An FDA-cleared artificial intelligence tool demonstrated frequent discordance with radiologist reports for lung nodule assessment on chest CT.

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.

Abstract Small cell lung cancer (SCLC) is a neuroendocrine malignancy characterized by high metastatic potential and poor clinical outcomes. Recently, tarlatamab, a DLL3-directed Bispecific T-cell Engager Therapy (BiTE), has demonstrated effectiveness in SCLC, but clinical outcomes vary, and there is no available biomarker to stratify patients. Efforts to identify predictive biomarkers for tarlatamab have largely centered on immunohistochemistry staining of tumor tissue, but the near-universal expression of DLL3 in archival biopsies does not reflect the clinical response rates of ∼40%. Here, we aimed to determine whether single-cell analysis of DLL3 expression in circulating tumor cells (CTCs) immediately prior to initiation of tarlatamab therapy could identify patients most likely to benefit.We quantified DLL3 protein expression on CTCs isolated with the CTC-iChip, an automated microfluidic platform that enriches intact tumor cells through negative depletion of red blood cells and platelets using inertial microfluidics and removal of leukocytes using immunomagnetic sorting. Enriched cells were analyzed by single-cell multispectral fluorescence imaging. In parallel, single-cell RNA sequencing of SCLC tumor biopsies was performed to assess heterogeneity in DLL3 expression. In our study, we performed pre-treatment CTC profiling of a prospective cohort of 20 patients with advanced SCLC, distinguishing patients as DLL3High (≥25% DLL3-positive CTCs) or DLL3Low. We found that DLL3High patients consistently derived clinical benefit (SD/PR), whereas most DLL3Low patients progressed on therapy (85% sensitivity, 100% specificity). In addition, 3 of 5 patients with clinical grade 2 cytokine release syndrome were found to have evidence of tumor cell lysis (circulating tumor fragments) in the days following the first tarlatamab infusion. Subsequent ongoing longitudinal analysis of CTCs at the time of tarlatamab acquired resistance revealed two distinct patterns: loss of DLL3 expression on CTCs or persistence of epitope expression, accompanied by systemic T cell dysfunction. Importantly, in the case of a reduction in DLL3 expression, other neuroendocrine or SCLC-enriched epitopes (SEZ6 or B7-H3) remained detectable, indicating preserved lineage identity.Together, these findings demonstrate that CTC-based quantitation of DLL3 using unbiased microfluidic enrichment provides a real-time, non-invasive biomarker for stratifying patients most likely to benefit from the bispecific antibody tarlatamab. For immune-based cancer therapies that are uniquely dependent upon epitope expression by cancer cells, CTC-based measurements may provide a robust biomarker for guiding therapeutic interventions. Beyond SCLC, future directions include assessing generalizability to extra-pulmonary neuroendocrine cancers known to express DLL3, including medullary thyroid cancer, GI, and GU cancers. Citation Format: Avanish Mishra, Catherine Meador, Kruthika Kikkeri, Quinn Cunneely, Maoxuan Lin, Thomas Carmona-LaSalle, Shih-Bo Huang, Remy Bell, Victor Putaturo, Weikun Xia, Joyce Liang, Jacy Fang, Sarah San Vicente, Caroline Zielinski, Subba Digumarthy, Yin Hung, Beow Yeap, Jon Edd, Michael Lawrence, Moshe Sade-Feldman, Debattama Sen, Mehmet Toner, Shyamala Maheswaran, Justin Gainor, Daniel Haber. DLL3 expression on circulating tumor cells predicts response to bispecific antibody tarlatamab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB005.

Supplemental Figure 3. Immunohistochemical molecular subtyping of SCLC tumors.

Supplemental Data 1. Study Protocol.

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

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.

Introduction: Chemoimmunotherapy is associated with promising activity in mesothelioma in phase II to III trials. Studies exploring this approach in patients ineligible for clinical trials are lacking. We assembled a cohort of patients receiving pemetrexed-based chemotherapy with durvalumab outside of clinical trials. Methods: Patients with pleural mesothelioma received pemetrexed plus durvalumab or carboplatin plus pemetrexed plus durvalumab via off-label authorization at Massachusetts General Hospital. Response to chemoimmunotherapy was assessed per modified Response Evaluation Criteria in Solid Tumors version 1.1. A retrospective chart review was conducted to assess safety per Common Terminology Criteria for Adverse Events version 5.0. Results: Twelve patients were included in the series. Nine patients were treated with triplet chemoimmunotherapy. Three patients received doublet chemoimmunotherapy because of platinum ineligibility. Concurrent active malignancies and symptomatic cardiac disease were present in three patients (25%) and two patients (17%), respectively. Ten patients had measurable disease at baseline. With the triplet regimen, partial responses were observed in four of the seven (57%) patients with measurable disease. All three patients receiving pemetrexed plus durvalumab had measurable disease and experienced a partial response. Primary progression was not observed with either regimen. Overall, eight patients (75%) remained on treatment for more than 6 months without progression. Five patients developed immune-related adverse events (n = 1 each pyrexia, arthritis, neutropenia, Raynaud's disease, stomatitis). Three patients discontinued treatment because of toxicity or symptomatic comorbid conditions (n = 1 grade 3 heart failure, n = 1 grade 2 fever & thorn; progressive kidney cancer, n = 1 grade 2 fatigue). Conclusions: Antitumor activity of chemoimmunotherapy reported in phase II to III clinical trials is generalizable to the broader patient population with mesothelioma. However, the tolerability of chemoimmunotherapy is impacted by comorbid conditions in real-world patients. (c) 2024 The Authors. Published by Elsevier Inc. on behalf of the International Association for the Study of Lung Cancer. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/).

