Impact of Incidental Germline BRCA1/2 and PALB2 Alterations on EGFR Monotherapy Real-World Outcomes for Patients With Advanced Non-Small-Cell Lung Cancer.

Introduction: Several studies have sought to determine the prevalence of BRCA1/BRCA2 in patient populations, but few have studied impacts of such alterations on patient outcomes beyond breast, ovarian, prostate and pancreatic cancers. This study assessed patient outcomes from a large real-world evidence (RWE) database for patients with EGFR-mutated advanced non-small-cell lung cancer (aNSCLC) who also had incidental pathogenic germline variants (iPGVs) in BRCA1, BRCA2 or PALB2 identified by a well-validated liquid biopsy.

Materials And Methods: Outcomes from patients included in GuardantINFORM, a RWE database, from Oct 2018-June 2024 with a diagnosis of aNSCLC and an incidental pathogenic germline variant (iPGV) in BRCA1/2 or PALB2 included in OncoKB treated with EGFR monotherapy (gBRCA/PALB2+) were matched in 1:5 using coarsened exact matching to a control cohort without iPGVs (control).

Activity of Brigatinib in Patients With Crizotinib-Resistant ALK-positive Non-Small-Cell Lung Cancer According to ALK Fusion and Mutation Status.

Background: Brigatinib, a selective ALK inhibitor, demonstrated preclinical activity against a range of crizotinib-resistant ALK alterations in NSCLC. We examined associations between brigatinib efficacy and tumor- and plasma-detected driver mutations in crizotinib-resistant ALK fusion-positive NSCLC.

Patients And Methods: Tumor tissue and plasma circulating tumor DNA (ctDNA) from patients with crizotinib-exposed ALK-positive NSCLC receiving brigatinib in phase 1/2 and phase 2 ALTA trials were analyzed by next-generation sequencing.

Outcomes Following First-Line Immune Checkpoint Inhibitors With or Without Chemotherapy Stratified by KRAS Mutational Status-A Real-World Analysis in Patients With Advanced NSCLC.

Introduction: Prior studies evaluating the efficacy of first line (1 L) immune checkpoint inhibitor (ICI) monotherapy or combined chemoimmunotherapy in advanced NSCLC found improved outcomes with chemoimmunotherapy independent of PD-L1 and KRAS mutation status. As such, combined chemoimmunotherapy was proposed as the preferred comparator arm for 1 L trials in KRAS mutated (KRAS mt) NSCLC. Herein, we report a multimodal, real world data (RWD) analysis for outcomes with 1 L therapy in patients with advanced NSCLC stratified by KRAS mutation status and PD-L1 levels.

Elevated ctDNA Tumor Fraction Is Associated with Improved Mutation Detection but Worse Overall Survival in Advanced Non-Small Cell Lung Cancer: A Lung-MAP Study.

Purpose: ctDNA is a powerful diagnostic companion to tissue profiling. Tumor fraction (TF) is a global assessment of an individual's ctDNA burden. We evaluated the impact of plasma TF on mutation detection and clinical outcomes in patients with previously treated, advanced non-small cell lung cancer on the Lung Master Protocol (Lung-MAP).

Case Report: Severe brigatinib-induced pneumonitis in a patient with EML4-ALK+ metastatic non-small cell lung adenocarcinoma.

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs), such as brigatinib, are targeted therapies for metastatic non-small cell lung cancer (mNSCLC). We present a patient with echinoderm microtubule-associated protein-like 4 () and fusion protein-positive mNSCLC who developed severe hypoxemia and pneumonitis requiring intubation within 2 days of initiating brigatinib therapy. The workup for alternative etiologies of respiratory distress was unrevealing, and the patient was treated for presumed brigatinib-induced pneumonitis with high-dose methylprednisolone.

Dosing immune-checkpoint inhibitors: Opportunities for the future.

