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.

Activity of Platinum Monotherapy in Patients With Metastatic Castration-Resistant Prostate Cancer and DNA Damage Repair Gene Alterations.

Purpose: Up to 30% of patients with metastatic castration-resistant prostate cancer (mCRPC) have DNA damage repair (DDR) gene alterations, mainly in . PARP inhibitors (PARPi) are standard treatments for -altered patients with mCRPC, and evidence for platinum agents is limited. This study assesses single-agent platinum therapy in patients with mCRPC with and without DDR alterations.

Molecular Tumor Boards: A Consensus Statement From the International Association for the Study of Lung Cancer.

Context: Molecular tumor boards (MTBs) are multidisciplinary meetings of specialists dedicated to analyzing biomarker test results to provide personalized treatment recommendations. However, global disparities in the successful implementation of MTBs exist, driven by unequal access to molecular diagnostics and supportive multidimensional expertise.

Objective: To establish recommendations for MTB implementation, outline practical frameworks for their operation, and address disparities in expertise and resources between new and established MTBs.

Expression of Membrane Targets for Therapeutics in RET-Positive Non-Small Cell Lung Cancer.

Importance: Patients with advanced RET fusion-positive (RET+) non-small cell lung cancer (NSCLC) who experience disease progression following treatment with RET inhibitors (RETis) have limited treatment options. Identifying membrane protein targets may support the assessment of novel therapies, such as antibody-drug conjugates and bispecific antibodies.

Objective: To evaluate membrane target expression in RET+ NSCLC.

AP1-mediated reprogramming of EGFR expression triggers resistance to BLU-667 and LOXO-292 in RET-rearranged tumors.

Background: Non-small cell lung cancer (NSCLC) is a significant global health challenge, with 2% of cases fuelled by RET rearrangements. RET inhibitors (RETi) have revolutionized treatment for these patients, but resistance remains an important clinical challenge limiting therapy effectiveness. This study investigated the mechanisms underlying resistance to RETi.

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.

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.

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.

Utilizing ctDNA to discover mechanisms of resistance to targeted therapies in patients with metastatic NSCLC: towards more informative trials.

Advances in targeted therapies for patients with non-small-cell lung cancer have substantially improved the outcomes of those with actionable alterations in certain oncogenic driver genes. However, acquired resistance to these targeted therapies remains a major challenge. Understanding the mechanisms underlying acquired resistance will be crucial for the development of strategies that might either overcome this effect or delay the onset.

Anti-ALK autoantibodies in patients with ALK-positive Non-Small Cell Lung Cancer (NSCLC): A monocentric experience.

Importance: Deregulation of anaplastic lymphoma kinase (ALK) occurs in 3-7% of advanced NSCLC mainly because of chromosomic rearrangements at the ALK locus. Next to its oncogenic function, ALK chimeric oncoprotein is a possible antigen for human immune system. The prognostic value of natural anti-ALK immunogenicity remains poorly explored in ALK ​+ ​NSCLC.

Personalized Therapy in a Patient With -Mutated NSCLC Developing Sequential Fusion and V600E Mutation as Bypass Resistance Mechanisms.

In this case report, we describe a case of sequential acquired fusion and V600E mutation observed in a patient with -mutated NSCLC treated with osimertinib and with combined selpercatinib and osimertinib. The discovery of genomic resistance mechanisms was facilitated by serial liquid and tissue biopsies and molecular tumor board discussion. After the identification of fusion, the patient received a combination of selpercatinib and osimertinib with prolonged benefit and manageable toxicity.

Real-World Outcomes of Pralsetinib in RET Fusion-Positive NSCLC.

Introduction: Pralsetinib is a RET inhibitor found to have antitumor activity in advanced, metastatic, fusion-positive NSCLC.

Objective: To assess real-world efficacy of pralsetinib and treatment sequences in patients with RET fusion-positive NSCLC.

Design: Retrospective study of consecutive patients enrolled in the French expanded-access program for pralsetinib from December 1, 2019, to December 31, 2021.

Artificial intelligence-based biomarkers for treatment decisions in oncology.

The development of new therapeutic strategies such as immune checkpoint inhibitors (ICIs) and targeted therapies has increased the complexity of the treatment landscape for solid tumors. At the current rate of annual FDA approvals, the potential treatment options could increase by tenfold over the next 5 years. The cost of personalized medicine technologies limits its accessibility, thus increasing socioeconomic disparities in the treated population.

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.

Antecedent viral immunization and efficacy of immune checkpoint blockade: an extensive serum antibody profile to predict outcomes in non-small cell lung cancer.

Introduction: Immune checkpoint blockers (ICBs) revolutionized the treatment of patients with advanced non-small cell lung cancer (NSCLC) but only a fraction of them obtain a response, and clinical benefit from these treatments is often difficult to predict. The aim of our study is to unveil the potential implications of antibody response to previous viral infections in predicting response to ICBs in patients with NSCLC.

Methods: Sera from patients treated with ICBs alone, chemotherapy (CT) or a combination of CT-ICBs were analyzed with VirScan (CDI Labs, USA), a high-throughput method that comprehensively analyzes epitope-level antiviral IgG antibodies via programmable phage display and immunoprecipitation sequencing.

Liquid Biopsy versus CT: Comparison of Tumor Burden Quantification in 1065 Patients with Metastases.

Background Tumor fraction (TF) at liquid biopsy is a potential noninvasive marker for tumor burden, but validation is needed. Purpose To evaluate TF as a potential surrogate for tumor burden, assessed at contrast-enhanced CT across diverse metastatic cancers. Methods This retrospective monocentric study included patients with cancer and metastatic disease, with TF results and contemporaneous contrast-enhanced CT performed between January 2021 and January 2023.

Response to Crizotinib After Entrectinib Resistance in -Rearranged, -Amplified Lung Adenocarcinoma.

Crizotinib successfully overcomes MET amplification in ROS1-rearranged NSCLC after entrectinib failure.

Disease Course and Treatment Outcomes in Patients With De Novo Small-Cell Lung Cancer and Epidermal Growth Factor Receptor Exon 20 Insertion: Two Case Reports.

We report the first two cases of EGFR exon20ins SCLC, treated with amivantamab and TKIs.

Impact of pembrolizumab treatment duration on overall survival and prognostic factors in advanced non-small cell lung cancer: a nationwide retrospective cohort study.

Background: The efficacy of front-line pembrolizumab has been established in studies that limit treatment duration to 2 years, but decision to stop pembrolizumab after 2 years is often at physician's discretion. ATHENA is a retrospective cohort study using a comprehensive administrative database aimed firstly at exploring the optimal duration of pembrolizumab and secondly real-life prognosis factors in patients with advanced non-small cell lung cancer (NSCLC).

Methods: Using the French National Health Insurance database (SNDS), we identified patients with incident lung cancer in France from 2015 to 2022.