudinal data studying the impact of COVID-19 on individuals with thoracic malignancies. Patients from North America with thoracic malignancies and confirmed COVID-19 infection were included for this analysis of racial and ethnic disparities. Patients with missing race data or races and ethnicities with fewer than 50 patients were excluded from analysis. Multivariable analyses for endpoints of hospitalization and death were performed on these 471 patients., Results: Of the 471 patients, 73% were White and 27% were Black. The majority (90%) were non-Hispanic ethnicity, 5% were Hispanic, and 4% were missing ethnicity data. Black patients were more likely to have an Eastern Cooperative Oncology Group (ECOG) Performance Status ≥ 2 (p-value = 0.04). On multivariable analysis, Black patients were more likely than White patients to require hospitalization (Odds Ratio (OR): 1.69, 95% CI: 1.01-2.83, p-value = 0.044). These differences remained across different waves of the pandemic. However, no statistically significant difference in mortality was found between Black and White patients (OR 1.29, 95% CI: 0.69-2.40, p-value = 0.408)., Conclusions: Black patients with thoracic malignancies who acquire COVID-19 infection are at a significantly higher risk of hospitalization compared to White patients, but there is no significant difference in mortality. The underlying drivers of racial disparity among patients with thoracic malignancies and COVID-19 infection require ongoing investigation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Importance: Patients with relapsed small cell lung cancer (SCLC), a high replication stress tumor, have poor prognoses and few therapeutic options. A phase 2 study showed antitumor activity with the addition of the ataxia telangiectasia and Rad3-related kinase inhibitor berzosertib to topotecan., Objective: To investigate whether the addition of berzosertib to topotecan improves clinical outcomes for patients with relapsed SCLC., Design, Setting, and Participants: Between December 1, 2019, and December 31, 2022, this open-label phase 2 randomized clinical trial recruited 60 patients with SCLC and relapse after 1 or more prior therapies from 16 US cancer centers. Patients previously treated with topotecan were not eligible., Interventions: Eligible patients were randomly assigned to receive topotecan alone (group 1), 1.25 mg/m2 intravenously on days 1 through 5, or with berzosertib (group 2), 210 mg/m2 intravenously on days 2 and 5, in 21-day cycles. Randomization was stratified by tumor sensitivity to first-line platinum-based chemotherapy., Main Outcomes and Measures: The primary end point was progression-free survival (PFS) in the intention-to-treat population. Secondary end points included overall survival (OS) in the overall population and among patients with platinum-sensitive or platinum-resistant tumors. The PFS and OS for each treatment group were estimated using the Kaplan-Meier method. The log-rank test was used to compare PFS and OS between the 2 groups, and Cox proportional hazards models were used to estimate the treatment hazard ratios (HRs) and the corresponding 2-sided 95% CI., Results: Of 60 patients (median [range] age, 59 [34-79] years; 33 [55%] male) included in this study, 20 were randomly assigned to receive topotecan alone and 40 to receive a combination of topotecan with berzosertib. After a median (IQR) follow-up of 21.3 (18.1-28.3) months, there was no difference in PFS between the 2 groups (median, 3.0 [95% CI, 1.2-5.1] months for group 1 vs 3.9 [95% CI, 2.8-4.6] months for group 2; HR, 0.80 [95% CI, 0.46-1.41]; P = .44). Overall survival was significantly longer with the combination therapy (5.4 [95% CI, 3.2-6.8] months vs 8.9 [95% CI, 4.8-11.4] months; HR, 0.53 [95% CI, 0.29-0.96], P = .03). Adverse event profiles were similar between the 2 groups (eg, grade 3 or 4 thrombocytopenia, 11 of 20 [55%] vs 20 of 40 [50%], and any grade nausea, 9 of 20 [45%] vs 14 of 40 [35%])., Conclusions and Relevance: In this randomized clinical trial, treatment with berzosertib plus topotecan did not improve PFS compared with topotecan therapy alone among patients with relapsed SCLC. However, the combination treatment significantly improved OS., Trial Registration: ClinicalTrials.gov Identifier: NCT03896503.

