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Background: High-risk cases of neuroblastoma have poor survival rates, and novel therapies are needed. Vandetanib (ZD6474, Zactima) is an inhibitor of the vascular endothelial growth factor receptor, epidermal growth factor receptor, and rearranged during transfection (RET) tyrosine kinases, which have each been implicated in neuroblastoma pathogenesis. The authors hypothesized that vandetanib combined with 13-cis-retinoic acid (CRA), a differentiating agent used in most current neuroblastoma treatment regimens, would be effective against neuroblastoma tumor models.Methods: The authors evaluated the effects of vandetanib with and without CRA on RET phosphorylation and on the proliferation and survival of human neuroblastoma cell lines in vitro. Using a subcutaneous mouse xenograft model of human neuroblastoma, they analyzed tumors treated with CRA, vandetanib, and the combination of vandetanib plus CRA for growth, gross and histologic appearance, vascularity, and apoptosis.Results: Vandetanib treatment inhibited RET phosphorylation and resulted in induction of apoptosis in the majority of neuroblastoma cell lines in vitro, whereas CRA treatment induced morphologic differentiation and cell-cycle arrest. Treatment with vandetanib plus CRA resulted in more significant reduction in neuroblastoma cell viability than either alone. In a mouse xenograft model, the combination of vandetanib with CRA demonstrated significantly more growth inhibition than either alone, via both reduction in tumor vascularity and induction of apoptosis.Conclusions: Vandetanib induces neuroblastoma tumor cell death in vitro and reduces tumor growth and vascularity in vivo. The combination of vandetanib with CRA was more effective in reducing tumor growth than either treatment alone. The antitumor effects of vandetanib plus CRA suggest a novel combination for use in neuroblastoma patients. [ABSTRACT FROM AUTHOR]

Background: Biologically targeted therapies have been postulated as a viable strategy to improve outcomes for women with ovarian cancer. We assessed the safety, tolerance, pharmacokinetics, relevant circulating and image-derived biomarkers, and clinical activity of combination aflibercept and docetaxel in this population.Methods: For the phase 1 (pharmacokinetic) study, eligible patients had measurable, recurrent or persistent epithelial ovarian, primary peritoneal, or fallopian tube carcinoma with a maximum of two prior chemotherapy regimens. Aflibercept was administered intravenously over three dose levels (2, 4, or 6 mg/kg; one dose every 21 days) to identify the maximum tolerated dose for the phase 2 study. Pharmacokinetics were assessed and dynamic imaging was done during a lead-in phase with single-agent aflibercept (cycle 0) and during combination therapy with intravenous docetaxel (75 mg/m(2)). Eligibility for the phase 2 study was the same as for phase 1. Patients were enrolled in a two-stage design and given aflibercept 6 mg/kg intravenously and docetaxel 75 mg/m(2) intravenously, every 3 weeks. The primary endpoint was objective response rate (ORR) as assessed by Response Evaluation Criteria in Solid Tumors version 1.0. The trial has completed enrolment and all patients are now off study. The trial is registered at ClinicalTrials.gov, number NCT00436501.Findings: From the phase 1 study, the recommended phase 2 doses of aflibercept and docetaxel were found to be 6 mg/kg and 75 mg/m(2), respectively. Log-linear pharmacokinetics (for unbound aflibercept) were observed for the three dose levels. No dose-limiting toxicities were noted. 46 evaluable patients were enrolled in the phase 2 trial; 33 were platinum resistant (15 refractory) and 13 were platinum sensitive. The confirmed ORR was 54% (25 of 46; 11 patients had a complete response and 14 had a partial response). Grade 3-4 toxicities observed in more than two patients (5%) were: neutropenia in 37 patients (80%); leucopenia in 25 patients (54%); fatigue in 23 patients (50%); dyspnoea in ten patients (22%); and stomatitis in three patients (7%). Adverse events specifically associated with aflibercept were grade 1-2 hypertension in five patients (11%), and grade 2 proteinuria in one patient (2%).Interpretation: Combination aflibercept plus docetaxel can be safely administered at the dose and schedule reported here, and is associated with substantial antitumour activity. These findings suggest that further clinical development of this combination in ovarian cancer is warranted.Funding: US National Cancer Institute, US Department of Defense, Sanofi-Aventis, Gynecologic Cancer Foundation, Marcus Foundation, and the Commonwealth Foundation. [ABSTRACT FROM AUTHOR]

Introduction: Small cell lung cancer (SCLC) is known to express high levels of the proangiogenic factor vascular endothelial growth factor (VEGF). We assessed the safety and tolerability of cediranib, an oral inhibitor of VEGF receptor tyrosine kinases, in combination with etoposide and cisplatin as first-line therapy for extensive-stage (ES) SCLC or metastatic lung neuroendocrine cancer (NEC)., Methods: Patients received up to six 21-day cycles of etoposide (100 mg/m 2 , days 1-3) and cisplatin (80 mg/m 2 , day 1) with once-daily cediranib until disease progression or unacceptable toxicity. Cediranib dosing started at 30 mg with de-escalation cohorts planned based on cycle 1 dose-limiting toxicities (DLTs). An expansion cohort of 12 patients was enrolled at the recommended phase II dose., Results: Twenty-two patients (18 with ES SCLC, 4 with NEC) received treatment. Only 4 patients were enrolled at the 30 mg cediranib dose before other studies established 20 mg/day as the recommended dose with chemotherapy. Among the 18 patients enrolled at the 20-mg dose, common adverse events included nausea/vomiting, neutropenia, and diarrhea; 8 patients (44%) had grade 1 or 2 hypertension, and 2 (11%) had grade 3 hemoptysis. For all 18 patients, the objective response rate and median progression-free survival duration were 67% and 7.9 months. Plasma levels of VEGF were significantly higher, and those of soluble VEGFR2 were significantly lower, on day 22 than at baseline but were not correlated with tumor shrinkage., Conclusions: Cediranib (20 mg) plus etoposide and cisplatin is well tolerated and has promising clinical activity., Competing Interests: Disclosure Kyle F. Concannon, MD: None. Bonnie S. Glisson, MD: None – Retired. Robert C. Doebele, MD, PhD: Licensing Fees for Biologic Materials: Roche, Foundation Medicine, ThermoFisher, Voronoi, Loxo, Takeda, Casma Therapeutics, Black Diamond, Histocyte. Payment or Honoraria: Clinical Cancer Research Journal (AACR), Guardant. Licensing Fees for Patent: Rain Oncology. Shareholder: Rain Oncology. Chao Huang, MD: None. Marcelo Marotti, MD, PhD: Employee: Summit Therapeutics. Shareholder: AstraZeneca, Summit Therapeutics. D. Ross Camidge, MD, PhD: Consulting Fees: Abbvie,Anheart, Apollomics, AstraZeneca/Daiichi, Beigene, BMS, Eli Lilly, Genesis, Sutro, Takeda. John V. Heymach, MD, PhD: Consulting Fees: AbbVie, AnHeart Therapeutics, ArriVent Biopharma, AstraZeneca, BioCurity Pharmaceuticals, BioNTech AG, Blueprint Medicines, BI, BMS, Chugai Pharmaceutical, Curio Science, DAVA Oncology, Eli Lily & Co, EMD Serono, Genentech, GlaxoSmithKline, IDEOlogy Health, Immunocore, InterVenn Biosciences, Janssen Biotech, Janssen Pharmaceuticals, Mirati Therapeutics, Moffitt Cancer Center, ModeX, Nexus Health Systems, Novartis Pharmaceuticals, OncoCyte, RefleXion, Regeneron Pharmaceuticals, Roche, Sandoz Pharmaceutical, Sanofi, Spectrum Pharmaceuticals, Takeda, uniQure. Honoraria or Speaker Fees: MJH Events, Dr. Neil Love. Support for Attending Meetings: AACR., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Resistance to inactive state-selective RASG12C inhibitors frequently entails accumulation of RASGTP, rendering effective inhibition of active RAS potentially desirable. Here, we evaluated the antitumor activity of the RAS(ON) multiselective tricomplex inhibitor RMC-7977 and dissected mechanisms of response and tolerance in KRASG12C-mutant non-small cell lung cancer (NSCLC). Broad-spectrum reversible RASGTP inhibition with or without concurrent covalent targeting of active RASG12C yielded superior and differentiated antitumor activity across diverse comutational KRASG12C-mutant NSCLC mouse models of primary or acquired RASG12C(ON) or RASG12C(OFF) inhibitor resistance. Interrogation of time-resolved single-cell transcriptional responses established an in vivo atlas of multimodal acute and chronic RAS pathway inhibition in the NSCLC ecosystem and uncovered a regenerative mucinous transcriptional program that supports long-term tumor cell persistence. In patients with advanced KRASG12C-mutant NSCLC, the presence of mucinous histologic features portended poor response to sotorasib or adagrasib. Our results have potential implications for personalized medicine and the development of rational RAS inhibitor-anchored therapeutic strategies. Significance: Our work reveals robust and durable antitumor activity of the preclinical RAS(ON) multiselective inhibitor RMC-7977 against difficult-to-treat subsets of KRASG12C-mutant NSCLC with primary or acquired RASG12C inhibitor resistance and identifies a conserved mucinous transcriptional state that supports RAS inhibitor tolerance. See related commentary by Marasco and Misale, p. 2018., (©2024 American Association for Cancer Research.)

