Immunoprofiling at an Institutional Scale Reveals That High Numbers of Intratumoral CD8 and PD-1 Cells Predict Superior Patient Survival Across Major Cancer Types Independent of Major Risk Factors.

Purpose: Retrospective studies have found associations between the number of intratumoral immune cells and patient outcomes for specific cancers treated with targeted therapies. However, the clinical value of routinely quantifying intratumoral immune biomarkers using a digital pathology platform in the pan-cancer setting within an active clinical laboratory has not been established.

Methods: We developed ImmunoProfile, a daily clinical workflow that integrates automated multiplex immunofluorescence tissue staining, digital slide imaging, and machine learning-assisted scoring to quantify intratumoral CD8, PD-1, CD8PD-1, and FOXP3 immune cells and PD-L1 expression in formalin-fixed, paraffin-embedded tissue samples in a standardized and reproducible manner.

First-line MET tyrosine kinase inhibitors versus immunotherapy ± chemotherapy for patients with MET exon 14 skipping mutant metastatic NSCLC.

Purpose: First-line treatment options for MET exon 14 skipping (METex14) mutant metastatic non-small cell lung cancer (NSCLC) vary due to differences in drug approvals and clinical experience. This study investigates factors influencing outcomes with first-line MET tyrosine kinase inhibitors (TKI) versus immune checkpoint inhibitors (ICI)±chemotherapy.

Experimental Design: Clinicopathologic data were collected from patients with metastatic METex14 mutant NSCLC receiving first-line MET TKI or ICI±chemotherapy at five centers.

Upfront osimertinib and as sequential therapy in patients with -mutant non-small cell lung cancer (NSCLC): benefit across patients groups in a real-world retrospective cohort-the smile study.

Background: Osimertinib is the preferred first-line (L1) treatment for epidermal growth factor receptor-mutant (m) advanced non-small cell lung cancer (aNSCLC). Intensification of L1 with chemotherapy or amivantamab has shown improved outcomes at the cost of increased toxicity, raising questions about the optimal patients selection. A sequence involving first-generation tyrosine kinase inhibitor (TKI) (1G) followed by osimertinib might be considered.

Distinct Clinicogenomic Features and Immunotherapy Associations in Pulmonary Sarcomatoid Carcinoma: A Multicenter Retrospective Study.

Introduction: Pulmonary sarcomatoid carcinoma (PSC) is a rare NSCLC subtype with poor prognosis. Outcomes to immune checkpoint inhibitors (ICIs) and genomic features in PSC remain underexplored compared with other NSCLC subtypes.

Methods: Patients from three institutions and the National Cancer Database (NCDB) with metastatic NSCLC treated with ICI alone or with chemotherapy were identified.

Machine-learning driven strategies for adapting immunotherapy in metastatic NSCLC.

Immune checkpoint inhibitors (ICIs), either as monotherapy (ICI-Mono) or combined with chemotherapy (ICI-Chemo), improves survival in advanced non-small cell lung cancer (NSCLC). However, prospective guidance for choosing between these options remains limited, and single-feature biomarkers like PD-L1 prove inadequate. We develop a machine learning model using clinicogenomic data from four cohorts (MD Anderson n = 750; Mayo Clinic n = 80; Dana-Farber n = 1077; Stand Up To Cancer n = 393) to predict individual benefit from adding chemotherapy.

Efficacy and Safety of TROP-2-Targeting Antibody-Drug Conjugate Treatment in Previously Treated Patients with Advanced Non-Small Cell Lung Cancer: A Systematic Review and Pooled Analysis of Reconstructed Patient Data.

Background: Docetaxel is the standard of care for advanced non-small cell lung cancer (NSCLC) after platinum-based chemotherapy and/or immunotherapy but is associated with modest clinical outcomes and considerable toxicity. Sacituzumab govitecan and datopotamab deruxtecan are trophoblast cell surface antigen (TROP)-2-directed antibody-drug conjugates (ADCs) that showed encouraging activity in pretreated patients with advanced NSCLC. This systematic review and pooled analysis aims to comprehensively assess the efficacy and safety of anti-TROP-2 ADCs compared to docetaxel in pretreated patients with advanced NSCLC.

Neoadjuvant PD-1 and PD-L1 Blockade With Chemotherapy for Borderline Resectable and Unresectable Stage III Non-Small Cell Lung Cancer.

