INTRODUCTION:Thyroid transcription factor-1 (TTF-1) expression, routinely assessed through immunohistochemistry in the diagnostic evaluation of lung adenocarcinomas (LUADs), is negative (TTF-1Neg) in approximately 15% to 20% of cases. Although worse outcomes have been reported for these tumors compared with TTF-1-positive (TTF-1Pos) LUAD, a comprehensive characterization of TTF-1 negativity is currently lacking. METHODS:Patients with LUAD and available TTF-1 immunohistochemistry from five institutions, The Cancer Genome Atlas, the Stand Up To Cancer-Mark Foundation, and the POPLAR/OAK data sets, were included. Features and outcomes were analyzed according to TTF-1 expression. RESULTS:Among 3297 patients, TTF-1Neg (15%, n = 496), compared with TTF-1Pos (85%, n = 2801), was associated with a more frequent tobacco use history and lower PD-L1 expression. TTF-1Neg LUAD was enriched for STK11, KEAP1, SMARCA4, NKX2-1, CDKN2A, and KRAS mutations (q < 0.05). Patients with metastatic TTF-1Neg LUAD treated with immune checkpoint inhibitors (n = 233), compared with TTF-1Pos cases (n = 1179), had worse objective response rates (ORR, 17% versus 28%, p = 0.001), median progression-free survival (mPFS, 2.5 versus 4.4 mo, p < 0.0001), and median overall survival (mOS, 9.6 versus 20.2 mo, p < 0.0001). Similarly, TTF-1Neg cases had worse outcomes to chemoimmunotherapy (ORR, 26% versus 41%, p < 0.0001; mPFS, 4.6 versus 8.2 mo, p < 0.0001; mOS, 11.2 versus 23.4 mo, p < 0.0001), durvalumab after chemoradiation for unresectable stage III disease (mPFS, 8.0 versus 24.8 mo, p = 0.016; mOS, 20.0 mo versus not reached, p = 0.004), and KRASG12C inhibitors in KRASG12C-mutant LUAD (ORR, 13% versus 36%, p = 0.03; mPFS, 2.7 versus 5.9 mo, p < 0.0001; mOS, 4.4 versus 12.1 mo, p < 0.0001). CONCLUSIONS:TTF-1 negativity identifies a subset of LUAD with worse outcomes to immunotherapy, chemoimmunotherapy, and KRASG12C inhibitors.

PURPOSE:Methylthioadenosine phosphorylase (MTAP) is deleted in 13% of NSCLC, and MTAP two-copy deleted (MTAPdel) cancer cells are vulnerable to protein arginine methyltransferase 5 inhibitors being examined in trials. Outcomes for MTAPdel NSCLC are poorly characterized. EXPERIMENTAL DESIGN:Patients with advanced MTAPdel and MTAPwt NSCLC who underwent large panel, tissue-based, NGS at a single center and received systemic therapy and from 10/2016-3/2024, were included in this retrospective study. Treatments of interest included platinum doublet + anti-PD-(L)1 therapy, anti-PD-(L)1 monotherapy, and docetaxel-based chemotherapy. Baseline characteristics, PFS, and OS were compared between cohorts. RESULTS:Compared to the MTAPwt cohort (n=307), the MTAPdel cohort (n=93) had more female patients (65.6% vs. 51.5%, p=0.018), less of a smoking history (33.3% vs. 49.0% >30 pack-years, p=0.008), more stage IV disease at diagnosis (78.8% vs. 60.9%, p=0.002), lower PD-L1 TPS (37.9% vs. 24.3% TPS <1%, p=0.017), and lower tumor mutational burden (median 7.6 vs. 9.9 mutations/Mb, p=0.012). Patients with MTAPdel (vs. MTAPwt) NSCLC had shorter PFS on anti-PD-(L)1 monotherapy (HR 1.70 [95% CI 1.02-2.82], p=0.040) and platinum doublet + anti-PD-(L)1 therapy (HR 1.89 [95% CI 1.20-2.97], p=0.006) when controlling for histology, age, smoking pack-years, PD-L1 TPS, targetable co-mutations, and treatment line. OS was similar between MTAPdel and MTAPwt cohorts across regimens. CONCLUSIONS:MTAPdel NSCLC has more features of aggressive disease, including CNS metastasis, and associates with PD-L1 TPS <1%. Compared to patients with MTAPwt NSCLC, patients with MTAPdel NSCLC have worse outcomes to anti-PD-(L)1-based therapies. Effective therapies targeting MTAPdel NSCLC are needed.