Aims: Despite known short-term mortality risk of immune checkpoint inhibitor (ICI) pneumonitis, its impact on 1-year mortality, long-term pulmonary function, symptom persistence, and radiological resolution remains unclear., Methods: We retrospectively analyzed 71 nonsmall cell lung cancer (NSCLC) patients treated with anti-PD(L)1 monoclonal antibodies between 2018-2021, who developed pneumonitis. Clinical and demographic covariates were collected from electronic medical record. Cox regression assessed associations with mortality, while logistic regression evaluated associations with persistent symptoms, hypoxemia, and radiological resolution., Results: Steroid-refractory pneumonitis (hazard ratio [HR] = 15.1, 95% confidence interval [95% CI]:3.9-57.8, P < .0001) was associated with higher 1-year mortality compared to steroid-responsive cases. However, steroid-resistant (odds ratio [OR] = 1.4, 95% CI: 0.4-5.1, P = .58) and steroid-dependent (OR = 0.4, 95% CI: 0.1-1.2, P = .08) pneumonitis were not. Nonadenocarcinoma histology (OR = 6.7, 95% CI: 1.6-46.6, P = .01), grade 3+ pneumonitis (OR = 4.6, 95% CI: 1.3-22.7, P = .03), and partial radiological resolution (OR = 6.3, 95% CI: 1.8-23.8, P = .004) were linked to increased pulmonary symptoms after pneumonitis resolution. Grade 3+ pneumonitis (OR = 8.1, 95% CI: 2.3-31.5, P = .001) and partial radiological resolution (OR = 5.45, 95% CI: 1.29-37.7, P = .03) associated with residual hypoxemia. Nonadenocarcinoma histology (OR = 3.6, 95% CI: 1.01-17.6, P = .06) and pretreatment ILAs (OR = 4.8, 95% CI: 1.14-33.09, P = .05) were associated with partial radiological resolution., Conclusions: Steroid refractory pneumonitis increases 1-year mortality in NSCLC patients. Pretreatment ILAs may signal predisposition to fibrosis-related outcomes, seen as partial resolution, which in turn is associated with postresolution symptoms and residual hypoxemia. These findings offer insights for identifying patients at risk of adverse outcomes post-pneumonitis resolution., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Neoadjuvant immune checkpoint inhibitors (ICIs) have improved survival outcomes compared with chemotherapy in resectable non-small cell lung cancer (NSCLC). However, the impact of actionable genomic alterations (AGAs) on the efficacy of neoadjuvant ICIs remains unclear. We report the influence of AGAs on treatment failure (TF) in patients with resectable NSCLC treated with neoadjuvant ICIs., Methods: Tumor molecular profiles were obtained from patients with stage I-IIIA resectable NSCLC (American Joint Committee on Cancer seventh edition) treated with either neoadjuvant nivolumab (N, n=23) or nivolumab+ipilimumab (NI, n=21) followed by surgery in a previously reported phase-2 randomized study (NCT03158129). TF was defined as any progression of primary lung cancer after neoadjuvant ICI therapy in patients without surgery, radiographic and/or biopsy-proven primary lung cancer recurrence after surgery, or death from possibly treatment-related complications or from primary lung cancer since randomization. Tumors with AGAs (n=12) were compared with tumors without AGAs and non-profiled squamous cell carcinomas (non-AGAs+NP SCC, n=20)., Results: With a median follow-up of 60.2 months, the overall TF rate was 34.1% (15/44). Tumor molecular profiling was retrospectively obtained in 47.7% (21/44) of patients and select AGAs were identified in 12 patients: 5 epidermal growth factor receptor (EGFR) , 2 KRAS , 1 ERBB2 , and 1 BRAF mutations, 2 anaplastic lymphoma kinase (ALK) and 1 RET fusions. The median time to TF in patients with AGAs was 24.7 months (95% CI: 12.6 to 40.4), compared with not reached (95% CI: not evaluable (NE)-NE) in the non-AGAs+NP SCC group. The TF risk was higher in AGAs (HR: 5.51, 95% CI: 1.68 to 18.1), and lower in former/current smokers (HR: 0.24, 95% CI: 0.08 to 0.75). The odds of major pathological response were 4.71 (95% CI: 0.49 to 45.2) times higher in the non-AGAs+NP SCC group, and the median percentage of residual viable tumor was 72.5% in AGAs compared with 33.0% in non-AGS+NP SCC tumors., Conclusions: Patients with NSCLC harboring select AGAs, including EGFR and ALK alterations, have a higher risk for TF, shorter median time to TF, and diminished pathological regression after neoadjuvant ICIs. The suboptimal efficacy of neoadjuvant chemotherapy-sparing, ICI-based regimens in this patient subset underscores the importance of tumor molecular testing prior to initiation of neoadjuvant ICI therapy in patients with resectable NSCLC., Competing Interests: Competing interests: NZ reports consulting fee, travel, dining expenses from Ethicon. WW reports consulting fees, speaker fees and/or honoraria from Amgen, AstraZeneca, Genentech/Roche, Astellas, Boehringer Ingelheim, Merck, Eli Lilly, BMS, MSD, Bayer, Pfizer, Janssen, Sanofi-Aventis, Takeda, Novartis, United Medical; and research grants (to institution) from Amgen, AstraZeneca, Genentech/Roche, Astellas, Boehringer Ingelheim, Eli Lilly, BMS, MSD, Pfizer, Janssen, Sanofi-Aventis. GRB reports grants or contracts from Amgen, Bayer, Adaptimmune, Exelixis, Daiichi Sankyo, GlaxoSmithKline, Immatics, Immunocore, Incyte, Kite Pharma, Macrogenics, Torque, AstraZeneca, Bristol Myers Squibb, Celgene, Genentech, MedImmune, Merck, Novartis, Roche, Sanofi, Xcovery, Tmunity Therapeutics, Regeneron, BeiGene, Repertoire Immune Medicines, Verastem. CytomX Therapeutics, Duality Biologics, Mythic Therapeutics, Takeda, Aulos Bioscience, Seagen, Nuvalent, Turning Point Therapeutics; Consulting fees from AbbVie, Adicet, Amgen, Ariad, Bayer, Clovis Oncology, AstraZeneca, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Instil Bio, Genentech, Genzyme, Gilead, Lilly, Janssen, MedImmune, Merck, Novartis, Roche, Sanofi, Tyme Oncology, Xcovery, Virogin Biotech, Maverick Therapeutics, BeiGene, Regeneron, CytomX Therapeutics, Intervenn Biosciences, Onconova Therapeutics, Seagen, Scorpion Therapeutics, Immunocore. Advisory board for Virogin Biotech SAB, Beigene, Immunocore, Regeneron. XL reports consulting/advisory fees from Eli Lilly, EMD Serono (Merck KGaA), AstraZeneca, Spectrum Pharmaceutics, Novartis, Regeneron, Boehringer Ingelheim, Hengrui Therapeutics, Bayer, Teligene, Taiho, Daiichi Sankyo, Janssen, Blueprint Medicines, Sensei Biotherapeutics, SystImmune, ArriVent, Abion, and AbbVie; Research Funding to Institution from Eli Lilly, EMD Serono, ArriVent, Dizal, Teligene, Regeneron, Janssen, ThermoFisher, Takeda, and Boehringer Ingelheim; Travel support from EMD Serono, Janssen, and Spectrum Pharmaceutics. MA reports research funding from Genentech, Nektar Therapeutics, Merck, GlaxoSmithKline, Novartis, Jounce Therapeutics, Bristol Myers Squibb, Eli Lilly, Adaptimmune, Shattuck Labs, Gilead; Consulting fees from GlaxoSmithKline, Shattuck Labs, Bristol Myers Squibb, AstraZeneca, Insight; Speaker fees from AstraZeneca, Nektar Therapeutics, SITC; and participation of safety review committee for Nanobiotix-MDA Alliance, Henlius. JAR reports consulting fee, stock, patents issued and pending with Genprex. MVN reports receiving research funding to institution from Mirati, Novartis, Checkmate, Alaunos, AstraZeneca, Pfizer, Genentech, Navire; a consultant or advisory role for Mirati, Merck/MSD, Novartis, Genentech, Sanofi, Pfizer; and other support from Ziopharm Oncology, ApotheCom, Ashfield Healthcare. HTT reports consulting fee for Abion Bio. JZ reports grants from Merck, Helius, grants and personal fees from Johnson and Johnson and Novartis, personal fees from Bristol Myers Squibb, AstraZeneca, GenePlus, Innovent, Varian, Catalyst and Hengrui outside the submitted work. DLG has served on scientific advisory committees for Menarini Ricerche, 4D Pharma, Onconova, and Eli Lilly and has received research support from Takeda, Astellas, NGM Biopharmaceuticals, Boehringer Ingelheim and Mirati. JVH reports Advisory Committees—AbbVie, AnHeart Therapeutics, AstraZeneca, BioNTech AG, BI, BMS, DAVA Oncology, Eli Lily Research Support—AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb and Takeda; Licensing/Royalties—Spectrum. BS reports consulting fees from AstraZeneca, BMS, Medscape; dining from AstraZeneca. BMS; Speaker fees from AstraZeneca, Medscape, Peer View; advisory board from AstraZeneca, BMS. TC reports (over the past 24 months) speaker fees/honoraria (including travel/meeting expenses) from ASCO Post, AstraZeneca, Bio Ascend, Bristol Myers Squibb, Clinical Care Options, IDEOlogy Health, Medical Educator Consortium, Medscape, OncLive, PEAK Medicals, PeerView, Physicians' Education Resource, Targeted Oncology; advisory role/consulting fees (including travel/meeting expenses) from AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Genentech, Merck, oNKo-innate, Pfizer, RAPT Therapeutics, Regeneron; institutional research funding from AstraZeneca and Bristol Myers Squibb., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Large cell neuroendocrine carcinoma (LCNEC) is a high-grade neuroendocrine malignancy that, like small cell lung cancer (SCLC), is associated with the absence of druggable oncogenic drivers and dismal prognosis. In contrast to SCLC, however, there is little evidence to guide optimal treatment strategies, which are often adapted from SCLC and non-small cell lung cancer approaches., Experimental Design: To better define the biology of LCNEC, we analyzed cell line and patient genomic data and performed IHC and single-cell RNA sequencing of core needle biopsies from patients with LCNEC and preclinical models., Results: In this study, we demonstrate that the presence or absence of YAP1 distinguishes two subsets of LCNEC. The YAP1-high subset is mesenchymal and inflamed and is characterized, alongside TP53 mutations, by co-occurring alterations in CDKN2A/B and SMARCA4. Therapeutically, the YAP1-high subset demonstrates vulnerability to MEK- and AXL-targeting strategies, including a novel preclinical AXL chimeric antigen receptor-expressing T cell. Meanwhile, the YAP1-low subset is epithelial and immune-cold and more commonly features TP53 and RB1 co-mutations, similar to those observed in pure SCLC. Notably, the YAP1-low subset is also characterized by the expression of SCLC subtype-defining transcription factors, especially ASCL1 and NEUROD1, and as expected, given its transcriptional similarities to SCLC, exhibits putative vulnerabilities reminiscent of SCLC, including delta-like ligand 3 and CD56 targeting, as is with novel preclinical delta-like ligand 3 and CD56 chimeric antigen receptor-expressing T cells, and DNA damage repair inhibition., Conclusions: YAP1 defines distinct subsets of LCNEC with unique biology. These findings highlight the potential for YAP1 to guide personalized treatment strategies for LCNEC., (©2024 American Association for Cancer Research.)

For patients with advanced non-small-cell lung cancer (NSCLC), dual immune checkpoint blockade (ICB) with CTLA4 inhibitors and PD-1 or PD-L1 inhibitors (hereafter, PD-(L)1 inhibitors) is associated with higher rates of anti-tumour activity and immune-related toxicities, when compared with treatment with PD-(L)1 inhibitors alone. However, there are currently no validated biomarkers to identify which patients will benefit from dual ICB 1,2 . Here we show that patients with NSCLC who have mutations in the STK11 and/or KEAP1 tumour suppressor genes derived clinical benefit from dual ICB with the PD-L1 inhibitor durvalumab and the CTLA4 inhibitor tremelimumab, but not from durvalumab alone, when added to chemotherapy in the randomized phase III POSEIDON trial 3 . Unbiased genetic screens identified loss of both of these tumour suppressor genes as independent drivers of resistance to PD-(L)1 inhibition, and showed that loss of Keap1 was the strongest genomic predictor of dual ICB efficacy-a finding that was confirmed in several mouse models of Kras-driven NSCLC. In both mouse models and patients, KEAP1 and STK11 alterations were associated with an adverse tumour microenvironment, which was characterized by a preponderance of suppressive myeloid cells and the depletion of CD8 + cytotoxic T cells, but relative sparing of CD4 + effector subsets. Dual ICB potently engaged CD4 + effector cells and reprogrammed the tumour myeloid cell compartment towards inducible nitric oxide synthase (iNOS)-expressing tumoricidal phenotypes that-together with CD4 + and CD8 + T cells-contributed to anti-tumour efficacy. These data support the use of chemo-immunotherapy with dual ICB to mitigate resistance to PD-(L)1 inhibition in patients with NSCLC who have STK11 and/or KEAP1 alterations., (© 2024. The Author(s).)

