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One patient, two years in complete remission on gefitinib, then relapse. Sequencing the new biopsy found a second mutation in the same gene, at position 790, that stopped the drug binding.
Kobayashi, Boggon, Dayaram and colleagues at Beth Israel Deaconess and Dana-Farber reported a patient with EGFR-mutant, gefitinib-responsive advanced non-small-cell lung cancer who relapsed after two years of complete remission. The biopsy at relapse carried a second point mutation producing a threonine-to-methionine change at position 790 of EGFR, and structural modelling with biochemical studies showed this second mutation caused the resistance.
A single case report that changed a field. T790M went on to account for roughly half of acquired resistance to first-generation EGFR inhibitors, and the drug built against it, osimertinib, is now the first-line standard. The chain from one re-biopsy to a global standard of care is the strongest argument in oncology for biopsying at progression.
Resistance to a targeted drug usually has a cause you can read off a sequence, which means it can be targeted in turn. Osimertinib exists because of this paper.
One of the most cited trial reports Europe PMC returns for Osimertinib in Non-small-cell lung cancer, so it is a natural first reading for anyone weighing the idea it is linked from. The record was linked automatically by title and abstract; read the abstract above and the paper itself before relying on any figure.
The case for re-biopsy at progression, for treating resistance as a diagnosis rather than an endpoint, and for the idea of a drug holiday. It is also the origin of resistance-directed sequencing: what you give next should depend on what the tumour became.
The template for every driver mutation since: find the responders, sequence them, and give the drug only to people whose tumour carries the lesion it was built for. Gefitinib had been close to abandonment on the strength of unselected trials.
Shares Matthew Meyerson, Pasi A. Jänne, Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib, Gefitinib and the tag lung-evidence.
Shares Make resistance a diagnosis: sequence at every progression and choose the next line from what the tumour became, Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors, Driver mutation, Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch and the tag lung-evidence.
Shares Make resistance a diagnosis: sequence at every progression and choose the next line from what the tumour became, Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors, Driver mutation, Next-generation sequencing (NGS) and the tag lung-evidence.
Shares Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib, Gefitinib, Driver mutation, Next-generation sequencing (NGS) and the tag lung-evidence.
Shares Pasi A. Jänne, Driver mutation, Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch, Acquired resistance to every therapy and the tag lung-evidence.
Shares Driver mutation, Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch, Acquired resistance to every therapy, Osimertinib and the tag lung-evidence.
Shares Driver mutation, Next-generation sequencing (NGS), Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch, Receptor tyrosine kinase activation and the tag lung-evidence.
Shares Driver mutation, Next-generation sequencing (NGS), Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch, New England Journal of Medicine and the tag lung-evidence.