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When a targeted drug stops working, the tumour has usually changed in a way you can read. Most patients still move to the next treatment on a protocol rather than on a test of what actually happened.
Sequist's 37 re-biopsied patients showed that acquired resistance to EGFR inhibitors is a heterogeneous set of diagnoses: T790M, MET amplification, PIK3CA mutation, a change of cell state, and in 14 percent an outright transformation into small-cell lung cancer, which is sensitive to entirely different drugs. Three patients lost their resistance mechanism when the drug was withdrawn and responded again. Kobayashi's single patient in 2005 produced osimertinib.
Despite this, sequencing at progression is inconsistent: tissue re-biopsy is invasive and often declined, plasma testing is not reimbursed everywhere, and the result frequently arrives after the next line has started. The idea is to make a resistance profile, tissue where safe and plasma always, a required step before the next line, and to fund the pathway that makes it fast enough to act on.
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.
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.
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 TRACERx first 100: tracking how lung cancers evolve, and how chromosomal chaos predicts relapse, 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, ctDNA tests roadmap: from a curiosity in plasma to blood tests that decide treatment, Tumour heterogeneity and clonal evolution and the tag lung-evidence.
Shares Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors, Diagnostics roadmap: stains → gene panels → blood tests that decide treatment, 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 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, Acquired resistance to every therapy, EGFR-mutated non-small-cell lung cancer and the tag lung-evidence.
Shares EGFR mutation and resistance of non-small-cell lung cancer to 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, 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), Lung cancer (all types) and the tag lung-evidence.
Shares 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, Liquid biopsy (ctDNA), Lung cancer (all types) and the tag lung-evidence.
Shares 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, Lung cancer (all types) and the tag lung-evidence.
Shares ALK-positive non-small-cell 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, EGFR-mutated non-small-cell lung cancer, Lung cancer (all types) and the tag lung-evidence.