Non-Small Cell Lung Cancer Targeted Therapy
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Direct answer
Non-small cell lung cancer targeted therapy uses drugs that act on a specific driver mutation or protein, so the tumour must be tested before treatment is chosen. EGFR mutations are treated with osimertinib, ALK rearrangements with crizotinib or a later-generation ALK inhibitor, and high PD-L1 expression guides pembrolizumab when no driver is present. Molecular testing for EGFR, ALK and ROS1 is therefore done at diagnosis, not after the disease progresses.
What you must remember
- Testing first: tissue or plasma next-generation sequencing covers EGFR, ALK, ROS1, BRAF V600E, MET exon 14 skipping, RET, NTRK and KRAS G12C.
- EGFR exon 19 deletion or L858R: osimertinib is the standard first-line drug and also acts against the T790M resistance mutation.
- Older EGFR inhibitors: erlotinib, gefitinib and afatinib are first and second generation options; rash and diarrhoea are the common adverse effects.
- ALK rearrangement: alectinib, brigatinib and lorlatinib are preferred over crizotinib because they penetrate the central nervous system better.
- ROS1 fusion: crizotinib, entrectinib and repotrectinib are active, and entrectinib also has central nervous system activity.
- PD-L1 tumour proportion score of 50 per cent or more: with no actionable driver, pembrolizumab monotherapy is the usual first-line choice.
- Immune adverse effects: pneumonitis, colitis, hepatitis, thyroiditis, hypophysitis and rash need recognition, and steroids treat significant cases.
A driver-based pathway from biopsy to first-line drug
Treatment in advanced disease starts with the molecular report, not the histology alone. The steps below follow a typical sequence for a newly diagnosed adenocarcinoma with a metastatic pattern.
- Confirm histology: adenocarcinoma, squamous or large cell type decides which biomarker panel is needed, and adenocarcinoma is the histology most often driver-positive.
- Send for molecular profiling: request NGS on tissue, and plasma testing if tissue is scant, covering all listed drivers before treatment starts.
- Test PD-L1: immunohistochemistry gives a tumour proportion score that guides immunotherapy when no driver is found.
- Match the driver: an EGFR exon 19 deletion or L858R points to osimertinib, while an ALK fusion points to an ALK inhibitor with proven central nervous system activity.
- Use immunotherapy when no driver exists: high PD-L1 favours pembrolizumab alone, while lower values favour pembrolizumab with platinum-based chemotherapy.
- Rebiopsy at progression: a repeat biopsy or plasma test looks for resistance mechanisms, such as EGFR T790M or ALK secondary mutations, before the next line is chosen.
Where the exam tries to catch you
The stem usually names a mutation or a PD-L1 value, and the trap is the drug that sounds plausible but does not match the marker.
- Trap: giving chemotherapy first to an EGFR-mutant tumour Correct: EGFR-mutant disease responds to tyrosine kinase inhibitors, and chemotherapy is kept for later or resistant disease.
- Trap: choosing crizotinib for an EGFR mutation Correct: crizotinib targets ALK, ROS1 and MET, so EGFR-mutant disease needs an EGFR inhibitor instead.
- Trap: using pembrolizumab in an EGFR-mutant or ALK-positive tumour with high PD-L1 Correct: immunotherapy is less effective in driver-positive disease, so targeted therapy comes first.
- Trap: ignoring PD-L1 when no driver is found Correct: a tumour proportion score of 50 per cent or more favours pembrolizumab monotherapy.
Frequently asked questions
Which EGFR mutations respond to osimertinib?
Osimertinib is used for common activating EGFR mutations, chiefly exon 19 deletions and the L858R point mutation in exon 21. It is also the standard drug for the T790M resistance mutation that appears after first or second generation EGFR inhibitors.
Which investigation identifies an ALK rearrangement?
Immunohistochemistry for ALK, usually the D5F3 clone, is used as a screen, and fluorescence in situ hybridisation or next-generation sequencing confirms the rearrangement. Plasma testing is an alternative when tissue is limited.
What PD-L1 cut-off favours pembrolizumab monotherapy?
A tumour proportion score of 50 per cent or more, in a tumour without an actionable EGFR or ALK alteration, favours pembrolizumab alone as first-line therapy. Lower scores are usually treated with pembrolizumab combined with platinum-based chemotherapy.
Why are CNS-penetrant ALK inhibitors preferred in some patients?
Brain metastases are common in ALK-positive disease, so drugs that cross the blood-brain barrier, such as alectinib and lorlatinib, are favoured. Crizotinib has limited central nervous system penetration and is generally replaced by these drugs.
What is the most common adverse effect of EGFR tyrosine kinase inhibitors?
Skin rash and diarrhoea are the commonest adverse effects of EGFR tyrosine kinase inhibitors. Both are usually manageable with dose adjustment, skin care and antidiarrhoeal measures, and rarely require stopping the drug.