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Purpose: ATM is the most commonly mutated DNA damage and repair gene in non-small cell lung cancer (NSCLC); however, limited characterization has been pursued., Experimental Design: Clinicopathologic, genomic, and treatment data were collected for 5,172 patients with NSCLC tumors which underwent genomic profiling. ATM IHC was performed on 182 NSCLCs with ATM mutations. Multiplexed immunofluorescence was performed on a subset of 535 samples to examine tumor-infiltrating immune cell subsets., Results: A total of 562 deleterious ATM mutations were identified in 9.7% of NSCLC samples. ATM-mutant (ATMMUT) NSCLC was significantly associated with female sex (P = 0.02), ever smoking status (P < 0.001), non-squamous histology (P = 0.004), and higher tumor mutational burden (DFCI, P < 0.0001; MSK, P < 0.0001) compared with ATM-wild-type (ATMWT) cases. Among 3,687 NSCLCs with comprehensive genomic profiling, co-occurring KRAS, STK11, and ARID2 oncogenic mutations were significantly enriched among ATMMUT NSCLCs (Q < 0.05), while TP53 and EGFR mutations were enriched in ATMWT NSCLCs. Among 182 ATMMUT samples with ATM IHC, tumors with nonsense, insertions/deletions, or splice site mutations were significantly more likely to display ATM loss by IHC (71.4% vs. 28.6%; P < 0.0001) compared with tumors with only predicted pathogenic missense mutations. Clinical outcomes to PD-(L)1 monotherapy (N = 1,522) and chemo-immunotherapy (N = 951) were similar between ATMMUT and ATMWT NSCLCs. Patients with concurrent ATM/TP53 mutations had significantly improved response rate and progression-free survival with PD-(L)1 monotherapy., Conclusions: Deleterious ATM mutations defined a subset of NSCLC with unique clinicopathologic, genomic, and immunophenotypic features. Our data may serve as resource to guide interpretation of specific ATM mutations in NSCLC., (©2023 American Association for Cancer Research.)

Medical artificial intelligence (AI) has tremendous potential to advance healthcare by supporting and contributing to the evidence-based practice of medicine, personalizing patient treatment, reducing costs, and improving both healthcare provider and patient experience. Unlocking this potential requires systematic, quantitative evaluation of the performance of medical AI models on large-scale, heterogeneous data capturing diverse patient populations. Here, to meet this need, we introduce MedPerf, an open platform for benchmarking AI models in the medical domain. MedPerf focuses on enabling federated evaluation of AI models, by securely distributing them to different facilities, such as healthcare organizations. This process of bringing the model to the data empowers each facility to assess and verify the performance of AI models in an efficient and human-supervised process, while prioritizing privacy. We describe the current challenges healthcare and AI communities face, the need for an open platform, the design philosophy of MedPerf, its current implementation status and real-world deployment, our roadmap and, importantly, the use of MedPerf with multiple international institutions within cloud-based technology and on-premises scenarios. Finally, we welcome new contributions by researchers and organizations to further strengthen MedPerf as an open benchmarking platform., Competing Interests: Competing interests These authors declare the following competing interests: B.R. is on the Regeneron advisory board. M.M.A. receives consulting fees from Genentech, Bristol-Myers Squibb, Merck, AstraZeneca, Maverick, Blueprint Medicine, Mirati, Amgen, Novartis, EMD Serono and Gritstone and research funding (to the Dana–Farber Cancer Institute) from AstraZeneca, Lilly, Genentech, Bristol-Myers Squibb and Amgen. N.P. is a scientific advisor to Caresyntax. V.N. is employed by Google and owns stock as part of a standard compensation package. The other authors declare no competing interests.

Background: Single-agent PD-(L)1 blockade (IO) alone or in combination with chemotherapy (Chemotherapy-IO) is approved first-line therapies in patients with advanced lung adenocarcinomas (LUADs) with PD-L1 expression ≥1%. These regimens have not been compared prospectively. The primary objective was to compare first-line efficacies of single-agent IO to Chemotherapy-IO in patients with advanced LUADs. Secondary objectives were to explore if clinical, pathological, and genomic features were associated with differential response to Chemotherapy-IO versus IO., Methods: This was a multicenter retrospective cohort study. Inclusion criteria were patients with advanced LUADs with tumor PD-L1 ≥1% treated with first-line Chemotherapy-IO or IO. To compare the first-line efficacies of single-agent IO to Chemotherapy-IO, we conducted inverse probability weighted Cox proportional hazards models using estimated propensity scores., Results: The cohort analyzed included 866 patients. Relative to IO, Chemotherapy-IO was associated with improved objective response rate (ORR) (44% vs 35%, p=0.007) and progression-free survival (PFS) in patients with tumor PD-L1≥1% (HR 0.84, 95% CI 0.72 to 0.97, p=0.021) or PD-L1≥50% (ORR 55% vs 38%, p<0.001; PFS HR 0.68, 95% CI 0.53 to 0.87, p=0.002). Using propensity-adjusted analyses, only never-smokers in the PD-L1≥50% subgroup derived a differential survival benefit from Chemotherapy-IO vs IO (p=0.013). Among patients with very high tumor PD-L1 expression (≥90%), there were no differences in outcome between treatment groups. No genomic factors conferred differential survival benefit to Chemotherapy-IO versus IO., Conclusions: While the addition of chemotherapy to PD-(L)1 blockade increases the probability of initial response, never-smokers with tumor PD-L1≥50% comprise the only population identified that derived an apparent survival benefit with treatment intensification., Competing Interests: Competing interests: JEC has consulted for: AstraZeneca, BMS, Genentech, Merck, Flame Biosciences, Regeneron-Sanofi, Guardant Health, Arcus Biosciences and also declared research funding to institution from: AstraZeneca, BMS, Genentech, Merck, Novartis. CMR has consulted with AbbVie, Amgen, Astra Zeneca, D2G, Daiichi Sankyo, Epizyme, Genentech/Roche, Ipsen, Jazz, Kowa, Lilly, Merck, and Syros. He serves on the scientific advisory boards of Bridge Medicines, Earli, and Harpoon Therapeutics. GJR reports institutional research support from Mirati, Lilly, Takeda, Merck, Roche, Pfizer, and Novartis. MGK reports honoraria from AstraZeneca, Pfizer, Merus, and BerGenBio. MDH reports grants from BMS; and personal fees from Achilles; Adagene; Adicet; Arcus; AstraZeneca; Blueprint; BMS; DaVolterra; Eli Lilly; Genentech/Roche; Genzyme/Sanofi; Janssen; Immunai; Instil Bio; Mana Therapeutics; Merck; Mirati; Natera; Pact Pharma; Shattuck Labs; and Regeneron; as well as equity options from Factorial, Immunai, Shattuck Labs, Arcus, and Avail Bio. A patent filed by Memorial Sloan Kettering related to the use of tumor mutational burden to predict response to immunotherapy (PCT/US2015/062208) is pending and licensed by PGDx. Subsequent to the completion of this work, MDH began as an employee (and equity holder) at AstraZeneca. MA reports that he was a consultant to: Bristol-Myers Squibb, Merck, Genentech, AstraZeneca, Mirati, Novartis, Blueprint Medicine, Abbvie, Gritstone, NextCure, EMD Serono and received research funding (to institute) from: Bristol-Myers Squibb, Eli Lilly, Genentech, AstraZeneca, Amgen. AS reports consulting/advising role to J&J, KSQ therapeutics, BMS, Merck, Enara Bio, Perceptive Advisors, Oppenheimer and Co, Umoja Biopharma, Legend Biotech, Iovance Biotherapeutics, Lyell Immunopharma and Heat Biologics, research funding from GSK (Inst), PACT pharma (Inst), Iovance Biotherapeutics (Inst), Achilles therapeutics (Inst), Merck (Inst), BMS (Inst), Harpoon Therapeutics (Inst) and Amgen (Inst). AS reports consulting/advising role to J&J, KSQ therapeutics, BMS, Merck, Enara Bio, Perceptive Advisors, Oppenheimer and Co, Umoja Biopharma, Legend Biotech, Iovance Biotherapeutics, Lyell Immunopharma and Heat Biologics. Research funding: GSK (Inst), PACT pharma (Inst), Iovance Biotherapeutics (Inst), Achilles therapeutics (Inst), Merck (Inst), BMS (Inst), Harpoon Therapeutics (Inst) and Amgen (Inst)., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Although programmed cell death protein 1 and programmed death-ligand 1 (PD-L1) blockade in combination with platinum-doublet chemotherapy has become a mainstay of first-line treatment for advanced NSCLC, factors associated with efficacy of chemoimmunotherapy (CIT) are not well characterized., Methods: In this multicenter retrospective analysis, clinicopathologic and genomic data were collected from patients with advanced NSCLC (lacking sensitizing genomic alterations in EGFR and ALK) and evaluated with clinical outcomes to first-line CIT., Results: Among 1285 patients treated with CIT, a worsening performance status and increasing derived neutrophil-to-lymphocyte ratio in the blood were associated with a significantly reduced objective response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS). With increasing PD-L1 tumor proportion scores of less than 1%, 1% to 49%, 50% to 89%, and greater than or equal to 90%, there was a progressive improvement in ORR (32.7% versus 37.5% versus 51.6% versus 61.7%, p < 0.001), mPFS (5.0 versus 6.1 versus 6.8 versus 13.0 mo, p < 0.001), and generally mOS (12.9 versus 14.6 versus 34.7 versus 23.1 mo, p = 0.009), respectively. Of 789 NSCLCs with comprehensive genomic data, NSCLCs with a tumor mutational burden (TMB) greater than or equal to the 90th percentile had an improved ORR (53.5% versus 36.4%, p = 0.004), mPFS (10.8 versus 5.5 mo, p < 0.001), and mOS (29.2 versus 13.1 mo, p < 0.001), compared with those with a TMB less than the 90th percentile. In all-comers with nonsquamous NSCLC, the presence of an STK11, KEAP1, or SMARCA4 mutation was associated with significantly worse ORR, mPFS, and mOS to CIT (all p < 0.05); this was also observed in the KRAS-mutant subgroup of NSCLCs with co-occurring mutations in STK11, KEAP1, or SMARCA4 (all p < 0.05). In KRAS wild-type NSCLC, KEAP1 and SMARCA4 mutations were associated with a significantly shorter mPFS and mOS to CIT (all p < 0.05), but STK11 mutation status had no significant impact on mPFS (p = 0.16) or mOS (p = 0.38)., Conclusions: In advanced NSCLC, better patient performance status, low derived neutrophil-to-lymphocyte ratio, increasing PD-L1 expression, a very high TMB, and STK11/KEAP1/SMARCA4 wild-type status are associated with improved clinical outcomes to first-line CIT., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Anti-PD-1/PD-L1 agents have transformed the treatment landscape of advanced non-small cell lung cancer (NSCLC). To expand our understanding of the molecular features underlying response to checkpoint inhibitors in NSCLC, we describe here the first joint analysis of the Stand Up To Cancer-Mark Foundation cohort, a resource of whole exome and/or RNA sequencing from 393 patients with NSCLC treated with anti-PD-(L)1 therapy, along with matched clinical response annotation. We identify a number of associations between molecular features and outcome, including (1) favorable (for example, ATM altered) and unfavorable (for example, TERT amplified) genomic subgroups, (2) a prominent association between expression of inducible components of the immunoproteasome and response and (3) a dedifferentiated tumor-intrinsic subtype with enhanced response to checkpoint blockade. Taken together, results from this cohort demonstrate the complexity of biological determinants underlying immunotherapy outcomes and reinforce the discovery potential of integrative analysis within large, well-curated, cancer-specific cohorts., (© 2023. The Author(s).)

