Trials to Overcome Drug Resistance to EGFR and ALK Targeted Therapies - Past, Present, and Future
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Updated: Apr 23, 2026
Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
Published on: August 11, 2017
Johanna N Spaans1, Glenwood D Goss2
1Ottawa Hospital Research Institute , Ottawa, ON , Canada.
Abstract:
Molecularly targeted agents are changing the therapeutic landscape in advanced non-small cell lung cancer. Since the discovery of sensitizing mutations in the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) domain, clinical investigations have focused on optimizing the efficacy of EGFR and ALK tyrosine kinase inhibitors by addressing therapeutic resistance that commonly develops within a year of treatment initiation. Here, we review the clinical trials of novel therapies and combination regimens that have been undertaken in response to our evolving understanding of the mechanisms of resistance to targeted therapy. The aim of these trials was to enhance the therapeutic efficacy of targeted therapies by improving blockade and/or inhibiting parallel or compensatory signaling pathways. We have documented the sequential conduct of EGFR and ALK biomarker-driven trials in order to highlight particular pitfalls and successes, which should be considered in the design of future trials. Although there remain significant challenges, substantial gains have been made in our understanding of cellular resistance. This knowledge will drive the design of future trials to the benefit of lung cancer patients.
Insights
Targeted therapies for advanced non-small cell lung cancer show promise but face resistance. Research is exploring new treatments and combinations to overcome resistance and improve patient outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Advanced non-small cell lung cancer (NSCLC) treatment is evolving with molecularly targeted agents.
- Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations drive targeted therapy efficacy.
- Therapeutic resistance to EGFR and ALK inhibitors develops rapidly, necessitating new strategies.
Purpose of the Study:
- To review clinical trials of novel therapies and combination regimens for overcoming resistance to targeted therapies in NSCLC.
- To enhance the efficacy of targeted therapies by improving pathway blockade and inhibiting compensatory signaling.
- To analyze EGFR and ALK biomarker-driven trials to inform future research design.
Main Methods:
- Review of clinical trials investigating novel therapies and combination regimens.
- Analysis of mechanisms of resistance to EGFR and ALK tyrosine kinase inhibitors.
- Examination of sequential EGFR and ALK biomarker-driven trial conduct.
Main Results:
- Significant progress in understanding cellular resistance mechanisms to targeted therapies.
- Identification of pitfalls and successes in sequential biomarker-driven trials.
- Development of strategies to improve targeted therapy efficacy through enhanced blockade and pathway inhibition.
Conclusions:
- Substantial gains in understanding resistance pave the way for improved NSCLC treatments.
- Future trial designs will benefit from insights into resistance mechanisms and trial conduct.
- Continued research is crucial for advancing the therapeutic landscape for lung cancer patients.
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