Importance: Patients with borderline resectable or unresectable stage III non-small cell lung cancer (NSCLC) with T4 and/or N2-N3 involvement face limited treatment options and poor outcomes. Neoadjuvant chemoimmunotherapy has shown promise in improving resectability and pathological responses.

Objective: To evaluate the efficacy of neoadjuvant programmed cell death 1 protein (PD-1) or programmed cell death 1 ligand 1 (PD-L1) blockade combined with chemotherapy in enhancing surgical outcomes and pathological responses in patients with T4 and/or N2-N3 stage III NSCLC.

Factors Associated with Disease Progression after Discontinuation of Immune Checkpoint Inhibitors for Immune-Related Toxicity in Patients with Advanced Non-Small Cell Lung Cancer.

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.

Antitumor Activity of Vebreltinib and Characterization of Clinicogenomic Features in Solid Tumors with MET Rearrangements.

Unlabelled: Oncogenic translocations involving the MET gene have been reported in several cancer types, but detailed clinicogenomic characterization of these cancers is not well defined. In addition, prospective clinical trials evaluating the antitumor activity of MET inhibitors in MET rearrangement-positive cancers are limited. In this study, in a pan-cancer analysis of >46,000 solid tumors with comprehensive genomic profiling, we identified oncogenic MET rearrangements in ∼0.

Current diagnostic and therapeutical approaches to bone metastases in patients with non-small cell lung cancer: A cross-sectional study.

Introduction: The current study aims to investigate the current practice of bone metastasis management in patients with non-small cell lung cancer.

Methods: An online questionnaire was administered to 92 oncologists. A survey was developed and revised by dedicated experts and was composed of five sections: i) general and work characteristics, ii) diagnostic issues, ii) bone-targeted agents issues, iii) radiotherapy issues, and iv) supportive care issues.

Activating Mutations in the MET Kinase Domain Co-Occur With Other Driver Oncogenes and Mediate Resistance to Targeted Therapy in NSCLC.

Introduction: MET tyrosine kinase domain (TKD) mutations have recently been characterized as de novo oncogenic drivers in NSCLC. Nevertheless, whether activating MET TKD mutations can confer resistance to targeted therapy in non-MET, oncogene-driven NSCLCs remains unclear.

Methods: To characterize the genomic features of tumors with MET TKD mutations in oncogene-driven NSCLC, we performed tumor genomic profiling on two different cohorts of patients with NSCLC.

Early monitoring of plasma KRAS G12C with digital PCR predicts antitumor response to immunotherapy or sotorasib in advanced NSCLC: A brief report.

Background: The frontline management of non-oncogene addicted non-small cell lung cancer (NSCLC) involves immune-checkpoint inhibitors (ICI) alone or combined with chemotherapy (CT-ICI). The dynamic landscape of KRAS-positive NSCLC presents a spectrum of treatment options, including ICIs, targeted therapy and combination strategies currently under investigation.

Methods: We conducted a prospective project to detect circulating tumor DNA (ctDNA) in patients with KRAS G12C, advanced NSCLC.

Tumor Immunophenotypic Correlates in Patients Aged 80 Years or Older With Non-Small Cell Lung Cancer and Outcomes to First-Line Pembrolizumab in PD-L1 High (≥50%) Patients.

Background: Non-small cell lung cancer (NSCLC) patients aged ≥80 years [y] are underrepresented in clinical trials. We evaluated whether age correlates with a distinct immunophenotype or impacts outcomes to first-line pembrolizumab in patients with advanced NSCLC, PD-L1 Tumor Proportion Score (TPS) of ≥50%, and aged ≥80y.

Methods: Three NSCLC cohorts were retrospectively analyzed to assess the impact of age (<80y versus ≥80y) on pembrolizumab efficacy and the tumor microenvironment (TME).

Determinants of 5-year survival in patients with advanced NSCLC with PD-L1≥50% treated with first-line pembrolizumab outside of clinical trials: results from the Pembro-real 5Y global registry.

Background: Pembrolizumab monotherapy is an established front-line treatment for advanced non-small cell lung cancer (NSCLC) with programmed cell death-ligand 1 (PD-L1) tumor proportion score (TPS)≥50%. However, real-world data on its long-term efficacy remains sparse.

Methods: This study assessed 5-year outcomes of first-line pembrolizumab monotherapy in a large, multicenter, real-world cohort of patients with advanced NSCLC and PD-L1 TPS≥50%, referred to as Pembro-real 5Y.

Gene Copy Deletion of STK11, KEAP1, and SMARCA4: Clinicopathologic Features and Association With the Outcomes of Immunotherapy With or Without Chemotherapy in Nonsquamous NSCLC.

