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Sequence: targeted therapy before immunotherapy in driver-positive NSCLC

If a lung cancer has a targetable mutation, give the pill first; immunotherapy works poorly in these tumours and raises the risk of severe side effects when a pill follows.

EGFR-, ALK-, ROS1-, and RET-driven NSCLC respond poorly to PD-1 blockade (IMMUNOTARGET) and osimertinib after PD-1 causes pneumonitis in up to 15%. LIBRETTO-431 and FLAURA/CROWN-type data make first-line targeted therapy standard; chemotherapy ± ADC or IO comes later.

Rationale
Oncogene-addicted tumours have low TMB and immunosuppressive microenvironments; immune priming persists and interacts with subsequent TKIs.
Evidence
Randomised first-line TKI trials plus retrospective toxicity data.

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