Focal adhesion kinase-YAP signaling axis drives drug-tolerant persister cells and residual disease in lung cancer.

Targeted therapy is effective in many tumor types including lung cancer, the leading cause of cancer mortality. Paradigm defining examples are targeted therapies directed against non-small cell lung cancer (NSCLC) subtypes with oncogenic alterations in EGFR, ALK and KRAS. The success of targeted therapy is limited by drug-tolerant persister cells (DTPs) which withstand and adapt to treatment and comprise the residual disease state that is typical during treatment with clinical targeted therapies.

Small-molecule targeted therapies induce dependence on DNA double-strand break repair in residual tumor cells.

Residual cancer cells that survive drug treatments with targeted therapies act as a reservoir from which eventual resistant disease emerges. Although there is great interest in therapeutically targeting residual cells, efforts are hampered by our limited knowledge of the vulnerabilities existing in this cell state. Here, we report that diverse oncogene-targeted therapies, including inhibitors of epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), KRAS, and BRAF, induce DNA double-strand breaks and, consequently, ataxia-telangiectasia mutated (ATM)-dependent DNA repair in oncogene-matched residual tumor cells.

Hypersensitivity Reactions to Selpercatinib Treatment With or Without Prior Immune Checkpoint Inhibitor Therapy in Patients With NSCLC in LIBRETTO-001.

Introduction: Immune checkpoint inhibitor (ICI) therapy has been found to increase the risk/severity of immune-mediated adverse events with subsequent kinase inhibitor treatment in oncogenically driven cancers. We explored the risk for hypersensitivity with selpercatinib, a first-in-class highly selective and potent, central nervous system-active RET inhibitor, in prior ICI-treated patients with RET fusion-positive NSCLC compared with their ICI-naive counterparts.

Methods: Data from patients enrolled by December 16, 2019, in the ongoing phase 1/2 LIBRETTO-001 (NCT03157128) trial were analyzed for hypersensitivity reactions reported using preferred terms of hypersensitivity/drug hypersensitivity and defined as a constellation of symptoms/findings characterized by maculopapular rash, often preceded by fever with arthralgias/myalgias, followed by greater than or equal to 1 of the following signs/symptoms: thrombocytopenia, increased aspartate aminotransferase or alanine aminotransferase, hypotension, tachycardia, or increased creatinine.

Patient-Reported Outcomes with Selpercatinib Among Patients with RET Fusion-Positive Non-Small Cell Lung Cancer in the Phase I/II LIBRETTO-001 Trial.

Background: LIBRETTO-001 is an ongoing, global, open-label, phase I/II study of selpercatinib in patients with advanced or metastatic solid tumors. We report interim patient-reported outcomes in patients with RET fusion-positive non-small cell lung cancer (NSCLC).

Patients And Methods: Patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) version 3.

Brain Metastases in EGFR- and ALK-Positive NSCLC: Outcomes of Central Nervous System-Penetrant Tyrosine Kinase Inhibitors Alone Versus in Combination With Radiation.

Introduction: Management of central nervous system (CNS) metastases in patients with driver-mutated NSCLC has traditionally incorporated both tyrosine kinase inhibitors (TKIs) and intracranial radiation. Whether next generation, CNS-penetrant TKIs can be used alone without upfront radiation, however, remains unknown. This multi-institutional retrospective analysis aimed to compare outcomes in patients with EGFR- or ALK-positive NSCLC who received CNS-penetrant TKI therapy alone versus in combination with radiation for new or progressing intracranial metastases.

Therapeutic Advances in the Management of Patients with Advanced RET Fusion-Positive Non-Small Cell Lung Cancer.

Screening for activating driver gene alterations at the time of diagnosis is the standard of care for advanced non-small cell lung cancer (NSCLC). Activating RET fusions are identified in approximately 1-2% of NSCLCs and have emerged as a targetable driver alteration. Selpercatinib and pralsetinib are RET-selective tyrosine kinase inhibitors (TKIs) with encouraging efficacy, intracranial activity, and tolerability that we recommend as first-line therapy.

Intracranial Efficacy of Selpercatinib in Fusion-Positive Non-Small Cell Lung Cancers on the LIBRETTO-001 Trial.

Purpose: We report the intracranial efficacy of selpercatinib, a highly potent and selective RET inhibitor, approved in the United States for fusion-positive non-small cell lung cancers (NSCLC).

Patients And Methods: In the global phase 1/2 LIBRETTO-001 trial (NCT03157128) in advanced -altered solid tumors, selpercatinib was dosed orally (160 mg twice every day) in 28-day cycles. Patients with baseline intracranial metastases had MRI/CT scans every 8 weeks for 1 year (12 weeks thereafter).

Phase I/II Study of Capmatinib Plus Erlotinib in Patients With MET-Positive Non-Small-Cell Lung Cancer.

Purpose: MET dysregulation is an oncogenic driver in non-small-cell lung cancer (NSCLC), as well as a mechanism of TKI (tyrosine kinase inhibitor) resistance in patients with epidermal growth factor receptor ()-mutated disease. This study was conducted to determine safety and preliminary efficacy of the combination EGFR and MET inhibitors as a strategy to overcome and/or delay EGFR-TKI resistance.

Methods: A standard 3 + 3 dose-escalation trial of capmatinib in combination with erlotinib in patients with MET-positive NSCLC was used.

A tyrosine kinase inhibitor-induced interferon response positively associates with clinical response in EGFR-mutant lung cancer.