Background: Molecular testing is crucial for the implementation of personalized therapy in patients with lung cancer. Whether routine biomarker testing and access to personalized therapies are limited in some Italian regions is unclear., Patients and Methods: We conducted a national cross-sectional survey between April and June 2019 among Italian oncologists to determine differences in biomarker testing and access to personalized therapies for lung cancer., Results: Based on GIMBE report n. 3/2018, 32 respondents (37.6%) were defined as belonging to budget deficit regions (BDRs) while 53 (62.4%) were from balanced/positive budget regions (BPRs). Diagnostic assays for EGFR/ALK/ROS1 and PD-L1 were reported to be available in 47/53 (88.7%) and 22/32 (68.85%) centers from BPRs and BDRs, respectively (p=0.04).Liquid biopsy accessibility was wider in BPRs than in BDRs (75.5% (40/53) vs. 50% (16/32), respectively; p=0.03). 84/85 (98.8%) oncologists reported that ⩾75% of eligible patients received first-line targeted therapies. Reason for not administering first-line targeted therapies was defined as clinically-unrelated (molecular testing not available or incomplete, pharmacoeconomic issues) by 25/42 (59.5%) of respondents from BPRs and 21/26 (80.6%) from BDRs (p=0.12). Reason for not administering first-line pembrolizumab was defined as clinically-unrelated by 8/43 (18.6%) of respondents from BPRs and 10/22 (45.4%) from BDRs (p=0.039)., Conclusion: Disparities in access to diagnostic assay and first line immunotherapy exist between BPRs and BDRs.

Immune checkpoint inhibitors (ICI) are widely used in advanced nonsmall cell lung cancer (NSCLC) treatment, and the immune-related adverse events involving many organs have been recognized. This article investigated the incidence and imaging characteristics of immune-related thyroiditis in NSCLC patients and correlated the findings with clinical features. A total of 534 NSCLC patients treated with ICI were included. Imaging findings indicative of thyroiditis included changes in morphology and attenuation on restaging chest CT scans and FDG uptake on PET/CT during ICI therapy. Fifty patients (9.4%) had imaging findings indicative of thyroiditis. The median time to onset was 9.5 weeks (range: 0.9-87.4 weeks). The most common finding was diffuse hypoattenuation of the gland (72%), with enlargement in 15 and atrophy in 12 patients. Heterogeneous attenuation of the gland was noted in 12 patients (24%), with enlargement in 7 and atrophy in 1 patient. Two patients (4%) showed increased FDG uptake in the gland on PET/CT without changes in the CT scan. Twenty-two patients who had both clinical and radiologic diagnoses of thyroiditis were more frequently managed with hormone replacement than those with thyroiditis without an imaging abnormality ( p < 0.0001). Therefore, awareness of the imaging findings of immune-related thyroiditis may alert clinicians to the presence of clinically relevant thyroiditis.

Importance: Currently, predictive biomarkers for response to immune checkpoint inhibitor (ICI) therapy in lung cancer are limited. Identifying such biomarkers would be useful to refine patient selection and guide precision therapy., Objective: To develop a machine-learning (ML)-based tumor-infiltrating lymphocytes (TILs) scoring approach, and to evaluate TIL association with clinical outcomes in patients with advanced non-small cell lung cancer (NSCLC)., Design, Setting, and Participants: This multicenter retrospective discovery-validation cohort study included 685 ICI-treated patients with NSCLC with median follow-up of 38.1 and 43.3 months for the discovery (n = 446) and validation (n = 239) cohorts, respectively. Patients were treated between February 2014 and September 2021. We developed an ML automated method to count tumor, stroma, and TIL cells in whole-slide hematoxylin-eosin-stained images of NSCLC tumors. Tumor mutational burden (TMB) and programmed death ligand-1 (PD-L1) expression were assessed separately, and clinical response to ICI therapy was determined by medical record review. Data analysis was performed from June 2021 to April 2022., Exposures: All patients received anti-PD-(L)1 monotherapy., Main Outcomes and Measures: Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were determined by blinded medical record review. The area under curve (AUC) of TIL levels, TMB, and PD-L1 in predicting ICI response were calculated using ORR., Results: Overall, there were 248 (56%) women in the discovery cohort and 97 (41%) in the validation cohort. In a multivariable analysis, high TIL level (≥250 cells/mm2) was independently associated with ICI response in both the discovery (PFS: HR, 0.71; P = .006; OS: HR, 0.74; P = .03) and validation (PFS: HR = 0.80; P = .01; OS: HR = 0.75; P = .001) cohorts. Survival benefit was seen in both first- and subsequent-line ICI treatments in patients with NSCLC. In the discovery cohort, the combined models of TILs/PD-L1 or TMB/PD-L1 had additional specificity in differentiating ICI responders compared with PD-L1 alone. In the PD-L1 negative (<1%) subgroup, TIL levels had superior classification accuracy for ICI response (AUC = 0.77) compared with TMB (AUC = 0.65)., Conclusions and Relevance: In these cohorts, TIL levels were robustly and independently associated with response to ICI treatment. Patient TIL assessment is relatively easily incorporated into the workflow of pathology laboratories at minimal additional cost, and may enhance precision therapy.

Immune checkpoint inhibitors (ICIs) have yielded remarkable responses but often lead to immune-related adverse events (irAEs). Although germline causes for irAEs have been hypothesized, no individual variant associated with developing irAEs has been identified. We carried out a genome-wide association study of 1,751 patients on ICIs across 12 cancer types. We investigated two irAE phenotypes: (1) high-grade (3-5) and (2) all-grade events. We identified 3 genome-wide significant associations (P < 5 × 10 -8 ) in the discovery cohort associated with all-grade irAEs: rs16906115 near IL7 (combined P = 3.6 × 10 -11 ; hazard ratio (HR) = 2.1); rs75824728 near IL22RA1 (combined P = 3.5 × 10 -8 ; HR = 1.8); and rs113861051 on 4p15 (combined P = 1.2 × 10 -8 , HR = 2.0); rs16906115 was replicated in 3 independent studies. The association near IL7 colocalized with the gain of a new cryptic exon for IL7, a critical regulator of lymphocyte homeostasis. Patients carrying the IL7 germline variant exhibited significantly increased lymphocyte stability after ICI initiation, which was itself predictive of downstream irAEs and improved survival., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Constitutive KRAS signalling drives tumorigenesis across several cancer types. In non-small-cell lung cancer (NSCLC) activating KRAS mutations occur in ~30% of cases, and the glycine to cysteine substitution at codon 12 (G12C) is the most common KRAS alteration. Although KRAS mutations have been considered undruggable for over 40 years, the recent discovery of allelic-specific KRAS inhibitors has paved the way to personalized cancer medicine for patients with tumours harbouring these mutations. Here, we review the current treatment landscape for patients with advanced NSCLCs harbouring a KRAS G12C mutation, including PD-(L) 1-based therapies and direct KRAS inhibitors as well as sequential treatment options. We also explore the possible mechanisms of resistance to KRAS inhibition and strategies to overcome resistance in patients with KRAS G12C-mutant NSCLC., Competing Interests: Disclosure and potential conflicts of interest: The authors declare that they have no conflicts of interest relevant to this manuscript. The International Committee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests form for the authors is available for download at: https://www.drugsincontext.com/wp-content/uploads/2022/10/dic.2022-7-4-COI.pdf, (Copyright © 2022 Ricciuti B, Mira A, Andrini E, Scaparone P, Vietti Michelina S, Pecci F, Cantini L, De Giglio A, Lamberti G, Ambrogio C, Metro G.)

The RAS family of small GTPases represents the most commonly activated oncogenes in human cancers. To better understand the prevalence of somatic RAS mutations and the compendium of genes that are coaltered in RAS-mutant tumors, we analyzed targeted next-generation sequencing data of 607,863 mutations from 66,372 tumors in 51 cancer types in the AACR Project GENIE Registry. Bayesian hierarchical models were implemented to estimate the cancer-specific prevalence of RAS and non-RAS somatic mutations, to evaluate co-occurrence and mutual exclusivity, and to model the effects of tumor mutation burden and mutational signatures on comutation patterns. These analyses revealed differential RAS prevalence and comutations with non-RAS genes in a cancer lineage-dependent and context-dependent manner, with differences across age, sex, and ethnic groups. Allele-specific RAS co-mutational patterns included an enrichment in NTRK3 and chromatin-regulating gene mutations in KRAS G12C-mutant non-small cell lung cancer. Integrated multiomic analyses of 10,217 tumors from The Cancer Genome Atlas (TCGA) revealed distinct genotype-driven gene expression programs pointing to differential recruitment of cancer hallmarks as well as phenotypic differences and immune surveillance states in the tumor microenvironment of RAS-mutant tumors. The distinct genomic tracks discovered in RAS-mutant tumors reflected differential clinical outcomes in TCGA cohort and in an independent cohort of patients with KRAS G12C-mutant non-small cell lung cancer that received immunotherapy-containing regimens. The RAS genetic architecture points to cancer lineage-specific therapeutic vulnerabilities that can be leveraged for rationally combining RAS-mutant allele-directed therapies with targeted therapies and immunotherapy., Significance: The complex genomic landscape of RAS-mutant tumors is reflective of selection processes in a cancer lineage-specific and context-dependent manner, highlighting differential therapeutic vulnerabilities that can be clinically translated., (©2022 The Authors; Published by the American Association for Cancer Research.)

