Abstract Background: RET fusions occur in ∼1-2% of advanced NSCLC (aNSCLC). Selective RET inhibitors (SRIs) significantly improve outcomes, yet ∼10% of patients progress by 6 months and ∼30% by 12 months. Predictors of response or early progression remain poorly defined. Methods: A multicenter retrospective analysis (RET-MAP) of RET+ aNSCLC from 47 international centers evaluated clinical/genomic correlates of SRI outcomes. Multivariable Cox models estimated progression-free (PFS) and overall survival (OS) and tested interactions with first-line (1L) SRI versus chemotherapy ± immune checkpoint inhibitor (CH±ICI). In parallel, genomic/transcriptomic features were characterized in an external Caris Life Sciences (CLS) RET+ aNSCLC cohort. Results: Among 510 RET-MAP patients (median age 63; 59% female; 36% ever-smokers; 92% adenocarcinoma), 401 received an SRI (1L n=151; later lines n=250). Median PFS on SRI (any line) was 17.1 months (95% CI, 14.5-21.1), median OS 30.4 months (95% CI, 27.0-41.1). TP53 co-mutation was present in 27% (78/292 tested) and was associated with shorter PFS (8.9 vs 19.2 months; p<0.001) and OS (22.7 vs 30.9 months; p=0.002), without a significant treatment-by-TP53 interaction for 1L SRI versus CH±ICI (p=0.22). Fusion partner contributed with additional signal: KIF5B (73%, 274/373) had inferior PFS (13.4 vs 60.2 months; p<0.001) and OS (26.6 vs 73.0 months; p=0.002) compared with CCDC6 (17%, 65/373), and a significant treatment-by-fusion interaction favored SRI over CH±ICI in CCDC6 versus KIF5B (p=0.007). On multivariate analysis, shorter PFS and OS were independently associated with TP53 mutation (HR 1.74, p<0.001; HR 1.77, p=0.001), KIF5B fusion (HR 1.98, p=0.002; HR 1.64, p=0.040), ECOG ≥2 (HR 2.20, p<0.001; HR 3.06, p<0.001), and brain metastases (HR 1.59, p=0.003; HR 1.88, p<0.001); worse OS was associated with non-adenocarcinoma histology (HR 1.74, p=0.049) and smoking (HR 1.42, p=0.034). Notably, KIF5B fusions were enriched for TP53 mutations versus CCDC6 (40% vs 19.6%, p=0.011), suggesting partially overlapping biology. In the CLS cohort (N=211), TP53-mutant tumors (74/211) were enriched for RB1 mutations, had higher PD-L1 expression and tumor mutational burden, and demonstrated increased M1 macrophage/B-cell infiltration with reduced neutrophils; by fusion partner, CCDC6 showed higher PD-L1, while global transcriptomes were otherwise similar to KIF5B. Conclusions: In RET+ aNSCLC, TP53 mutation is prognostic for inferior outcomes on SRIs but not predictive of differential benefit versus CH±ICI. Fusion partner carries both prognostic and predictive relevance; CCDC6 is associated with a more indolent course and greater relative benefit from SRI. External profiling supports an inflammatory microenvironment in TP53-mutant disease, reinforcing biologically distinct—and clinically meaningful—subsets within RET-driven lung cancer. Citation Format: Daniela Miliziano, Julia K. Rotow, Meghanne Lomibao, Tolulope Adeyelu, Arianna Marinello, Helena Bote-de Cabo, Jamie Feng, Andrea De Giglio, Mariana Brandão, Florian Guisier, Michael Duruisseaux, Christina Falcon, Massimiliano Cani, Francesca Colamartini, Barliz Waissengrin, Isabelle Monnet, Anna Eisert, Emilio Bria, Amin H. Nassar, Ayesha Aijaz, Patricia Iranzo, Colin R. Lindsay, Elizabeth Fabre, Vladmir Cordeiro de Lima, Judith Raimbourg, Laura Mezquita, Nicolas Minatta, Sophie Cousin, Katarzyna Szymczak, Vincent Fallet, Clarisse Audigier-Valette, Helene Doubre, Philippe Rochigneux, Annarita Avanzo, Antonio Calles, Marco Tagliamento, Diego Cortinovis, Balazs Halmos, Nicholas Girard, Andrew Elliott, Jair Bar, Alessio Cortellini, Diana N. Ionescu, Frances A. Shepherd, Fabrice Barlesi, Karen L. Reckamp, David Planchard, Benjamin Besse, Alexander Drilon, Mihaela Aldea. Prognostic and predictive effects of TP53 co-mutations and RET fusion partners in RET-rearranged advanced NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2434.