Supplemental Figure 1. Overview of study participants.

Progression-free survival (left) and overall survival (right) according to co-mutation status for (A) CHEK2 and (B) ATRX in the overall mutation-evaluable population.

List of major molecular profiling platforms included in the cohort

BACKGROUND:Effective treatments for patients with advanced lung carcinoids remain limited. The prevalence of potentially actionable genomic alterations (AGAs) among lung carcinoids is not well-understood. MATERIALS AND METHODS:Lung carcinoids submitted for next-generation sequencing (NGS) at a Clinical Laboratory Improvement Amendments (CLIA)-certified genomics laboratory from September 2013 to March 2024 were retrospectively investigated to determine prevalence of AGAs. We evaluated outcomes with genotype-matched targeted therapies in patients with advanced lung carcinoids with AGAs identified across 3 institutions and comprehensive literature search. RESULTS:Among 321 cases of lung carcinoids profiled by NGS, 8 (2.5%) harbored potential AGAs (4 [1.2%] with commercially available targeted therapies), including KRAS mutations (n = 4, 1.2%: G12C, G12D, G12R, G12V), ALK fusions (n = 2, 0.6%), BRAF D594N (n = 1, 0.3%), and RET fusion (n = 1, 0.3%). None of the 24 typical carcinoids harbored an AGA. Collectively across these database-identified patients, our multi-institutional cohort, and literature review, we identified 36 cases of lung carcinoids with potential AGAs (24 with commercially available targeted therapies), predominantly comprising fusions of ALK (n = 14), RET (n = 5), and NTRK (n = 2). Of 27 with known disease stage, 19 had stage 4 disease, and 13 (68.4%) had outcomes reported following targeted therapies. Median treatment duration was 12.0 months (95% CI: 6.7-16.0). Median progression-free survival (PFS) was 10.6 months (95% CI: 6.7-16.0) across all targeted therapy lines and 14.0 months (95% CI: 1.3-NA) with first-line targeted therapies. Objective response rate with at least one targeted therapy was 61.5%. CONCLUSIONS:Patients with advanced lung carcinoids harboring AGAs can derive meaningful benefit from genotype-matched targeted therapies, highlighting potential role for NGS in patients with advanced carcinoids.

Supplemental Table 2. Representativeness of Study Participants.

A) ORR (left), PFS (middle) and OS (right) in patients with ECOG-PS 0 or 1, at least 1 prior line of therapy for metastatic disease and without untreated brain metastases; B) Survival outcomes in patients with treated or untreated brain metastases prior to starting KRAS G12Ci; C) Survival outcomes according to PD-L1 status (TPS: tumor proportion score); D) survival outcomes in patients with or without prior immune checkpoint inhibitor therapy.

A) Venn diagram depicting co-mutation overlap between KEAP1, SMARCA4, and CDKN2A – KSC genes; survival outcomes according to co-mutation overlap in any of the KSC genes - PFS (B) and OS (C). Only patients whose tumor was profiled with a NGS panel providing coverage for all 3 genes were included in this analysis.

Supplemental Figure 2. Study design.

Purpose: Temozolomide plus PARP inhibition has shown promise in small cell lung cancer (SCLC). We previously reported outcomes from the first 50 patients (cohort 1) of a phase I/II trial of olaparib/temozolomide in recurrent SCLC. In this study, we report a final analysis of this trial, including a second cohort with an alternate dosing strategy and an exploratory analysis of central nervous system (CNS)-specific outcomes.Patients and Methods: This was an open-label phase I/II trial testing the combination of olaparib and temozolomide in relapsed SCLC. The primary endpoint was objective response rate (ORR). Secondary endpoints were safety, progression-free survival, and overall survival. We tested escalating doses of olaparib/temozolomide across two cohorts, both of which had temozolomide dosed on days 1 to 7 of each 21-day cycle. In previously published cohort 1, olaparib was dosed on days 1 to 7; in cohort 2, olaparib was dosed continuously.Results: Sixty-six patients were enrolled across the two cohorts: 50 in cohort 1 and 16 in cohort 2. The confirmed ORR of cohort 1 was 41.7% (20/48 evaluable), and the confirmed ORR of cohort 2 was 7% (1/14 evaluable; closed after dose escalation to enrollment for lack of observed efficacy). Among 15/66 patients (22.7%) with untreated brain metastases at enrollment, the best overall intracranial response was complete response in 6/15 patients, partial response in 4/15 patients, and stable disease in 3/15 patients for a CNS disease control rate of 87% (95% confidence interval, 59.5%-98.3%).Conclusions: Olaparib/temozolomide may be effective in relapsed SCLC, especially for patients with CNS disease. Ongoing analyses with regard to optimal dosing schedule will inform potential for future use of this combination in SCLC.