Purpose: Preclinical studies demonstrated that dual inhibition of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways delay the emergence of resistance to EGFR tyrosine kinase inhibitors (TKIs), and in trials with first-generation EGFR TKIs, the combination of EGFR VEGF pathway inhibitors prolonged progression-free survival (PFS)., Methods: The RAMOSE trial (ClinicalTrials.gov identifier: NCT03909334, HCRN LUN-18-335) is a randomized, open-label multicenter phase II study comparing osimertinib with ramucirumab (arm A) to osimertinib (arm B) for initial treatment of metastatic EGFR -mutant non-small cell lung cancer (NSCLC) with 2:1 random assignment. The primary end point is PFS for evaluable patients; secondary end points include objective response rates (ORRs), disease control rate (DCR), overall survival, and safety. The stratification criteria were EGFR mutation type and the presence of CNS metastasis., Results: At data cutoff on August 29, 2023, 160 patients consented, 147 patients received treatment, and 139 patients were evaluable with at least one scan. In this preplanned interim analysis, the median follow-up was 16.6 months. Among the evaluable patients, 57 PFS events occurred. The median PFS was 24.8 (A) versus 15.6 (B) months (hazard ratio, 0.55 [95% CI, 0.32 to 0.93]; log-rank P = .023), 12-month PFS rate was 76.7% (A) versus 61.9% (B; P = .026). No significant difference was observed in the ORRs and DCRs between arms. Any-grade (G) adverse events (AEs) occurred in 100% (A) and 98% (B) of patients, with no G5 treatment-related AE (TRAE), one G4 TRAE (hyponatremia, A), and 53% (A) versus 41% (B) G3 TRAEs. AE-related discontinuation occurred in 13 patients (9.7% in A and 8.7% in B). The safety profile was in line with known safety of each drug., Conclusion: Ramucirumab plus osimertinib significantly prolonged PFS compared with osimertinib alone in patients with TKI-naïve EGFR -mutant NSCLC. The combination is safe and well tolerated.

Lung Cancer remains the leading cause of cancer deaths in the USA and worldwide. Non-small cell lung cancer (NSCLC) harbors high transcriptomic intratumor heterogeneity (RNA-ITH) that limits the reproducibility of expression-based prognostic models. In this study, we used multiregional RNA-seq data (880 tumor samples from 350 individuals) from both public (TRACERx) and internal (MDAMPLC) cohorts to investigate the effect of RNA-ITH on prognosis in localized NSCLC at the gene, signature, and tumor microenvironment levels. At the gene level, the maximal expression of hazardous genes (expression negatively associated with survival) but the minimal expression of protective genes (expression positively associated with survival) across different regions within a tumor were more prognostic than the average expression. Following that, we examined whether multiregional expression profiling can improve the performance of prognostic signatures. We investigated 11 gene signatures collected from previous publications and one signature developed in this study. For all of them, the prognostic prediction accuracy can be significantly improved by converting the regional expression of signature genes into sample-specific expression with a simple function-taking the maximal expression of hazardous genes and the minimal expression of protective genes. In the tumor microenvironment, we found a similar rule also seems applicable to immune ITH. We calculated the infiltration levels of major immune cell types in each region of a sample based on expression deconvolution. Prognostic analysis indicated that the region with the lowest infiltration level of protective or highest infiltration level of hazardous immune cells determined the prognosis of NSCLC patients. Our study highlighted the impact of RNA-ITH on the prognostication of NSCLC, which should be taken into consideration to optimize the design and application of expression-based prognostic biomarkers and models. Multiregional assays have the great potential to significantly improve their applications to prognostic stratification., (© 2024. The Author(s).)

ERBB2 (HER2) represents a newly recognized actionable oncogenic driver in non-small cell lung cancer (NSCLC), with approved targeted therapy available. Understanding the landscape of ERBB2 alterations and co-occurring mutations is essential for guiding treatment decisions. We conducted an analysis involving 3000 NSCLC patients with all types of ERBB2 alterations, drawn from two extensive retrospective cohorts: 1281 from Geneplus (Chinese) and 1719 from Guardant360 (the United States, US). The incidence of all types of ERBB2 alterations was found to be 5.6% in the Chinese group and 5.2% in the US group. In both cohorts, among oncogenic alterations of ERBB2, exon 20 insertion Y772&#95;A775dupYVMA was the most frequent alteration (58% vs 41.6% in the Chinese vs the US), followed by G776delinsVC/LC/VV/IC (10.7% vs 9.7%), and S310X (10.5% vs 15.4%). EGFR ex20 insertions were identified in the A767-V774 region, whereas ERBB2 ex20 insertions were observed in the Y772-P780 region. Notably, EGFR ex20 insertions exhibited greater insertion diversity. Clinical characteristics of EGFR and ERBB2 ex20 NSCLC were similar, characterized by low tumor mutation burden (TMB), a predominant never-smoker population, and a majority of lung adenocarcinoma cases., (© 2024. The Author(s).)

Introduction: Germline mutations driving lung cancer have been infrequently reported in the literature, with EGFR T790M being a known germline mutation identified in 1% of NSCLCs. Typically, a somatic EGFR mutation is acquired to develop lung adenocarcinoma. Osimertinib has become a standard-of-care treatment for EGFR T790M-positive lung cancer., Methods: We perform a retrospective analysis through the Lung Cancer Moon Shot GEMINI database at the University of Texas MD Anderson Cancer Center. Of the patients that underwent cell-free DNA analysis, germline mutations were identified by those with high variant allelic fraction approximating 50%, followed by further confirmation on genetic testing., Results: We identified 22 patients with germline EGFR mutations, with the majority harboring an EGFR T790M mutation (95.5%) and an EGFR L858R somatic mutation (50%). Notably, most patients were female (86.4%), non-smokers (81.8%), white (86.4%), had a family history of lung cancer (59.1%), and stage IV at diagnosis (72.7%). A distinct radiographic pattern of small multifocal ground-glass pulmonary nodules was observed in the majority of our cohort (72.7%). Among the 18 with advanced-stage NSCLC, 12 patients (66.7%) were treated with first-line osimertinib, demonstrating a median progression-free survival (PFS) of 16.9 months (95% confidence interval [CI]: 6.3-not reached [NR]). Others were treated with first-line afatinib (11.1%) or chemotherapy (22.2%). Among the 17 patients treated with osimertinib (in first or second-line), median PFS was 20.4 months (95% CI: 6.3-NR) and median overall survival was 82.0 months (95% CI: 28.4-NR)., Conclusions: Based on our institutional cohort, NSCLC driven by EGFR germline mutations occurs more frequently in non-smoking, white females with multi-focal pulmonary nodules radiographically. Osimertinib for advanced germline EGFR-mutated NSCLC renders similar PFS compared to somatic T790M EGFR-mutated NSCLC., Competing Interests: Disclosure Dr. Elamin reports receiving research support from AstraZeneca, Spectrum Pharmaceuticals, and Takeda Pharmaceuticals; and has served on scientific advisory Boards for AstraZeneca, Eli Lilly, Novartis, Spectrum Pharmaceuticals, Sanofi, Takeda Pharmaceuticals, Turning Point Therapeutics, and Bristol-Myers Squibb. Dr. Zhang reports serving on the consulting/advisory board of Bristol-Myers Squibb, AstraZeneca, Novartis, Johnson & Johnson, GenePlus, Innovent, Varian, and Catalyst; receiving research grants to the institution from Merck, Novartis, and Johnson & Johnson. Dr. Negrao reports receiving research funding to institution from Mirati, Novartis, Checkmate, Alaunos, AstraZeneca, Pfizer, Genentech, and Navire; serving on the consultant/advisory board of Mirati, Merck/Merck Sharp & Dohme, Novartis, and Genentech; and receiving other support from Ziopharm Oncology, Apothecom, and Ashfield Healthcare. Dr. Altan reports research funding from Genentech, Nektar Therapeutics, Merck, GlaxoSmithKline, Novartis, Jounce Therapeutics, Bristol Myers Squibb, Eli Lilly, Adaptimmune, Shattuck Lab, Gilead, Lyell, and Insightec and speaker fees from AstraZeneca, Nektar Therapeutics, SITC, and ASTRO, as well as participation on the safety review committee for the Nanobiotix-MDA Alliance, and is on the Hengenix Advisory Board for GlaxoSmithKline, Shattuck Lab, Bristol Myers Squibb, and AstraZeneca. Dr. Skoulidis reports receiving research grants to the institution from Revolution Medicines, Mirati Therapeutics, Pfizer, Merck, Amgen, and Novartis; serving on the consulting/advisory board of AstraZeneca, Amgen, Novartis, BeiGene, Guardant Health, Bergen Bio, Navire Pharma, Tango Therapeutics, Calithera Biosciences, Intellisphere LLC, and Medscape LLC; receiving honoraria from VSPO Mc Gill Universite de Montreal and RV Mais Promocao Eventos LTDS; receiving meeting support/travel grant from Amgen, Tango Therapeutics, and Dava Oncology; and having stock from Moderna and BioNTech SE. Dr. Tsao reports receiving research funding to the institution from Ariad, Bristol-Myers Squibb, Eli Lilly, Genentech, Millennium, Polaris, AstraZeneca, Boehringer Ingelheim, Epizyme, Merck, Novartis, and Seattle Genetics; serving on the consulting/advisory board of Ariad, Bristol-Myers Squibb, Eli Lilly, Genentech, Merck, Pfizer, Seattle Genetics, AstraZeneca, Boehringer Ingelheim, EMD Serono, GlaxoSmithKline, Novartis, and Roche. Dr. Cascone reports receiving speaker fees/honoraria from Society for Immunotherapy of Cancer (SITC), Mark Foundation for Cancer Research, Bristol-Myers Squibb, Roche, Medscape, IDEOlogy Health, Physicians' Education Resource LLC (PER), OncLive, and PeerView; having consulting/advisory role from MedImmune/AstraZeneca, Bristol-Myers Squibb, Merck, Genentech, Arrowhead Pharmaceuticals, Pfizer Inc., and Regeneron; receiving travel, food, and beverage expenses from Physicians' Education Resource LLC (PER), Dava Oncology, SITC, International Association for the Study of Lung Cancer, Parker Institute for Cancer Immunotherapy, IDEOlogy Health, OncLive, MedImmune/AstraZeneca, and Bristol-Myers Squibb; and receiving research funding to institution from MedImmune/AstraZeneca, Bristol-Myers Squibb, and EMD Serono. Dr. Heymach reports having stock and other ownership interests from Cardinal Spine and Bio-Tree; having consulting or advisory roles from AstraZeneca, Bristol-Myers Squibb, Spectrum Pharmaceuticals, Guardant Health, Hengrui Pharmaceutical, GlaxoSmithKline, EMD Serono, Lilly, Takeda, Sanofi/Aventis, Genentech/Roche, Boehringer Ingelheim, Catalyst Biotech, Foundation medicine, Novartis, Mirati Therapeutics, BrightPath Biotherapeutics, Janssen, Nexus Health Systems, Pneuma Respiratory, Kairos Ventures, Roche, and Leads Biolabs; receiving research funding to institution from AstraZeneca (Inst), Spectrum Pharmaceuticals, and GlaxoSmithKline; having patents, royalties, and other intellectual property on licensing agreement between Spectrum and MD Anderson (including Dr. Heymach himself) regarding intellectual property for treatment of EGFR and HER2 exon 20 mutations. Dr. Ostrin reports consulting/ travel fees from GeneSystems, participation on the scientific advisory board of Grail, and receiving an honorarium from the Texas Association of Family Practitioners. Dr. Le reports consulting/advisory fees from Eli Lilly, EMD Serono (Merck KGaA), AstraZeneca, Spectrum Pharmaceutics, Novartis, Regeneron, Boehringer Ingelheim, Hengrui Therapeutics, Bayer, Teligene, Taiho, Daiichi Sankyo, Janssen, Blueprint Medicines, Sensei Biotherapeutics, SystImmune, ArriVent, Abion, and AbbVie, research funding to Institution from Eli Lilly, EMD Serono, ArriVent, Dizal, Teligene, Regeneron, Janssen, ThermoFisher, Takeda, and Boehringer Ingelheim, and Travel Support from EMD Serono, Janssen, and Spectrum Pharmaceutics. The remaining authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Non-small-cell lung cancer (NSCLC) is one of the most frequent cancer types and is responsible for the majority of cancer-related deaths worldwide. The management of NSCLC has improved considerably, especially in the past 10 years. The systematic screening of populations at risk with low-dose CT, the implementation of novel surgical and radiotherapeutic techniques and a deeper biological understanding of NSCLC that has led to innovative systemic treatment options have improved the prognosis of patients with NSCLC. In non-metastatic NSCLC, the combination of various perioperative strategies and adjuvant immunotherapy in locally advanced disease seem to enhance cure rates. In metastatic NSCLC, the implementation of novel drugs might prolong disease control together with preserving quality of life. The further development of predictive clinical and genetic markers will be essential for the next steps in individualized treatment concepts., (© 2024. Springer Nature Limited.)

