Project 2: Optimizing Precision Medicine Approaches to Treat EGFR-Driven Lung Cancer

Yale University, New Haven CT

Investigators

Linked publications, trials & patents

Abstract

PROJECT SUMMARY Targeted therapies have transformed the diagnostic and treatment landscape for patients with genetically- defined subsets of lung adenocarcinoma. Although these agents have significantly improved the lives of most patients, they are not curative and drug resistance inevitably emerges. These challenges are exemplified in EGFR-driven lung adenocarcinoma, where significant advances were recently made with the approval of the third-generation tyrosine kinase inhibitor (TKI) osimertinib for the first-line treatment of patients with advanced disease. Osimertinib has been shown to extend the overall survival of patients with EGFR mutant lung cancer compared to earlier generation TKIs. However, there is substantial variability in the depth and duration of responses across patients, and resistance remains inescapable. A major determinant of the heterogeneity of responses to TKIs is the identity of the baseline oncogenic mutation. For example, patients with tumors that harbor the EGFR L858R (L858R) mutation have been shown to have worse outcomes with EGFR TKI treatment than those with EGFR EX19DEL (EX19DEL) mutations. Co-occurring alterations in other genes, like tumor suppressor genes, can also modulate sensitivity of EGFR-driven tumors to TKIs. Accordingly, a significant proportion of patients should benefit from therapeutic modalities that augment the efficacy of osimertinib. Which treatment approaches are needed to reach the full potential of targeted therapy for this disease remain to be identified. We posit that increasing the depth of the initial response to therapy, to more effectively eliminate residual disease will prevent or delay the emergence of drug resistance. Based on preliminary results, we propose to achieve this via two orthogonal and complementary approaches: 1) Optimally deploying ERBB- targeting cytotoxic antibody-drug conjugates (ADCs), like trastuzumab deruxtecan (TDXd) and, 2) Leveraging novel synthetic lethalities (such as SMARCA4 loss that we uncovered) in mutant EGFR-driven lung cancer, that will synergize with EGFR targeted therapies in the first line setting including in the L858R subset which is at higher risk of early progression on TKI monotherapy. We hypothesize that TDXd and/or agents that target SMARCA4 may represent valuable potential approaches to treat EGFR-driven lung adenocarcinomas in combination with osimertinib. To test this, we plan to: 1) Identify the mechanistic basis for optimal use of antibody drug conjugates that target EGFR family members and 2) Elucidate the mechanistic basis for the SMARCA4-EGFR synthetic lethal interaction in mutant EGFR driven lung cancer and leverage it therapeutically. In summary, through this project we will investigate new ways of treating EGFR-driven lung adenocarcinomas with the goal of treating these tumors as effectively as possible from the start to achieve long-term benefits for patients.