Oncogene addiction in non-small-cell lung cancer (NSCLC) has profound diagnostic and therapeutic implications. ALK , ROS1 and NTRK rearrangements are found in about 2-7%, 1-2% and 0.2% of unselected NSCLC samples, respectively; however, their frequency is markedly higher in younger and never-smoker patients with adenocarcinoma histology. Moreover, ALK , ROS1 and NTRK rearrangements are often mutually exclusive with other known driver alterations in NSCLC. Due to such a low frequency, diagnostic screening with accurate and inexpensive techniques such as immunohistochemistry is useful to identify positive cases; however, confirmation with fluorescent in situ hybridization or next-generation sequencing is often required due to higher specificity. In ALK -rearranged NSCLC, sequential treatment with second-generation and third-generation tyrosine kinase inhibitors leads to long-lasting disease control with most patients surviving beyond 5 years with metastatic disease. In ROS1 -rearranged NSCLC, first-line treatment with crizotinib or entrectinib and subsequent treatment with lorlatinib at disease progression leads to similar results in patients with metastatic disease. NTRK1-3 fusions are extremely rare in unselected NSCLC. However, treatment with TRK inhibitors yields high response rates and durable disease control in most patients; diagnostic screening through multigene DNA/RNA-based next-generation sequencing testing is therefore crucial to identify positive cases. This article is part of the Treatment of advanced non-small-cell lung cancer: one size does not fit all Special Issue: https://www.drugsincontext.com/special&#95;issues/treatment-of-advanced-non-small-cell-lung-cancer-one-size-does-not-fit-all/., Competing Interests: Disclosure and potential conflicts of interest: AJ Gelibter received honoraria for advisory board involvement from Astra Zeneca, MSD, BMS, Roche and Boheringer. The authors declare that they have no other conflicts of interest relevant to this manuscript. The International Committee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests form for the authors is available for download at: https://www.drugsincontext.com/wp-content/uploads/2022/09/dic.2022-3-1-COI.pdf, (Copyright © 2022 Marinelli D, Siringo M, Metro G, Ricciuti B, Gelibter AJ.)

Background: Allele-specific KRAS inhibitors are an emerging class of cancer therapies. KRAS-mutant (KRAS MUT ) non-small-cell lung cancers (NSCLCs) exhibit heterogeneous outcomes, driven by differences in underlying biology shaped by co-mutations. In contrast to KRAS G12C NSCLC, KRAS G12D NSCLC is associated with low/never-smoking status and is largely uncharacterized., Patients and Methods: Clinicopathologic and genomic information were collected from patients with NSCLCs harboring a KRAS mutation at the Dana-Farber Cancer Institute (DFCI), Memorial Sloan Kettering Cancer Center, MD Anderson Cancer Center, and Imperial College of London. Multiplexed immunofluorescence for CK7, programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), Foxp3, and CD8 was carried out on a subset of samples with available tissue at the DFCI. Clinical outcomes to PD-(L)1 inhibition ± chemotherapy were analyzed according to KRAS mutation subtype., Results: Of 2327 patients with KRAS-mutated (KRAS MUT ) NSCLC, 15% (n = 354) harbored KRAS G12D . Compared to KRAS non-G12D NSCLC, KRAS G12D NSCLC had a lower pack-year (py) smoking history (median 22.5 py versus 30.0 py, P < 0.0001) and was enriched in never smokers (22% versus 5%, P < 0.0001). KRAS G12D had lower PD-L1 tumor proportion score (TPS) (median 1% versus 5%, P < 0.01) and lower tumor mutation burden (TMB) compared to KRAS non-G12D (median 8.4 versus 9.9 mt/Mb, P < 0.0001). Of the samples which underwent multiplexed immunofluorescence, KRAS G12D had lower intratumoral and total CD8 + PD1 + T cells (P < 0.05). Among 850 patients with advanced KRAS MUT NSCLC who received PD-(L)1-based therapies, KRAS G12D was associated with a worse objective response rate (ORR) (15.8% versus 28.4%, P = 0.03), progression-free survival (PFS) [hazard ratio (HR) 1.51, 95% confidence interval (CI) 1.45-2.00, P = 0.003], and overall survival (OS; HR 1.45, 1.05-1.99, P = 0.02) to PD-(L)1 inhibition alone but not to chemo-immunotherapy combinations [ORR 30.6% versus 35.7%, P = 0.51; PFS HR 1.28 (95%CI 0.92-1.77), P = 0.13; OS HR 1.36 (95%CI 0.95-1.96), P = 0.09] compared to KRAS non-G12D ., Conclusions: KRAS G12D lung cancers harbor distinct clinical, genomic, and immunologic features compared to other KRAS-mutated lung cancers and worse outcomes to PD-(L)1 blockade. Drug development for KRAS G12D lung cancers will have to take these differences into account., (Copyright © 2022 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Background: A proinflammatory diathesis, as measured by the neutrophil to lymphocyte ratio (NLR), heralds an adverse disease course for non-small cell lung cancer (NSCLC)., Methods: This post hoc analysis used data from the phase 3 OAK trial (NCT02008227), which randomized previously treated patients with NSCLC to atezolizumab or docetaxel. The main objective was assessing the differential impact of the pretreatment NLR on overall survival according to the treatment modality. In addition, patients' genomic characteristics were assessed according to their inflammatory status with a circulating free DNA (cfDNA) next-generation sequencing (NGS) analysis., Results: In all, 600 and 575 patients with NLR data were included in the atezolizumab and docetaxel cohorts, respectively, with a median NLR of 4 (interquartile range, 2.6-6.7) for the pooled population. An NLR ≥4 was associated with a positive smoking status (88.6% vs. 78.1%; p < .01), male sex (66.4% vs. 57.6%; p = .01), a worse performance status (71.3% vs. 55.2%; p < .01), a higher number of metastatic sites (63.2% vs. 51.6%; p = .01), squamous histology (32.1% vs. 21.4%; p < .01), and tissue KRAS mutations (30% vs. 18.7%; p = .02) but not with programmed death ligand 1 (PD-L1) expression or the tissue epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) status. A pretreatment NLR ≥4 was more strongly associated with mortality after atezolizumab (adjusted hazard ratio [HR], 1.64; 95% confidence interval [CI], 1.35-2.01) versus docetaxel (HR, 1.32; 95% CI, 1.08-1.60; multivariable [MVA] interaction p = .08). The HR for an increased risk of death for PD-L1-negative/NLR ≥4 patients (compared with PD-L1-positive/NLR <4 patients) was significantly higher in the atezolizumab cohort (MVA interaction p = .01). The exclusion of EGFR/ALK-positive patients further increased the prognostic ability of the baseline NLR in favor of atezolizumab (MVA interaction p = .02). Pretreatment cfDNA data from NGS showed that patients with a high blood tumor mutation burden (cutoff, 16 mut/Mb) had a higher median NLR (4.6 vs. 3.7; p = .01). After adjustments for multiple comparisons, none of the selected variants of interest (EGFR, KRAS, TP53, KEAP1, STK11, SMARCA4, ARID1A, and targeted DNA damage response and repair genes) were significantly associated with the NLR., Conclusions: A low baseline NLR identified patients with NSCLC who derived a greater survival benefit from atezolizumab in comparison with those identified in the docetaxel cohort. The NLR could complement PD-L1 expression in tailoring treatment in this setting., (© 2022 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

The treatment of non-small-cell lung cancer (NSCLC) harbouring EGFR mutations has witnessed some major breakthroughs in the last years. On the one hand, the recent advent of the third-generation tyrosine kinase inhibitor (TKI) osimertinib has reshaped the therapeutic algorithm both in the first-line and adjuvant settings for patients with common activating Ex19del and L858R EGFR mutations. On the other hand, the availability of new comprehensive next-generation sequencing panels, to be used on tumour tissue or on liquid biopsy, has revealed the existence of uncommon as well as compound mutations that partially explain the onset of resistance. Nevertheless, dissecting the biological mechanisms underlying primary and secondary resistance to EGFR-TKIs is crucial to developing alternative therapeutic strategies and further improving patient outcomes. Herein, we provide an updated and comprehensive summary of the latest advancements in the quest for compounds targeting EGFR -mutant advanced non-small-cell lung cancer, discussing the biological rationale underlying the development of a forefront combination of TKI and/or new antibody-drug conjugates. We also suggest a treatment algorithm that could be followed considering the latest published data., Competing Interests: Disclosure and potential conflicts of interest: RB is a consultant/advisory board member for Astra Zeneca, Boehringer Ingelheim, Novartis, MSD, Otsuka, Eli-Lilly, Roche. The remaining authors have no conflicts of interest to disclose. The International Committee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests form for the authors is available for download at: https://www.drugsincontext.com/wp-content/uploads/2022/06/dic.2022-4-1-COI.pdf, (Copyright © 2022 Pecci F, Cantini L, Metro G, Ricciuti B, Lamberti G, Farooqi AA, Berardi R.)

Importance: Although tumor mutation burden (TMB) has been explored as a potential biomarker of immunotherapy efficacy in solid tumors, there still is a lack of consensus about the optimal TMB threshold that best discriminates improved outcomes of immune checkpoint inhibitor therapy among patients with non-small cell lung cancer (NSCLC)., Objectives: To determine the association between increasing TMB levels and immunotherapy efficacy across clinically relevant programmed death ligand-1 (PD-L1) levels in patients with NSCLC., Design, Setting, and Participants: This multicenter cohort study included patients with advanced NSCLC treated with immunotherapy who received programmed cell death-1 (PD-1) or PD-L1 inhibition in the Dana-Farber Cancer Institute (DFCI), Memorial Sloan Kettering Cancer Center (MSKCC), and in the Stand Up To Cancer (SU2C)/Mark Foundation data sets. Clinicopathological and genomic data were collected from patients between September 2013 and September 2020. Data analysis was performed from November 2021 to February 2022., Exposures: Treatment with PD-1/PD-L1 inhibition without chemotherapy., Main Outcomes and Measures: Association of TMB levels with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS)., Results: In the entire cohort of 1552 patients with advanced NSCLC who received PD-1/PD-L1 blockade, the median (range) age was 66 (22-92) years, 830 (53.5%) were women, and 1347 (86.8%) had cancer with nonsquamous histologic profile. A regression tree modeling ORR as a function of TMB identified 2 TMB groupings in the discovery cohort (MSKCC), defined as low TMB (≤19.0 mutations per megabase) and high TMB (>19.0 mutations per megabase), which were associated with increasing improvements in ORR, PFS, and OS in the discovery cohort and in 2 independent cohorts (DFCI and SU2C/Mark Foundation). These TMB levels also were associated with significant improvements in outcomes of immunotherapy in each PD-L1 tumor proportion score subgroup of less than 1%, 1% to 49%, and 50% or higher. The ORR to PD-1/PD-L1 inhibition was as high as 57% in patients with high TMB and PD-L1 expression 50% or higher and as low as 8.7% in patients with low TMB and PD-L1 expression less than 1%. Multiplexed immunofluorescence and transcriptomic profiling revealed that high TMB levels were associated with increased CD8-positive, PD-L1-positive T-cell infiltration, increased PD-L1 expression on tumor and immune cells, and upregulation of innate and adaptive immune response signatures., Conclusions and Relevance: These findings suggest that increasing TMB levels are associated with immune cell infiltration and an inflammatory T-cell-mediated response, resulting in increased sensitivity to PD-1/PD-L1 blockade in NSCLC across PD-L1 expression subgroups.