Mutations in HER2 occur in 2-4% of non-small cell lung cancer (NSCLC) and confer poor prognosis. ERBB-targeting tyrosine kinase inhibitors, approved for treating other HER2-dependent cancers, are ineffective in HER2 mutant NSCLC due to dose-limiting toxicities or suboptimal potency. We report the discovery of zongertinib (BI 1810631), a covalent HER2 inhibitor. Zongertinib potently and selectively blocks HER2, while sparing EGFR, and inhibits the growth of cells dependent on HER2 oncogenic driver events, including HER2-dependent human cancer cells resistant to trastuzumab deruxtecan. Zongertinib displays potent anti-tumor activity in HER2-dependent human NSCLC xenograft models and enhances the activities of antibody-drug conjugates and KRASG12C inhibitors, without causing obvious toxicities. The preclinical efficacy of zongertinib translates in objective responses in patients with HER2-dependent tumors, including cholangiocarcinoma (SDC4-NRG1 fusion) and breast cancer (V777L HER2 mutation) thus supporting the ongoing clinical development of zongertinib.

Introduction: A hallmark of small cell lung cancer (SCLC) is its recalcitrance to therapy. While most SCLCs respond to frontline therapy, resistance inevitably develops. Identifying phenotypes potentiating chemoresistance and immune evasion is a crucial unmet need. Previous reports have linked upregulation of the DNA damage response (DDR) machinery to chemoresistance and immune evasion across cancers. However, it is unknown if SCLCs exhibit distinct DDR phenotypes., Methods: To study SCLC DDR phenotypes, we developed a new DDR gene analysis method and applied it to SCLC clinical samples, in vitro , and in vivo model systems. We then investigated how DDR regulation is associated with SCLC biology, chemotherapy response, and tumor evolution following therapy., Results: Using multi-omic profiling, we demonstrate that SCLC tumors cluster into three DDR phenotypes with unique molecular features. Hallmarks of these DDR clusters include differential expression of DNA repair genes, increased replication stress, and heightened G2/M cell cycle arrest. SCLCs with elevated DDR phenotypes exhibit increased neuroendocrine features and decreased "inflamed" biomarkers, both within and across SCLC subtypes. Treatment naive DDR status identified SCLC patients with different responses to frontline chemotherapy. Tumors with initial DDR Intermediate and DDR High phenotypes demonstrated greater tendency for subtype switching and emergence of heterogeneous phenotypes following treatment., Conclusions: We establish that SCLC can be classified into one of three distinct, clinically relevant DDR clusters. Our data demonstrates that DDR status plays a key role in shaping SCLC phenotypes, chemotherapy response, and patterns of tumor evolution. Future work targeting DDR specific phenotypes will be instrumental in improving patient outcomes.

Objectives: Recent randomized trials have demonstrated a survival advantage with the use of local consolidative therapy in oligometastatic non-small cell lung cancer; however, the indications for and outcomes after pulmonary resection as a component of local consolidative therapy remain ill defined. We sought to characterize the perioperative and long-term survival outcomes among patients with resected oligometastatic non-small cell lung cancer., Methods: Patients presenting to a single center (2000-2017) with oligometastatic non-small cell lung cancer (≤3 synchronous metastases, intrathoracic nodal disease counted as a single site) who underwent resection of the primary tumor were retrospectively identified. Charts were reviewed, and demographic, clinical, pathologic, oncologic, and survival outcomes were recorded. Survival outcomes were analyzed from the date of surgery., Results: A total of 52 patients met inclusion criteria, among whom most (38, 73.1%) were ever smokers, had nonsquamous tumors (48, 92.3%), had no intrathoracic nodal disease (33, 63.5%), and had 1 to 2 sites of metastases (49, 94.2%). The majority (41, 78.9%) received systemic therapy, predominantly in the neoadjuvant setting (24/41, 58.5%). After resection, there were no 30- or 90-day deaths. After a median follow-up of 94.6 months (95% CI, 69.0-139.1), 37 patients (71.2%) progressed and 38 patients (73.1%) died. Median postoperative progression-free survival and overall survival were 9.4 (5.5-11.6) months and 51.7 (22.3-65.3) months, respectively., Conclusions: Pulmonary resection as a means of maximum locoregional control in oligometastatic non-small cell lung cancer is feasible and safe, and may be associated with durable long-term survival benefits. The frequency of systemic postoperative progression highlights an urgent need to characterize perioperative and oncologic outcomes after pulmonary resection in the current era of novel systemic therapies., Competing Interests: Conflict of Interest Statement S.G.S. has participated in advisory committees for Ethicon and the Peter MacCallum Cancer Center. J.V.H. has received research support from AstraZeneca, Bayer, GlaxoSmithKline, and Spectrum; participated in advisory committees for AstraZeneca, Boehringer Ingelheim, Exelixis, Genentech, GlaxoSmithKline, Guardant Health, Hengrui, Lilly, Novartis, Spectrum, EMD Serono, and Synta; and received royalties or licensing fees from Spectrum. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2023 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: We explored potential predictive biomarkers of immunotherapy response in patients with extensive-stage small-cell lung cancer (ES-SCLC) treated with durvalumab (D) + tremelimumab (T) + etoposide-platinum (EP), D + EP, or EP in the randomized phase 3 CASPIAN trial., Methods: 805 treatment-naïve patients with ES-SCLC were randomized (1:1:1) to receive D + T + EP, D + EP, or EP. The primary endpoint was overall survival (OS). Patients were required to provide an archived tumor tissue block (or ≥ 15 newly cut unstained slides) at screening, if these samples existed. After assessment for programmed cell death ligand-1 expression and tissue tumor mutational burden, residual tissue was used for additional molecular profiling including by RNA sequencing and immunohistochemistry., Results: In 182 patients with transcriptional molecular subtyping, OS with D ± T + EP was numerically highest in the SCLC-inflamed subtype (n = 10, median 24.0 months). Patients derived benefit from immunotherapy across subtypes; thus, additional biomarkers were investigated. OS benefit with D ± T + EP versus EP was greater with high versus low CD8A expression/CD8 cell density by immunohistochemistry, but with no additional benefit with D + T + EP versus D + EP. OS benefit with D + T + EP versus D + EP was associated with high expression of CD4 (median 25.9 vs. 11.4 months) and antigen-presenting and processing machinery (25.9 vs. 14.6 months) and MHC I and II (23.6 vs. 17.3 months) gene signatures, and with higher MHC I expression by immunohistochemistry., Conclusions: These findings demonstrate the tumor microenvironment is important in mediating better outcomes with D ± T + EP in ES-SCLC, with canonical immune markers associated with hypothesized immunotherapy mechanisms of action defining patient subsets that respond to D ± T., Trial Registration: ClinicalTrials.gov, NCT03043872., (© 2024. The Author(s).)