With recent breakthroughs in immunotherapy, particularly with the approval of immune checkpoint inhibitors for various cancer indications, patients now have a wider array of treatment options, even for those with metastatic disease. Still, the survival benefit of immune-checkpoint inhibitors is modest, and there is concern about drug toxicity. In addition, there is ongoing exploration into combination therapy involving immune-checkpoint inhibitors, which come at the risk of increased toxicity.

Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.3.

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The Impact of Next-Generation Sequencing Workflows on Outcomes in Advanced Lung Cancer: A Retrospective Analysis at One Academic Health System.

Purpose: Broad-based molecular testing with next-generation sequencing (NGS) is now the standard of care in advanced non-small cell lung cancer (NSCLC). Two approaches to molecular testing are (1) reflexive testing at pathologic NSCLC confirmation, often using an in-house molecular panel, and (2) send-out testing to private vendors, ordered by a clinician. This study explored the outcomes with reflex versus send-out testing.

The Society of Thoracic Surgeons Expert Consensus on the Multidisciplinary Management and Resectability of Locally Advanced Non-small Cell Lung Cancer.

Background: The contemporary management and resectability of locally advanced lung cancer are undergoing significant changes as new data emerge regarding immunotherapy and targeted treatments. The objective of this document is to review the literature and present consensus among a group of multidisciplinary experts to guide the determination of resectability and management of locally advanced non-small cell lung cancer (NSCLC) in the context of contemporary evidence.

Methods: The Society of Thoracic Surgeon Workforce on Thoracic Surgery assembled a multidisciplinary expert panel composed of thoracic surgeons and medical and radiation oncologists with established expertise in the management of lung cancer.

Safety of combined ablative radiotherapy and immune checkpoint inhibitors in three phase I trials.

Background: Stereotactic body radiotherapy (SBRT) is safe and effective for treatment of extracranial metastatic disease, but its safety when combined with immune checkpoint inhibitors (ICI) has not yet been comprehensively reported. Here we report adverse events (AEs) associated with combined SBRT and ICI using prospectively-collected data on patients in three trials investigating multi-site SBRT combined with ICI.

Methods: Patients were included from three prospective trials of ICI (pembrolizumab; nivolumab/urelumab or nivolumab/cabiralizumab; nivolumab/ipilimumab) with SBRT to 1-4 sites.

Dynamic Changes in Circulating Tumor Fraction as a Predictor of Real-World Clinical Outcomes in Solid Tumor Malignancy Patients Treated with Immunotherapy.

Introduction: A dynamic molecular biomarker that can identify early efficacy of immune checkpoint inhibitor (ICI) therapy remains an unmet clinical need. Here we evaluate if a novel circulating tumor DNA (ctDNA) assay, xM, used for treatment response monitoring (TRM), that quantifies changes in ctDNA tumor fraction (TF), can predict outcome benefits in patients treated with ICI alone or in combination with chemotherapy in a real-world (RW) cohort.

Methods: This retrospective study consisted of patients with advanced cancer from the Tempus de-identified clinical genomic database who received longitudinal liquid-based next-generation sequencing.

Addition of Trastuzumab Deruxtecan to Selpercatinib in a Patient With RET Fusion-Driven NSCLC and an Acquired HER2 Amplification: Case Report.

Despite the high activity of selective RET inhibitors in RET-driven NSCLC, resistance eventually develops and there is unmet need to better define therapeutic options for patients. This is a case of a patient initially thought to have no targetable alterations, then found to have a RET fusion, and subsequently HER2 amplification on three distinct biopsies. She was treated initially with chemotherapy and immune therapy, then switched to selpercatinib, and eventually had fam-trastuzumab deruxtecan added to selpercatinib.

Disparities in outcomes between Black and White patients in North America with thoracic malignancies and COVID-19 infection (TERAVOLT).

Background: Patients with thoracic malignancies who develop COVID-19 infection have a higher hospitalization rate compared to the general population and to those with other cancer types, but how this outcome differs by race and ethnicity is relatively understudied.

