Overcoming heterogeneity and resistance in EGFR-mutant NSCLC

2017

Zofia Piotrowska, MD

Massachusetts General Hospital

Boston

Targeted therapies have become a mainstay of treatment for non-small cell lung cancer patients whose tumors test positive for a targetable driver mutation. The EGFR mutation is one such targetable mutation. New third-generation EGFR inhibitors have recently entered the clinic and can be very effective therapies for some patients who develop resistance to first- and second-generation EGFR inhibitors. Unfortunately, we are now seeing that cancer cells can also learn how to outsmart these third-generation inhibitors, and new and more effective treatments are needed. Dr. Zofia Piotrowska is studying how lung cancer cells become resistant to third-generation EGFR inhibitors, such as osimertinib, and how the heterogeneity of EGFR-mutant lung cancers can contribute to resistance to drugs like osimertinib. During the period of this award, Dr. Piotrowska will also be conducting a clinical trial testing a novel drug combination developed to prevent or delay the development of drug resistance among patients with EGFR-mutant lung cancer.

Research Summary

EGFR tyrosine kinase inhibitors (TKIs) have led to dramatic improvements in clinical outcomes among patients with EGFR-mutant lung cancer, but patients typically become resistant after about one year. In 50-60% of cases, resistance is driven by the secondary EGFR T790M resistance mutation. There is now growing evidence that resistant cancers are heterogeneous and that this influences resistance to subsequent therapies. In this proposal, we will take a comprehensive approach to study and characterize the heterogeneity of EGFR-mutant lung cancers and its impact on how cancers respond and become resistant to treatment. We will utilize innovative methods to study heterogeneity on multiple levels, including cell-by-cell variations within individual tumors, variations across different sites of cancer within an individual patient, and fluctuations in heterogeneity over time through “liquid biopsy” analysis. Finally, we will test a new combination treatment strategy designed to delay the emergence of resistance, and use the clinical trial to collect patient samples which will facilitate further studies of how resistance and cancer heterogeneity develops. Ultimately, we aim to identify more effective therapies to decrease heterogeneity, induce more durable responses and improve clinical outcomes.

Technical Abstract

Background: Osimertinib and other “third-generation” EGFR TKIs effectively overcome T790M-mediated resistance in EGFR-mutant lung cancer, but our understanding of acquired resistance in this setting remains limited. Importantly, the intrinsic heterogeneity of resistant cancers leads to clinical challenges. We hypothesize that in-depth study of 3rd-generation TKI resistance and the impact of genetic heterogeneity on treatment response will lead to improved therapeutic options and clinical outcomes. Study Design: We will analyze tumor biopsies, ctDNA and autopsy specimens using a variety of techniques such as next-generation sequencing, digital droplet PCR and whole exome sequencing to characterize heterogeneity in resistant cancers. In addition, we will run a prospective clinical trial to test a novel therapeutic combination designed to minimize heterogeneity and delay progression. On-treatment biopsies and ctDNA collection will be used to study how resistance develops. Impact: This project will leverage our broad array of clinical specimens, well-established translational research program and preexisting industry and academic collaborations to characterize the heterogeneity of resistance in EGFR-mutant lung cancer. We hope to illuminate clinical and biologic implications of heterogeneity, with the ultimate goal of identifying more effective therapies for patients.

Key words

Acquired resistance

Adenocarcinoma

Biomarker or biomarker testing

Circulating tumor DNA

Epidermal growth factor receptor (EGFR)

Non-small cell lung cancer (NSCLC)

Stage IV

Targeted therapy

Tyrosine kinase inhibitors (TKIs)

Overcoming heterogeneity and resistance in EGFR-mutant NSCLC

LUNGevity Foundation

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