# Sequence: targeted therapy before immunotherapy in driver-positive NSCLC

Source: https://onco.cc/pairings/targeted-before-io-nsclc/  
OnCo record `targeted-before-io-nsclc` (Pairing). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Summary

This sequence rule says that in non-small-cell lung cancer with a targetable driver such as EGFR, ALK, ROS1 or RET, a small-molecule kinase inhibitor comes first and immune checkpoint inhibitors later. Oncogene-addicted tumours have a low mutational burden and an immunosuppressive microenvironment, so PD-1 blockade works poorly, as the IMMUNOTARGET series showed, and the immune priming it leaves behind raises the risk of pneumonitis when osimertinib follows. Randomised first-line trials such as LIBRETTO-431, CROWN and MARIPOSA make targeted therapy with drugs such as osimertinib, lorlatinib and selpercatinib the standard. Chemotherapy, with or without an antibody-drug conjugate or immunotherapy, is held for later lines.

## Fields

- Kind: Pairing
- Last checked: 2026-09-06
- Pairs: Small-molecule kinase inhibitors + Immune checkpoint inhibitors
- Type: sequence
- 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.

## Sources

- ClinicalTrials.gov NCT04194944: LIBRETTO-431: https://clinicaltrials.gov/study/NCT04194944
- ClinicalTrials.gov NCT03052608: CROWN: https://clinicaltrials.gov/study/NCT03052608

## Connected records

- cancers: [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)
- targets: [ALK](https://onco.cc/targets/alk/), [EGFR](https://onco.cc/targets/egfr/), [RET](https://onco.cc/targets/ret/), [ROS1](https://onco.cc/targets/ros1/)
- drugs: [Lorlatinib](https://onco.cc/drugs/lorlatinib/), [Osimertinib](https://onco.cc/drugs/osimertinib/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Selpercatinib](https://onco.cc/drugs/selpercatinib/)
- trials: [CROWN](https://onco.cc/trials/crown/), [LIBRETTO-431](https://onco.cc/trials/libretto-431/), [MARIPOSA](https://onco.cc/trials/mariposa/)
- technologies: [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/), [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/)

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