{"entity":{"id":"targeted-before-io-nsclc","kind":"pairing","name":"Sequence: targeted therapy before immunotherapy in driver-positive NSCLC","aka":[],"tldr":"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.","asOf":"2026-09-06","links":[{"label":"ClinicalTrials.gov NCT04194944: LIBRETTO-431","url":"https://clinicaltrials.gov/study/NCT04194944"},{"label":"ClinicalTrials.gov NCT03052608: CROWN","url":"https://clinicaltrials.gov/study/NCT03052608"}],"tags":[],"related":[],"cancers":["nsclc"],"sections":[],"technologies":[],"targets":["egfr","alk","ret","ros1"],"drugs":["osimertinib","lorlatinib","selpercatinib","pembrolizumab"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["libretto-431","crown","mariposa"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"a":"kinase-inhibitors","b":"checkpoint-inhibitor","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.","pairingType":"sequence"},"route":"/pairings/targeted-before-io-nsclc/","neighbours":{"cancer":[{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"}],"target":[{"id":"alk","kind":"target","name":"ALK","route":"/targets/alk/"},{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"},{"id":"ret","kind":"target","name":"RET","route":"/targets/ret/"},{"id":"ros1","kind":"target","name":"ROS1","route":"/targets/ros1/"}],"drug":[{"id":"lorlatinib","kind":"drug","name":"Lorlatinib","route":"/drugs/lorlatinib/"},{"id":"osimertinib","kind":"drug","name":"Osimertinib","route":"/drugs/osimertinib/"},{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"},{"id":"selpercatinib","kind":"drug","name":"Selpercatinib","route":"/drugs/selpercatinib/"}],"trial":[{"id":"crown","kind":"trial","name":"CROWN","route":"/trials/crown/"},{"id":"libretto-431","kind":"trial","name":"LIBRETTO-431","route":"/trials/libretto-431/"},{"id":"mariposa","kind":"trial","name":"MARIPOSA","route":"/trials/mariposa/"}],"technology":[{"id":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}]}}