Introduction: We hypothesized that ramucirumab could increase previously reported objective response rate (ORR) of 11% of single-agent nivolumab in the second-line therapy of unresectable mesothelioma., Methods: This was a cooperative group, single-arm, phase 2 trial enrolling patients with unresectable mesothelioma after progression on more than or equal to one pemetrexed-containing regimen. Ramucirumab and nivolumab were given intravenously every 14 days for up to 24 months. The primary end point was ORR; secondary end points were progression-free survival (PFS) rate at 24 weeks and overall survival (OS)., Results: Between April 2018 and October 2021, 34 patients were recruited. Median age was 72 (range: 40-89) years, 12% were women, and 79% of tumors had epithelial histology. Median follow-up was 10.2 months (interquartile range 19.6 mo [4.3-23.8]). ORR was 22.6% (95% confidence interval [CI]: 9.6%-41.1%) in all population and 43% (95% CI: 10%-82%) in patients with nonepithelioid histology. Of all patients, 45.2% (95% CI: 27.3%-64.0%) had stable disease. PFS rate at 24 weeks was 32% (95% CI: 17%-51%). Median PFS was 4.2 months (95% CI: 1.9-6.4 mo). Median OS was 12.5 months (95% CI: 6.3-23.5 mo). There was no grade greater than or equal to four toxicity. Programmed death-ligand 1 expression in the tumor did not correlate with benefit from treatment. Activation of tumor-infiltrating lymphocytes in response to treatment was associated with a trend toward improvement in PFS., Conclusions: Nivolumab and ramucirumab combination was safe and generated PFS and OS rates and ORR that compare favorably with single-agent nivolumab in a similar patient population. The primary end point of 40% ORR was not reached. Further investigation of this regimen in mesothelioma with nonepithelioid histology may be warranted. Clinical Trial Information: NCT03502746., (© 2023 The Authors.)

Background: The incidence of lung cancer in the US has been decreasing but a bigger decline has been observed in men despite similar declines in tobacco use between men and women. Multiple theories have been proposed, including exposure to exogenous estrogens. Our study seeks to understand the relationship between hormone receptors (HR), gender, and the genomic landscape of non-small lung cancer (NSCLC)., Methods: 3,256 NSCLC tumor samples submitted for molecular profiling between 2013-2018 were retrospectively identified and assessed for HR expression. Hormone receptor (HR+) was defined as ≥ 1% nuclear staining of estrogen receptor-alpha (ER-a) or progesterone receptor (PR) by immunohistochemistry. DNA sequencing by NGS included cases sequenced by the Illumina MiSeq hot spot 47 gene panel (n=2753) and Illumina NextSeq 592 gene panel (n=503). An adjusted p-value (q-value) <0.05 was determined significant., Results: HR+ was identified in 18.3% of NSCLC. HR+ occurred more commonly in women compared to men (19.6% vs 11.4%, p <0.0001, q <0.0001). EGFR mutations occurred more commonly in HR+ NSCLC than HR- NSCLC (20.2% vs. 14.6%, p = 0.002, q=0.007). Overall, men with EGFR mutations were affected by HR status with a higher prevalence in HR+ NSCLC while such differences were not seen in women. However, in women ages ≤45, there was a trend towards greater prevalence HR+ NSCLC (25.25% vs. 11.32%, q= 0.0942) and 10/25 (40.0%) of HR+ cases in young women were found to be EGFR mutated. KRAS mutations and ALK+ IHC expression occurred more in HR+ NSCLC whereas TP53 mutations occurred more in HR- NSCLC., Conclusions: Women were more likely to have HR+ NSCLC than men and EGFR and KRAS mutations occurred more commonly in HR+ NSCLC. Additional studies with more strict inclusion criteria for HR+ are warranted to see if there is benefit to targeting HR in these subgroups., Competing Interests: RH is a consultant for Targeted Oncology and received honorarium from DAVA Oncology and The Dedham Group outside of the submitted work. BX is an employee of Janssen Pharmaceuticals. RF is an employee of Caris Life Sciences. L.E.R. reports research funding from Genentech/Roche, Merck Serono, Boehringer Ingelheim, Novartis, Pfizer, Syndax, Loxo, Merck, Bristol