EGFR exon 20 insertion mutations (Ex20ins) and HER 2 mutations characterize an oncogene-addicted subtype of non-small-cell lung cancer (NSCLC) typically associated with a never or light smoking history, female sex, and adenocarcinoma histology. Nevertheless, Ex20ins-mutant and HER 2-mutant advanced NSCLCs are still difficult to treat for various reasons. First, there is a need for sophisticated diagnostic tools (e.g. next-generation sequencing) that could allow the identification of these relatively rare molecular drivers. Second, highly active targeted drugs that might support a significant change in patients' prognosis when used as first-line therapy are required. In fact, although a few targeted drugs have so far demonstrated antitumour activity for these patients, mainly selective human epidermal receptor-tyrosine kinase inhibitors such as poziotinib and mobocertinib (for both molecular alterations), monoclonal antibodies such as amivantamab (for Ex20ins), and antibody-drug conjugates such as trastuzumab deruxtecan (for HER2 mutants), they are mostly confined for clinical use in pretreated patients. Finally, Ex20ins-targeted or HER2-targeted drugs might be difficult to access in different countries or regions worldwide. In the present review, we provide a concise but comprehensive summary of the challenges that lie ahead as we move towards personalized treatment of Ex20ins-mutant and HER2 -mutant advanced NSCLC, also suggesting a treatment algorithm that could be followed for patients with these genetic aberrations., Competing Interests: Disclosure and potential conflicts of interest: RB declares Data Safety Monitoring Board or Advisory Board participation for AstraZeneca, Boehringer Ingelheim, Novartis, Amgen, Eisai, MSD, Eli Lilly, Roche, GSK and BMS. The authors declare that they have no other conflicts of intereset relevant to this manuscript. The International Committee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests form for the authors is available for download at: https://www.drugsincontext.com/wp-content/uploads/2022/07/dic.2022-3-9-COI.pdf, (Copyright © 2022 Metro G, De Giglio A, Ricciuti B, Siringo M, Marinelli D, Gelibter A, Pecci F, Berardi R, Cantini L, Di Federico A, Andrini E, Mosca M, Lamberti G, Brambilla M, Mountzios G.)

Targeted therapy has dramatically changed the history and outcomes of oncogene-addicted non-small-cell lung cancer (NSCLC). RET rearrangements are typically observed in about 1-2% of NSCLC, resulting in constitutive activation of downstream signalling pathways commonly involved in cell growth and survival. RET -positive NSCLCs are generally associated with young age, non-smoking history, a high rate of brain metastases at diagnosis and an immunologically 'cold' tumour microenvironment. Multi-kinase inhibitors, such as cabozantinib, lenvatinib and vandetanib, showed limited efficacy but significant toxicity mainly linked to off-target effects. In contrast, two RET-selective tyrosine kinase inhibitors (TKIs), selpercatinib and pralsetinib, demonstrated high response rates and manageable safety profiles, and have received FDA approval for the treatment of advanced RET -positive NSCLC regardless of previous lines of treatment. Despite the initial high response rate to RET-TKIs, most patients inevitably develop disease progression due to acquired resistance mechanisms by both on-target or off-target mechanisms. To date, new potent and selective next-generation RET-TKIs are currently being evaluated in ongoing clinical trials in order to overcome resistance and improve efficacy and blood-brain barrier crossing. Genomic recharacterization at progression could help guide treatment choice or enrolment in clinical trials of specific next-generation RET inhibitors. Here, we review the biology, clinicopathological characteristics, targeted therapies and mechanisms of resistance of advanced NSCLC harbouring RET fusions to provide treatment guidance for these patients., Competing Interests: Disclosure and potential conflicts of interest: The authors declare that they have no conflicts of interest relevant to this manuscript. The International Committee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests form for the authors is available for download at: https://www.drugsincontext.com/wp-content/uploads/2022/06/dic.2022-1-5-COI.pdf, (Copyright © 2022 Andrini E, Mosca M, Galvani L, Sperandi F, Ricciuti B, Metro G, Lamberti G.)

The therapeutic approach to patients affected by advanced non-small-cell lung cancer (NSCLC) is facing rapid and continuous evolution. In recent years, the emergence of new treatment strategies, such as immunotherapy and tyrosine kinase inhibitors, has revolutionized the treatment algorithm and the prognosis of patients with NSCLC. In the non-oncogene-addicted disease, immune-checkpoint inhibitors, either as single agents or combined with chemotherapy, outperformed standard chemotherapy in both untreated and previously treated patients. However, many patients still do not derive the expected benefit from current treatments. Despite representing the only biomarker currently used in clinical practice to guide treatment selection, PD-L1 expression has been proven an imperfect predictor of immunotherapy outcomes. The evaluation of clinical factors remains essential to detect patients that would benefit the most from a particular treatment approach, but the identification of additional biological and molecular predictive tools is a priority. Herein, we provide a comprehensive though concise review of the current treatment approaches to advanced NSCLC in patients without molecular driver alterations, with an additional focus on special populations, concomitant medications, and other considerations that might be useful for daily clinical practice., Competing Interests: Disclosure and potential conflicts of interest: The authors declare that they have no conflicts of interest relevant to this manuscript. The International Committee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests form for the authors is available for download at: https://www.drugsincontext.com/wp-content/uploads/2022/06/dic.2022-2-4-COI.pdf, (Copyright © 2022 De Giglio A, Di Federico A, Deiana C, Ricciuti B, Brambilla M, Metro G.)

Background: The combination of radiotherapy (RT) and programmed death 1 inhibitors seems to increase antitumor immune responses., Objective: To assess the outcome and the role of the best combination sequence, i.e. immunotherapy given before, during, and/or after RT, in patients with non-small cell lung cancer (NSCLC)., Methods: We conducted an observational, retrospective analysis of 95 consecutive patients with advanced NSCLC who received any radiotherapy treatment and nivolumab, as clinically indicated. Median overall survival (OS) and the 95% confidence interval (CI) were estimated with the Kaplan-Meier method. Cox model was used to obtain hazard ratio (HR) and associated 95% CI with statistical inference by log-rank statistic., Results: Median OS was 11.9 months (95% CI, 6.6-17.2). Patients who received radiotherapy during an immune checkpoint inhibitor treatment started more than 60 days before showed a better outcome than patients who started immunotherapy over 60 days after RT ending (HR, 2.90 [1.37-6.12], p = 0.005; median OS, 22.4 months vs 8.6 months, p = 0.005). Median progression-free survival was 6.3 months (95% CI, 4.6-8.0)., Conclusions: This study shows that combining irradiation with nivolumab for the treatment of advanced NSCLC leads to improved OS. The optimal time window for the combination of RT and immunotherapy seems to play a critical role for therapeutic antitumor response derived by abscopal effect.

Purpose: Activating missense mutations of KRAS are the most frequent oncogenic driver events in lung adenocarcinoma (LUAD). However, KRAS isoforms are highly heterogeneous, and data on the potential isoform-dependent therapeutic vulnerabilities are still lacking., Experimental Design: We developed an isogenic cell-based platform to compare the oncogenic properties and specific therapeutic actionability of KRAS-mutant isoforms. In parallel, we analyzed clinicopathologic and genomic data from 3,560 patients with non-small cell lung cancer (NSCLC) to survey allele-specific features associated with oncogenic KRAS mutations., Results: In isogenic cell lines expressing different mutant KRAS isoforms, we identified isoform-specific biochemical, biological, and oncogenic properties both in vitro and in vivo. These exclusive features correlated with different therapeutic responses to MEK inhibitors, with KRAS G12C and Q61H mutants being more sensitive compared with other isoforms. In vivo, combined KRAS G12C and MEK inhibition was more effective than either drug alone. Among patients with NSCLCs that underwent comprehensive tumor genomic profiling, STK11 and ATM mutations were significantly enriched among tumors harboring KRAS G12C, G12A, and G12V mutations. KEAP1 mutation was significantly enriched among KRAS G12C and KRAS G13X LUADs. KRAS G13X-mutated tumors had the highest frequency of concurrent STK11 and KEAP1 mutations. Transcriptomic profiling revealed unique patterns of gene expression in each KRAS isoform, compared with KRAS wild-type tumors., Conclusions: This study demonstrates that KRAS isoforms are highly heterogeneous in terms of concurrent genomic alterations and gene-expression profiles, and that stratification based on KRAS alleles should be considered in the design of future clinical trials., (©2022 American Association for Cancer Research.)

