Evaluation of immune checkpoint inhibitor efficacy for solid tumors with (PD-L1 gene) amplification identified by comprehensive genomic profiling: retrospective study based on a nationwide database.

Background: Amplification of the programmed cell death-ligand 1 gene () is highly prevalent and associated with a high response rate to immune checkpoint inhibitors (ICIs) in lymphomas, and is also a potential biomarker for ICI treatment of solid tumors. However, the efficacy of ICIs for solid tumors with amplification identified by comprehensive genomic profiling (CGP) has been unclear. We here examined ICI efficacy for solid tumors with amplification identified by CGP in a national database.

Alternating Therapy With Osimertinib and Afatinib Blockades EGFR Secondary Mutation in EGFR-Mutant Lung Cancer: A Single-Arm Phase II Trial.

Background: Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has limited treatment options for patients with EGFR-mutated non-small-cell lung cancer (NSCLC). Although osimertinib or afatinib alone induced drug-resistant clones with EGFR secondary mutation in a preclinical model, its combination prevented the appearance of these mutations. We investigated alternating-dose therapy of osimertinib and afatinib in patients with EGFR-mutant NSCLC in a single-arm Phase II trial.

Successful treatment with atezolizumab combination chemotherapy in a patient with high-grade fetal adenocarcinoma of the lung: A case report.

High-grade fetal lung adenocarcinoma (H-FLAC) is a rare tumor, with little known of its response to chemotherapy with or without an immune checkpoint inhibitor or of its molecular profile. We report the first case of a 56-year-old man with stage IV H-FLAC who was successfully treated with carboplatin plus nab-paclitaxel in combination with atezolizumab. In addition, the tumor was found to be positive for amplification of the human epidermal growth factor receptor 2 gene.

Implication of changes in PD-L1 expression during neoadjuvant chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (DCF) regimen in esophageal squamous cell carcinoma.

Background: Neoadjuvant docetaxel plus cisplatin and 5-FU (NAC-DCF) and adjuvant nivolumab monotherapy are the standard care for locally advanced resectable esophageal squamous cell carcinoma (ESCC). However, no effective biomarkers have been found in perioperative setting. We investigated how programmed death-ligand 1 (PD-L1) changes before and after NAC-DCF and how it relates to the therapeutic effect of NAC-DCF in resectable ESCC.

Alternating therapy with osimertinib and afatinib for treatment-naive patients with EGFR-mutated advanced non-small cell lung cancer: A single-group, open-label phase 2 trial (WJOG10818L).

Introduction: Alternation of osimertinib and afatinib is a potential approach to overcome osimertinib resistance and to allow complementation of drug efficacy without compromising safety in patients with epidermal growth factor receptor gene (EGFR)-mutated non-small cell lung cancer (NSCLC).

Methods: Treatment-naive patients with stage IV NSCLC harboring an activating EGFR mutation (L858R or exon-19 deletion) were enrolled. Alternating cycles of osimertinib at 80 mg/day for 8 weeks followed by afatinib at 20 mg/day for 8 weeks were administered.

HER3 Augmentation via Blockade of EGFR/AKT Signaling Enhances Anticancer Activity of HER3-Targeting Patritumab Deruxtecan in EGFR-Mutated Non-Small Cell Lung Cancer.

Purpose: EGFR-tyrosine kinase inhibitor (TKI) is a standard first-line therapy for activated -mutated non-small cell lung cancer (NSCLC). Treatment options for patients with acquired EGFR-TKI resistance are limited. HER3 mediates EGFR-TKI resistance.

KRAS Inhibitor Resistance in -Amplified Non-Small Cell Lung Cancer Induced By RAS- and Non-RAS-Mediated Cell Signaling Mechanisms.

Purpose: Treatment with inhibitors such as sotorasib can produce substantial regression of tumors in some patients with non-small cell lung cancer (NSCLC). These patients require alternative treatment after acquiring resistance to the inhibitor. The mechanisms underlying this acquired resistance are unclear.