Concurrent driver mutations according to oncogenic / likely oncogenic MET TKD mutations detected in cohort #2.

MET TKD mutations in NSCLC cohort of Caris Life Sciences. (A) Flowchart of the NSCLC subgroup in the Caris Life Sciences dataset. (B) Prevalence of MET TKD mutations in NSCLC cases in the Caris Life Sciences dataset (MET TKD mutations in 280 unique patients). (C) Lollipop plot of the oncogenic / likely oncogenic MET TKD mutations detected in NSCLC cases in the Caris Life Sciences dataset (35 oncogenic / likely oncogenic MET TKD mutations in 35 unique patients). (D) concurrent driver alterations (information available for 24 cases, unavailable for 11 cases) and (E) concurrent MET amplification status (information available for 33 cases, unavailable for 2 cases) of NSCLC cases harboring oncogenic / likely oncogenic MET TKD mutations in the Caris Life Sciences dataset.

Equilibration of interactions that drives ATP affinity in the presence MET R1170Q mutant. (A) Representative structure of ATP bound MET R1170Q with the regions of interest highlighted [hinge site (green), and mutation site (blue)]. (B) Mutation at position 1170 facilitates the formation of a hydrogen bonding network. (C) Interatomic distances for non solvent mediated hydrogen bonding.

BACKGROUND:While PDZ-LIM domain-containing protein (PDLIM2) suppresses lung cancer, its clinical significance and therapeutic potential remain to be fully explored. METHODS:Next-generation sequencing and immunohistochemistry of programmed death ligand 1 (PD-L1) were performed on lung adenocarcinoma (LUAD) tissues from 15,765 patients. PDLIM2 gene therapy was tested in syngeneic LUAD mouse models using intravenous nano-complexed plasmid DNA, alone or with chemoimmunotherapy. RESULTS:PDLIM2-high tumors were more common in primary/local biopsies versus metastatic samples (73.1% vs 53.0%; p < 0.001). High PDLIM2 expression was linked to lower mutation rates in RB1, TP53, SMARCA4, STK11, and KEAP1, but increased EGFR mutations (all p < 0.01). PDLIM2-high tumors also showed increased immune cell infiltration, T cell-inflamed scores, and PD-L1 positivity (all p < 0.008). High PDLIM2 was associated with improved survival (24.1 vs 18.1 months; p < 0.001, HR = 0.84) and remained prognostic in multivariate analysis (HR = 0.88, 95% CI 0.83-0.93), as well as with longer pembrolizumab time, especially with platinum-based therapy (p = 0.012, HR = 0.867). In two LUAD mouse models, nanoPDLIM2 improved median overall survival versus chemoimmunotherapy alone (10-12.5 vs 8-9 days; N = 8; p = 0.0001, 0.0003). CONCLUSION:PDLIM2 is a promising prognostic biomarker in LUAD linked to immune-receptive tumors. Preclinically, PDLIM2-based therapy enhances chemoimmunotherapy efficacy, though its predictive role warrants further evaluation.

Single trajectory generalized Born and surface area solvation (MM/GBSA) calculated free energy of ATP binding into the orthosteric pocket.