Studying lung adenocarcinoma (LUAD) early carcinogenesis is challenging, primarily due to the lack of LUAD precursors specimens. We amassed multi-omics data from 213 LUAD and LUAD precursors to identify molecular features underlying LUAD precancer evolution. We observed progressively increasing mutations, chromosomal aberrations, whole genome doubling and genomic instability from precancer to invasive LUAD, indicating aggravating chromosomal instability (CIN). Telomere shortening, a crucial genomic alteration linked to CIN, emerged at precancer stage. Moreover, later-stage lesions demonstrated increasing cancer stemness and decreasing alveolar identity, suggesting epithelial de-differentiation during early LUAD carcinogenesis. The innate immune cells progressively diminished from precancer to invasive LUAD, concomitant with a gradual recruitment of adaptive immune cells (except CD8 + and gamma-delta T cells that decreased in later stages) and upregulation of numerous immune checkpoints, suggesting LUAD precancer evolution is associated with a shift from innate to adaptive immune response and immune evasion mediated by various mechanisms., Competing Interests: J.J.Z. reports research funding from Merck, Johnson and Johnson, Novartis, Summit, Hengenix and consultant fees from BMS, Johnson and Johnson, AstraZeneca, Geneplus, OrigMed, Innovent, Varian, Catalyst outside the submitted work. I.I.W reports Honoraria from Genentech/Roche, Bayer, Bristol-Myers Squibb, Astra Zeneca/Medimmune, Pfizer, HTG Molecular, Asuragen, Merck, GlaxoSmithKline, Guardant Health, Oncocyte, Flame, and MSD; Research support from Genentech, Oncoplex, HTG Molecular, DepArray, Merck, Bristol-Myers Squibb, Medimmune, Adaptive, Adapt immune, EMD Serono, Pfizer, Takeda, Amgen, Karus, Johnson & Johnson, Bayer, Iovance, 4D, Novartis, and Akoya. J.V.H. reports honorariums from AstraZeneca, Boehringer-Ingelheim, Catalyst, Genentech, GlaxoSmithKline, Guardant Health, Foundation medicine, Hengrui Therapeutics, Eli Lilly, Novartis, Spectrum, EMD Serono, Sanofi, Takeda, Mirati Therapeutics, BMS, BrightPath Biotherapeutics, Janssen Global Services, Nexus Health Systems, EMD Serono, Pneuma Respiratory, Kairos Venture Investments, Roche and Leads Biolabs. D.E.G. reports research funding from Astra-Zeneca, BerGenBio, Karyopharm, and Novocure; stock ownership in Gilead; consultant/advisory fees from Abbvie, Astra-Zeneca, Catalyst Pharmaceuticals, Daiichi-Sankyo, Elevation Oncology, Janssen Scientific Affairs, LLC, Jazz Pharmaceuticals, Regeneron Pharmaceuticals, and Sanofi; and serving as co-founder and chief scientific officer of OncoSeer Diagnostics, Inc. S.H. reports consulting fees from Guardant Health and AstraZeneca. S.M.D serves on the Scientific Advisory Boards for Early Diagnostics Inc. and LungLife AI, Inc. and has received research funding from Johnson & Johnson Lung Cancer Initiative and Novartis. The other authors declare no competing interests.

The curative treatment of multiple solid tumors, including head and neck squamous cell carcinoma (HNSCC), utilizes radiation. The outcomes for HPV/p16-negative HNSCC are significantly worse than HPV/p16-positive tumors, with increased radiation resistance leading to worse locoregional recurrence (LRR) and ultimately death. This study analyzed the relationship between immune function and outcomes following radiation in HPV/p16-negative tumors to identify mechanisms of radiation resistance and prognostic immune biomarkers. A discovery cohort of 94 patients with HNSCC treated uniformly with surgery and adjuvant radiation and a validation cohort of 97 similarly treated patients were utilized. Tumor immune infiltrates were derived from RNAseq gene expression. The immune cell types significantly associated with outcomes in the discovery cohort were examined in the independent validation cohort. A positive association between high Th2 infiltration and LRR was identified in the discovery cohort and validated in the validation cohort. Tumor mutations in CREBBP/EP300 and CASP8 were significantly associated with Th2 infiltration. A pathway analysis of genes correlated with Th2 cells revealed the potential repression of the antitumor immune response and the activation of BRCA1-associated DNA damage repair in multiple cohorts. The Th2 infiltrates were enriched in the HPV/p16-negative HNSCC tumors and associated with LRR and mutations in CASP8, CREBBP/EP300, and pathways previously shown to impact the response to radiation.

Background: Pulmonary sarcomatoid carcinoma (PSC) is a rare and aggressive subtype of non-small cell lung cancer (NSCLC), characterized by the presence of epithelial and sarcoma-like components. The molecular and immune landscape of PSC has not been well defined., Methods: Multiomics profiling of 21 pairs of PSCs with matched normal lung tissues was performed through targeted high-depth DNA panel, whole-exome, and RNA sequencing. We describe molecular and immune features that define subgroups of PSC with disparate genomic and immunogenic features as well as distinct clinical outcomes., Results: In total, 27 canonical cancer gene mutations were identified, with TP53 the most frequently mutated gene, followed by KRAS . Interestingly, most TP53 and KRAS mutations were earlier genomic events mapped to the trunks of the tumors, suggesting branching evolution in most PSC tumors. We identified two distinct molecular subtypes of PSC, driven primarily by immune infiltration and signaling. The Immune High (IM-H) subtype was associated with superior survival, highlighting the impact of immune infiltration on the biological and clinical features of localized PSCs., Conclusions: We provided detailed insight into the mutational landscape of PSC and identified two molecular subtypes associated with prognosis. IM-H tumors were associated with favorable recurrence-free survival and overall survival, highlighting the importance of tumor immune infiltration in the biological and clinical features of PSCs., Competing Interests: Ignacio I. Wistuba reports consulting or advisory roles for AstraZeneca/MedImmune, Bayer, Bristol‐Myers Squibb, Genentech/Roche, GlaxoSmithKline, Guardant Health, HTG Molecular Diagnostics, Merck, MSD Oncology, OncoCyte, Jansen, Novartis, Flame Inc, and Pfizer; has received grants and personal fees from Genentech/Roche, Bristol Myers Squibb, AstraZeneca/MedImmune, HTG Molecular, Merck, and Guardant Health; has received personal fees from GlaxoSmithKline and Oncocyte, Daiichi‐Sankyo, Roche, Astra Zeneca, Pfizer, and Bayer; has received research funding to his institution from 4D Molecular Therapeutics, Adaptimmune, Adaptive Biotechnologies, Akoya Biosciences, Amgen, Bayer, EMD Serono, Genentech, Guardant Health, HTG Molecular Diagnostics, Iovance Biotherapeutics, Johnson & Johnson, Karus Therapeutics, MedImmune, Merck, Novartis, OncoPlex Diagnostics, Pfizer, Takeda, and Novartis. Jianjun Zhang reports research funding from Merck, Johnson and Johnson, and consultant fees from BMS, Johnson and Johnson, AstraZeneca, Geneplus, OrigMed, and Innovent outside the submitted work. John V. Heymach reports honorariums from AstraZeneca, Boehringer‐Ingelheim, Catalyst, Genentech, GlaxoSmithKline, Guardant Health, Foundation Medicine, Hengrui Therapeutics, Eli Lilly, Novartis, Spectrum, EMD Serono, Sanofi, Takeda, Mirati Therapeutics, BMS, BrightPath Biotherapeutics, Janssen Global Services, Nexus Health Systems, EMD Serono, Pneuma Respiratory, Kairos Venture Investments, Roche and Leads Biolabs. Runzhe Chen reports stock options from BeiGene outside the submitted work. Cara Haymaker received funding to institution from Avenge Bio, Sanofi, Dragonfly, BTG, Iovance Biotherapeutics, KSQ, Obsidian and Virogen, personal fees from Regeneron and stock options from BriaCell as a member of the scientific advisory board outside the submitted work. Alexandre Reuben serves on the Scientific Advisory Board and has received honoraria from Adaptive Biotechnologies. Natalie I Vokes reports consulting roles for Sanofi, Oncocyte, Lilly, Regeneron, Amgen, Xencor, Astra Zeneca, Tempus and Pfizer, and travel reimbursement from regeneron. Professor Jianjun Zhang is a member of the Cancer Innovation Editorial Board. To minimize bias, he was excluded from all editorial decision‐making related to the acceptance of this article for publication. The remaining authors declare no conflict of interest., (© 2024 The Authors. Cancer Innovation published by John Wiley & Sons Ltd on behalf of Tsinghua University Press.)

