AZD9291 in epidermal growth factor receptor inhibitor-resistant non-small-cell lung cancer

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Advanced EGFR mutant non-small cell lung cancer (NSCLC) typically shows response to EGFR tyrosine kinase inhibitors (TKIs).
• Acquired resistance to EGFR TKIs, often due to the T790M mutation, limits long-term efficacy.
• A significant unmet need exists for therapies effective against resistance mechanisms in NSCLC.

Purpose of the Study:

• To evaluate the efficacy and safety of AZD9291, a third-generation EGFR TKI, in patients with advanced EGFR mutant NSCLC who progressed on prior EGFR TKI therapy.
• To assess the activity of AZD9291 in patients with and without the T790M resistance mutation.

Main Methods:

• Phase I trial with expansion cohorts including patients with EGFR TKI resistance.
• Patients were enrolled regardless of T790M mutation status.
• Objective response rate (ORR) and progression-free survival (PFS) were assessed based on centrally confirmed T790M mutation status.

Main Results:

• AZD9291 demonstrated an ORR of 61% in patients with the T790M mutation versus 21% in those without.
• Median PFS was 9.6 months for T790M-positive patients and 2.8 months for T790M-negative patients.
• At 80 mg daily, drug-related adverse events were manageable, with low rates of severe diarrhea (1%) and rash (0%).

Conclusions:

• AZD9291 exhibits significant activity in patients with acquired T790M resistance mutations in EGFR-mutant NSCLC.
• The development of AZD9291 highlights a successful strategy for targeting acquired resistance mutations.
• This approach provides a model for developing future targeted therapies for acquired resistance to cancer treatments.