Introduction: STK11 and KEAP1 mutations (STK11 mutant [STK11 MUT ] and KEAP1 MUT ) are among the most often mutated genes in lung adenocarcinoma (LUAD). Although STK11 MUT has been associated with resistance to programmed death-(ligand)1 (PD-[L]1) inhibition in KRAS MUT LUAD, its impact on immunotherapy efficacy in KRAS wild-type (KRAS WT ) LUAD is currently unknown. Whether KEAP1 MUT differentially affects outcomes to PD-(L)1 inhibition in KRAS MUT and KRAS WT LUAD is also unknown., Methods: Clinicopathologic and genomic data were collected from September 2013 to September 2020 from patients with advanced LUAD at the Dana-Farber Cancer Institute/Massachusetts General Hospital cohort and the Memorial Sloan Kettering Cancer Center/MD Anderson Cancer Center cohort. Clinical outcomes to PD-(L)1 inhibition were analyzed according to KRAS, STK11, and KEAP1 mutation status in two independent cohorts. The Cancer Genome Atlas transcriptomic data were interrogated to identify differences in tumor gene expression and tumor immune cell subsets, respectively, according to KRAS/STK11 and KRAS/KEAP1 comutation status., Results: In the combined cohort (Dana-Farber Cancer Institute/Massachusetts General Hospital + Memorial Sloan Kettering Cancer Center/MD Anderson Cancer Center) of 1261 patients (median age = 61 y [range: 22-92], 708 women [56.1%], 1065 smokers [84.4%]), KRAS mutations were detected in 536 cases (42.5%), and deleterious STK11 and KEAP1 mutations were found in 20.6% (260 of 1261) and 19.2% (231 of 1202) of assessable cases, respectively. In each independent cohort and in the combined cohort, STK11 and KEAP1 mutations were associated with significantly worse progression-free (STK11 hazard ratio [HR] = 2.04, p < 0.0001; KEAP1 HR = 2.05, p < 0.0001) and overall (STK11 HR = 2.09, p < 0.0001; KEAP1 HR = 2.24, p < 0.0001) survival to immunotherapy uniquely among KRAS MUT but not KRAS WT LUADs. Gene expression ontology and immune cell enrichment analyses revealed that the presence of STK11 or KEAP1 mutations results in distinct immunophenotypes in KRAS MUT , but not in KRAS WT , lung cancers., Conclusions: STK11 and KEAP1 mutations confer worse outcomes to immunotherapy among patients with KRAS MUT but not among KRAS WT LUAD. Tumors harboring concurrent KRAS/STK11 and KRAS/KEAP1 mutations display distinct immune profiles in terms of gene expression and immune cell infiltration., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: It has been recognized that increasing body mass index (BMI) is associated with improved outcome from immune checkpoint inhibitors (ICIs) in patients with various malignancies including non-small cell lung cancer (NSCLC). However, it is unclear whether baseline BMI may influence outcomes from first-line chemoimmunotherapy combinations., Methods: In this international multicenter study, we evaluated the association between baseline BMI, progression-free survival (PFS) and overall survival (OS) in a cohort of patients with stage IV NSCLC consecutively treated with first-line chemoimmunotherapy combinations. BMI was categorized according to WHO criteria., Results: Among the 853 included patients, 5.3% were underweight; 46.4% were of normal weight; 33.8% were overweight; and 14.5% were obese. Overweight and obese patients were more likely aged ≥70 years (p=0.00085), never smokers (p<0.0001), with better baseline Eastern Cooperative Oncology Group-Performance Status (p=0.0127), and had lower prevalence of central nervous system (p=0.0002) and liver metastases (p=0.0395). Univariable analyses showed a significant difference in the median OS across underweight (15.5 months), normal weight (14.6 months), overweight (20.9 months), and obese (16.8 months) patients (log-rank: p=0.045, log rank test for trend: p=0.131), while no difference was found with respect to the median PFS (log-rank for trend: p=0.510). Neither OS nor PFS was significantly associated with baseline BMI on multivariable analysis., Conclusions: In contrast to what was observed in the context of chemotherapy-free ICI-based regimens, baseline BMI does not affect clinical outcomes from chemoimmunotherapy combinations in patients with advanced NSCLC., Competing Interests: Competing interests: AC received speaker fees and grant consultancies from AstraZeneca, MSD, BMS, Roche, Novartis, and EISAI. GLB received grant consultancies from AstraZeneca and Astellas Pharma. LM reports receiving research grant/funding (self) from Bristol-Myers Squibb, Boehringer Ingelheim, Amgen, Stilla, and Inivata; serving in advisory/consultancy for Roche and Takeda; receiving honoraria (self) from Bristol-Myers Squibb, Takeda, and Roche; receiving travel/accommodation/expenses from Roche, Bristol-Myers Squibb, Takeda, and AstraZeneca; and having non-remunerated activities from AstraZeneca. AA received consulting fees from BMS, AstraZeneca, Boehringer-Ingelheim, Roche, MSD, Pfizer, Eli Lilly, and Astellas; speakers fees from Eli Lilly and AstraZeneca. MT received speaker and consultant fees from AstraZeneca, Pfizer, Eli-Lilly, BMS, Novartis, Roche, MSD, Boehringer Ingelheim, Otsuka, Takeda, Pierre Fabre, Amgen, and Merck. MT received institutional research grants from AstraZeneca, and Boehringer Ingelheim. CC received honorarium/educational grants from Lilly, Pfizer, and Boehringer-Inghelheim. DJP received lecture fees from ViiV Healthcare and Bayer Healthcare and travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche, AstraZeneca, DaVolterra, and BMS; and received research funding (to institution) from MSD and BMS. All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The timing of immune-related adverse events (irAE) associated with immune checkpoint inhibitors (ICI) is highly variable. Although the development of irAE has been associated with ICI clinical benefit, how irAE timing influences this association is unknown. We analyzed two independent cohorts including 154 patients with non-small cell lung cancer (NSCLC) treated with PD-1/PD-L1 inhibitors at a single institution (UTSW cohort) and a multi-center cohort of 433 patients with NSCLC who received second-line anti-PD-1/PD-L1 therapy (Global cohort) to assess the association between ICI outcomes and irAE timing. In both cohorts, late-onset irAE occurring more than 3 months after ICI initiation compared to irAE occurring earlier were associated with greater rates of radiographic response (UTSW cohort, 41% versus 28%, P = .26; Global cohort, 60% versus 35%, P = .02), longer progression-free (UTSW cohort, 13.7 versus 5.6 months, P < .01; Global cohort, not reached versus 6.0 months, P < .01) and overall survival (UTSW cohort, 30.9 versus 14.6 months, P < .01; Global cohort, not reached versus 10.6 months, P < .01). Modified landmark analysis at 6 months confirmed an overall survival difference between early- and late-onset irAE. Late-onset irAE was similarly associated with greater response rates and prolonged survival in a cohort of 130 patients with non-NSCLC malignancies, suggesting a conserved association across tumor types. The favorable association between irAE and ICI clinical outcomes may be attributed to later-onset events, which is not wholly explained by survivor bias. These results allude to a distinct biology between early- and late-onset irAE and may guide clinician expectations and thresholds for continuing or modifying immunotherapy., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Objectives: Axillary lymphadenopathy from coronavirus disease 2019 (COVID-19) vaccine is an emerging phenomenon during unprecedented mass vaccinations, which can be incidentally found on computed tomography (CT) scans. This study investigated the incidence, predisposing factors, and imaging characteristics of vaccine-related axillary lymphadenopathy in patients with thoracic malignancy who underwent CT scans before and after COVID-19 vaccinations., Methods: The study included patients with thoracic malignancies who received two doses of mRNA-based COVID-19 vaccinations and had prevaccine and postvaccine chest CT scans. Postvaccine chest CT scan results were reviewed for increase in size of lymph nodes in the axilla and subpectoral areas, comparing with the prevaccine scan results. The cases with lymphadenopathy were further reviewed independently by two radiologists referring to clinical information to find whether lymphadenopathy was attributed to the vaccinations., Results: Vaccine-related axillary lymphadenopathy was noted in 21 of 232 patients (9.0%). The median short-axis diameter of the largest node was 7 mm (range: 5-14 mm). The median number of increased nodes was 4 (range: 1-10). The median time to the postvaccine scan revealing lymphadenopathy was 1.7 weeks (range: -2.9 to 6.6) from the second dose. Vaccine-related lymphadenopathy was noted more often in women than in men (18 of 144, 12.5% versus 3 of 88, 3.4%, respectively; p = 0.019) and with mRNA-1273 vaccines than BNT162b2 vaccines (6 of 28, 21% versus 15 of 204, 7.4%, respectively; p = 0.026)., Conclusions: The incidence of lymphadenopathy was 9%, with a median onset time of 1.7 weeks after the second vaccine dose. Female sex and vaccine type (mRNA-1273 vaccine) were associated with higher frequency of lymphadenopathy, providing initial observations to inform further investigations in larger cohorts., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Importance: Geriatric (aged ≥80 years) patients are historically underrepresented in cancer clinical trials. Little is known about the efficacy of immune checkpoint inhibitors (ICIs) in geriatric patients. These agents are associated with immune-related adverse events (irAEs), which may be particularly associated with morbidity in this population., Objective: To provide insight into the clinical outcomes and safety of ICIs among geriatric patients (aged ≥80 years) with cancer., Design, Setting, and Participants: A Multicenter, international retrospective study of 928 geriatric patients with different tumors treated with single-agent ICIs between 2010 to 2019 from 18 academic centers in the US and Europe. Analyses were conducted from January 2021 to April 2021., Main Outcomes and Measures: Clinical outcomes and irAE patterns in geriatric patients treated with single-agent ICIs., Results: Median (range) age of the 928 patients at ICI initiation was 83.0 (75.8-97.0) years. Most patients (806 [86.9%]) were treated with anti-programmed cell death 1 therapy. Among the full cohort, the 3 most common tumors were non-small cell lung cancer (NSCLC, 345 [37.2%]), melanoma (329 [35.5%]), and genitourinary (GU) tumors (153 [16.5%]). Objective response rates for patients with NSCLC, melanoma, and GU tumors were 32.2%, 39.3%, and 26.2%, respectively. Median PFS and OS, respectively, were 6.7 and 10.9 months (NSCLC), 11.1 and 30.0 months (melanoma), and 6.0 and 15.0 months (GU). Within histologically specific subgroups (NSCLC, melanoma, and GU), clinical outcomes were similar across age subgroups (aged <85 vs ≥85 years). Among all 928 patients, 383 (41.3%) experienced ≥1 irAE(s), including 113 (12.2%) that were reported to be grade (G) 3 to 4 based on Common Terminology Criteria for Adverse Events (version 5.0). The median time to irAE onset was 9.8 weeks; 219 (57%) occurred within the first 3 months after ICI initiation. Discontinuation of treatment with ICIs owing to irAEs occurred in 137 (16.1%) patients. There was no significant difference in the rate of irAEs among patients aged younger than 85, 85 to 89, and 90 years or older. Despite the similar rate of G3 or higher irAEs, ICIs were discontinued due to irAEs more than twice as often among patients aged 90 years or older compared with patients younger than 90 years (30.9% vs 15.1%, P = .008)., Conclusions and Relevance: The findings of this international cohort study suggest that treatment with ICIs may be effective and generally well tolerated among older patients with cancer, though ICI discontinuation owing to irAEs was more frequent with increasing age.