List of missense mutations with unknown biologic function and their pathogenicity scores using all three in silico tools in cohort #1

8079 Background: Lurbi received accelerated approval in 2020 for ES-SCLC that progressed on or after platinum-based treatment (Tx) based on a phase 2 basket trial and full approval in 2025 combined with atezolizumab as 1st-line maintenance Tx for ES-SCLC based on the phase 3 IMforte trial. Methods: The phase 4, prospective, observational Jazz EMERGE 402 trial (NCT04894591) evaluated lurbi for previously treated ES-SCLC in RW practice in North America (final data cut: July 17, 2025). The primary endpoint was overall response rate (ORR). Key secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. Effectiveness was assessed in all patients (pts) and in prespecified subgroups. Results: At the final data cut, 267 pts had received ≥1 cycle of lurbi. At baseline (BL), median (min–max) age was 67 (29–89) years, 52 (19%) pts had an ECOG PS ≥2, 67 (25%) had brain metastases, 84 (31%) had liver metastases, 88 (33%) had a chemotherapy-free interval (CTFI) <90 days, and 196 (73%) had ES-SCLC as the initial diagnosis. Pts received lurbi as 2nd-line (169 [63%]), 3rd-line (78 [29%]), or later (20 [7%]) Tx. Median (Q1–Q3) number of lurbi Tx cycles and Tx duration were 4 (2–7) and 91 (56–170) days. Granulocyte colony-stimulating factor was used in 99 (37%) pts (71 [27%] as primary prophylaxis). Six (2%) pts were receiving Tx at study completion; 261 (98%) discontinued Tx, with disease progression (183 [70%]) the primary reason. While lurbi was effective among all pts and poor-prognosis subgroups, better outcomes tended to occur in pts with CTFI ≥90 days and ECOG PS <2 (Table). Eighty-eight (33%) pts had Tx-related adverse events (TRAE); anemia (21 [8%]) and neutropenia (19 [7%]) were most common. Rates of serious neutropenic infection (5 [2%]), anemia (4 [1%]), and neutropenia (3 [1%]) were low. Conclusions: Lurbi was associated with clinically meaningful effectiveness and predictable/manageable safety in previously treated ES-SCLC in a RW population that included poor-prognosis subgroups. Clinical trial information: NCT04894591 . Effectiveness among all pts and by subgroup. AllN = 267 Age <65 Yearsn = 101 Age ≥65 Yearsn = 166 CTFI <90 Daysn = 88 a CTFI ≥90 Daysn = 137 a Initial LSn = 69 b Initial ESn = 196 b ECOG PS <2n = 178 c ECOG PS ≥2 n = 52 c ORR, d % (95% CI e ) 29 (23, 36) 30 (20, 43) 28 (20, 37) 24 (14, 37) 28 (19, 38) 33 (21, 47) 27 (20, 36) 26 (19, 35) 41 (24, 59) PFS, d months, median (95% CI) 3.3 (2.6, 4.1) 4.1 (2.8, 4.5) 2.9 (2.2, 3.8) 2.9 (2.0, 4.1) 3.3 (2.4, 4.2) 4.0 (2.4, 5.8) 3.3 (2.5, 4.1) 3.3 (2.6, 4.2) 2.6 (1.7, 5.2) OS, months, median (95% CI) 7.6 (6.4, 8.7) 8.2 (7.0, 10.6) 6.6 (5.8, 8.7) 5.8(4.6, 6.6) 9.3(7.1, 10.9) 8.7 (6.2, 10.6) 6.8 (6.0, 8.7) 8.1(6.6, 9.6) 5.2 (2.4, 7.9) a CTFI missing for 42 pts. b Stage missing for 2 pts. c ECOG PS missing for 37 pts. d Per RECIST v1.1 in pts with BL measurable disease. e Estimated using Clopper-Pearson exact method. LS, limited stage.