Tyrosine kinase inhibitors (TKIs) targeting EGFR-mutant lung cancers promote a range of tumor regression responses to yield variable residual disease, a likely incubator for acquired resistance. Herein, rapid transcriptional responses induced by TKIs early in treatment that associate with the range of patient responses were explored. RNAseq was performed on EGFR mutant cell lines treated in vitro with osimertinib and on tumor biopsies of eight EGFR mutant lung cancer patients before and after 2 weeks of TKI treatment.

Durvalumab for Stage III EGFR-Mutated NSCLC After Definitive Chemoradiotherapy.

Introduction: In 2018, durvalumab was approved by the U.S. Food and Drug Administration as consolidation immunotherapy for patients with stage III NSCLC after definitive chemoradiotherapy (CRT).

Efficacy of Selpercatinib in Fusion-Positive Non-Small-Cell Lung Cancer.

Background: fusions are oncogenic drivers in 1 to 2% of non-small-cell lung cancers (NSCLCs). In patients with fusion-positive NSCLC, the efficacy and safety of selective RET inhibition are unknown.

Methods: We enrolled patients with advanced fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated separately in a phase 1-2 trial of selpercatinib.

Tumor evolution in epidermal growth factor receptor mutated non-small cell lung cancer.

As the incidence of cancer increases worldwide there is an unmet need to understand cancer evolution to improve patient outcomes. Our growing knowledge of cancer cells' clonal expansion, heterogeneity, adaptation, and relationships within the tumor immune compartment and with the tumor microenvironment has made clear that cancer is a disease that benefits from heterogeneity and evolution. This review outlines recent knowledge of non-small cell lung cancer (NSCLC) pathogenesis and tumor progression from an evolutionary standpoint, focused on the role of oncogenic driver mutations as epidermal growth factor receptor ().

Molecular Landscape of BRAF-Mutant NSCLC Reveals an Association Between Clonality and Driver Mutations and Identifies Targetable Non-V600 Driver Mutations.

Introduction: Approximately 4% of NSCLC harbor BRAF mutations, and approximately 50% of these are non-V600 mutations. Treatment of tumors harboring non-V600 mutations is challenging because of functional heterogeneity and lack of knowledge regarding their clinical significance and response to targeted agents.

Methods: We conducted an integrative analysis of BRAF non-V600 mutations using genomic profiles of BRAF-mutant NSCLC from the Guardant360 database.

Role of MPR as an Early Signal for Efficacy in Neoadjuvant Studies.

Overall survival and disease-free survival have been the gold standard primary endpoints for neoadjuvant clinical trials. Major pathologic response is a clinically proven surrogate of efficacy and when used as the primary endpoint, can allow for more efficient evaluation of drugs in the neoadjuvant setting..

Co-occurring Alterations in the RAS-MAPK Pathway Limit Response to MET Inhibitor Treatment in MET Exon 14 Skipping Mutation-Positive Lung Cancer.

Purpose: Although patients with advanced-stage non-small cell lung cancers (NSCLC) harboring exon 14 skipping mutations (ex14) often benefit from MET tyrosine kinase inhibitor (TKI) treatment, clinical benefit is limited by primary and acquired drug resistance. The molecular basis for this resistance remains incompletely understood.

Experimental Design: Targeted sequencing analysis was performed on cell-free circulating tumor DNA obtained from 289 patients with advanced-stage ex14-mutated NSCLC.

Engineering Multidimensional Evolutionary Forces to Combat Cancer.

With advances in technology and bioinformatics, we are now positioned to view and manage cancer through an evolutionary lens. This perspective is critical as our appreciation for the role of tumor heterogeneity, tumor immune compartment, and tumor microenvironment on cancer pathogenesis and evolution grows. Here, we explore recent knowledge on the evolutionary basis of cancer pathogenesis and progression, viewing tumors as multilineage, multicomponent organisms whose growth is regulated by subcomponent fitness relationships.

Differential Subcellular Localization Regulates Oncogenic Signaling by ROS1 Kinase Fusion Proteins.

Chromosomal rearrangements involving receptor tyrosine kinases (RTK) are a clinically relevant oncogenic mechanism in human cancers. These chimeric oncoproteins often contain the C-terminal kinase domain of the RTK joined to various N-terminal, nonkinase fusion partners. The functional role of the N-terminal fusion partner in RTK fusion oncoproteins is poorly understood.

Current Status and Future Perspectives on Neoadjuvant Therapy in Lung Cancer.

This Review Article provides a multi-stakeholder view on the current status of neoadjuvant therapy in lung cancer. Given the success of oncogene-targeted therapy and immunotherapy for patients with advanced lung cancer, there is a renewed interest in studying these agents in earlier disease settings with the opportunity to have an even greater impact on patient outcomes. There are unique opportunities and challenges with the neoadjuvant approach to drug development.

Resistance Mechanisms to Targeted Therapies in and Non-small Cell Lung Cancer.

Despite initial benefit from tyrosine kinase inhibitors (TKIs), patients with advanced non-small cell lung cancer (NSCLC) harboring (ALK) and (ROS1) gene fusions ultimately progress. Here, we report on the potential resistance mechanisms in a series of patients with ALK and ROS1 NSCLC progressing on different types and/or lines of -targeted therapy. We used a combination of next-generation sequencing (NGS), multiplex mutation assay, direct DNA sequencing, RT-PCR, and FISH to identify fusion variants/partners and copy-number gain (CNG), kinase domain mutations (KDM), and copy-number variations (CNVs) in other cancer-related genes.