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1.
Ann Oncol ; 35(5): 437-447, 2024 May.
Article in English | MEDLINE | ID: mdl-38369013

ABSTRACT

BACKGROUND: Human epidermal growth factor receptor 3 (HER3) is broadly expressed in non-small-cell lung cancer (NSCLC) and is the target of patritumab deruxtecan (HER3-DXd), an antibody-drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. U31402-A-U102 is an ongoing phase I study of HER3-DXd in patients with advanced NSCLC. Patients with epidermal growth factor receptor (EGFR)-mutated NSCLC that progressed after EGFR tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy (PBC) who received HER3-DXd 5.6 mg/kg intravenously once every 3 weeks had a confirmed objective response rate (cORR) of 39%. We present median overall survival (OS) with extended follow-up in a larger population of patients with EGFR-mutated NSCLC and an exploratory analysis in those with acquired genomic alterations potentially associated with resistance to HER3-DXd. PATIENTS AND METHODS: Safety was assessed in patients with EGFR-mutated NSCLC previously treated with EGFR TKI who received HER3-DXd 5.6 mg/kg; efficacy was assessed in those who also had prior PBC. RESULTS: In the safety population (N = 102), median treatment duration was 5.5 (range 0.7-27.5) months. Grade ≥3 adverse events occurred in 76.5% of patients; the overall safety profile was consistent with previous reports. In 78/102 patients who had prior third-generation EGFR TKI and PBC, cORR by blinded independent central review (as per RECIST v1.1) was 41.0% [95% confidence interval (CI) 30.0% to 52.7%], median progression-free survival was 6.4 (95% CI 4.4-10.8) months, and median OS was 16.2 (95% CI 11.2-21.9) months. Patients had diverse mechanisms of EGFR TKI resistance at baseline. At tumor progression, acquired mutations in ERBB3 and TOP1 that might confer resistance to HER3-DXd were identified. CONCLUSIONS: In patients with EGFR-mutated NSCLC after EGFR TKI and PBC, HER3-DXd treatment was associated with a clinically meaningful OS. The tumor biomarker characterization comprised the first description of potential mechanisms of resistance to HER3-DXd therapy.


Subject(s)
Antibodies, Monoclonal, Humanized , Carcinoma, Non-Small-Cell Lung , ErbB Receptors , Lung Neoplasms , Mutation , Receptor, ErbB-3 , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/mortality , Lung Neoplasms/pathology , ErbB Receptors/genetics , ErbB Receptors/antagonists & inhibitors , Female , Receptor, ErbB-3/genetics , Receptor, ErbB-3/antagonists & inhibitors , Middle Aged , Male , Aged , Adult , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/adverse effects , Aged, 80 and over , Camptothecin/analogs & derivatives , Camptothecin/therapeutic use , Camptothecin/administration & dosage , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Broadly Neutralizing Antibodies , Immunoconjugates/therapeutic use , Immunoconjugates/adverse effects , Immunoconjugates/administration & dosage
2.
Ann Oncol ; 29(suppl_1): i20-i27, 2018 01 01.
Article in English | MEDLINE | ID: mdl-29462255

ABSTRACT

Osimertinib was the first third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) to receive FDA and EMA approval for metastatic EGFR-mutant non-small-cell lung cancer (NSCLC) patients that have acquired the EGFR T790M resistance mutation. Clinical trials have demonstrated the efficacy of osimertinib in this patient population and clinical trials of other third-generation EGFR TKI are currently under way. Additional challenges in this patient population, such as the upfront efficacy of osimertinib, validation of T790M in liquid biopsies as a dynamic predictive marker of efficacy, along with combination with immune checkpoint inhibitors are being explored, representing an extraordinary time of development for EGFR-mutant NSCLC.


Subject(s)
Acrylamides/therapeutic use , Aniline Compounds/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Acrylamides/pharmacology , Aniline Compounds/pharmacology , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/mortality , Clinical Trials as Topic , Disease-Free Survival , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/genetics , Gain of Function Mutation , Humans , Lung Neoplasms/genetics , Lung Neoplasms/mortality , Protein Kinase Inhibitors/pharmacology
3.
Clin Pharmacol Ther ; 97(5): 488-91, 2015 May.
Article in English | MEDLINE | ID: mdl-25676724

ABSTRACT

Although the proportion of patients with squamous cell carcinoma of the lung has declined over the last two decades, the disease is still fatal for tens of thousands of patients each year. The treatment of non-small cell lung cancer has advanced rapidly over the past decade, providing novel, targeted therapeutic options to patients, but has mostly been limited to the adenocarcinoma histology. Efforts are currently underway to bring squamous cell carcinoma of the lung into this new era of targeted therapy. This article reviews the rationale and trial design for the "LUNG-MAP: S1400 Phase II/III Biomarker-Driven Master Protocol for Second Line Therapy of Squamous Cell Lung Cancer" study. This multi-institutional, multi-cooperative group trial aims to individualize treatment for patients with metastatic squamous cell carcinoma to one of five arms based on the genomic profile of the tumor. The goal of this clinical trial is to rapidly identify new active drugs and bring them as soon as possible through a registration process for patients with squamous cell lung cancer by utilizing a novel trial design and involving all key stakeholders in drug development in a national effort. This could serve as a paradigm for drug development for malignancies with wide molecular heterogeneity.


Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Squamous Cell/drug therapy , Clinical Trials, Phase II as Topic/methods , Clinical Trials, Phase III as Topic/methods , Lung Neoplasms/drug therapy , Molecular Targeted Therapy , Research Design , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/secondary , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/secondary , Genetic Predisposition to Disease , Genomics , Humans , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Phenotype , Precision Medicine , Signal Transduction/drug effects
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