8519 Background: Non-classical mutations (NCM) of epidermal growth factor receptor (EGFR) represent a broad group of oncogenic mutations in non-small cell lung cancer (NSCLC), often associated with resistance to osimertinib (e.g., P-loop and αC-helix compressing [PACC] mutations). Patients (pts) with NCM have inferior clinical outcomes with a high incidence of CNS metastases (CNSm). Silevertinib (BDTX-1535) is a fourth-generation, covalent EGFR TKI with high CNS penetrance targeting both EGFR classical mutations and NCM. The antitumor activity and safety of silevertinib in pts with advanced NSCLC were evaluated in a Phase 2 trial (NCT05256290). Methods: Pts with advanced EGFR NCM NSCLC who received no prior systemic therapy were enrolled (Cohort 3) based on a local molecular test. Silevertinib 200 mg was administered orally once daily. The primary endpoint of objective response rate (ORR) was assessed using RECIST v1.1. CNS ORR was assessed using Response Assessment in Neuro-Oncology for Brain Metastases (RANO-BM) in pts with no prior CNS therapy. Secondary endpoints include progression-free survival (PFS), duration of response (DOR), disease control rate (DCR), and safety. Results: From February 2024 to July 2025, 43 pts with 35 unique NCMs (including 25 pts with PACC mutations) were enrolled in Cohort 3: median age 70.0 years, 72% female, 74% white, and 42% never smoked cigarettes. As of November 3, 2025, median follow-up was 7.2 months. ORR by RECIST v1.1 is shown in the table. Sixteen pts (37%) had CNSm, including 7 pts (16%) with measurable CNS disease. RANO-BM CNS response was 86% (n=6/7). Complete clearance of EGFR VAF ctDNA was observed in 21/26 (81%) evaluable pts. Serious treatment-related adverse events (TRAEs) were reported in 5 pts (12%), and 4 pts (9%) discontinued treatment due to TRAEs. The most common TRAEs included rash (19%, grade 3), diarrhea (19%, grade 3), stomatitis (9%, grade 3), and paronychia (5%, grade 3). While 77% of pts had a dose reduction, 19/22 (86%) patients with a radiographic response maintained or deepened their response after dose reduction, including all patients with CNS response. Conclusions: Silevertinib demonstrated robust antitumor activity in treatment-naïve pts with a broad spectrum of NCM EGFR driver mutations with high intracranial activity in pts with brain metastases. The safety profile was consistent with the known AEs of the EGFR TKI class. Clinical trial information: NCT05256290 . Data as of November 3, 2025 N ORR n (%) 95% CI DCR n (%) 95% CI ITT Population * 43 26 (60) (44.4, 75.0) 39 (91) (77.9, 97.4) PACC mutations 25 14 (56) (34.9, 75.6) 22 (88) (68.8, 97.5) Compound mutations † 16 11 (69) (41.3, 89.0) 15 (94) (69.8, 99.8) *No pts with classical (E746_A750del or L858R) mutations were enrolled. † Presence of ≥ 2 NCMs. As of December 27, 2025, the 6-month PFS rate was 86% overall and 80% in pts with CNSm; available PFS and DOR data will be presented.

Non-small-cell lung cancer (NSCLC) is responsible for the majority of cancer-related mortality worldwide. Lung adenocarcinoma (LUAD) is the most common NSCLC subtype. Despite advances in targeted therapies, treatment resistance remains a critical challenge. Ribonucleotide reductase (RNR), a crucial enzyme in deoxyribonucleotide triphosphate (dNTP) biosynthesis, is frequently upregulated in cancer, contributing to genomic instability and poor prognosis in multiple malignancies. However, the role of the RNR complex in driving tumorigenesis is not fully understood in oncogenic-driven LUAD. Transcriptomic analysis of more than 27,000 real-world NSCLC patient samples revealed that RNR subunits (RRM1 and RRM2) are significantly upregulated in TP53 mutated NSCLC and correlated with significantly poor prognosis in multiple oncogene-driven LUAD. Using pharmacologic and genetic approaches to inhibit RNR in LUAD models, we assessed functional consequences through molecular, biochemical, and imaging techniques. RNR inhibition induced appreciable replication stress and triggered DNA damage, leading to cell death in LUAD cells. Notably, we uncovered that RNR suppression preferentially induced ferroptosis, an iron-dependent cell death driven by lipid peroxidation. This represents a previously unrecognized mechanism of RNR-mediated cell death by which mutant LUAD cells can be selectively targeted. Our study establishes RNR inhibition as a potent strategy to selectively induce ferroptosis in oncogenic addicted LUAD, offering a new therapeutic avenue for genetically defined patient subgroups. Targeting nucleotide metabolism could serve as an effective approach to overcome treatment resistance and improve clinical outcomes for patients with high-risk LUAD.