8647 Background: BRAF V600E mutations occur in approximately 2–3% of non–small cell lung cancer (NSCLC). BRAF/MEK inhibition (BRAFi+MEKi) yields high response rates and durable clinical benefit but acquired resistance is inevitable. BRAFi+MEKi therapy may select for resistant tumor clones, induce secondary genomic alterations, and drive changes in the tumor immunophenotype. However, the landscape of resistance mechanisms to BRAFi+MEKi in NSCLC remains largely unknown. Methods: We conducted a global, multicenter analysis of patients with advanced BRAF V600E–mutant NSCLC treated with BRAFi±MEKi across multiple academic centers and available public datasets. Eligible patients had matched pre- and post-treatment next-generation sequencing (NGS). Analyses were restricted to oncogenic or likely oncogenic alterations per OncoKB and/or ClinVar. Results: Among 33 patients with matched pre- and post– BRAFi±MEKi samples, median age was 66 years; 39.4% were women, 67.7% had a history of tobacco use, and 97.0% had adenocarcinoma at diagnosis. Objective response to BRAFi±MEKi in this cohort was 81.8%, while median progression-free survival was 8 months; only 3 patients (9.1%) had primary resistance. Acquired resistance mechanisms were diverse, encompassing reactivation of the RAS/RAF/ERK signaling pathway (via BRAF -dependent and BRAF -independent mechanisms), activation of alternative bypass pathways (e.g. PI3K/AKT and HIPPO), and alterations associated with cell-cycle dysregulation. Concurrent resistance mechanisms were identified in 12.1% of cases, and one patient developed histologic transformation to small-cell lung cancer (SCLC). No identifiable resistance mechanism was detected in 11 patients (33.3%). The most common acquired genomic alterations were RAS mutations, observed in 21.2% of cases ( NRAS Q61K, n = 1; NRAS Q61R, n = 1; KRAS G12D, n = 1; KRAS G12V, n = 1; KRAS Q61R, n = 1; NRAS Q61R + KRAS 61H, n = 1; KRAS G12V + KRAS Q61H, n = 1), followed by MET amplifications (12.1%, n = 4). Additional acquired events included BRAF kinase-domain duplication, MAP2K1 and NF2 mutations, and FGFR4 amplification. Putative resistance alterations involving DNA damage repair genes (e.g., CHEK2, BRIP1) were also identified. Clinically, one patient with acquired MET amplification showed loss of the MET -amplified clone on liquid biopsy after adding crizotinib to BRAFi+MEKi, without grade≥3 adverse events, suggesting a potentially targetable resistance mechanism with therapeutic implications. Conclusions: Our findings define the genomic landscape of acquired resistance to BRAFi+MEKi in BRAF V600E–mutant NSCLC and highlight the emergence of diverse resistance mechanisms, including SCLC transformation, MET amplification, and RAS mutations, several of which are potentially actionable and may inform rational post-BRAFi/MEKi therapeutic strategies.

