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A drug that worked spectacularly in about one patient in ten and did nothing in the rest. Sequencing the tumours of nine responders found the answer: eight of them had a mutation in the gene the drug targets.
Lynch, Bell, Sordella and colleagues at Massachusetts General Hospital, with Haber as senior author, searched for mutations in EGFR in primary tumours from patients who had responded to gefitinib, patients who had not, and patients never exposed to it, then expressed the mutant proteins in cultured cells to test their function.
It appeared on the same day as Paez and colleagues' independent report in Science (paper-paez-egfr-mutations-gefitinib-science-2004). Together they are the founding papers of precision oncology in solid tumours: not a new drug, but an explanation of why an existing drug worked in a minority, which converted a failure into a triumph by changing who received it.
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.
The trial that turned EGFR testing into a standard of care rather than a research assay, and the clearest demonstration in oncology that a clinically selected population can hide two opposite treatment effects inside one positive result.
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.
Why a drug can look useless in one trial and transformative in another: the trials had different proportions of the patients the drug was for. It is the argument for genotyping before drawing conclusions from a response rate.
Shares Lecia V. Sequist, EGFR mutation and resistance of non-small-cell lung cancer to gefitinib, Gefitinib, Erlotinib and the tag lung-evidence.
Shares Oncogene addiction, Adenocarcinoma of the lung, Driver mutation, Next-generation sequencing (NGS) and the tag lung-evidence.
Shares Oncogene addiction, Massachusetts General Hospital Cancer Center, Driver mutation, Next-generation sequencing (NGS) and the tag lung-evidence.
Shares Oncogene addiction, 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, EGFR-mutated non-small-cell lung cancer 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, Biomarkers are not validated or standardised 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, Biomarkers are not validated or standardised, EGFR-mutated non-small-cell lung cancer 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, Biomarkers are not validated or standardised and the tag lung-evidence.
Shares Adenocarcinoma of the lung, 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, Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall, Biomarkers are not validated or standardised and the tag lung-evidence.