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Why cancer drugs stop working: the tumour either never depended on the target or evolves around the block.
Primary: no target dependence, poor drug penetration, pre-existing resistant clones. Acquired: on-target mutations (EGFR T790M/C797S, ESR1, BRCA reversion, ALK G1202R), bypass signalling (MET amplification), lineage change (SCLC transformation), antigen loss (CD19-negative relapse), efflux, epigenetic plasticity. Tumours are evolving populations; combination and sequential strategies are the response.
Showing the technology this term belongs to: Small-molecule kinase inhibitors.
The glossary entry explains the word; the readout page carries the scoring rule, the thresholds approvals use, the companion diagnostics and the tests.
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.
Patients with KRAS G12C lung cancer that has progressed after chemo-immunotherapy can take an oral KRAS inhibitor instead of docetaxel and gain a somewhat longer time to progression with fewer severe side effects, but should understand that most tumours become resistant within a year and that survival is not improved. KRAS G12C testing is worthwhile, but first-generation inhibitors are a step rather than a cure; combinations and next-generation inhibitors are the active research fronts.
Patients with metastatic colorectal cancer carrying a KRAS G12C mutation (about 3-4% of cases) who have exhausted standard chemotherapy now have a targeted option that works far better than trifluridine-tipiracil or regorafenib. The higher sotorasib dose is clearly superior, and the EGFR antibody is essential because KRAS inhibition alone has little effect in bowel cancer. Responses are still modest and short-lived compared with EGFR or ALK inhibitors in lung cancer.
Patients with small-cell lung cancer that has relapsed after chemotherapy now have a drug that works far better than topotecan or lurbinectedin, and it is the first T-cell engager approved for a solid tumour. Treatment requires inpatient monitoring for the first doses because of cytokine release syndrome, which most centres now manage on a short-stay basis. It does not yet apply to first-line treatment, where trials are ongoing.
It offers the first credible explanation for why only a minority of small-cell patients get a durable benefit from checkpoint blockade, and it introduces subtype switching, which would mean retesting at relapse rather than typing once.
The current first choice for ALK-positive lung cancer in most guidelines, and the strongest evidence in solid tumour oncology that a drug can be designed to work inside the brain. Five-year follow-up has since shown the majority of patients still progression-free.
It turned the laboratory prediction into a clinical rule: after a second-generation ALK inhibitor, genotype the tumour, and treat the absence of an ALK mutation as evidence that the cancer has stopped depending on ALK.
It gives the sequencing report a prognostic reading that does not depend on a repeat biopsy: an EGFR-mutant cancer that also carries RB1 and TP53 alterations will stop responding sooner and should be watched for a change of histology.
Shares Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer, Nuclear-localised androgen receptor splice variant 7 in circulating tumour cells as a predictive biomarker in castration-resistant prostate cancer, PTEN protein loss and clinical outcome from castration-resistant prostate cancer treated with abiraterone acetate, Genomic correlates of clinical outcome in advanced prostate cancer.
Shares EGFRvIII, EGFR C797S, Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M, Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain.
Shares Genomic correlates of clinical outcome in advanced prostate cancer, Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancer, Androgen receptor pathway-independent prostate cancer is sustained through FGF signalling, Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas.
Shares Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer, Nuclear-localised androgen receptor splice variant 7 in circulating tumour cells as a predictive biomarker in castration-resistant prostate cancer, PTEN protein loss and clinical outcome from castration-resistant prostate cancer treated with abiraterone acetate, Genomic correlates of clinical outcome in advanced prostate cancer.
Shares EGFR C797S, Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M, Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain, EGFR C797S (and its phase with T790M).
Shares Genomic correlates of clinical outcome in advanced prostate cancer, Substantial interindividual and limited intraindividual genomic diversity among tumours from men with metastatic prostate cancer, Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas, Concurrent RB1 and TP53 alterations define a subset of EGFR-mutant lung cancers at risk for histologic transformation and inferior clinical outcomes.
Shares Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer, Nuclear-localised androgen receptor splice variant 7 in circulating tumour cells as a predictive biomarker in castration-resistant prostate cancer, Genomic correlates of clinical outcome in advanced prostate cancer, Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancer.
Shares Fund a biopsy at progression, every time, as standard care, SMART designs to test treatment strategies, not just single drugs, Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M, EGFR C797S (and its phase with T790M).