BACKGROUND:Paraseptal emphysema (PSE) is often underrecognized because it has minimal impact on pulmonary function. Recent studies suggest its frequent coexistence with interstitial lung abnormalities (ILA) and potential clinical significance, yet population-based data on its prevalence and prognostic impact remain unclear. PURPOSE:To examine the associations between visual emphysema subtypes and ILA, and to evaluate the prognostic impact of ILA in individuals with emphysema subtypes. MATERIALS AND METHODS:We analyzed 5,059 participants from Age Gene/Environment Susceptibility Reykjavik Study. Emphysema was classified as no emphysema, pure PSE, mixed emphysema, or pure centrilobular emphysema (CLE), and ILA as no ILA, indeterminate ILA, or ILA. Associations were assessed using multivariable logistic regression, and all-cause mortality was evaluated with Kaplan-Meier and Cox proportional hazards analyses. RESULTS:Pure PSE prevalence is 5.0%. Pure PSE (adjusted odds ratio [OR], 4.99; 95% confidence interval [CI], 3.30-7.42) and mixed emphysema (adjusted OR, 5.07; 95% CI, 3.71-6.92) were associated with ILA, whereas pure CLE was not. Over a mean follow-up time of 8.3 ± 2.6 years, mixed emphysema was linked to increased mortality compared with no emphysema (adjusted hazard ratio [HR], 1.47; 95% CI, 1.29-1.67). PSE severity was not significantly associated with ILA prevalence or with prognosis. Among PSE and CLE participants, ILA prevalence increased mortality risk (adjusted HR, 1.48 and 1.44, respectively). CONCLUSION:In our large, longitudinal cohort, pure PSE or mixed emphysema is strongly associated with ILA. ILA was consistently associated with increased mortality regardless of emphysema subtype. These findings support the importance of assessing ILA in patients with emphysema as a key marker for risk stratification.

PURPOSE:Predictive biomarkers of response to immune checkpoint inhibitors (ICI) remain poorly defined in patients with non-small cell lung cancer (NSCLC) without a history of tobacco use and lacking actionable genomic alterations (AGA). We aimed to identify clinical and molecular predictors of response to ICI-based regimens in patients who have never smoked and lack AGAs. EXPERIMENTAL DESIGN:We retrospectively analyzed patients with metastatic, AGA-negative NSCLC who never smoke treated with ICI-based regimens across multiple independent cohorts. Tumor-infiltrating lymphocyte (TIL) densities were quantified using a machine learning-based algorithm, and immune cell biomarkers were assessed with multiplexed immunofluorescence. Transcriptomic correlates of ICI response were analyzed in the Stand Up To Cancer cohort. RESULTS:Among 741 patients with AGA-negative NSCLC and no history of tobacco use, the objective response rate (ORR) was 23.2%, median progression-free survival (mPFS) was 4.5 months, and median overall survival (mOS) was 16.8 months. PD-L1 ≥90% and tumor mutational burden (TMB) ≥90th percentile were independently and significantly associated with improved ORR, mPFS, and mOS (all P <0.01). PD-(L)1 + CTLA-4 combinations outperformed chemoimmunotherapy and PD-(L)1 monotherapy in terms of mPFS and mOS. Transcriptomic analysis revealed enrichment of innate and adaptive immune pathways in responders, including increased MHC class I/II antigen presentation and T-cell activity. High TIL density was also associated with superior ORR and PFS. Multiplexed immunophenotyping confirmed higher immune cell infiltration in patients who experienced durable clinical benefit. CONCLUSIONS:We demonstrated how combination therapies may improve ICI outcomes in patients with AGA-negative NSCLC and no history of tobacco exposure. Very high PD-L1, TMB, and immune-enriched phenotypes may guide treatment personalization.

INTRODUCTION:Tumor mutational burden (TMB) has been established as a predictor of response to immune checkpoint inhibitors (ICIs) with or without chemotherapy in advanced non-small cell lung cancer (NSCLC). However, less is known about its role as a predictor of immune-related adverse events (irAEs). METHODS:This monocentric cohort study included patients with advanced NSCLC receiving ICIs with or without chemotherapy who had available TMB assessed by OncoPanel next-generation sequencing. Baseline TMB was correlated with irAEs using both logistic regression and Cox proportional hazards models. Multiplex immunofluorescence was used to assess immune cells density (CD8+, PD-1+, CD8+PD-1+, FOXP3+) in tumor tissue according to TMB. RESULTS:Among 1215 patients with advanced NSCLC receiving ICIs with or without chemotherapy, 63.4% were treated with ICI alone and 61.4% were treated in the first line. A total of 421 patients (34.7%) developed irAEs. Higher baseline TMB was associated with an increased risk of developing irAE (adjusted odds ratio = 1.04, p < 0.001) and earlier irAE onset (adjusted hazard ratio = 1.02, p = 0.002). Baseline TMB more than or equal to the 90th percentile (19 mut/Mb) was the strongest predictor of both increased irAE risk (adjusted odds ratio = 2.14, p < 0.001) and earlier irAE onset (adjusted hazard ratio = 1.58, p = 0.004), compared with TMB less than the 90th percentile. Using 6-, 9-, and 12-week landmark analyses, adjusting for age, sex, Eastern Cooperative Oncology Group Performance Status, PD-L1, and treatment type, TMB more than or equal to the 90th percentile was associated with a higher risk of irAE at 6, 9, and 12 weeks. Tumors with TMB more than or equal to the 90th percentile were enriched with CD8+ cells (p = 0.04) compared with tumors with TMB less than the 90th percentile. CONCLUSION:These findings indicate that a high TMB, particularly TMB more than or equal to the 19 mut/Mb, is associated with an increased risk and earlier irAE onset, independent of longer immunotherapy exposure. This association seems to be biologically driven by tumors enriched in CD8+ cells, supporting the role of elevated TMB as an irAEs biomarker.