Myers Squibb, Guardant Health, Heat Biologics, Amgen, Calithera Biosciences, Daiichi Sankyo/UCB Japan, NantHealth outside of the submitted work. HB consulting fees and advisory board involvement from BMS, Lilly, Genentech, Pfizer, Merck, EMD-Serono, Boehringer Ingelheim, AstraZeneca, Novartis, Genmab, Regeneron, BioNTech, Amgen, Axiom, PharmaMar, Takeda, Mirati, Daiichi, Guardant, Natera, Oncocyte, Beigene, iTEO, Jazz, Janssen, Da Volterra, Puma, BerGenBio, Bayer, and Iobiotech; reports being on the data and safety monitoring board of Takeda, Incyte, Novartis, Springworks, and University of Pennsylvania CAR-T program; reports stock options in Sonnetbio, Inspirna, and Nucleai; reports honoraria from Amgen, Pfizer, Daiichi, Regeneron; reports research support from BMS, Lilly, and Amgen; reports travel support from Amgen, BMS, Merck, Lilly, EMD-Serono, Genentech, and Regeneron outside of the submitted work. CK reports grants from AstraZeneca, BMS, Regeneron, Tesaro, Karyopharm, Debiopharm, Mirati, Genentech, Spectrum, and Merck; grants and personal fees from Novartis and Janssen; and personal fees from PierianDx, Sanofi, Diffusion, Mirati, Jazz Pharmaceuticals outside the submitted work. MN reports personal fees from AstraZeneca, Daiichi Sankyo, Takeda, Novartis, EMD Serono, Janssen, Pfizer, Caris Life Sciences, Blueprint Medicines, Regeneron, Mirati, and Lilly, and non-financial support from An Heart outside of the submitted work. H.M. reports personal fees from AstraZeneca and Genentech and research funding from AstraZeneca outside of the submitted work. AMV reports employment from Caris Life Sciences, personal fees from Bristol Myers Squibb, Caris Life Sciences, Compugen, ConcertoHealthAI, Elsevier, and Inivata; non-financial support from Roche/Genentech and AstraZeneca; and grants from Amgen, Merck, Replimune, EMD Serono, Immunomedics/Gilead outside the submitted work. GL reports stock in Lucence Diagnostics, Xilis, honoraria from Boehringer Ingelheim, Blueprint Medicines, AstraZeneca, Merck, consulting fees from Pfizer, AstraZeneca, research funding from Merck, EMD Serono, AstraZeneca, Blueprint Medicines, Tesaro, Bavarian Nordic, Novartis, G1 Therapeutics, Adaptimmune, BMS, GlaxoSmithKline, AbbVie, Rgenix, Pfizer, Roche, Genentech, Lilly, Janssen, Lucence, Silis, E.R. Squibb Sons, LLC, and non-financial support from Boehringer Ingelheim, Pfizer, E.R. Squibb Sons, LLC, Janssen, Seattle Genetics, Celgene, Ipsen, Pharmacyclics, Merck, AstraZeneca outside of the submitted work. M.A.S reports grants and personal fees from Genentech, AstraZeneca, Merck, and Novartis; personal fees from Jazz, Lilly, Mirati, Regeneron, Guardant, AbbVie, Blueprint, and Janssen; grants from Spectrum, BeiGene, and Daiichi Sankyo during the conduct of the study; grants and personal fees from Genentech, AstraZeneca, Merck, and Novartis outside of the submitted work. AJW reports personal fees from Premier, Beigene, Incyte, Novocure, Janssen, GlaxoSmithKline, Regeneron, and AstraZeneca; other support from BeyondSpring and Odronate outside the submitted work. AIS reports grants and personal fees from Amgen and Mirati; personal fees from Novartis, Pfizer, Merck, and AstraZeneca outside the submitted work. SVL reports personal fees from AstraZeneca, Beigene, Daiichi Sankyo, G1 Therapeutics, Guardant Health, Inivata, Janssen, Jazz Pharmaceuticals, PharmaMar, Regeneron, Takeda, Novartis, Eisai, Sanofi, Catalyst Pharmaceuticals, Candel Therapeutics, MSD Oncology, and Amgen; grants and personal fees from Blueprint, Bristol Myers Squibb, Genentech, Lilly, Merck, Pfizer, Elevation Oncology, Gilead Sciences, and Turning Point Therapeutics; grants from Alkermes, Bayer, Merus, Rain Therapeutics, and RAPT outside of the submitted work. JJN reports personal fees from AstraZeneca, Naveris, AADi, Bioatla, Mindmed, stock in Epic Sciences, Cansera, Quantgene, Indee P/L, and research funding from Merck and Genentech outside of the submitted work. The remaining 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 Hsu, Chen, Xia, Feldman, Cozen, Raez, Borghaei, Kim, Nagasaka, Mamdani, Vanderwalde, Lopes, Socinski, Wozniak, Spira, Liu and Nieva.)