8538 Background: Class I BRAF mutant ( BRAF mut) non–small cell lung cancer (NSCLC) is biologically heterogeneous, occurring in both smokers and never-smokers with disparate benefits from immunotherapy (IO). Genomically defined tobacco-induced damage may better identify biologically and clinically distinct subsets than self-reported smoking history. We evaluated COSMIC mutational signature-SBS4 as a genomic surrogate of smoking exposure and examined its association with molecular features, tumor microenvironment (TME) and outcomes in BRAF mut NSCLC. Methods: Retrospective review of 33,217 NSCLC specimens that underwent whole exome and whole transcriptome sequencing at Caris Life Sciences. Mutation profiles of specimens were deconvolved using the COSMIC SBS4 signature to estimate tobacco-associated mutational exposure (filter: total mutation count>=200, Nfiltered=26448; BRAF mut = 276). TME was estimated using QuanTIseq method. Overall survival (OS) and survival on IO (IO-OS) were obtained from insurance claims and calculated from date of tumor biopsy (for OS) or initiation of IO (for IO-OS) to last contact using Kaplan-Meier estimates and Cox proportional hazards models. Statistical significance was determined by Fishers Exact, chi-square and Mann-Whitney U test with p-values adjusted for multiple comparisons ( P <0.05). Results: Among 6,405 patients with smoking history and SBS4 data, SBS4+ (SBS4>0) was strongly associated with smoking (OR 11.2, P <0.001). SBS4+ tumors exhibited elevated TMB (mean:13 vs 9 mut/Mb, and TMB-High [>=10 mut/Mb], P <0.05, Table). SBS4+ BRAF mut tumors had a lower prevalence of mutations in SETD2 (OR 0.33), PIK3CA (OR 0.26) and SMAD4 (OR 0.25, all P <0.05). Regardless of SBS4 status, BRAF mut tumors were more often PD-L1+ (OR 3.2, TPS>=1), while mutations in STK11, KEAP1 , and SMARCA4 were less frequent (OR 0.07-0.37, all P <0.05). Evaluation of the TME revealed that SBS4+ BRAF mut were enriched for regulatory T cells (vs. SBS4-,1.44 fold, P <0.05). In metastatic disease, BRAF mut showed improved OS (HR 0.8[0.66-0.97], P =0.03) and IO-OS (HR 0.8[0.66-0.99], P =0.04) compared to WT. The OS benefit was preserved in the SBS4+ tumors (HR 0.64[0.43-0.95], P =0.03), but not in SBS4- tumors. No difference in IO-OS was observed in SBS4+ subgroups likely due to small size. Conclusions: SBS4 identifies biologically distinct subsets in class I BRAF mut NSCLC, with differences in mutational landscape, TMB, and TME. SBS4+ tumors show a survival benefit over WT disease, whereas SBS4- tumors do not. These findings support SBS4 as a genomic marker of smoking-related biology and a potential tool to refine therapeutic decision-making between targeted therapy and IO in NSCLC and potentially other smoking-associated cancers. Smoking signature in BRAF mut NSCLC (% prevalence and OS). Characteristics SBS4 + SBS4 - SETD2 20 43 PIK3CA 6 19 SMAD4 3 12 TMB-high 41 18 OS (months) 29.9 vs. 11.9 ( P =0.03) 16.0 vs. 10.9 ( P =0.47)

Precision oncology in non-small cell lung cancer (NSCLC) is driven by identification of actionable genomic alterations; however, trials establishing these paradigms often underrepresent racial/ethnic minorities and report mutations without comprehensive subtype characterization. We aim to define real-world biomarker patterns, including subtype distributions, across a diverse lung adenocarcinoma cohort. A retrospective analysis of patients undergoing surgical resection for lung adenocarcinoma (2021–2025) at a single urban academic center was performed. Patients with available next-generation sequencing (NGS) were included. EGFR mutations were categorized as typical versus atypical (PACC variants, exon 20 insertions, T790M, non-L858R exon 21 alterations), and KRAS mutations as G12C versus non-G12C. Of 292 patients, 40.8

Concurrent genomic drivers in cases with oncogenic / likely oncogenic MET tyrosine kinase domain (TKD) mutations and co-occurring MET gene amplification in cohort #2.

