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Starting with the third-generation EGFR drug osimertinib, rather than saving it for later, kept EGFR-mutated lung cancer under control for almost twice as long and later helped patients live longer.
Double-blind phase 3 trial of 556 patients with untreated advanced non-small-cell lung cancer carrying an EGFR exon 19 deletion or L858R mutation, randomised to osimertinib or a first-generation EGFR inhibitor (gefitinib or erlotinib). Primary endpoint was investigator-assessed PFS.
Median PFS was 18.9 vs 10.2 months (HR 0.46), with fewer central nervous system progressions and less grade 3 toxicity. The 2020 overall survival report showed 38.6 vs 31.8 months (HR 0.80) despite crossover. It made osimertinib the global first-line standard and the backbone on which FLAURA2 and MARIPOSA later built.
Anyone diagnosed with advanced lung cancer should have EGFR testing before treatment, because osimertinib as the first drug gives the longest disease control, protects the brain, and is well tolerated. Chemotherapy is not the first step for these patients. The remaining questions are whether to intensify upfront (adding chemotherapy or amivantamab) and how to treat resistance when it develops.
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.
Stage III lung cancer is now treated by genotype as well as by stage: an EGFR mutation moves a patient from durvalumab consolidation to osimertinib consolidation. It is also the strongest hazard ratio in the lung cancer literature, which is a reason to read the overall survival data carefully when they arrive.
Adding chemotherapy to osimertinib delays progression. Whether it extends life, and whether the same benefit could be had by giving the chemotherapy later to the patients who need it, is what the overall survival analysis and the registry watch on this roadmap are for.
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.
Shares Slow the tumour's mutation engine with APOBEC inhibitors during targeted therapy, Add a drug when the blood test turns, without stopping the one that works, Treat brain metastases as a disease with its own trials programme, Autonomous closed-loop adaptive therapy driven by blood tests and evolutionary models.
Shares Look for the resistant sub-population before the first dose, ctDNA-guided dose holidays for lung cancer targeted therapy, Kill drug-tolerant persisters through ferroptosis, Add the second drug on day one when the escape route is predictable.
Shares Look for the resistant sub-population before the first dose, ctDNA-guided dose holidays for lung cancer targeted therapy, Kill drug-tolerant persisters through ferroptosis, Add the second drug on day one when the escape route is predictable.
Shares Slow the tumour's mutation engine with APOBEC inhibitors during targeted therapy, Add a drug when the blood test turns, without stopping the one that works, Treat brain metastases as a disease with its own trials programme, Autonomous closed-loop adaptive therapy driven by blood tests and evolutionary models.
Shares Osimertinib after chemoradiotherapy in stage III EGFR-mutated NSCLC, ADAURA, Oncogene addiction, 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.
Shares Test alternating drug schedules against giving both drugs at once, FLAURA2, Lines of therapy, Osimertinib.
Shares Autonomous closed-loop adaptive therapy driven by blood tests and evolutionary models, Osimertinib after chemoradiotherapy in stage III EGFR-mutated NSCLC, Osimertinib, EGFR-mutated non-small-cell lung cancer.
Shares Byoung Chul Cho, Osimertinib after chemoradiotherapy in stage III EGFR-mutated 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, Progression-free survival (PFS).