Introduction: ERBB2 or HER2 alterations are found in approximately 2% to 5% of NSCLCs; most are exon 20 insertion mutations. The efficacy and safety of poziotinib, an oral tyrosine kinase inhibitor, were assessed in patients with treatment-naive NSCLC whose tumors harbor HER2 exon 20 insertions., Methods: ZENITH20 is an open-label, multicohort, multicenter, global, phase 2 trial. ZENITH20-C4 enrolled treatment-naive patients with NSCLC with tumors harboring HER2 exon 20 insertions. Poziotinib was administered 16 mg once daily (QD) or 8 mg twice daily (BID). The primary end point was objective response rate (ORR) by independent central review. Secondary and exploratory end points included disease control rate, duration of response, progression-free survival, and safety., Results: A total of 80 patients (16 mg QD, n = 47; 8 mg BID, n = 33) were treated in ZENITH20-C4. ORR was 39% (95% confidence interval [CI]: 28%-50%; 31 of 80), with a disease control rate of 73% (95% CI: 61%-82%; 58 of 80); 80% of the patients experienced tumor reduction. Median duration of response was 5.7 (95% CI: 4.6-11.9) months, and median progression-free survival was 5.6 (95% CI: 5.4-7.3) months. The most common grade 3 treatment-related adverse events were rash (QD, 45%; BID, 39%), stomatitis (QD, 21%; BID, 15%), and diarrhea (QD, 15%; BID, 21%). Among all subtypes of HER2 exon 20 insertions, seven patients (9%) harboring tumors with G778&#95;P780dupGSP had the best clinical outcomes (ORR, 71%)., Conclusions: Poziotinib was found to have clinically meaningful efficacy with a manageable toxicity profile for patients with treatment-naive NSCLC harboring HER2 exon 20 mutations., (Copyright © 2023. Published by Elsevier Inc.)

Background: Historically, limited stage Small Cell Lung Cancer (SCLC) has been treated with concurrent chemoradiation (CRT). While current NCCN guidelines recommend consideration of lobectomy in node-negative cT1-T2 SCLC, data regarding the role of surgery in very limited SCLC is lacking., Methods: Data from the National VA Cancer Cube were compiled. A total of 1,028 patients with pathologically confirmed stage I SCLC were studied. Only 661 patients that either received surgery or CRT were included. Interval-censored Weibull and Cox proportional hazard regression models were used to estimate median overall survival (OS) and hazard ratio (HR), respectively. Two survival curves were compared by a Wald test. Subset analysis was performed based on the location of the tumor in the upper vs. lower lobe as delineated by ICD-10 codes C34.1 and C34.3., Results: Four-hundred and forty-six patients received concurrent CRT; while 223 underwent treatment that contained surgery (93 surgery only, 87 surgery/chemo, 39 surgery/chemo/radiation and 4 surgery/radiation). The median OS for the surgery-inclusive treatment was 3.87 years (95% CI 3.21-4.48) while median OS for the CRT cohort was 2.45 years (95% CI 2.17-2.74). HR of death for surgery-inclusive treatment when compared to CRT is 0.67 (95% CI 0.55-0.81; P < .001). Subset analysis based on the location of the tumor in both the upper or lower lobes showed improved survival with surgery as compared to CRT regardless of the location. HR for the upper lobe was 0.63 (95% CI 0.50-0.80; P < .001) and lower lobe 0.61 (95% CI 0.42-0.87; P = .006). Multivariable regression analysis accounting for age and ECOG-PS shows a HR 0.60 (95% CI 0.43-0.83; P = .002) favoring surgery., Conclusions: Surgery was used in less than a third of patients with stage I SCLC who received treatment. Surgery-inclusive multimodality treatment was associated with a longer overall survival as compared to chemoradiation, independent of age, performance status or tumor location. Our study suggests a more expansive role for surgery in stage I