Tumor Agnostic Models for NSCLC Drug Development

Abstract

<h3>Purpose/Objective(s)</h3> To demonstrate evidence-based methods for the establishment of tumor agnostic models for non-small cell lung carcinoma (NSCLC) drug development. Tumor agnostic drugs comprise targeted therapies or immunotherapies that target the cancer cell based on the malignancy's genetic alteration, rather than histological subtype. Thus, far three tumor agnostic drugs have been FDA-approved: the immunotherapy pembrolizumab for MMR-D; and targeted agents larotrectinib for tumors harboring the NRTK fusion, and entrectinib for ROS-1 positive tumors. The development and mechanistic details of these drugs and their applicability to NSCLC will be described. <h3>Materials/Methods</h3> Literature reviews will be conducted on biomedical literature databases (MEDLINE, PubMed, ASCO databases, etc.) with terms "tumor agnostic drugs", "NSCLC", "oncogenic drivers" "MMR-D alterations", "NRTK fusions", "ROS-1 positive", "pembrolizumab", Larotrectinib" and "entrectinib" "tumor agnostic clinical trials" "adverse events tumor agnostic". <h3>Results</h3> The tumor agnostic drugs enumerated here have efficacy for NSCLC, with manageable safety profiles. Data from open-label prospective clinical trials performed on NSCLC patients who harbor these genetic alterations with pembrolizumab, larotectinib, entrectinib demonstrated robust outcomes and manageable toxicity with median progression-free survival and median overall survival (as primary endpoints) being met, when compared to other therapies. As an example, entrectinib was evaluated in clinical studies with 51 adult NSCLC patients who were ROS1 positive. Overall response rate was 78%, with 5.9% of patients experiencing complete response, which persisted at a follow-up of 12 months. Common grade 1 side effects were fatigue, constipation, dizziness and diarrhea. More severe adverse events included congestive heart failure, cognitive impairment, and hepatotoxicity. <h3>Conclusion</h3> Elucidating and outlining the rich literature on tumor agnostic drugs for NSCLC sheds insight into the effective clinical management of tumor agnostic drugs for NSCLC and their unique role in precision medicine.