Pleural plaques are frequent in Iceland and independently associated with interstitial lung abnormalities, highlighting the persistent threat of asbestos-related disease and stressing the urgent need for continued monitoring https://bit.ly/4u4riGW.

Supplementary Figure 7. (A) Histograms showing the distribution of deleterious class I and class II ATM mutations with lost or intact ATM protein expression by IHC. (B) Histograms showing the distribution of deleterious missense, nonsense, splice site, and insertion/deletion mutations with lost or intact ATM protein expression by IHC. (C) proportion of NSCLCs with predicted benign and predicted pathogenic ATM missense mutations with lost and intact ATM expression by IHC.

Integrated model for patient stratification and clinical outcome prediction with KRAS G12Ci monotherapy in KRASG12C-mutant NSCLC.

Baseline Patient Characteristics – Cohort B

Supplementary Figure 17. (A) Objective response rate, (B) progression-free survival, and (C) overall survival to PD-(L)1 inhibition among patients with advanced/metastatic NSCLC, according to ATM expression by immunohistochemistry.

Background Despite immunotherapy±chemotherapy has transformed the therapeutic landscape for patients with non-small cell lung cancer (NSCLC), critical questions remain regarding how detailed smoking history affects the evolving treatment options and the underlying molecular mechanisms driving these effects. Methods We analyzed 4157 patients with advanced NSCLC who were treated with immunotherapy monotherapy (IO alone) (n=2768) or chemoimmunotherapy (chemo-IO) (n=1389) at the Dana-Farber Cancer Institute and Memorial Sloan Kettering Cancer Center (2010–2023). Associations between detailed smoking history (status and cumulative pack-years) and clinical outcomes were assessed using multivariable analyses. First-line chemo-IO versus IO alone was compared in programmed death receptor ligand 1 (PD-L1) Tumor Proportion Score (TPS) of ≥50% EGFR/ALK wild-type patients. Tobacco smoking-related mutational signature (TSMS) was inferred from the targeted next generation sequencing (NGS) panel. We investigated relationships between detailed smoking history and tumor genomics/transcriptomics, PD-L1 expression, tumor-infiltrating lymphocytes, and circulating plasma proteomics. Results In patients receiving IO alone, both smoking status and intensity showed dose-dependent associations with improved response and survival outcomes. In contrast, among patients receiving chemo-IO, smoking history did not affect initial response but patients with active (HR=0.73, 95% CI 0.57 to 0.94, p=0.01) and heavy tobacco use (HR=0.76, 95% CI 0.62 to 0.93, p=0.001) showed improved progression-free survival (PFS), and a trend toward improved overall survival (OS). Importantly, these associations remained independent of STK11 , KEAP1 , and KRAS co-mutation status. In patients with PD-L1 TPS of ≥50% lacking EGFR/ALK alterations, patients who do not smoke derived significant benefit from first-line chemo-IO versus IO alone with higher response rates (70.0% vs 23.9%, p=0.001), prolonged PFS (median PFS 9.5 vs 3.7 months, HR=0.51, 95% CI 0.27 to 0.95, p=0.04), and a trend toward prolonged OS, while patients who smoke showed comparable outcomes with either strategy. TSMS independently predicted improved outcomes of IO alone, even after tumor mutational burden (TMB) adjustment. Molecular analyses revealed associations between tobacco use and higher TMB, increased tumor-infiltrating lymphocytes (CD8 + , PD-1 + , CD8 + PD-1 + , FOXP3 + ) and distinct plasma protein profiles involved in immune signaling pathways (CCL7, CXCL17, CDCP1, TNFRSF6B). Conclusions Detailed smoking history provides crucial insights for optimizing IO selection in advanced NSCLC through mechanistic alterations in both the tumor microenvironment and systemic plasma protein profiles.