Introduction Small cell lung cancer (SCLC) and extrapulmonary neuroendocrine (NE) tumors are aggressive malignancies with limited treatment options. Seizure-related homolog 6 (SEZ6) is a potential therapeutic target, but its expression in these tumors remains poorly understood. Lineage plasticity contributes to resistance in non-small cell lung cancer (NSCLC), where some cases can undergo SCLC-transformation after targeted therapy. We aimed to characterize SEZ6 expression across NE tumors and presumed NSCLC-to-SCLC transformations. Methods DNA and RNA sequencing were performed for SCLC, NSCLC, and NE samples. Samples were stratified by SEZ6 RNA expression quartiles and classified into subtypes based on ASCL1, NEUROD1, and POU2F3 expression. Significance was tested using the Mann-Whitney U test. Real-world overall survival was obtained from insurance claims data, with p-values calculated using the log-rank test. Paired samples for NSCLC-to-SCLC transformation were identified by sequential biopsies classified as NSCLC followed by SCLC. Results RNA sequencing was performed on 1318 SCLC and 2218 NE samples. Median SEZ6expression was higher in SCLC (39.7 transcripts per million (TPM)) than in NE tumors (20.8 TPM, p<0.0001) and NSCLC (1.34 TPM, p<0.001). Among NE tumors, median SEZ6 expression was highest in prostate (52.0 TPM, p=0.0016 vs SCLC) and lowest in adrenal gland tumors (1.2 TPM, p<0.0001 vs SCLC). In SCLC,SEZ6expression was positively correlated with ASCL1(p=0.44, p<0.0001) andNEUROD1(p=0.16, p<0.0001) expression but notPOU2F3(p=-0.04, p=0.1253). Median survival was longest in SEZ6-Q2 for both SCLC and NE (13.0 mos. and 33.7 mos., respectively). NSCLC-to-SCLC transformation samples showed numerically higher SEZ6 expression post-transformation (median: 86.2 vs 2.4 TPM). Conclusions SEZ6expression is higher in SCLC than in NE tumors, with notable heterogeneity by subtype, warranting consideration of expanded use of SEZ6-directed therapy.Translational Relevance Statement:This study establishes SEZ6 as a promising therapeutic target in small cell lung cancer (SCLC) and transformed non-small cell lung cancer (NSCLC), demonstrating its significantly elevated expression compared to neuroendocrine (NE) tumors and NSCLC. The positive correlation of SEZ6 expression with NE lineage markers, particularly in ASCL1 and NEUROD1 subtypes, highlights its role as a lineage-specific marker, guiding the development of SEZ6-targeted antibody-drug conjugates (ADCs). Additionally, the increased SEZ6 expression following NSCLC-to-SCLC transformation suggests that SEZ6-targeted therapies could address resistance mechanisms in transformed tumors. Importantly, the association between high SEZ6 expression and shorter survival indicates that integrating SEZ6 status into diagnostic workflows could help stratify patients by risk and guide therapeutic decision-making. The findings from this study will inform future clinical trials, aiming to implement SEZ6-targeted treatments as part of precision oncology strategies for aggressive NE malignancies.

Additional information regarding the methods used in this study

Detailed genomic characteristics for each case of NSCLC with oncogenic / likely oncogenic MET tyrosine kinase domain (TKD) mutations in cohort #1.

Clinicopathologic and genomic characteristics of 171 cases of cancers other than NSCLC harboring oncogenic / likely oncogenic MET TKD mutations in cohort #2.

Study flowchart. Cohort #1 (multi-institutional cohort): GENIE V.11.0, China Pan-cancer (OrigiMed2020, Nature 2022), The Cancer Genome Atlas (TCGA) Pan-Cancer Atlas studies, Dana-Farber Cancer Institute (DFCI) and NSCLC from Memorial Sloan Kettering Cancer Center (MSKCC); cohort #2: Foundation Medicine Pan-Cancer cohort.