CAPP-seq analysis of circulating tumor DNA from patients with EGFR T790M-positive lung cancer after osimertinib.

Background: We here applied cancer personalized profiling by deep sequencing (CAPP-seq) to analysis of circulating tumor DNA (ctDNA) to identify resistance mechanisms in osimertinib-treated patients with EGFR T790M-positive non-small cell lung cancer (NSCLC).

Methods: The study included patients with EGFR activating mutation-positive advanced NSCLC who were positive for T790M in tumor tissue or plasma after previous treatment with an EGFR tyrosine kinase inhibitor, who received osimertinib at Kindai University Hospital between August 2014 and September 2017, and for whom plasma collected after progression on osimertinib was available. Clinical data were extracted from medical records.

HER2-/HER3-Targeting Antibody-Drug Conjugates for Treating Lung and Colorectal Cancers Resistant to EGFR Inhibitors.

Epidermal growth factor receptor (EGFR) is one of the anticancer drug targets for certain malignancies, including nonsmall cell lung cancer (NSCLC), colorectal cancer (CRC), and head and neck squamous cell carcinoma. However, the grave issue of drug resistance through diverse mechanisms persists, including secondary EGFR-mutation and its downstream RAS/RAF mutation. Since the discovery of the role of human epidermal growth factor receptor 2 (HER2) and HER3 in drug resistance, HER2- or HER3-targeting treatment strategies using monoclonal antibodies have been intensively examined and have demonstrated impressive responsiveness and limitations.

Clinical Application of the FoundationOne CDx Assay to Therapeutic Decision-Making for Patients with Advanced Solid Tumors.

Background: Implementation of personalized medicine requires the accessibility of tumor molecular profiling in order to allow prioritization of appropriate targeted therapies for individual patients. Our aim was to study the role of comprehensive genomic profiling assays that may inform treatment recommendations for patients with solid tumors.

Materials And Methods: We performed a prospective study to evaluate the feasibility of application of the FoundationOne CDx panel-which detects substitutions, insertions and deletions, and copy number alterations in 324 genes, select gene rearrangements, and genomic signatures including microsatellite instability and tumor mutation burden (TMB)-to patients with advanced or recurrent solid tumors before its approval in Japan.

Nintedanib promotes antitumour immunity and shows antitumour activity in combination with PD-1 blockade in mice: potential role of cancer-associated fibroblasts.

Background: Cancer-associated fibroblasts (CAFs) in the tumour microenvironment (TME) suppress antitumour immunity, and the tyrosine kinase inhibitor nintedanib has antifibrotic effects.

Methods: We performed a preclinical study to evaluate whether nintedanib might enhance antitumour immunity by targeting CAFs and thereby improve the response to immune checkpoint blockade (ICB).

Results: Whereas nintedanib did not suppress the growth of B16-F10 melanoma cells in vitro, it prolonged survival in a syngeneic mouse model of tumour formation by these cells, suggestive of an effect on the TME without direct cytotoxicity.

Heregulin expression and its clinical implication for patients with EGFR-mutant non-small cell lung cancer treated with EGFR-tyrosine kinase inhibitors.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are standard therapy for EGFR-mutant non-small cell lung cancer (NSCLC). Preclinically, HER3 ligand heregulin induces resistance to EGFR-TKIs, whereas the pan-human EGFR family inhibitor afatinib remains effective. Here, we examined whether soluble heregulin levels have clinical implications for EGFR-mutant NSCLC treated with EGFR-TKIs.

Impact of coexisting gene mutations in EGFR-mutated non-small cell lung cancer before treatment on EGFR T790M mutation status after EGFR-TKIs.

Objectives: The T790M secondary mutation of epidermal growth factor receptor gene (EGFR) is the most common mechanism of acquired resistance to first- or second-generation EGFR tyrosine kinase inhibitors (TKIs). We investigated the association between gene mutation profile in EGFR mutation-positive non-small cell lung cancer (NSCLC) before EGFR-TKI treatment and T790M status after EGFR-TKI treatment.