SCLC., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Living guidelines are developed for selected topic areas with rapidly evolving evidence that drives frequent change in recommended clinical practice. Living guidelines are updated on a regular schedule by a standing expert panel that systematically reviews the health literature on a continuous basis; as described in the ASCO Guidelines Methodology Manual. ASCO Living Guidelines follow the ASCO Conflict of Interest Policy Implementation for Clinical Practice Guidelines. Living Guidelines and updates are not intended to substitute for independent professional judgment of the treating provider and do not account for individual variation among patients. See appendix for disclaimers and other important information (Appendix 1 and Appendix 2). Updates are published regularly and can be found at https://ascopubs.org/nsclc-da-living-guideline .

There is a need to improve response rates of immunotherapies in lung adenocarcinoma (AC). Extended (7-14 days) treatment of high glucocorticoid receptor (GR) expressing lung AC cells with dexamethasone (Dex) induces an irreversible senescence phenotype through chronic induction of p27. As the senescence-associated secretory phenotype (SASP) may have either tumor supporting or antitumor immunomodulatory effects, it was interest to examine the effects of Dex-induced senescence of lung AC cells on immune cells. Dex-induced senescence resulted in sustained production of CCL2, CCL4, CXCL1 and CXCL2, both in vitro and in vivo. After Dex withdrawal, secretion of these chemokines by the senescent cells attracted peripheral blood monocytes, T-cells, and NK cells. Following treatment with Dex-induced SASP protein(s), the peripheral blood lymphocytes exhibited higher cell count and tumor cytolytic activity along with enhanced Ki67 and perforin expression in T and NK cells. This cytolytic activity was partially attributed to NKG2D, which was upregulated in NK cells by SASP while its ligand MICA/B was upregulated in the senescent cells. Enhanced infiltrations of T and NK cells were observed in human lung AC xenografts in humanized NSG mice, following treatment with Dex. The findings substantiate the idea that induction of irreversible senescence in high-GR expressing subpopulations of lung AC tumors using Dex pretreatment enhances tumor immune infiltration and may subsequently improve the clinical outcome of current immunotherapies., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: FN-1501, a potent inhibitor of receptor FMS-like tyrosine kinase 3 ( FLT3 ) and CDK4/6 , KIT , PDGFR , VEGFR2 , ALK, and RET tyrosine kinase proteins, has demonstrated significant in vivo activity in various solid tumor and leukemia human xenograft models. Anomalies in FLT3 have an established role as a therapeutic target where the gene has been shown to play a critical role in the growth, differentiation, and survival of various cell types in hematopoietic cancer and have shown promise in various solid tumors. An open-label, Phase I/II study (NCT03690154) was designed to evaluate the safety and PK profile of FN-1501 as monotherapy in patients (pts) with advanced solid tumors and relapsed, refractory (R/R) AML., Methods: Pts received FN-1501 IV three times a week for 2 weeks, followed by 1 week off treatment in continuous 21-day cycles. Dose escalation followed a standard 3 + 3 design. Primary objectives include the determination of the maximum tolerated dose (MTD), safety, and recommended Phase 2 dose (RP2D). Secondary objectives include pharmacokinetics (PK) and preliminary anti-tumor activity. Exploratory objectives include the relationship between pharmacogenetic mutations (e.g., FLT3 , TP53 , KRAS , NRAS , etc.), safety, and efficacy; as well as an evaluation of the pharmacodynamic