Molecular mechanisms of acquired osimertinib resistance explored
medwireNews: An analysis of patients with T790M-positive, advanced non-small-cell lung cancer (NSCLC) who developed resistance to osimertinib points to heterogeneous underlying molecular mechanisms.
Drawing on the databases of four cancer centers, the researchers identified 143 patients who received single-agent osimertinib after acquiring resistance to prior treatment with an epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI); all patients were positive for the EGFR T790M mutation.
Of these, 41 patients with disease progression following osimertinib treatment underwent a tumor biopsy, which was analyzed using next-generation sequencing.
The majority (68%) of patients lost the T790M mutation at the time of acquiring resistance to osimertinib, while the remaining 32% retained the mutation.
Among those who retained T790M, the key mechanism of osimertinib resistance appeared to be the previously identified EGFR C797S mutation, which was observed in 69% of these patients.
For now, I would consider this work as a significant contribution that will need to be repeated in patients who develop acquired resistance on first-line osimertinib.
By contrast, a variety of resistance mechanisms were detected in patients who lost T790M, some of which were expected, while others were novel, say the investigators.
They report that just under half (46%) of these patients showed the presence of resistance mechanisms that are “well described after first-generation EGFR TKIs,” including small-cell lung cancer transformations, MET amplifications, and PIK3CA and BRAF mutations.
The remaining patients developed “unexpected” resistance mechanisms, with individual reports of RET, FGFR3, and BRAF fusions and a KRAS Q61K mutation.
Furthermore, the clinical benefit of osimertinib appeared to differ between patients who lost and those who retained the T790M mutation, such that T790M loss was associated with a significantly shorter time to treatment discontinuation, at a median of 6.1 and 15.2 months, respectively.
Writing in JAMA Oncology, researcher Geoffrey Oxnard (Dana-Farber Cancer Institute, Boston, Massachusetts, USA) and co-workers summarize that “[p]atients who develop early resistance to osimertinib likely have competing resistance mechanisms in other tumor subclones, and patients who develop late resistance are more likely to have maintained T790M and acquired C797S; different targeted therapies could be considered for these biologically varying populations.”
They continue: “Another strategy would be to improve the efficacy of osimertinib by developing combination approaches that prevent the development of resistance.
“However, the complex range of resistance mechanisms seen after osimertinib treatment make it difficult for any single combination approach to significantly delay osimertinib resistance overall.”
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