Methods: The TERAVOLT database is an international, multi-center repository of cross-sectional and longitudinal data studying the impact of COVID-19 on individuals with thoracic malignancies. Patients from North America with thoracic malignancies and confirmed COVID-19 infection were included for this analysis of racial and ethnic disparities.

Current and Emerging Treatment Options for Patients with Metastatic EGFR-Mutated Non-small Cell Lung Cancer After Progression on Osimertinib and Platinum-Based Chemotherapy: A Podcast Discussion.

Patients with metastatic epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) are widely treated with osimertinib, the preferred first-line treatment option. However, disease progression inevitably occurs, driven by EGFR-dependent or EGFR-independent mechanisms of resistance. Platinum-based chemotherapy is the recommended treatment following progression with osimertinib but responses to platinum-based chemotherapy are transient.

Representativeness of Patients Enrolled in the Lung Cancer Master Protocol (Lung-MAP).

Purpose: Lung Cancer Master Protocol (Lung-MAP), a public-private partnership, established infrastructure for conducting a biomarker-driven master protocol in molecularly targeted therapies. We compared characteristics of patients enrolled in Lung-MAP with those of patients in advanced non-small-cell lung cancer (NSCLC) trials to examine if master protocols improve trial access.

Methods: We examined patients enrolled in Lung-MAP (2014-2020) according to sociodemographic characteristics.

Phase II Randomized Trial of Carboplatin, Pemetrexed, and Bevacizumab With and Without Atezolizumab in Stage IV Nonsquamous Non-Small-Cell Lung Cancer Patients Who Harbor a Sensitizing EGFR Mutation or Have Never Smoked.

Introduction: Patients with non-small-cell lung cancer (NSCLC) who have never smoked or have tumors with mutations in EGFR generally derive minimal benefit from single-agent PD-1/PD-L1 checkpoint inhibitors. Prior data indicate that adding PD-L1 inhibition to anti-VEGF and cytotoxic chemotherapy may be a promising approach to overcoming immunotherapy resistance in these patients, however prospective validation is needed. This trial in progress (NCT03786692) is evaluating patients with stage IV NSCLC who have never smoked or who have tumors with sensitizing EGFR alterations to determine if a 4-drug combination of atezolizumab, carboplatin, pemetrexed, and bevacizumab can improve outcomes compared to carboplatin, pemetrexed and bevacizumab without atezolizumab.

Phase I/II Trial of Carboplatin, Nab-paclitaxel, and Pembrolizumab for Advanced Non-Small Cell Lung Cancer: Hoosier Cancer Research Network LUN13-175.

Background: Combination chemotherapy and immunotherapy regimens have significantly improved survival for patients with previously untreated advanced non-small cell lung cancer (NSCLC). Improvements in overall survival (OS) in two separate pembrolizumab trials have demonstrated survival improvements over chemotherapy alone, regardless of PD-L1 status. The optimal chemotherapy backbone for combination with immunotherapy is unknown.

Regulation of VEGFR2 and AKT Signaling by Musashi-2 in Lung Cancer.

Lung cancer is the most frequently diagnosed cancer type and the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) represents most of the diagnoses of lung cancer. Vascular endothelial growth factor receptor-2 (VEGFR2) is a member of the VEGF family of receptor tyrosine kinase proteins, which are expressed on both endothelial and tumor cells, are one of the key proteins contributing to cancer development, and are involved in drug resistance.

Indirect comparison of mobocertinib and real-world therapies for pre-treated non-small cell lung cancer with EGFR exon 20 insertion mutations.

Objectives: Mobocertinib, a novel oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is available for the treatment of non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion (ex20ins) mutations after platinum chemotherapy. We performed an indirect comparison of clinical trial data and real-world data (RWD) to determine the relative efficacy of mobocertinib vs. other treatments for these patients.