Background: Despite the therapeutic efficacy of immune checkpoint inhibitors (ICIs) in a subset of patients, consistent and easily obtainable predictors of efficacy remain elusive., Methods: This study was conducted on 644 advanced non-small cell lung cancer (NSCLC) patients treated with ICI monotherapy between April 2013 and September 2020 at the Dana-Farber Cancer Institute and Brigham and Women's Hospital. Patient smoking history, clinicopathological characteristics, tumor mutation burden (TMB) by clinical targeted next-generation sequencing, and programmed death ligand-1 (PD-L1) tumor proportion score (TPS) by immunohistochemistry were prospectively collected. The association of smoking history with clinical outcomes of ICI monotherapy in metastatic NSCLC patients was evaluated after adjusting for other potential predictors. All statistical tests were 2-sided., Results: Of 644 advanced NSCLC patients, 105 (16.3%) were never smokers, 375 (58.2%) were former smokers (median pack-years = 28), and 164 (25.4%) were current smokers (median pack-years = 40). Multivariable logistic and Cox proportional hazards regression analyses suggested that doubling of smoking pack-years is statistically significantly associated with improved clinical outcomes of patients treated with ICI monotherapy (objective response rate odds ratio = 1.21, 95% confidence interval [CI] = 1.09 to 1.36, P < .001; progression-free survival hazard ratio = 0.92, 95% CI = 0.88 to 0.95, P < .001; overall survival hazard ratio = 0.94, 95% CI = 0.90 to 0.99, P = .01). Predictive models incorporating pack-years and PD-L1 TPS yielded additional information and achieved similar model performance compared with using TMB and PD-L1 TPS., Conclusions: Increased smoking exposure had a statistically significant association with improved clinical outcomes in metastatic NSCLC treated with ICI monotherapy independent of PD-L1 TPS. Pack-years may serve as a consistent and readily obtainable surrogate of ICI efficacy when TMB is not available to inform prompt clinical decisions and allow more patients to benefit from ICIs., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: Next-generation sequencing (NGS) is an important component of first-line treatment selection for metastatic non-small-cell lung cancer (NSCLC) and is typically ordered by medical oncologists in the outpatient setting after the pathologic diagnosis has been established. Time to treatment initiation is an important clinical challenge, especially for patients with rapidly progressive disease., Methods: Plasma cell-free DNA (cfDNA) NGS was performed on 20 patients with suspected metastatic NSCLC hospitalized at an academic cancer center, before pathologic diagnosis. Clinicopathologic and treatment data were analyzed. Time from pathologic diagnosis to genotyping result was compared with standard care groups who underwent plasma or tumor NGS in routine clinical care., Results: The median time from pathologic diagnosis to the plasma cfDNA NGS result was 3 days in the study cohort, versus 18 days and 35.5 days in the standard care plasma and tumor NGS groups, respectively. 68.4% of evaluable patients had metastatic NSCLC, and 21.1% had another advanced solid tumor. Forty-five percent of plasma cfDNA results demonstrated actionable or informative genomic variants, and 20% of patients received standard or investigational first-line targeted therapy as a direct result of the plasma cfDNA NGS., Conclusion: Plasma cfDNA NGS before pathologic diagnosis in hospitalized patients with suspected metastatic NSCLC results in substantially shorter time to genotyping result compared with standard outpatient workflows. This provides important initial evidence for the use of plasma-based genotyping earlier in the diagnostic journey, especially for patients with clinically aggressive disease. Additional studies and innovative approaches toward regulatory and reimbursement considerations are needed., Competing Interests: Michael L. ChengHonoraria: The Lynx Group, WebMD, Potomac Center for Medical EducationConsulting or Advisory Role: AstraZeneca, Inivata, Boehringer IngelheimResearch Funding: Palleon PharmaceuticalsTravel, Accommodations, Expenses: Daiichi Sankyo, AstraZeneca, Genzyme Kenneth L. KehlHonoraria: Roche, IBMConsulting or Advisory Role: Aetion Mark M. AwadConsulting or Advisory Role: Genentech, Merck, Pfizer, Boehringer Ingelheim, Abbvie, AstraZeneca/MedImmune, Clovis Oncology, Nektar, Bristol Myers Squibb, ARIAD, Foundation Medicine, Syndax, Novartis, Blueprint Medicines, Maverick Therapeutics, Achilles Therapeutics, Neon Therapeutics, Hengrui Therapeutics, Gritstone Oncology, Archer, Mirati Therapeutics, NextCure, EMD Serono, AstraZeneca, PanasonicResearch Funding: Genentech/Roche, Lilly, AstraZeneca, Bristol Myers Squibb Lynette M. ShollStock and Other Ownership Interests: Moderna TherapeuticsConsulting or Advisory Role: EMD Serono, GenentechResearch Funding: Roche/Genentech Cloud P. PaweletzStock and Other Ownership: XSphera BiosciencesHonoraria: Bio-RadConsulting or Advisory Role: DropWorks, XSphera BiosciencesResearch Funding: Daiichi Sankyo, Bicycle Therapeutics, Transcenta, Bicara Therapeutics, AstraZeneca, Intellia Therapeutics, Janssen Pharmaceuticals, Array BiopharmaPatents, Royalties, Other Intellectual Property: DFCI has a patent pending titled “Non-invasive blood-based monitoring of genomic alterations in cancer” on which I am a co-inventor Pasi A. JänneStock and Other Ownership Interests: Gatekeeper Pharmaceuticals, Loxo OncologyConsulting or Advisory Role: Pfizer, Boehringer Ingelheim, AstraZeneca, Merrimack, Chugai Pharma, Roche/Genentech, LOXO, Mirati Therapeutics, Araxes Pharma, Ignyta, Lilly, Takeda, Novartis, Biocartis, Voronoi, SFJ Pharmaceuticals Group, Sanofi, Daiichi Sankyo, Silicon Therapeutics, Nuvalent Inc, Eisai, BayerResearch Funding: AstraZeneca, Astellas Pharma, Daiichi Sankyo, Lilly, Boehringer Ingelheim, Puma Biotechnology, Takeda, Revolution MedicinesPatents, Royalties, Other Intellectual Property: I am a co-inventor on a DFCI owned patent on EGFR mutations licensed to Lab Corp. I receive post-marketing royalties from this inventionNo other potential conflicts of interest were reported.

Background: An elevated peripheral blood derived neutrophil-to-lymphocyte ratio (dNLR) is a negative prognostic marker for patients with non-small cell lung cancer (NSCLC) receiving chemotherapy and immune checkpoint inhibitors. Whether dNLR is also associated with clinical outcomes to first-line pembrolizumab among patients with NSCLC and a programmed cell death ligand 1 (PD-L1) Tumor Proportion Score (TPS) of ≥50% is uncertain. How dNLR relates to the tumor immune microenvironment is also unclear., Methods: In two participating academic centers, we retrospectively analyzed the dNLR (defined as the absolute neutrophil count/white cell count - absolute neutrophil count) prior to initiation of first-line pembrolizumab in patients with metastatic NSCLC and a PD-L1 TPS ≥50% and lacking genomic alterations in EGFR and ALK . An unbiased recursive partitioning algorithm was used to investigate an optimal dNLR cut-off with respect to objective response rate (ORR). Multiplexed immunofluorescence for CD8+, FOXP3+, PD-1+, and PD-L1 was performed on a separate cohort of NSCLCs to determine the immunophenotype associated with dNLR., Results: A total of 221 patients treated with first-line pembrolizumab were included in this study. The optimal dNLR cut-off to differentiate treatment responders from non-responders was 2.6. Compared with patients with a dNLR ≥2.6 (n=97), patients with dNLR <2.6 (n=124) had a significantly higher ORR (52.4% vs 24.7%, p<0.001), a significantly longer median progression-free survival (mPFS 10.4 vs 3.4 months, HR 0.48, 95% CI 0.35 to 0.66, p<0.001), and a significantly longer median overall survival (mOS 36.6 vs 9.8 months, HR 0.34, 95% CI 0.23 to 0.49, p<0.001). After adjusting for age, sex, tobacco use, performance status, histology, serum albumin level, oncogenic driver status, and PD-L1 distribution (50%-89% vs ≥90%), a dNLR <2.6 was confirmed to be an independent predictor of longer mPFS (HR 0.47, 95% CI 0.33 to 0.67, p<0.001) and mOS (HR 0.32, 95% CI 0.21 to 0.49, p<0.001). Among advanced NSCLC samples with a PD-L1 TPS of ≥50%, those with a dNLR <2.6 had significantly higher numbers of tumor-associated CD8+, FOXP3+, PD-1 +immune cells, and PD-1 +CD8+T cells than those with a dNLR ≥2.6., Conclusions: Among patients with NSCLC and a PD-L1 TPS ≥50%, a low dNLR has a distinct immune tumor microenvironment and more favorable outcomes to first-line pembrolizumab., Competing Interests: Competing interests: MMA serves as a consultant to Merck, Bristol-Myers Squibb, Genentech, AstraZeneca, Nektar, Maverick, Blueprint Medicine, Syndax, Abbvie, Gritstone, ArcherDX, Mirati, NextCure, and EMD Serono. Research Funding: Bristol-Myers Squibb, Lilly, Genentech and AstraZeneca. JFG has served as a compensated consultant or received honoraria from Bristol-Myers Squibb, Genentech, Ariad/Takeda, Loxo, Pfizer, Incyte, Novartis, Merck, Agios, Amgen, Jounce, Karyopharm, GlydeBio, Regeneron, Oncorus, Helsinn, Jounce, Array, and Clovis Oncology, has an immediate family member who is an employee with equity in Ironwood Pharmaceuticals, has received research funding from Novartis, Genentech/Roche, and Ariad/Takeda, and institutional research support from Tesaro, Moderna, Blueprint, BMS, Jounce, Array, Adaptimmune, Novartis, Genentech/Roche, Alexo and Merck. JJL has served as a compensated consultant for Genentech, C4 Therapeutics, Blueprint 2 Medicines, Nuvalent, Turning Point Therapeutics, and Elevation Oncology; received honorarium 3 and travel support from Pfizer; received institutional research funds from Hengrui Therapeutics, 4 Turning Point Therapeutics, Neon Therapeutics, Relay Therapeutics, Bayer, Elevation 5 Oncology, Roche, and Novartis; received CME funding from OncLive, MedStar Health, and 6 Northwell Health. MN Consultant to Daiichi Sankyo, AstraZeneca; Research grant from Merck, Canon Medical Systems, AstraZeneca, Daiichi Sankyo; Honorarium from Roche. MN is also supported by R01CA203636 and U01CA209414 (NCI)). JVA, BR, SLA, AAB, MS, VRV, JL, MMT, KP, BS, KDF, and SJR: nothing to disclose., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The SWItch/Sucrose Nonfermentable (SWI/SNF) chromatin remodeling complex acts as a regulatory component of transcription, and inactivating mutations (muts) within the complex are implicated in genomic instability, higher tumor mutational burden, and an aggressive cancer phenotype. Whether SMARCA4 and other SWI/SNF alterations are independent prognostic factors or associated with clinical outcomes to immune checkpoint inhibitors (ICIs) in NSCLC remains unclear., Methods: We collected clinicopathologic and genomic data from patients with NSCLC who underwent targeted next-generation sequencing at the Dana-Farber Cancer Institute. Tumors were characterized on the basis of the presence or absence of muts across a set of six SWI/SNF genes (ARID1A, ARID1B, ARID2, PBRM1, SMARCA4, and SMARCB1)., Results: Of 2689 patients with NSCLC, 20.6% (N = 555) had SWI/SNF genomic alterations. Compared with SWI/SNF wild-type (wt) NSCLC, patients with SWI/SNF-mutant NSCLCs had a lower prevalence of concurrent targetable driver muts (33.2% versus 22.2%; p < 0.001), a higher tumor mutational burden (median 8.5 versus 12.2 muts/megabase; p < 0.001), and a shorter median overall survival (mOS) from the time of advanced disease diagnosis (25.0 versus 19.3 mo, p = 0.01); the detrimental effect in OS seemed to be largely driven by SMARCA4 muts (mOS: 25.0 for SMARCA4 wt versus 15.6 mo for SMARCA4 mutant; p < 0.001). Among 532 patients who received ICIs, 25.5% (N = 136) harbored SWI/SNF muts. From the start of immunotherapy, there was no difference in objective response rate (ORR = 19.9% versus 25.0%, p = 0.2), median progression-free survival (mPFS = 3.0 versus 3.0 mo, hazard ratio [HR] = 0.96 [95% confidence interval [CI] = 0.77-1.18], p = 0.7), or mOS (13.1 versus 9.5 mo, HR = 0.81 [95% CI: 0.64-1.02], p = 0.07) in SWI/SNF-wt versus SWI/SNF-mutant NSCLC, respectively. Nevertheless, among KRAS-mutant NSCLCs treated with ICIs (N = 176), a concurrent SWI/SNF mut (N = 39) conferred a numerically lower ORR (21.9% versus 12.8%, p = 0.2), a significantly shorter mPFS (4.1 versus 1.8 mo, HR = 0.57 [95% CI: 0.38-0.84], p = 0.005), and a significantly shorter mOS (15.5 versus 8.2 mo, HR = 0.56 [95% CI: 0.36-0.86], p = 0.008). The deleterious effect on immunotherapy outcomes in KRAS-mutant NSCLC was most pronounced in the SMARCA4-mutant subset (N = 17), with a lower ORR (22% versus 0%, p = 0.03), a significantly shorter mPFS (4.1 versus 1.4 mo, HR = 0.25 [95% CI: 0.14-0.42], p < 0.001), and a significantly shorter mOS (15.1 versus 3.0 mo, HR = 0.29 [95% CI: 0.17-0.50], p < 0.001) compared with SMARCA4-wt KRAS-mutant NSCLCs., Conclusions: Although there were no associations between SWI/SNF mut status and immunotherapy efficacy in the overall NSCLC cohort, the presence of a SMARCA4 alteration may confer a worse outcome to immunotherapy among KRAS-mutant NSCLCs., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of lung cancer. However, their clinical benefit is limited to a minority of patients. To unravel immune-related factors that are predictive of sensitivity or resistance to immunotherapy, we performed a gene expression analysis by RNA-Seq using the Oncomine Immuno Response Assay (OIRRA) on a total of 33 advanced NSCLC patients treated with ICI evaluating the expression levels of 365 immune-related genes. We found four genes (CD1C, HLA-DPA1, MMP2, and TLR7) downregulated ( p < 0.05) and two genes (IFNB1 and MKI67) upregulated ( p < 0.05) in ICI-Responders compared to ICI-Non-Responders. The Bayesian enrichment computational analysis showed a more complex interaction network that involved 10 other genes (IFNA1, TLR4, CD40, TLR2, IL12A, IL12B, TLR9, CD1E, IFNG, and HLA-DPB1) correlated with different functional groups. Five main pathways were identified (FDR < 0.0001). High TLR7 expression levels were significantly associated with a lack of response to immunotherapy ( p < 0.0001) and worse outcome in terms of both PFS ( p < 0.001) and OS ( p = 0.03). The multivariate analysis confirmed TLR7 RNA expression as an independent predictor for both poor PFS (HR = 2.97, 95% CI, 1.16-7.6, p = 0.023) and OS (HR = 2.2, 95% CI, 1-5.08, p = 0.049). In conclusion, a high TLR7 gene expression level was identified as an independent predictor for poor clinical benefits from ICI. These data could have important implications for the development of novel single/combinatorial strategies TLR-mediated for an efficient selection of "individualized" treatments for NSCLC in the era of immunotherapy.