Introduction: Responses to first-line programmed cell death protein 1 inhibition vary among patients with metastatic NSCLC and a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) greater than or equal to 50%. We previously reported improved clinical outcomes to first-line programmed cell death protein 1 inhibition in patients with metastatic NSCLC with a PD-L1 TPS of greater than or equal to 90% versus 50% to 89% in a pilot study. Here, we report the three-year survival with first-line pembrolizumab and cemiplimab in two large independent cohorts of patients with PD-L1 TPS greater than or equal to 90% versus 50% to 89% and characterize genomic and immunophenotypic differences between these PD-L1 expression groups, which were largely unknown., Methods: We analyzed three-year outcomes of the following two independent cohorts: (1) a multicenter cohort of patients from four academic centers in the United States treated with pembrolizumab and (2) EMPOWER-Lung 1, randomized, phase III trial comparing first-line cemiplimab with chemotherapy. Tumor genomic profiling and multiplexed immunofluorescence were performed to evaluate genomic and immunophenotypic correlates of very high PD-L1 expression., Results: At three years of follow-up, progression-free survival (hazard ratio [HR], 0.69; p < 0.001) and overall survival (HR, 0.70; p < 0.01) to first-line commercial pembrolizumab were significantly improved in patients with a PD-L1 TPS greater than or equal to 90% versus 50% to 89%. In the EMPOWER-Lung 1, patients assigned to the cemiplimab arm with a PD-L1 TPS greater than or equal to 90% also had significant improvements in progression-free survival (HR, 0.53; p < 0.0001) and overall survival (HR, 0.63; p  = 0.007) compared with those with a PD-L1 of 50% to 89%. Tumor genomic profiling of 553 NSCLC samples revealed that mutations in STK11 and SMARCA4 were significantly more frequent in tumors with a PD-L1 TPS of 50% to 89% compared with those with a PD-L1 TPS greater than or equal to 90% (Q < 0.15), whereas BRCA2 was enriched in NSCLC samples with a PD-L1 TPS greater than or equal to 90% (Q < 0.15). Multiplexed immunofluorescence on 93 NSCLC samples identified higher intratumoral CD8 + PD1 + T cells ( p  = 0.02) in tumors with PD-L1 TPS greater than or equal to 90% versus 50% to 89%., Conclusion: Pembrolizumab and cemiplimab were found to have long-term survival benefit and favorable genomic and immunophenotypic profile in patients with advanced NSCLC with PD-L1 TPS greater than or equal to 90% compared with TPS 50% to 89%., Competing Interests: Dr. Ricciuti reports serving on the consulting/advisory board of AstraZeneca, Amgen, and Regeneron; receiving honoraria from Targeted Oncology; and receiving speaker fees from AstraZeneca. Dr. Lin reports receiving consulting from Genentech, C4 Therapeutics, Blueprint Medicines, Nuvalent, Bayer, Elevation Oncology, Novartis, Mirati Therapeutics, Regeneron, Pfizer, Takeda, Ellipses Pharma, Hyku BioSciences, AnHeart Therapeutics, Claim Therapeutics, Turning Point Therapeutics, Bristol-Myers Squibb, and Daiichi Sankyo; receiving institutional research funding from Hengrui Therapeutics, Turning Point Therapeutics, Neon Therapeutics, 10.13039/100019393Relay Therapeutics, 10.13039/100004326Bayer, Elevation Oncology, 10.13039/100004337Roche, Linnaeus Therapeutics, Nuvalent, and 10.13039/100004336Novartis. Dr. Altan reports receiving research funding (to institution) from Genentech, Nektar Therapeutics, Merck, GlaxoSmithKline, Novartis, Jounce Therapeutics, Bristol-Myers Squibb, Eli Lilly, Adaptimmune, Shattuck Lab, and Gilead; serving on the advisory board of GlaxoSmithKline, Shattuck Lab, Bristol-Myers Squibb, AstraZeneca, and Insightec; receiving speaker fees from AstraZeneca, Nektar Therapeutics, and SITC; and having participation of safety review committee for Nanobiotix-MDA Alliance and Hengenix. Dr. Zhang reports receiving grants from 10.13039/100004334Merck; grants and personal fees from Johnson and Johnson and Novartis; and personal fees from Bristol-Myers Squibb, AstraZeneca, GenePlus, Innovent, Varian, Catalyst, and Hengrui, outside the submitted work. Dr. Gainor has served as a compensated consultant or received honoraria from Bristol-Myers Squibb, Genentech/Roche, Takeda, Loxo/Lilly, Blueprint Medicine, Gilead, Moderna, AstraZeneca, Mariana Therapeutics, Mirati, Jounce, Merus Pharmaceuticals, Nuvalent, Pfizer, Novocure, AI Proteins, Novartis, Merck, iTeos, Karyopharm, and Silverback Therapeutics; has received research support from 10.13039/100004336Novartis, Genentech/Roche, and Takeda; has received institutional research support from 10.13039/100002491Bristol-Myers Squibb, Palleon, Tesaro, 10.13039/100019533Moderna, Blueprint, Jounce, 10.13039/100007174Array Biopharma, Merck, Adaptimmune, Novartis, and Alexo; has equity in AI Proteins; and has an immediate family member who is an employee with equity at Ironwood Pharmaceuticals. Dr. Heymach reports serving on the advisory committees of Genentech, Mirati Therapeutics, Eli Lilly & Co., Janssen Pharmaceuticals, Boehringer-Ingelheim Pharmaceuticals, Regeneron, Takeda Pharmaceuticals, BerGenBio, Jazz Pharmaceuticals, Curio Science, Novartis, AstraZeneca Pharmaceuticals, BioAlta, Sanofi, Spectrum Pharmaceuticals, GlaxoSmithKline, EMD Serono, BluePrint Medicine, and Chugai Pharmaceutical; receiving research support from 10.13039/100004325AstraZeneca, Boehringer-Ingelheim, 10.13039/100006399Spectrum, Mirati, Bristol-Myers Squibb, and Takeda; and receiving licensing/royalties from Spectrum. Dr. Pouliot reports being an employee at Regeneron and a Regeneron shareholder. Dr. McIntyre reports being an employee at Regeneron. Dr. Awad reports receiving research funding from Bristol-Myers Squibb, Lilly, 10.13039/100004328Genentech, AstraZeneca, and Elva J. and Clayton L. McLaughlin Fund for Lung Cancer Research; receiving consulting fees from/serving on the advisory board of Merck, Bristol-Myers Squibb, Genentech, AstraZeneca, Nektar, Maverick, Blueprint Medicine, Syndax, AbbVie, Gritstone, ArcherDX, Mirati, NextCure, and EMD Serono. Dr. Rietschel reports being an employee at Regeneron and a Regeneron shareholder with patent issued PCT/US2018/018747. Dr. Nishino reports receiving research funding from Merck, Canon Medical Systems, AstraZeneca, and 10.13039/501100022274Daiichi Sankyo; receiving consulting fees from Daiichi Sankyo and AstraZeneca; and receiving honoraria from Roche. Dr. Sholl reports receiving consulting fee from Genentech, Lilly, and GV20 Therapeutics. The remaining authors have no conflict of interests to disclose., (© 2024 The Authors.)

Background: Recent studies have reported the predictive and prognostic value of novel transcriptional factor-based molecular subtypes in small-cell lung cancer (SCLC). We conducted an in-depth analysis pairing multi-omics data with immunohistochemistry (IHC) to elucidate the underlying characteristics associated with differences in clinical outcomes between subtypes., Methods: IHC (n = 252), target exome sequencing (n = 422), and whole transcriptome sequencing (WTS, n = 189) data generated from 427 patients (86.4% males, 13.6% females) with SCLC were comprehensively analysed. The differences in the mutation profile, gene expression profile, and inflammed signatures were analysed according to the IHC-based molecular subtype., Findings: IHC-based molecular subtyping, comprised of 90 limited-disease (35.7%) and 162 extensive-disease (64.3%), revealed a high incidence of ASCL1 subtype (IHC-A, 56.3%) followed by ASCL1/NEUROD1 co-expressed (IHC-AN, 17.9%), NEUROD1 (IHC-N, 12.3%), POU2F3 (IHC-P, 9.1%), triple-negative (IHC-TN, 4.4%) subtypes. IHC-based subtype showing high concordance with WTS-based subtyping and non-negative matrix factorization (NMF) clusterization method. IHC-AN subtype resembled IHC-A (rather than IHC-N) in terms of both gene expression profiles and clinical outcomes. Favourable median overall survival was observed in IHC-A (15.2 months) compared to IHC-N (8.0 months, adjusted HR 2.3, 95% CI 1.4-3.9, p = 0.002) and IHC-P (8.3 months, adjusted HR 1.7, 95% CI 0.9-3.2, p = 0.076). Inflamed tumours made up 25% of cases (including 53% of IHC-P, 26% of IHC-A, 17% of IHC-AN, but only 11% of IHC-N). Consistent with recent findings, inflamed tumours were more likely to benefit from first-line immunotherapy treatment than non-inflamed phenotype (p = 0.002)., Interpretation: This study provides fundamental data, including the incidence and basic demographics of molecular subtypes of SCLC using both IHC and WTS from a comparably large, real-world Asian/non-Western patient cohort, showing high concordance with the previous NMF-based SCLC model. In addition, we revealed underlying biological pathway activities, immunogenicity, and treatment outcomes based on molecular subtype, possibly related to the difference in clinical outcomes, including immunotherapy response., Funding: This work was supported by AstraZeneca, Future Medicine 2030 Project of the Samsung Medical Center [grant number SMX1240011], the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) [grant number 2020R1C1C1010626] and the 7th AstraZeneca-KHIDI (Korea Health Industry Development Institute) oncology research program., Competing Interests: Declaration of interests The authors have declared that no conflict of interest exists., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Chemotherapy plus nivolumab is the standard of care neoadjuvant treatment for patients with resectable stage IB to IIIA non-small cell lung cancer. The influence of dual checkpoint blockade with chemotherapy on surgical outcomes remains unknown. We aimed to determine operative complexity and perioperative outcomes associated with neoadjuvant chemotherapy and nivolumab with or without ipilimumab., Methods: A total of 44 patients with stage IB (≥4 cm) to IIIA non-small cell lung cancer were treated on sequential platform arms of the NEOSTAR trial. A total of 22 patients were treated with nivolumab + chemotherapy, and 22 patients were treated with ipilimumab + nivolumab + chemotherapy. The safety of surgical resection after neoadjuvant therapy was estimated using 30-day complication rates. Operative reports and surgeons' narratives were evaluated to determine procedural complexity and operative conduct., Results: All 22 of 22 patients (100%) treated with nivolumab + chemotherapy underwent surgical resection: 20 R0 (90.9%), 17 (77.3%) lobectomies, 1 wedge resection, 2 segmentectomies, and 2 pneumonectomies. The majority, 21 of 22 (95%), were performed by thoracotomy. A total of 13 of 22 (59.1%) were rated as challenging resections. A total of 4 of 22 patients (18.2%) experienced grade 3 or greater Clavien-Dindo complication. A total of 20 of 22 patients (90.9%) treated with ipilimumab + nivolumab + chemotherapy underwent surgical resection: 19 R0 (95%), 18 (90%) lobectomies, 1 pneumonectomy, and 1 segmentectomy. A total of 16 of 20 (80%) resections were performed via thoracotomy, 3 of 20 (15%) via robotics, and 1 of 20 (5%) via thoracoscopy. A total of 9 of 20 (45%) resections were considered challenging. A total of 4 of 20 patients (20%) experienced grade 3 or greater Clavien-Dindo complication., Conclusions: Surgical resections are feasible and safe, with high rates of R0 after neoadjuvant chemotherapy and nivolumab with or without ipilimumab. Overall, approximately half of cases (22/42, 52.3%) were considered to be more challenging than a standard lobectomy., Competing Interests: Conflict of Interest Statement T.C. reports (over the past 36 months) speaker fees/honoraria from the Society for Immunotherapy of Cancer, Mark Foundation for Cancer Research, Bristol Myers Squibb, Roche, Medscape, IDEOlogy Health, Physicians' Education Resource LLC, OncLive, PeerView, and Clinical Care Options; advisory role/consulting fees from MedImmune/AstraZeneca, Bristol Myers Squibb, Merck & Co, Genentech, Ar Pharmaceuticals, Pfizer Inc, and Regeneron; institutional research funding from MedImmune/AstraZeneca and Bristol Myers Squibb; and travel, food, or beverage expenses from Physicians' Education Resource LLC, Dava Oncology, Society for Immunotherapy of Cancer, International Association for the Study of Lung Cancer, Parker Institute for Cancer Immunotherapy, IDEOlogy Health, OncLive, AstraZeneca, and Bristol Myers Squibb. W.N.W. reports consulting or advisory role fees from Clovis Oncology and AstraZeneca; speaker’s fees from Boehringer Ingelheim; honoraria from Roche/Genentech, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Merck, Bayer, Pfizer, and Eli Lilly; and research funding from OSI Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, and Merck. J.V.H. reports Advisory Committees – Genentech, Mirati Therapeutics, Eli Lilly & Co, Janssen Pharmaceuticals, Boehringer-Ingelheim Pharmaceuticals, Regeneron, Takeda Pharmaceuticals, BerGenBio, Jazz Pharmaceuticals, Curio Science, Novartis, AstraZeneca Pharmaceuticals, BioAlta, Sanofi, Spectrum Pharmaceuticals, GlaxoSmithKline, EMD Serono, BluePrint Medicine, and Chugai Pharmaceutical. Research Support—AstraZeneca, Boehringer-Ingelheim, Spectrum, Mirati, Bristol-Myer Squibb, and Takeda. Licensing/Royalties—Spectrum. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Adjuvant immunotherapy (IO) following concurrent chemotherapy and photon radiation therapy confers an overall survival (OS) benefit for patients with inoperable locally advanced non-small cell lung carcinoma (LA-NSCLC); however, outcomes of adjuvant IO after concurrent chemotherapy with proton beam therapy (CPBT) are unknown. We investigated OS and toxicity after CPBT with adjuvant IO versus CPBT alone for inoperable LA-NSCLC., Materials and Methods: We analyzed 354 patients with LA-NSCLC who were prospectively treated with CPBT with or without adjuvant IO from 2009 to 2021. Optimal variable ratio propensity score matching (PSM) matched CPBT with CPBT + IO patients. Survival was estimated with the Kaplan-Meier method and compared with log-rank tests. Multivariable Cox proportional hazards regression evaluated the effect of IO on disease outcomes., Results: Median age was 70 years; 71 (20%) received CPBT + IO and 283 (80%) received CPBT only. After PSM, 71 CPBT patients were matched with 71 CPBT + IO patients. Three-year survival rates for CPBT + IO vs CPBT were: OS 67% vs 30% (P < 0.001) and PFS 59% vs 35% (P = 0.017). Three-year LRFS (P = 0.137) and DMFS (P = 0.086) did not differ. Receipt of adjuvant IO was a strong predictor of OS (HR 0.40, P = 0.001) and PFS (HR 0.56, P = 0.030), but not LRFS (HR 0.61, P = 0.121) or DMFS (HR 0.61, P = 0.136). There was an increased incidence of grade ≥3 esophagitis in the CPBT-only group (6% CPBT + IO vs 17% CPBT, P = 0.037)., Conclusion: This study, one of the first to investigate CPBT followed by IO for inoperable LA-NSCLC, showed that IO conferred survival benefits with no increased rates of toxicity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