effects of treatment with FN-1501. Dose expansion at RP2D further explored the safety and efficacy of FN-1501 in this treatment setting., Results: A total of 48 adult pts with advanced solid tumors (N = 47) and AML (N = 1) were enrolled at doses ranging from 2.5 to 226 mg IV three times a week for two weeks in 21-day cycles (2 weeks on and 1 week off treatment). The median age was 65 years (range 30-92); 57% were female and 43% were male. The median number of prior lines of treatment was 5 (range 1-12). Forty patients evaluable for dose-limiting toxicity (DLT) assessment had a median exposure of 9.5 cycles (range 1-18 cycles). Treatment-related adverse events (TRAEs) were reported for 64% of the pts. The most common treatment-emergent adverse events (TEAEs), defined as those occurring in ≥20% of pts, primarily consisted of reversible Grade 1-2 fatigue (34%), nausea (32%), and diarrhea (26%). The most common Grade ≥3 events occurring in ≥5% of pts consisted of diarrhea and hyponatremia. Dose escalation was discontinued due to DLTs of Grade 3 thrombocytopenia (N = 1) and Grade 3 infusion-related reaction (N = 1) occurring in 2 pts. The maximum tolerated dose (MTD) was determined to be 170 mg., Conclusions: FN-1501 demonstrated reasonable safety, tolerability, and preliminary activity against solid tumors in doses up to 170 mg. Dose escalation was terminated based on 2 DLTs occurring at the 226 mg dose level.

Living guidelines are developed for selected topic areas with rapidly evolving evidence that drives frequent change in recommended clinical practice. Living guidelines are updated on a regular schedule by a standing expert panel that systematically reviews the health literature on a continuous basis, as described in the ASCO Guidelines Methodology Manual. ASCO Living Guidelines follow the ASCO Conflict of Interest Policy Implementation for Clinical Practice Guidelines. Living Guidelines and updates are not intended to substitute for independent professional judgment of the treating provider and do not account for individual variation among patients. See Appendix 1 (online only) for disclaimers and other important information. Updates are published regularly and can be found at https://ascopubs.org/nsclc-non-da-living-guideline .

ERCC1/XPF is a heterodimeric DNA endonuclease critical for repair of certain chemotherapeutic agents. We recently identified that ERCC1- and p53-deficient lung cancer cells are tolerant to platinum-based chemotherapy. ATR inhibition synergistically re-stored platinum sensitivity to platinum tolerant ERCC1-deficient cells. Mechanistically we show this effect is reliant upon several functions of ATR including replication fork protection and altered cell cycle checkpoints. Utilizing an inhibitor of replication protein A (RPA), we further demonstrate that replication fork protection and RPA availability are critical for platinum-based drug tolerance. Dual treatment led to increased formation of DNA double strand breaks and was associated with chromosome pulverization. Combination treatment was also associated with increased micronuclei formation which were capable of being bound by the innate immunomodulatory factor, cGAS, suggesting that combination platinum and ATR inhibition may also enhance response to immunotherapy in ERCC1-deficient tumors. In vivo studies demonstrate a significant effect on tumor growth delay with combination therapy compared with single agent treatment. Results of this study have led to the identification of a feasible therapeutic strategy combining ATR inhibition with platinum and potentially immune checkpoint blockade inhibitors to overcome platinum tolerance in ERCC1-deficient, p53-mutant lung cancers., (© The Author(s) 2023. Published by Oxford University Press on behalf of NAR Cancer.)