Lung carcinogenesis is a complex and stepwise process involving accumulation of genetic mutations in signaling and oncogenic pathways via interactions with environmental factors and host susceptibility. Tobacco exposure is the leading cause of lung cancer, but its relationship to clinically relevant mutations and the composite tumor mutation burden (TMB) has not been fully elucidated. In this study, we investigated the dose-response relationship in a retrospective observational study of 931 patients treated for advanced-stage non-small cell lung cancer (NSCLC) between April 2013 and February 2020 at the Dana Farber Cancer Institute and Brigham and Women's Hospital. Doubling smoking pack-years was associated with increased KRAS G12C and less frequent EGFR del19 and EGFR L858R mutations, whereas doubling smoking-free months was associated with more frequent EGFR L858R . In advanced lung adenocarcinoma, doubling smoking pack-years was associated with an increase in TMB, whereas doubling smoking-free months was associated with a decrease in TMB, after controlling for age, gender, and stage. There is a significant dose-response association of smoking history with genetic alterations in cancer-related pathways and TMB in advanced lung adenocarcinoma. SIGNIFICANCE: This study clarifies the relationship between smoking history and clinically relevant mutations in non-small cell lung cancer, revealing the potential of smoking history as a surrogate for tumor mutation burden., (©2021 American Association for Cancer Research.)

Background: Intrinsic or acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is common, thus strategies for the management of EGFR-TKIs resistance are urgently required. Ferroptosis is a recently discovered form of cell death that has been implicated in tumorigenesis and resistance treatment. Accumulating evidence suggests that ferroptosis can be therapeutically exploited for the treatment of solid tumors; however, whether ferroptosis can be targeted to treat EGFR mutant lung cancer and/or overcome the resistance to EGFR-TKIs is still unknown., Methods: The effect of ferroptosis inducers on a panel of EGFR mutant lung cancer cell lines, including those with EGFR-TKI intrinsic and acquired (generated by long-term exposure to the third-generation EGFR-TKI osimertinib), was determined using cytotoxicity assays. Further, drug candidates to enhance the effect of ferroptosis inducers were screened through implementing WGCNA (weighted gene co-expression network analysis) and CMAP (connectivity map) analysis. Flow cytometry-based apoptosis and lipid hydroperoxides measurement were used to evaluate the cell fates after treatment., Results: Compared with EGFR-TKI-sensitive cells, those with intrinsic or acquired resistance to EGFR-TKI display high sensitivity to ferroptosis inducers. In addition, Vorinostat, a clinically used inhibitor targeting histone deacetylase, can robustly enhance the efficacy of ferroptosis inducers, leading to a dramatic increase of hydroperoxides in EGFR mutant lung cancer cells with intrinsic or acquired resistance to EGFR-TKI. Mechanistically, Vorinostat promotes ferroptosis via xCT downregulation., Conclusions: Ferroptosis-inducing therapy shows promise in EGFR -activating mutant lung cancer cells that display intrinsic or acquired resistance to EGFR-TKI. Histone deacetylase inhibitor (HDACi) Vorinostat can further promote ferroptosis by inhibiting xCT expression., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-21-303). Dr. Yao reports that this research was supported by the Science and Technology Development project of Shanghai Chest Hospital and National Natural Science Foundation of China (NSFC82072570). The other authors have no conflicts of interest to declare., (2021 Translational Lung Cancer Research. All rights reserved.)

Emerging retrospective and prospective studies indicate that immune checkpoint inhibitors (ICIs) can be safe and effective cancer treatments among people living with human immunodeficiency virus (PLWH), however this high-cancer-risk population has often been excluded from groundbreaking cancer ICI trials. Our study aimed to characterize the current rate of exclusion and conditional inclusion of PLWH in cancer ICI trials by tumor type, trial phase, and year. ClinicalTrials.gov cancer ICI trials with planned starts between 1/1/2019 and 10/20/2020 were identified. Based on trial eligibility criteria, trials were categorized as "excluded" if PLWH could not enroll, "conditionally included" if only PLWH with adequate immune function were allowed, or "included/not specified" if HIV was not mentioned in the eligibility criteria. Trials from 2014 were separately collected for comparison over time. The number of trials excluding PLWH were compared to the included/not specified group using Fisher's exact test. Of 809 trials analyzed from 2019 to 2020, 74.4% excluded, 6.9% conditionally included, and 18.7% included/did not specify PLWH. Early phase trials excluded PLWH more frequently than late phase trials. The 2019-2020 trial cohort showed no significant change in exclusion of PLWH compared to 2014. Despite increasing evidence for safe and effective ICI use for PLWH, most cancer ICI trials exclude PLWH and few studies permit PLWH to participate, even if HIV is well-controlled.

The objectives of the study were to characterize the tumor burden dynamics on serial computed tomography scans in patients with advanced non-small-cell lung cancer treated with first-line pembrolizumab and to identify imaging markers for prolonged overall survival (OS)., Materials and Methods: Eighty-eight patients treated with first-line pembrolizumab monotherapy were evaluated on serial computed tomography scans to characterize their quantitative tumor burden during therapy. Tumor burden dynamics were studied for the association with OS., Results: The overall response rate was 42% (37/88), with the median tumor burden changes at the best overall response of -18.3% (range, -100.0% to +103.6%). Response rates were higher in men than in women ( P = .05) and in patients with higher programmed cell death ligand-1 expression levels ( P = .02). Tumor burden stayed below the baseline burden throughout therapy in 55 patients (63%). In an 8-week landmark analysis, patients with tumor burden below the baseline burden during the first 8 weeks of therapy had longer OS compared with patients who had ≥ 0% increase (median OS, 30.7 v 16.2 months; hazard ratio [HR] = 0.44; P = .01). In the extended Cox models, patients whose tumor burden stayed below the baseline burden throughout therapy had significantly reduced hazards of death (HR = 0.41, P = .003, univariate; HR = 0.35, P = .02, multivariate). Only one patient (1.1%) experienced pseudoprogression with initial tumor increase and subsequent tumor regression., Conclusion: In patients with advanced non-small-cell lung cancer treated with first-line single-agent pembrolizumab, tumor burden reduction below the baseline burden during therapy was an independent marker for prolonged OS, which may serve as a practical guide for treatment decisions., (© 2021 by American Society of Clinical Oncology.)

