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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.
Patients newly diagnosed with EGFR-mutated advanced lung cancer now have a first-line option that improves survival over osimertinib, particularly if they have high-risk features. The trade-off is intravenous (now subcutaneous) infusions and considerably more skin, nail and clotting toxicity, so osimertinib alone remains reasonable for those who prioritise convenience and tolerability. Both this regimen and osimertinib plus chemotherapy (FLAURA2) are approved; there is no direct comparison.
Lung cancers keep evolving after they form, and it is ongoing chromosomal instability rather than the number of mutations that best predicts who will relapse. This gives a rationale for targeting the earliest (clonal) drivers and neoantigens and for tracking evolution in blood after surgery.
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 Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data, RB1, Lineage plasticity & neuroendocrine transformation, Lab models that fail to predict what happens in patients and the tag lung-evidence.
Shares Histology, Gefitinib, 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, Next-generation sequencing (NGS) and the tag lung-evidence.
Shares TRACERx first 100: tracking how lung cancers evolve, and how chromosomal chaos predicts relapse, Clonal evolution & minimal residual disease, 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, Tumour heterogeneity and clonal evolution and the tag lung-evidence.
Shares TRACERx first 100: tracking how lung cancers evolve, and how chromosomal chaos predicts relapse, Clonal evolution & minimal residual disease, 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 MARIPOSA: amivantamab plus lazertinib versus osimertinib as first treatment for EGFR-mutated lung cancer, 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, Osimertinib, Acquired resistance to every therapy and the tag lung-evidence.
Shares Gefitinib, 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, Next-generation sequencing (NGS), EGFR-mutated non-small-cell lung cancer and the tag lung-evidence.
Shares MARIPOSA: amivantamab plus lazertinib versus osimertinib as first treatment for EGFR-mutated lung cancer, 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, Next-generation sequencing (NGS) and the tag lung-evidence.