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37 patients were re-biopsied when their EGFR drug stopped working. Some had the expected resistance mutation; five had turned into small-cell lung cancer. In three, the resistance disappeared when the drug was stopped.
Sequist, Waltman, Dias-Santagata and colleagues, with Engelman as senior author, performed systematic genetic and histological analysis of tumour biopsies from 37 patients with drug-resistant EGFR-mutant non-small-cell lung cancers.
Three findings in one paper remade how resistance is thought about. Resistance is heterogeneous in mechanism; it can be histological rather than genetic, with 14 percent of tumours transforming into small-cell lung cancer; and it can be reversible, with resistance mechanisms lost when the selective pressure is removed, so that a patient can respond again to a drug they had already failed.
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 first regimen to beat osimertinib as first-line treatment for EGFR-mutant lung cancer. It sets up the choice that now faces every newly diagnosed patient: a more effective but harder combination now, or a simpler tablet with something held back for later.
Why targeting a clonal driver works and targeting a subclonal one usually does not, and why a single-site biopsy can mislead. Chromosomal instability is now a candidate prognostic marker in its own right.
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.
Shares Lecia V. Sequist, EGFR mutation and resistance of non-small-cell lung cancer to gefitinib, Gefitinib, Erlotinib and the tag lung-evidence.
Shares Tracking the evolution of non-small-cell lung cancer, Clonal evolution & minimal residual disease, Next-generation sequencing (NGS), Tumour heterogeneity and clonal evolution and the tag lung-evidence.
Shares Tracking the evolution of non-small-cell lung cancer, Clonal evolution & minimal residual disease, Tumour heterogeneity and clonal evolution, 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 Histology, Gefitinib, 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 and the tag lung-evidence.
Shares Amivantamab plus lazertinib in previously untreated EGFR-mutated advanced NSCLC, 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 Gefitinib, 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, EGFR-mutated non-small-cell lung cancer and the tag lung-evidence.
Shares Amivantamab plus lazertinib in previously untreated EGFR-mutated advanced NSCLC, Next-generation sequencing (NGS), MET, 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 Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data, Next-generation sequencing (NGS), Lab models that fail to predict what happens in patients, 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.