Background: Currently available biomarkers are imperfect in their ability to predict responses to the multiple first-line treatment options available for patients with advanced non-small cell lung cancer (NSCLC). Having an early pharmacodynamic marker of treatment resistance may help redirect patients onto more effective alternative therapies. We sought to determine if changes in circulating tumor DNA (ctDNA) levels after initiation of first-line pembrolizumab±chemotherapy in NSCLC would enable early prediction of response prior to radiological assessment., Methods: Plasma collected from patients with advanced NSCLC prior to and serially after starting first-line pembrolizumab±platinum doublet chemotherapy was analyzed by next-generation sequencing using enhanced tagged-amplicon sequencing of hotspots and coding regions from 36 genes. Early change in ctDNA allele fraction (AF) was correlated with radiographic responses and long-term clinical outcomes., Results: Among 62 patients who received first-line pembrolizumab±platinum/pemetrexed and underwent ctDNA assessment, 45 had detectable ctDNA alterations at baseline. The median change in AF at the first follow-up (at a median of 21 days after treatment initiation) was -90.1% (range -100% to +65%) among patients who subsequently had a radiologic response (n=18), -19.9% (range: -100% to +1884%) among stable disease cases (n=15), and +28.8% (range: -100% to +410%) among progressive disease cases (n=12); p=0.003. In addition, there was a significant correlation between the percent change in ctDNA at the first follow-up and the percent change in tumor target lesions from baseline (R=0.66, p<0.001). AF decrease between the pretreatment and first on-treatment blood draw was associated with significantly higher response rate (60.7% vs 5.8%, p=0.0003), and significantly longer median progression-free survival (8.3 vs 3.4 months, HR: 0.29 (95% CI: 0.14 to 0.60), p=0.0007) and median overall survival (26.2 vs 13.2 months, HR: 0.34 (95% CI: 0.15 to 0.75), p=0.008) compared with cases with an AF increase., Conclusion: In patients with advanced NSCLC, rapid decreases in ctDNA prior to radiological assessment correlated with clinical benefit. These results suggest a potential role for ctDNA as an early pharmacodynamic biomarker of response or resistance to immunotherapies., Competing Interests: Competing interests: GJ and TF: current employee and shareholder of Inivata. MN: consultant: Toshiba Medical Systems, WorldCare Clinical, Daiichi Sankyo; Research grant: Merck, Canon Medical Systems, AstraZeneca; Honorarium: Bayer and Roche. MC: consultant/advisory board for AstraZeneca, Inivata. Honoraria: The Lynx Group (supported by Bristol-Myers Squibb), PCME (supported by Lilly and Merck), WebMD (supported by AstraZeneca). Travel/accommodation funding: Allergan, Sanofi-Aventis, Daiichi Sankyo, Natera, AstraZeneca. MA: consultant/advisory board for BMS, AstraZeneca, Achilles, AbbVie, Neon, Maverick, Nektar, Hegrui, Syndax, Gritstone Research funding from BMS, AstraZeneca, Lilly, Genentech., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

With 9.6 million deaths in 2018, cancer represents one of the most common causes of death, both in men and women. Despite recent advances in the understanding of molecular mechanisms involved in cancer development and progression, treatment options are still limited. Limitations of traditional chemotherapy include the lack of selectivity and the unfavorable safety profile. The efficacy of targeted therapies (e.g., tyrosine kinase inhibitors) is also limited by their cytostatic action, which inhibits tumor cell proliferation without inducing tumor cell death, and by the risk of acquired resistance. Antibody-drug conjugates (ADCs), a newly developed class of engineered anticancer drugs, consist of recombinant monoclonal antibodies against tumor-specific antigens that are covalently bound to cytotoxic agents. They have been designed to overcome the limitations of traditional chemotherapy and targeted therapies by combining the target selectivity of monoclonal antibodies with the high potency of cytotoxic drugs. Currently, ADCs that have received regulatory approval include brentuximab vedotin for CD30-positive Hodgkin lymphoma and trastuzumab emtansine for human epidermal growth factor receptor 2-positive breast cancer. However, over 80 novel ADCs are actively being investigated in preclinical studies and early-phase clinical trials. In this review, we will provide a comprehensive overview of the biological rational, efficacy and safety of ADCs as therapeutic agents against non-small cell lung cancer and small cell lung cancer., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Histologic transformation of non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is a rare mechanism of acquired resistance to epidermal growth factor receptor ( EGFR )-targeted tyrosine kinase inhibitors. However, the SCLC transformation has also been observed in non., Egfr: mutant NSCLC. In these cases, whether SCLC initially co-exists with NSCLC or originates from initial NSCLC remains to be determined., Methods: Whole exome sequencing was performed on 10 samples from 5 patients with SCLC transformation from lung adenocarcinoma (LUAD), a main subtype of NSCLC. Somatic mutations and copy number variations (CNVs) were analyzed to explore the differences between initial LUAD and transformed SCLC, as well as the origin of transformed SCLC., Results: After SCLC transformation, the mutation spectrum changed, with decreased C>T and increased C>A. Compared with initial LUAD, the CNV burden of transformed SCLC was greatly increased (39.0 vs . 61.1, Wilcoxon P=0.4). The higher the CNV burden of LUAD, the shorter the time to SCLC transformation was observed to be; and the higher the CNV burden of transformed SCLC, the shorter the overall survival (OS) after transformation. Clonal evolution analysis showed different clonal components between initial LUAD and transformed SCLC., Conclusions: The transformation of LUAD into SCLC may be promoted by CNV events rather than mutational events. CNV burden was associated with the time to SCLC transformation and with the OS of patients following SCLC transformation. Transformed SCLC did not evolve directly from the initial LUAD but branched off from LUAD before the time of initial diagnosis., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-20-1278). The authors have no conflicts of interest to declare., (2020 Translational Lung Cancer Research. All rights reserved.)

Importance: The spectrum of individual immune-related adverse events (irAEs) from anti-programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) immune checkpoint inhibitors (ICIs) has been reported widely, and their development is associated with improved patient survival across tumor types. The spectrum and impact on survival for patients with non-small cell lung cancer (NSCLC) who develop multisystem irAEs from ICIs, has not been described., Objective: To characterize multisystem irAEs, their association with survival, and risk factors for multisystem irAE development., Design, Setting, and Participants: This retrospective cohort study carried out in 5 academic institutions worldwide included 623 patients with stage III/IV NSCLC, treated with anti-PD-(L)1 ICIs alone or in combination with another anticancer agent between January 2007 and January 2019., Exposures: Anti-PD-(L)1 monotherapy or combinations., Main Outcomes and Measures: Multisystem irAEs were characterized by combinations of individual irAEs or organ system involved, separated by ICI-monotherapy or combinations. Median progression-free (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Differences in PFS and OS between irAE groups were assessed by multivariable models. Risk for multisystem irAE was estimated as odds ratios by multivariable logistic regression., Results: The 623 patients included in the study were mostly men (60%, n = 375) and White (77%, n = 480). The median (range) age was 66 (58-73) years, and 148 patients (24%) developed a single irAE, whereas 58 (9.3%) developed multisystem irAEs. The most common multisystem irAE patterns in patients receiving anti-PD-(L)1 monotherapy were pneumonitis thyroiditis (n = 7, 14%), hepatitis thyroiditis (n = 5, 10%), dermatitis pneumonitis (n = 5, 10%), and dermatitis thyroiditis (n = 4, 8%). Favorable Eastern Cooperative Oncology Group (ECOG) performance status (PS) (ECOG PS = 0/1 vs 2; adjusted odds ratio [aOR], 0.27; 95% CI, 0.08-0.94; P = .04) and longer ICI duration (aOR, 1.02; 95% CI, 1.01-1.03; P < .001) were independent risk factors for development of multisystem irAEs. Patients with 1 irAE and multisystem irAEs demonstrated incrementally improved OS (adjusted hazard ratios [aHRs], 0.86; 95% CI, 0.66-1.12; P = .26; and aHR, 0.57; 95% CI, 0.38-0.85; P = . 005, respectively) and PFS (aHR, 0.68; 95% CI, 0.55-0.85; P = .001; and aHR, 0.39; 95% CI, 0.28-0.55; P < .001, respectively) vs patients with no irAEs, in multivariable models adjusting for ICI duration., Conclusions and Relevance: In this multicenter cohort study, development of multisystem irAEs was associated with improved survival in patients with advanced NSCLC treated with ICIs.

Purpose: Investigate the incidence and imaging characteristics of radiologically-evident immune-related adverse events (irAEs) on body CT in patients with small-cell lung cancer (SCLC) treated with immune-checkpoint inhibitors., Methods: The study included 53 patients with relapsed/refractory SCLC (27 men, 26 women) treated with PD-1/PD-L1 inhibitors alone or in combination with CTLA-4 inhibition, who had baseline and at least one follow-up body CT during therapy. Body CT scans were reviewed to detect and characterize organ-specific irAEs including thyroiditis, pneumonitis, hepatitis, pancreatitis, enteritis, and colitis., Results: Nineteen patients (36 %) developed radiologically-evident irAEs. The median time from therapy initiation to irAE onset was 7.1 weeks. Pneumonitis and colitis were most common, noted in 9 patients (17 %) each. Seven colitis cases demonstrated pancolitis, and two cases showed segmental colitis associated with diverticulosis. The common radiographic patterns of pneumonitis were acute interstitial pneumonia (AIP)/acute respiratory distress syndrome (ARDS) pattern (n = 4) and cryptogenic organizing pneumonia (COP) pattern (n = 3). Other irAEs included thyroiditis (n = 3), enteritis (n = 2), hepatitis (n = 1), and pancreatitis (n = 1). Older age (p = 0.03) and prior radiotherapy to any organ (p = 0.03) was associated with overall irAEs. Prior chest radiotherapy was significantly associated with pneumonitis or thyroiditis (p = 0.0004)., Conclusion: Radiologically-evident irAEs were noted on body CT in 36 % of patients with SCLC treated with immune-checkpoint inhibitors. Colitis and pneumonitis were most common. Prior chest radiotherapy was a predictor of the development of both pneumonitis and thyroiditis. Awareness of risk factors and CT findings of irAEs is important for early detection and accurate diagnosis of potentially serious immunotherapy toxicities., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The role of immune-related adverse events (irAEs), as a surrogate predictor of the efficacy of checkpoint inhibitors, has not yet been described in the setting of first-line, single-agent pembrolizumab for patients with metastatic non-small-cell lung-cancer (NSCLC) with a programmed death-ligand 1 (PD-L1) expression of ≥ 50%., Patients and Methods: We previously conducted a multicenter retrospective analysis in patients with treatment-naive metastatic NSCLC and a PD-L1 expression of ≥ 50% receiving first-line pembrolizumab. Here, we report the results of the irAE analysis and the potential correlation between irAEs and clinical outcomes., Results: A total of 1010 patients were included in this analysis; after a 6-week landmark selection, 877 (86.8%) patients were included in the efficacy analysis. Any grade irAEs (P < .0001), grade 3/4 irAEs (P = .0025), leading to discontinuation irAEs (P = .0144), multiple-site and single-site irAEs (P < .0001), cutaneous irAEs (P = .0001), endocrine irAEs (P = .0227), pulmonary irAEs (P = .0479), and rheumatologic irAEs (P = .0018) were significantly related to a higher objective response rate. Any grade irAEs (P < .0001), single-site irAEs (P < .0001), multiple-site irAEs (P = .0005), cutaneous irAEs (P = .0042), endocrine irAEs (P < .0001), gastrointestinal irAEs (P = .0391), and rheumatologic irAEs (P = .0086) were significantly related to progression-free survival. Any grade irAEs (P < .0001), single-site irAEs (P < .0001), multiple-site irAEs (P = .0003), cutaneous irAEs (P = .0002), endocrine irAEs (P = .0001), and rheumatologic irAEs (P = .0214) were significantly related to overall survival., Conclusions: This study confirms the feasibility and the safety of first-line, single-agent pembrolizumab, in a large, real-world cohort of patients with NSCLC with PD-L1 expression ≥ 50%. The occurrence of irAEs may be a surrogate of clinical activity and improved outcomes in this setting., (Copyright © 2020 Elsevier Inc. All rights reserved.)