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AZD9291 in EGFR-mutant advanced non-small-cell lung cancer patients
Jordi Remon1, David Planchard1
1Gustave Roussy, Medical Oncology Department, Villejuif, France.
Abstract:
Non-small-cell lung cancer (NSCLC) patients whose tumors have an EGFR-activating mutation develop acquired resistance after a median of 9-11 months from the beginning of treatment with erlotinib, gefitinib and afatinib. T790M mutation is the cause of this resistance in approximately 60% of cases. AZD9291 is an oral, irreversible, mutant-selective EGF receptor (EGFR) tyrosine kinase inhibitor (TKI) developed to have potency against EGFR mutations, including T790M mutation, while sparing wild-type EGFR. A Phase I trial of AZD9291 in EGFR-mutant NSCLC patients, demonstrated high activity, essentially among T790M-mutant tumors, with a manageable tolerability profile. Ongoing Phase III trials are evaluating AZD9291 in EGFR-mutant patients as first-line treatment compared with erlotinib and gefitinib; and as second-line treatment compared with chemotherapy after progression on EGFR TKI in T790M-mutant tumors. Better identification of T790M-mutant tumors post EGFR TKI relapse and mechanisms of resistance to AZD9291 are the future challenges. This article reviews the emerging data regarding AZD9291 in the treatment of patients with advanced NSCLC.
Insights
Acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC) is often due to the T790M mutation. AZD9291 shows promise in overcoming this resistance, with ongoing trials evaluating its efficacy.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Non-small-cell lung cancer (NSCLC) with EGFR-activating mutations often develops resistance to EGFR tyrosine kinase inhibitors (TKIs) like erlotinib, gefitinib, and afatinib.
- The T790M mutation is responsible for acquired resistance in approximately 60% of these cases.
- Wild-type EGFR sparing is crucial for minimizing off-target toxicity.
Purpose of the Study:
- To review emerging data on AZD9291, a novel EGFR TKI, for advanced NSCLC treatment.
- To highlight AZD9291's potential in overcoming T790M-mediated resistance.
- To discuss ongoing clinical trials and future challenges in AZD9291 therapy.
Main Methods:
- Review of emerging clinical data for AZD9291.
- Analysis of Phase I trial results demonstrating activity in EGFR-mutant NSCLC.
- Discussion of ongoing Phase III trials comparing AZD9291 with existing therapies.
Main Results:
- AZD9291 demonstrated high activity in EGFR-mutant NSCLC, particularly in T790M-mutant tumors.
- The drug exhibits a manageable tolerability profile.
- Phase III trials are actively evaluating AZD9291 in first- and second-line settings.
Conclusions:
- AZD9291 is a promising mutant-selective EGFR TKI for NSCLC patients resistant to earlier TKIs.
- Further research is needed to identify T790M-mutant tumors post-relapse and understand resistance mechanisms to AZD9291.
- AZD9291 represents a significant advancement in targeted therapy for advanced NSCLC.
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