Materials And Methods: A total of 57 EGFR mutation-positive NSCLC patients who had undergone a repeat biopsy (tissue or liquid) after failure of treatment with a first- or second-generation EGFR-TKI and who had sufficient tumor tissue available from before treatment for genetic analysis was enrolled.

U3-1402 sensitizes HER3-expressing tumors to PD-1 blockade by immune activation.

Immunotherapy targeting programmed cell death-1 (PD-1) induces durable antitumor efficacy in many types of cancer. However, such clinical benefit is limited because of the insufficient reinvigoration of antitumor immunity with the drug alone; therefore, rational therapeutic combinations are required to improve its efficacy. In our preclinical study, we evaluated the antitumor effect of U3-1402, a human epidermal growth factor receptor 3-targeting (HER3-targeting) antibody-drug conjugate, and its potential synergism with PD-1 inhibition.

Aberrant HER3 ligand heregulin-expressing head and neck squamous cell carcinoma is resistant to anti-EGFR antibody cetuximab, but not second-generation EGFR-TKI.

The anti-epidermal growth factor receptor (EGFR) antibody cetuximab is standard therapy for head and neck squamous cell carcinoma (HNSCC). However, most HNSCC tumors are resistant to it and require alternative treatments. Here, we explored the mechanism of cetuximab resistance and evaluated its clinical relevance in HNSCC.

Tumor tissue and plasma levels of AXL and GAS6 before and after tyrosine kinase inhibitor treatment in EGFR-mutated non-small cell lung cancer.

Background: Non-small cell lung cancer (NSCLC) positive for activating mutations of the epidermal growth factor receptor (EGFR) gene is initially sensitive to EGFR-tyrosine kinase inhibitors (TKIs) but eventually develops resistance to these drugs. Upregulation of the receptor tyrosine kinase AXL in tumor tissue has been detected in about one-fifth of NSCLC patients with acquired resistance to EGFR-TKIs. However, the clinical relevance of the levels of AXL and its ligand GAS6 in plasma remains unknown.

A comparative study of curated contents by knowledge-based curation system in cancer clinical sequencing.

Medical oncologists are challenged to personalize medicine with scientific evidence, drug approvals, and treatment guidelines based on sequencing of clinical samples using next generation sequencer (NGS). Knowledge-based curation systems have the potential to help address this challenge. We report here the results of examining the level of evidence regarding treatment approval and clinical trials between recommendations made by Watson for Genomics (WfG), QIAGEN Clinical Insight Interpret (QCII), and Oncomine knowledge-based reporter (OKR).

[fam-] trastuzumab deruxtecan, antitumor activity is dependent on HER2 expression level rather than on HER2 amplification.

Therapies targeted to human epidermal growth factor receptor 2 (HER2) have proven effective against tumors positive for HER2 amplification, but there is an unmet clinical need for the treatment of tumors that express HER2 protein in the absence of HER2 amplification. [fam-] trastuzumab deruxtecan (DS-8201a) is a novel antibody-drug conjugate composed of the anti-HER2 antibody and the topoisomerase I inhibitor, an exatecan derivative. It has shown efficacy against tumors that express HER2 and is currently under evaluation in clinical trials.

Targeting of the HER2/HER3 signaling axis overcomes ligand-mediated resistance to trastuzumab in HER2-positive breast cancer.

HER2-targeted therapy, especially the anti-HER2 antibody trastuzumab, is standard for HER2-positive breast cancer; however, its efficacy is limited in a subpopulation of patients. HER3 ligand (heregulin)-dependent HER2-HER3 interactions play a critical role in the evasion of apoptosis and are therefore a target for oncotherapy to treat HER2-positive breast cancer. The anti-HER2 antibody pertuzumab and anti-HER3 antibody patritumab both target this heregulin-HER3-HER2 complex in different ways.