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Overcoming Resistance to Osimertinib by T790M Loss and C797S Acquisition Using Gefitinib in a Patient With
Diego Enrico1,2, Florencia Tsou1,2, Greta Catani3
1Thoracic Oncology Unit, Department of Medical Oncology, Alexander Fleming Cancer institute, Buenos Aires, Argentina.
Abstract:
Limited strategies are available at disease progression on osimertinib for patients with EGFR-mutant NSCLC. The emergence of the on-target EGFR C797S mutation has been described as one of the most common mechanisms of resistance. In addition, loss of the EGFR T790M mutation has been mainly investigated as a resistance phenomenon to second-line osimertinib exposure. Remarkably, by studying the molecular profile at progression, it has been reported that the presence of the EGFR-sensitizing mutation, concurrently with the T790M, and C797S resulted in resistance to the current available EGFR tyrosine kinase inhibitors. Here, we report the first clinical evidence of gefitinib efficacy at EGFR exon 19 deletion/C797S mutation/T790M loss-mediated resistance to first-line osimertinib. Our findings highlight that dynamic genetic monitoring is a crucial approach in the evolution of EGFR-mutant NSCLC to understand the acquired molecular mechanisms for driving the best treatment strategy.
Insights
Gefitinib shows efficacy in EGFR-mutant NSCLC resistant to osimertinib due to specific mutations. Dynamic genetic monitoring is crucial for guiding treatment strategies in advanced lung cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Non-small cell lung cancer (NSCLC) with EGFR mutations often develops resistance to targeted therapies like osimertinib.
- Mechanisms of resistance include the emergence of EGFR C797S mutations and loss of the T790M mutation.
Observation:
- Patients with EGFR-mutant NSCLC progressing on first-line osimertinib exhibited complex resistance profiles.
- These profiles included EGFR exon 19 deletion concurrently with C797S mutation and T790M loss.
Findings:
- This study presents the first clinical evidence of gefitinib's efficacy in patients with EGFR exon 19 deletion/C797S mutation/T790M loss-mediated resistance to first-line osimertinib.
- Gefitinib demonstrated effectiveness in overcoming this specific resistance pattern.
Implications:
- Dynamic genetic monitoring of EGFR mutations during treatment is essential for understanding acquired resistance.
- Identifying these evolving molecular mechanisms can guide the selection of optimal treatment strategies for NSCLC patients.
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