Background: With recent improvements in survival of cancer patients and common use of high-value care at end of life, the management of cardiovascular disease (CVD) in patients with cancer is increasingly important. To our knowledge, there are no current U.S. data examining how the presence and extent of cancer influence cardiologists' decision making for common cardiovascular conditions., Methods: An anonymous online vignette-based survey of cardiologists was conducted at five U.S. institutions investigating how the extent of gastrointestinal and thoracic malignancies (prior/localized, metastatic) would influence treatment recommendations for atrial fibrillation (AF), aortic stenosis, unstable angina (UA), and obstructive coronary artery disease (CAD)., Results: Thirty-three percent (86/259) of cardiologists completed the survey between September and November 2019. Participants were 67% male, 51% below age 40, and 58% had five or more years of clinical experience. Majority of cardiologists practiced at teaching hospitals (72%) and were noninterventional (63%). Cardiologists were more likely to recommend procedural interventions for patients with localized cancer than for those with metastatic disease: AF (left atrial appendage occlusion: 20% vs. 8%), atrial stenosis (aortic valve repair: 83% vs. 11%), UA (left heart catheter: 70% vs. 27%), and obstructive CAD (percutaneous coronary intervention: 81% vs. 38%). In patients with metastatic cancer, most cardiologists sought an oncology (82%) or a palliative care (69%) consultation. However, a persistent trend of undertreatment in patients with localized cancers and overtreatment in patients with end-of-life disease was apparent., Conclusions: Cardiologists were less likely to recommend invasive cardiovascular therapies to patients with metastatic cancer. This preference pattern likely reflects the influence of comorbidities and quality of life expectation on cardiologists' treatment recommendations but may also be related to the stigma of advanced cancer. Better communication between cardiologists and oncologists is necessary to provide a personalized care of patients with cancer and CVD that would maximize treatment benefit with least morbidity., Competing Interests: P.A. P.: honoraria—Array BioPharma; AstraZeneca; Bayer; Blueprint Medicines; Celgene; Ipsen; Merck; Syncore; TriSalus Life Sciences. Consulting or advisory role—Celgene; Daiichi Sankyo; Ipsen; Merck; Syncore; Taiho Pharmaceutical; TriSalus Life Sciences. Speakers' bureau—Bayer; Celgene; Incyte; Ipsen; Novartis. Travel, accommodations, expenses—Abbvie; Celgene; Rafael Pharmaceuticals. Uncompensated relationships—Caris MPI; Rafael Pharmaceuticals. A.F.S.: consulting or advisory role—Caris Life Sciences; ImaginAb. Speakers' bureau—Caris Life Sciences. Travel, accommodations, expenses—Caris Life Sciences; GE Healthcare; ImaginAb; Inovio Pharmaceuticals; TransTarget. H.M. is a consultant for Zentalis and has been a consultant for AstraZeneca, Caris Life Sciences, and Takeda., (© Ibrahim Azar et al., 2022; Published by Mary Ann Liebert, Inc.)

Importance: The current standard of care for the treatment of small cell lung cancer (SCLC) is concurrent chemoradiation for patients with limited-stage SCLC (LS-SCLC) and chemoimmunotherapy for extensive-stage SCLC (ES-SCLC). The backbone of chemotherapy regimens in both is a platinum-etoposide doublet: cisplatin is traditionally the preferred platinum agent in the curative intent setting, whereas carboplatin is preferred in ES-SCLC because of its favorable toxicity profile., Objective: To determine whether cisplatin is associated with better survival outcomes than carboplatin in treating LS-SCLC and ES-SCLC., Design, Setting, and Participants: In this cohort study, data were compiled from the National Veterans Affairs Central Cancer Registry for patients with SCLC who received platinum-based multiagent chemotherapy between 2000 and 2020 for ES-SCLC and 2000 and 2021 for LS-SCLC. Only patients with pathologically confirmed cases of LS-SCLC who received concurrent chemoradiation and ES-SCLC who received chemotherapy were included., Main Outcomes and Measures: The primary end point was overall survival (OS). The secondary end points included OS by Eastern Cooperative Oncology Group performance status, age, and laterality. Interval-censored Weibull and Cox proportional hazard regression models were