1. Pumped to share that our article “Consolidation Osimertinib versus Durvalumab versus Observation following Concurrent Chemoradiation in Unresectable EGFR-Mutant Non-Small-Cell Lung Cancer: A Multicenter Retrospective Cohort Study” is now out in JTO!.

11/11 Grateful to the incredible collaborators across 26 institutions, and to the patients whose data made this possible. Proud to contribute to the next chapter in LCNEC research and therapy.

10/11 This work lays the foundation for future prospective clinical trials, focused on subtype-specific vulnerabilities to transform outcomes for patients with this lethal disease.

9/11 Implications.Current treatments fail to improve outcomes in LCNEC. We propose a biology-driven roadmap that aligns genomic/transcriptomic subtypes with:.🔹 LAG-3 / FGL-1 inhibition (NSCLC-like).🔹 DLL3-directed therapies (SCLC-like).🔹 MAPK-targeted approaches (SPINK1+

8/11 Key finding #5.Machine-learned digital pathology revealed markedly fewer tumor–infiltrating lymphocytes in LCNEC compared with SCLC, LUAD, or LUSC → mechanistically consistent with the limited responses to immunotherapy seen in the clinic.

7/11 Key finding #4.We identified FGL-1 (ligand for LAG-3) and SPINK1 as potentially targetable vulnerabilities in the NSCLC-like subgroup — supported by RNAseq, DepMap proteomics, and immunofluorescence.

6/11 Key finding #3.DLL-3 is highly expressed in SCLC-like LCNEC and potentially targetable.

5/11 Key finding #2: .We developed a transcriptomic classifier that reclassified >70% of “unclassified” tumors into biologically coherent SCLC-like or NSCLC-like subtypes (AUC=0.98). ➡️ A practical framework for future precision trials.

4/11 Key finding #1: LCNEC consists of two major genomic subtypes:.• NSCLC-like (KEAP1, KRAS, STK11).• SCLC-like (concurrent RB1+TP53).BUT 👉 clinical outcomes were similarly poor regardless of subtype or regimen (chemo, chemo-IO, IO).

3/11 We analyzed 590 patients across two independent cohorts, integrating:.🔹 clinical outcomes.🔹 targeted and whole-exome sequencing.🔹 whole-transcriptome sequencing.🔹 digital pathology (machine learning-based TIL quantification).

2/11 Pulmonary LCNEC is a rare and aggressive lung cancer (~3% of all lung carcinomas, about 6000 patients in US annually) with no standard first-line treatment and exceptionally poor survival outcomes. Therapeutic decisions are currently extrapolated from either SCLC or NSCLC.

1/11 Pleased to share that our multi-institutional study “Integrated Molecular and Clinical Characterization of Pulmonary Large Cell Neuroendocrine Carcinoma” was published today. This represents the most comprehensive analysis of LCNEC to date. Grateful for the support of.

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