[ 18 F]Fluorodeoxyglucose positron emission tomography (FDG-PET) and computed tomography (CT) are indispensable components in modern medicine. Although PET can provide additional diagnostic value, it is costly and not universally accessible, particularly in low-income countries. To bridge this gap, we have developed a conditional generative adversarial network pipeline that can produce FDG-PET from diagnostic CT scans based on multi-center multi-modal lung cancer datasets (n = 1,478). Synthetic PET images are validated across imaging, biological, and clinical aspects. Radiologists confirm comparable imaging quality and tumor contrast between synthetic and actual PET scans. Radiogenomics analysis further proves that the dysregulated cancer hallmark pathways of synthetic PET are consistent with actual PET. We also demonstrate the clinical values of synthetic PET in improving lung cancer diagnosis, staging, risk prediction, and prognosis. Taken together, this proof-of-concept study testifies to the feasibility of applying deep learning to obtain high-fidelity PET translated from CT., Competing Interests: Declaration of interests T.C. reports speaker fees and honoraria from The Society for Immunotherapy of Cancer, Bristol Myers Squibb, Roche, Medscape, and PeerView; having an advisory role or receiving consulting fees from AstraZeneca, Bristol Myers Squibb, EMD Serono, Merck & Co., Genentech, and Arrowhead Pharmaceuticals; and institutional research funding from AstraZeneca, Bristol Myers Squibb, and EMD Serono. L.Y. has grant support from Lantheus Inc. D.L.G. has served on scientific advisory committees for Menarini Ricerche, 4D Pharma, Onconova, and Eli Lilly and has received research support from Takeda, Astellas, NGM Biopharmaceuticals, Boehringer Ingelheim, and AstraZeneca. N.I.V. receives consulting fees from Sanofi, Regeneron, Oncocyte, and Eli Lilly and research funding from Mirati, outside the submitted work. J.D.H. is on the Scientific Advisory Board of Imagion Biosystems. J.Y.C. reports research funding from BMS-MDACC and Siemens Healthcare, and consultation fees from Legion Healthcare Partners. L.Y. has grant support from Lantheus Inc. M.C.B.G. has received research funding from Siemens Healthcare. I.W. has received honoraria from Genentech/Roche, AstraZeneca, Merck, Guardant Health, Flame, Novartis, Sanofi, Daiichi Sankyo, Dava Oncology, Amgen, GlaxoSmithKline, HTG Molecular, Jansen, Merus, Imagene, G1 Therapeutics, Abbvie, Catalyst Therapeutics, Genzyme, Regeneron, Oncocyte, Medscape, Platform Health, Pfizer, Physicians’ Education Resource, HPM Education, and Aptitute Health; additionally, I.W. has received research support from Genentech, Merck, Bristol-Myers Squibb, Medimmune, Adaptive, Adaptimmune, EMD Serono, Pfizer, Takeda, Amgen, Karus, Johnson & Johnson, Bayer, Iovance, 4D, Novartis, and Akoya. D.L.G. has served on scientific advisory committees for Menarini Ricerche, 4D Pharma, Onconova, and Eli Lilly and has received research support from Takeda, Astellas, NGM Biopharmaceuticals, Boehringer Ingelheim, and AstraZeneca. J.V.H. reports being on scientific advisory boards for AstraZeneca, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Eli Lilly, Novartis, Spectrum, EMD Serono, Sanofi, Takeda, Mirati Therapeutics, BMS, and Janssen Global Services; receiving research support from AstraZeneca, Takeda, Boehringer Ingelheim, and Spectrum; and receiving licensing fees from Spectrum. C.C.W. reports research support from Medical Imaging and Data Resource Center from NIBIB/University of Chicago and royalties from Elsevier. J.Z. reports serving on the consulting/advisory board of Bristol-Myers Squibb, AstraZeneca, Novartis, Johnson & Johnson, GenePlus, Innovent, Varian, and Catalyst, and receiving research grants to institution from Merck, Novartis, and Johnson & Johnson. J.W. reports research funding from Siemens Healthcare., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Atezolizumab (anti-PD-L1), combined with carboplatin and etoposide (CE), is now a standard of care for extensive-stage small-cell lung cancer (ES-SCLC). A clearer understanding of therapeutically relevant SCLC subsets could identify rational combination strategies and improve outcomes. We conduct transcriptomic analyses and non-negative matrix factorization on 271 pre-treatment patient tumor samples from IMpower133 and identify four subsets with general concordance to previously reported SCLC subtypes (SCLC-A, -N, -P, and -I). Deeper investigation into the immune heterogeneity uncovers two subsets with differing neuroendocrine (NE) versus non-neuroendocrine (non-NE) phenotypes, demonstrating immune cell infiltration hallmarks. The NE tumors with low tumor-associated macrophage (TAM) but high T-effector signals demonstrate longer overall survival with PD-L1 blockade and CE versus CE alone than non-NE tumors with high TAM and high T-effector signal. Our study offers a clinically relevant approach to discriminate SCLC patients likely benefitting most from immunotherapies and highlights the complex mechanisms underlying immunotherapy responses., Competing Interests: Declaration of interests B.Y.N., H.H., and D.S.S. are co-inventors on a provisional patent application filed by Genentech/Roche related to this manuscript. B.Y.N. is an employee and stockholder of Roche/Genentech. H.H. is an employee and stockholder of Roche/Genentech. R.B. is an employee and shareholder of Roche/Genentech. S.M. is an employee and shareholder of Roche. L.A. is an employee and shareholder of Roche. V.G. is an employee of Rancho Biosciences and a consultant to Roche/Genentech. M.C.L. is an employee of Roche/Genentech. A.M.E. is an employee of Roche/Genentech. M.K.S. is an employee and shareholder of Roche/Genentech. N.S.P. is an employee and shareholder of Roche/Genentech. K.A.S. is an employee of Roche/Genentech. R.J. is an employee and shareholder of Roche/Genentech. C.C. is an employee and shareholder of Roche/Genentech. P.S.C. is an employee and shareholder of Roche/Genentech. M.F. is an employee of Roche/Genentech. S.R. is an employee and shareholder of Roche/Genentech. L.M.M. is an employee and shareholder of Roche/Genentech. H.K. is an employee and shareholder of Roche/Genentech. J.D.M. receives royalties from the NIH and UTSW for distribution of human tumor cell lines and has the following grants: CA070907, CA213274, and CA213338. C.M.G. reports consulting/advisory fees from AstraZeneca, Bristol Myers Squibb, Catalyst Pharmaceuticals, Daiichi Sankyo, G1 Therapeutics, Insights Driven Research, Jazz Pharmaceuticals, and Monte Rosa Therapeutics, as well as speaking/travel fees from Aptitude Health, BeiGene, DAVA Oncology, MJH, and OncLive, and royalties from UpToDate, Inc. J.M.C. has been paid as a consultant for Sonata Therapeutics and also owns stock in Mirati Therapeutics. J.V.H. has advisory or consulting relationships with Genentech, Mirati Therapeutics, Eli Lilly & Co, Janssen Pharmaceuticals, Boehringer-Ingelheim Pharmaceuticals, Regeneron, Takeda Pharmaceuticals, BerGenBio, Jazz Pharmaceuticals, Curio Science, Novartis, AstraZeneca Pharmaceuticals, BioAtla, Sanofi, Spectrum Pharmaceuticals, GlaxoSmithKline, EMD Serono, Blueprint Medicine, and Chugai Pharmaceuticals. C.M.R. has consulted regarding oncology drug development with AbbVie, Amgen, AstraZeneca, D2G, Daiichi Sankyo, Epizyme, Genentech/Roche, Ipsen, Jazz, Kowa, Lilly, Merck, and Syros. He serves on the scientific advisory boards of Auron, Bridge Medicines, DISCO, Earli, and Harpoon Therapeutics. L.A.B. has consulted regarding oncology drug development Merck Sharp & Dohme Corp., Arrowhead Pharmaceuticals, Chugai Pharmaceutical Co., AstraZeneca Pharmaceuticals, Genetech Inc., BeiGene, AbbVie, Jazz Pharmaceuticals, Puma Biotechnology, Amgen, and Daiichi Sankyo. S.V.L. served as a paid consultant/advisor for oncology drug development with AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Blueprint, Boehringer-Ingelheim, Bristol-Myers Squibb, Catalyst, AstraZeneca, D2G, Daiichi Sankyo, Eisai, Elevation Oncology Epizyme, Genentech/Roche, Gilead, Guardant Health, Janssen, Ipsen, Jazz Pharmaceuticals, Kowa, Lilly, Merck/MSD, Novartis, Regeneron, Sanofi, Takeda, Turning Point, and Syros. He serves on the scientific advisory boards of Bridge Medicines, Earli, and Harpoon Therapeutics and has received research funding (to institution). M.R. has received honoraria for lectures and consultancy from Amgen, AstraZeneca, BMS, BeiGene, Boehringer-Ingelheim, Daiichi Sankyo, GSK, Mirati, Merck, MSD, Lilly, Novartis, Pfizer, Regeneron, and Sanofi. He has received compensation for membership of DMSB by Daiichi Sankyo and Sanofi. D.S.S. is an employee and stockholder of Roche/Genentech., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Amivantamab-vmjw (amivantamab) is a bispecific EGFR/MET antibody approved for patients with advanced NSCLC with EGFR exon 20 insertion mutations, after prior therapy. Nevertheless, the benefits and safety of amivantamab in other EGFR-mutant lung cancer, with or without osimertinib, and with concurrent radiation therapy, are less known., Methods: We queried the MD Anderson Lung Cancer GEMINI, Fred Hutchinson Cancer Research Center, University of California Davis Comprehensive Cancer Center, and Stanford Cancer Center's database for patients with EGFR-mutant NSCLC treated with amivantamab, not on a clinical trial. The data analyzed included initial response, duration of treatment, and concomitant radiation safety in overall population and prespecified subgroups., Results: A total of 61 patients received amivantamab. Median age was 65 (31-81) years old; 72.1% were female; and 77% were patients with never smoking history. Median number of prior lines of therapies was four. On the basis of tumor's EGFR mutation, 39 patients were in the classical mutation cohort, 15 patients in the exon 20 cohort, and seven patients in the atypical cohort. There were 37 patients (58.7%) who received amivantamab concomitantly with osimertinib and 25 patients (39.1%) who received concomitant radiation. Furthermore, 54 patients were assessable for response in the overall population; 19 patients (45.2%) had clinical response and disease control rate (DCR) was 64.3%. In the classical mutation cohort of the 33 assessable patients, 12 (36.4%) had clinical response and DCR was 48.5%. In the atypical mutation cohort, six of the seven patients (85.7%) had clinical response and DCR was 100%. Of the 13 assessable patients in the exon 20 cohort, five patients (35.7%) had clinical response and DCR was 64.3%. Adverse events reported with amivantamab use were similar as previously described in product labeling. No additional toxicities were noted when amivantamab was given with radiation with or without osimertinib., Conclusions: Our real-world multicenter analysis revealed that amivantamab is a potentially effective treatment option for patients with EGFR mutations outside of exon 20 insertion mutations. The combination of osimertinib with amivantamab is safe and feasible. Radiation therapy also seems safe when administered sequentially or concurrently with amivantamab., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Understanding the cellular processes that underlie early lung adenocarcinoma (LUAD) development is needed to devise intervention strategies 1 . Here we studied 246,102 single epithelial cells from 16 early-stage LUADs and 47 matched normal lung samples. Epithelial cells comprised diverse normal and cancer cell states, and diversity among cancer cells was strongly linked to LUAD-specific oncogenic drivers. KRAS mutant cancer cells showed distinct transcriptional features, reduced differentiation and low levels of aneuploidy. Non-malignant areas surrounding human LUAD samples were enriched with alveolar intermediate cells that displayed elevated KRT8 expression (termed KRT8 + alveolar intermediate cells (KACs) here), reduced differentiation, increased plasticity and driver KRAS mutations. Expression profiles of KACs were enriched in lung precancer cells and in LUAD cells and signified poor survival. In mice exposed to tobacco carcinogen, KACs emerged before lung tumours and persisted for months after cessation of carcinogen exposure. Moreover, they acquired Kras mutations and conveyed sensitivity to targeted KRAS inhibition in KAC-enriched organoids derived from alveolar type 2 (AT2) cells. Last, lineage-labelling of AT2 cells or KRT8 + cells following carcinogen exposure showed that KACs are possible intermediates in AT2-to-tumour cell transformation. This study provides new insights into epithelial cell states at the root of LUAD development, and such states could harbour potential targets for prevention or intervention., (© 2024. The Author(s).)