used to estimate median OS and hazard ratios (HRs), respectively. Survival curves were compared by a Wald test., Results: A total of 4408 SCLC cases were studied. Most patients were White (3589 patients [81.4%]), male (4252 [96.5%]), and non-Hispanic (4142 [94.0%]); 2262 patients (51.3%) were 60 to 69 years old, followed by 1476 patients (33.5%) aged 70 years or older, 631 patients (14.3%) aged 50 to 59 years, and 39 patients (0.9%) aged 30 to 49 years. Among 2652 patients with ES-SCLC, 2032 were treated with carboplatin-based therapy and 660 received cisplatin; the median OS was 8.45 months (95% CI, 7.75-9.20 months) for cisplatin and 8.51 months (95% CI, 8.07-8.97 months) for carboplatin (HR, 1.01; 95% CI, 0.91-1.12; P = .90). Subset analysis showed no survival difference between the 2 agents in different age or performance status groups except for patients aged 70 years and older, for whom the median OS was 6.36 months (95% CI, 5.31-7.56 months) for cisplatin and 8.47 months (95% CI, 7.79-9.19 months) for carboplatin (HR, 0.77; 95% CI, 0.61-0.96; P = .02). Multivariable analysis of performance status and age did not show a significant difference in survival between the 2 groups (HR, 0.96; 95% CI, 0.83-1.10; P = .54). Of 1756 patients with LS-SCLC, 801 received carboplatin, and 1018 received cisplatin. The median OS was 26.92 months (95% CI, 25.03-28.81 months) for cisplatin and 25.58 months (95% CI, 23.64-27.72 months) for carboplatin (HR, 1.04; 95% CI, 0.94-1.16; P = .46). The median OS was not significantly different between 2 agents according to cancer stage (I-III), performance status, and age groups. A multivariable analysis of factors associated with OS accounting for stage (I-III), performance status, and age did not demonstrate a significant difference in survival between carboplatin and cisplatin in patients with LS-SCLC (HR, 0.995; 95% CI, 0.86-1.15; P = .95)., Conclusions and Relevance: Cisplatin is not associated with a survival advantage over carboplatin among patients with either ES-SCLC or LS-SCLC, irrespective of performance status and age. The favorable toxicity profile of carboplatin and comparable OS support its use in both LS-SCLC and ES-SCLC in clinical practice and may allow more room for combination with novel treatment strategies in clinical trials.

Purpose: To provide evidence-based recommendations updating the 2020 ASCO and Ontario Health (Cancer Care Ontario) guideline on systemic therapy for patients with stage IV non-small-cell lung cancer without driver alterations., Methods: ASCO updated recommendations on the basis of an ongoing systematic review of randomized clinical trials from 2018 to 2021., Results: This guideline update reflects changes in evidence since the previous update. Five randomized clinical trials provide the evidence base. Outcomes of interest include efficacy and safety., Recommendations: In addition to 2020 options for patients with high programmed death ligand-1 (PD-L1) expression (tumor proportion score [TPS] ≥ 50%), nonsquamous cell carcinoma (non-SCC), and performance status (PS) 0-1, clinicians may offer single-agent atezolizumab. With high PD-L1 expression (TPS ≥ 50%), non-SCC, and PS 0-1, clinicians may offer nivolumab and ipilumumab alone or nivolumab and ipilimumab plus chemotherapy. With negative (0%) and low positive PD-L1 expression (TPS 1%-49%), non-SCC, and PS 0-1, clinicians may offer nivolumab and ipilimumab alone or nivolumab and ipilimumab plus chemotherapy. With high PD-L1 expression, SCC, and PS 0-1, clinicians may offer single-agent atezolizumab. With high PD-L1 expression, squamous cell carcinoma (SCC), and PS 0-1, clinicians may offer nivolumab and ipilimumab alone or in combination with two cycles of platinum-based chemotherapy. With negative and low positive PD-L1 expression, SCC, and PS 0-1, clinicians may offer nivolumab and ipilimumab alone or in combination with two cycles of platinum-based chemotherapy. With non-SCC who received an immune checkpoint inhibitor and chemotherapy as first-line therapy, clinicians may offer second-line paclitaxel plus bevacizumab. With non-SCC, who received chemotherapy with or without bevacizumab and immune checkpoint inhibitor therapy, clinicians should offer the options of third-line single-agent pemetrexed, docetaxel, or paclitaxel plus bevacizumab.Additional information is available at www.asco.org/thoracic-cancer-guidelines.