An artificial intelligence (AI) system for detecting interstitial lung abnormalities (ILA) was previously developed but requires external validation. This study aimed to examine the robustness across different populations and investigate associations between the system outputs and traction bronchiectasis/bronchiolectasis severity patterns. CT scans from population-based samples of the Rotterdam Study (2018–2019) and the Age Gene/Environment Susceptibility Reykjavik (AGES-Reykjavik) Study (baseline CT: 2002–2006, follow-up CT: 2007–2011) were used in this secondary analysis of the two cohorts. The AI system calculated ILA probability score (AI score) in the range from 0 to 1. Three experienced readers evaluated independently all CT scans for ILA, and two chest radiologists assessed traction bronchiectasis/bronchiolectasis using the 4-scale traction bronchiectasis/bronchiolectasis index (TBI) for severity by consensus. Receiver operating characteristic (ROC) analysis and Kruskal–Wallis test were used for statistical analysis. The system analyzed 932 CT scans of the Rotterdam Study (mean participant age, 79.6 years ± 4.3 (SD), 482 women) and 5242 CT scans of the AGES-Reykjavik Study (mean participant age, 76.4 years ± 5.6, 3032 women), and achieved area under the ROC curve of 0.841 (95

Survival outcomes according to KEAP1 and STK11 co-mutation status: A) Cohort A; B) Cohort B; C) further subclassifying KEAP1MUT tumors according to STK11 mutation status; D) PFS and OS according to STK11 co-mutation status in KSCWT tumors in the overall study cohort.

Supplementary Figure 9. (A) Disease free- and overall survival among patients with (A) stage I, and (B) stage II NSCLC according to ATM mutation status.

PURPOSE:Among patients with advanced non-small cell lung cancer (NSCLC) who discontinue immune checkpoint inhibitors (ICI) because of immune-related adverse events (irAE), post-discontinuation clinical outcomes and factors associated with disease progression after discontinuation are largely unknown. EXPERIMENTAL DESIGN:Clinicopathologic data were abstracted from patients with advanced NSCLC who received ICI and discontinued treatment because of irAE. Factors associated with post-discontinuation progression-free survival (PFS) and post-discontinuation overall survival (OS) were evaluated. RESULTS:Of 2,794 patients, 10% (N = 271) discontinued ICI because of irAE, and the median duration of ICI treatment before discontinuation for irAE was 5.9 months (range, 0.03-73.5). A longer treatment duration before discontinuation for irAE was associated with improved post-discontinuation outcomes: for patients on ICI for <3 months (N = 89), 3 to 6 months (N = 49), and >6 months (N = 133) before discontinuing for irAE, the median post-discontinuation PFS was 6.2, 13.9, and 25.8 months (P < 0.001), respectively, and the median post-discontinuation OS was 21.7, 42.7, and 86.9 months (P < 0.001), respectively. At multivariable analyses, predictors of longer post-discontinuation PFS were PD-L1 ≥ 50%, complete response/partial response (CR/PR) to treatment, and treatment duration before discontinuation between 3 to 6 months and >6 months; predictors of longer post-discontinuation OS were nonsquamous histology, CR/PR, and treatment duration before discontinuation >6 months. The use of immunosuppressive agents for toxicity management did not affect post-discontinuation outcomes. CONCLUSIONS:A longer treatment duration before discontinuation, a best objective response of CR/PR, PD-L1 ≥50%, and nonsquamous histology may help clinicians identify patients who may experience long-term disease control after discontinuation of ICI for irAE.