Drug resistance (primary and acquired)

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 barely works in bowel cancer. Responses are still modest and short-lived compared with EGFR or ALK inhibitors in lung cancer.

For ALK-positive advanced lung cancer, lorlatinib as the first drug offers the possibility of many years without progression and strong protection against brain metastases. Alectinib and brigatinib remain alternatives with a gentler side-effect profile; the choice weighs lorlatinib's cognitive, metabolic and weight effects against its unmatched duration of control.

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.

A single biopsy is an incomplete picture of a patient's cancer. Truncal mutations shared by all cells (in kidney cancer, VHL) are the most reliable drug targets, whereas mutations in only some branches predict resistance. This is why liquid biopsy and multi-region sampling matter.