Introduction: Mutations in STK11, KEAP1, and SMARCA4 predispose to inferior immune checkpoint inhibitor (ICI) efficacy in NSCLC, particularly among KRAS-mutant cases. Nevertheless, the frequency, clinicopathologic features, and clinical impact of deletions in these genes are poorly characterized.

Methods: Clinicopathologic correlates of STK11, KEAP1, and SMARCA4 deletion were analyzed in cases of nonsquamous NSCLC at Dana-Farber Cancer Institute (DFCI).

18F-Fluorodeoxyglucose Uptake in PDGFRA-Mutant Gastrointestinal Stromal Tumors.

Importance: The D842V platelet-derived growth factor receptor α (PDGFRA) mutation identifies a molecular subgroup of gastrointestinal stromal tumors (GISTs), primarily resistant to standard tyrosine kinase inhibitors and with an overall more indolent behavior. Although functional imaging with 18F-fluorodeoxyglucose-labeled positron emission tomography ([18F]FDG-PET) plays a proven role in GISTs, especially in early assessment of tumor response, less is known about [18F]FDG uptake according to the GIST molecular subtypes.

Objective: To evaluate the degree of [18F]FDG uptake in PDGFRA-mutant GISTs and better define the role of functional imaging in this rare and peculiar subset of GISTs.

MAPK Pathway-Activating Alteration and Immunotherapy Efficacy in Squamous Cell Lung Carcinoma: Results from the Randomized, Prospective SQUINT Trial.

Purpose: The role of activating alterations in the MAPK pathway in predicting immunotherapy efficacy in patients with lung squamous cell carcinoma (LSCC) is largely unknown. The aims of the randomized, phase II SQUINT trial were to assess the efficacy of nivolumab plus ipilimumab (NI) versus platinum-based chemotherapy plus nivolumab (N-CT) and to identify clinically available biomarkers of response to immunotherapy in patients with advanced or metastatic LSCC.

Patients And Methods: SQUINT was an open-label, randomized, parallel, noncomparative, phase II trial of NI versus N-CT in chemo-naïve adult patients with metastatic or recurrent LSCC.

Brief Report: Clinical Characteristics and Outcomes of Patients With Thoracic SMARCA4-Deficient Undifferentiated Tumors.

Introduction: Thoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UTs) are a recently defined group of aggressive cancers in which the effectiveness of standard treatments for lung cancer is unknown.

Methods: We collected clinical, pathologic, and demographic variables from five institutions for patients whose tumors met criteria for SMARCA4-UTs (undifferentiated phenotype and loss of SMARCA4 (BRG1) by immunohistochemistry).

Results: We identified 92 patients with SMARCA4-UTs; 58 (63%) had stage IV disease at diagnosis and 16 (17%) developed recurrent or metastatic disease after initial diagnosis.

Deep Learning Model for Predicting Immunotherapy Response in Advanced Non-Small Cell Lung Cancer.

Importance: Only a small fraction of patients with advanced non-small cell lung cancer (NSCLC) respond to immune checkpoint inhibitor (ICI) treatment. For optimal personalized NSCLC care, it is imperative to identify patients who are most likely to benefit from immunotherapy.

Objective: To develop a supervised deep learning-based ICI response prediction method; evaluate its performance alongside other known predictive biomarkers; and assess its association with clinical outcomes in patients with advanced NSCLC.

STK11 mutations correlate with poor prognosis for advanced NSCLC treated with first-line immunotherapy or chemo-immunotherapy according to KRAS, TP53, KEAP1, and SMARCA4 status.

Background: The upfront treatment of non-oncogene-addicted NSCLC relies on immunotherapy alone (ICI) or in combination with chemotherapy (CT-ICI). Genomic aberrations such as KRAS, TP53, KEAP1, SMARCA4, or STK11 may impact survival outcomes.

Methods: We performed an observational study of 145 patients treated with first-line IO or CT-ICI for advanced non-squamous (nsq) NSCLC at our institution tested with an extensive lab-developed NGS panel.

Development and validation of a new tool to estimate early mortality in patients with advanced cancer treated with immunotherapy.

Background: Immune checkpoint inhibitors (ICIs) are standard treatments for advanced solid cancers. Resistance to ICIs, both primary and secondary, poses challenges, with early mortality (EM) within 30-90 days indicating a lack of benefit. Prognostic factors for EM, including the lung immune prognostic index (LIPI), remain underexplored.