For patients with non-small-cell lung cancer (NSCLC) tumors without currently targetable molecular alterations, standard-of-care treatment is immunotherapy with anti-PD-(L)1 checkpoint inhibitors, alone or with platinum-doublet therapy. However, not all patients derive durable benefit and resistance to immune checkpoint blockade is common. Understanding mechanisms of resistance-which can include defects in DNA damage response and repair pathways, alterations or functional mutations in STK11/LKB1, alterations in antigen-presentation pathways, and immunosuppressive cellular subsets within the tumor microenvironment-and developing effective therapies to overcome them, remains an unmet need. Here the phase 2 umbrella HUDSON study evaluated rational combination regimens for advanced NSCLC following failure of anti-PD-(L)1-containing immunotherapy and platinum-doublet therapy. A total of 268 patients received durvalumab (anti-PD-L1 monoclonal antibody)-ceralasertib (ATR kinase inhibitor), durvalumab-olaparib (PARP inhibitor), durvalumab-danvatirsen (STAT3 antisense oligonucleotide) or durvalumab-oleclumab (anti-CD73 monoclonal antibody). Greatest clinical benefit was observed with durvalumab-ceralasertib; objective response rate (primary outcome) was 13.9% (11/79) versus 2.6% (5/189) with other regimens, pooled, median progression-free survival (secondary outcome) was 5.8 (80% confidence interval 4.6-7.4) versus 2.7 (1.8-2.8) months, and median overall survival (secondary outcome) was 17.4 (14.1-20.3) versus 9.4 (7.5-10.6) months. Benefit with durvalumab-ceralasertib was consistent across known immunotherapy-refractory subgroups. In ATM-altered patients hypothesized to harbor vulnerability to ATR inhibition, objective response rate was 26.1% (6/23) and median progression-free survival/median overall survival were 8.4/22.8 months. Durvalumab-ceralasertib safety/tolerability profile was manageable. Biomarker analyses suggested that anti-PD-L1/ATR inhibition induced immune changes that reinvigorated antitumor immunity. Durvalumab-ceralasertib is under further investigation in immunotherapy-refractory NSCLC.ClinicalTrials.gov identifier: NCT03334617., (© 2024. The Author(s).)

Docetaxel +/- ramucirumab remains the standard-of-care therapy for patients with metastatic non-small-cell lung cancer (NSCLC) after progression on platinum doublets and immune checkpoint inhibitors (ICIs). The aim of our study was to investigate whether the cancer gene mutation status was associated with clinical benefits from docetaxel +/- ramucirumab. We also investigated whether platinum/taxane-based regimens offered a better clinical benefit in this patient population. A total of 454 patients were analyzed (docetaxel +/- ramucirumab n=381; platinum/taxane-based regimens n=73). Progression-free survival (PFS) and overall survival (OS) were compared among different subpopulations with different cancer gene mutations and between patients who received docetaxel +/- ramucirumab versus platinum/taxane-based regimens. Among patients who received docetaxel +/- ramucirumab, the top mutated cancer genes included TP53 (n=167), KRAS (n=127), EGFR (n=65), STK11 (n=32), ERBB2 (HER2) (n=26), etc. None of these cancer gene mutations or PD-L1 expression was associated with PFS or OS. Platinum/taxane-based regimens were associated with a significantly longer mQS (13.00 m, 95% Cl: 11.20-14.80 m versus 8.40 m, 95% Cl: 7.12-9.68 m, LogRank P=0.019) than docetaxel +/- ramcirumab. Key prognostic factors including age, histology, and performance status were not different between these two groups. In conclusion, in patients with metastatic NSCLC who have progressed on platinum doublets and ICIs, the clinical benefit from docetaxel +/- ramucirumab is not associated with the cancer gene mutation status. Platinum/taxane-based regimens may offer a superior clinical benefit over docetaxel +/- ramucirumab in this patient population.

Small cell lung cancer (SCLC) is an aggressive malignancy composed of distinct transcriptional subtypes, but implementing subtyping in the clinic has remained challenging, particularly due to limited tissue availability. Given the known epigenetic regulation of critical SCLC transcriptional programs, we hypothesized that subtype-specific patterns of DNA methylation could be detected in tumor or blood from SCLC patients. Using genomic-wide reduced-representation bisulfite sequencing (RRBS) in two cohorts totaling 179 SCLC patients and using machine learning approaches, we report a highly accurate DNA methylation-based classifier (SCLC-DMC) that can distinguish SCLC subtypes. We further adjust the classifier for circulating-free DNA (cfDNA) to subtype SCLC from plasma. Using the cfDNA classifier (cfDMC), we demonstrate that SCLC phenotypes can evolve during disease progression, highlighting the need for longitudinal tracking of SCLC during clinical treatment. These data establish that tumor and cfDNA methylation can be used to identify SCLC subtypes and might guide precision SCLC therapy., Competing Interests: Declaration of interests S.H., C.M.G., L.A.B., and J.V.H. own intellectual property on the classification of SCLC from DNA methylation and gene expression. D.F., A.W., A.S., and C.A.S. are full time employees of Nucleix and own stocks and stock options of Nucleix. Furthermore, S.H. reports consulting fees from Guardant Health, AstraZeneca, Boehringer Ingelheim, and Qiagen. C.M.G. is a member of the advisory board at Jazz Pharmaceuticals, AstraZeneca, and Bristol Myers Squibb and served as speaker for AstraZeneca and BeiGene. P.R. received travel support from AstraZeneca, BMS, and MSD. E.A. reports consulting fees from Eli Lilly, AstraZeneca, BMS, Boehringer Ingelheim, Takeda, Roche, and MSD, speaker’s fees from AstraZeneca, BMS, Boehringer Ingelheim, Roche, and MSD, research funding from Roche and AstraZeneca and travel support from AstraZeneca and Takeda. P.H. reports research grants from Thermo Fisher Scientific and Biocartis, and speakers’ fees from AstraZeneca, Roche, Novartis, Bristol-Myers Squibb, Pfizer, Bayer, Illumina, Biocartis, Thermo Fisher Scientific, AbbVie, Amgen, Janssen, Eli Lilly, Daiichi Sankyo, Pierre Fabre, and Guardant. V.H. reports speakers’ fees from BMS. C.M.L. reports personal fees from Amgen, Arrivent, AstraZeneca, Blueprints Medicine, Cepheid, D2G Oncology, Daiichi Sankyo, Eli Lilly, EMD Serono, Foundation Medicine, Genentech, Janssen, Medscape, Novartis, Pfizer, Puma, Syros, and Takeda. N.V. receives consulting fees from Sanofi, Regeneron, Oncocyte, and Eli Lilly, and research funding from Mirati. M.B.N. receives royalties and licensing fees from Spectrum Pharmaceuticals. I.H. received personal as well as institutional funding from Nucleix. J.Z. served on advisory board for AstraZeneca and Geneplus and received speaker’s fees from BMS, Geneplus, OrigMed, Innovent and grants from Merck, Johnson and Johnson. L.A.B received consulting fees and research funding from AstraZeneca, GenMab, Sierra Oncology, research funding from ToleroPharmaceuticals and served as advisor or consultant for PharmaMar, AbbVie, Bristol-Myers Squibb, Alethia, Merck, Pfizer, Jazz Pharmaceuticals, Genentech, and Debiopharm Group. J.V.H. served as advisor for AstraZeneca, EMD Serono, Boehringer-Ingelheim, Catalyst, Genentech, GlaxoSmithKline, Guardant Health, Foundation medicine, Hengrui Therapeutics, Eli Lilly, Novartis, Spectrum, Sanofi, Takeda, Mirati Therapeutics, BMS, BrightPath Biotherapeutics, Janssen Global Services, Nexus Health Systems, Pneuma Respiratory, Kairos Venture Investments, Roche, Leads Biolabs, RefleXion, Chugai Pharmaceuticals, received research support from AstraZeneca, GlaxoSmithKline, Spectrum as well as royalties and licensing fees from Spectrum., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)