{"entity":{"id":"libretto-431","kind":"trial","name":"LIBRETTO-431","aka":[],"tldr":"Proved that a RET pill is better than chemotherapy with or without immunotherapy as first treatment for RET-fusion lung cancer.","summary":"LIBRETTO-431, trial NCT04194944 sponsored by Eli Lilly and reported in 2023, proved that the RET inhibitor selpercatinib is better than platinum-pemetrexed chemotherapy, with or without pembrolizumab, as first treatment for RET-fusion advanced non-small-cell lung cancer. It randomised 261 patients, met its primary progression-free survival endpoint by blinded review with a large effect, and produced more intracranial responses than the chemotherapy-based arm. OnCo links it to RET as a target, to LIBRETTO-531 in thyroid cancer, and to the pairing that places targeted therapy before immunotherapy in driver-positive lung cancer, a rule this trial reinforced; the result is consistent with LIBRETTO-001 and with pralsetinib in ARROW. Whether resistance after selpercatinib can be met by next-generation RET inhibitors is the open question. Selpercatinib has its own page.","status":"positive","asOf":"2026-09-06","links":[{"label":"ClinicalTrials.gov NCT04194944","url":"https://clinicaltrials.gov/study/NCT04194944"}],"tags":[],"related":[],"cancers":["nsclc","ret-fusion-nsclc"],"sections":[],"technologies":["kinase-inhibitors"],"targets":["ret"],"drugs":["selpercatinib"],"companies":["eli-lilly"],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-libretto-431-nejm-2023"],"journals":[],"dependsOn":[],"notes":[],"nct":"NCT04194944","phase":"3","setting":"First-line RET-fusion advanced NSCLC: selpercatinib vs platinum-pemetrexed ± pembrolizumab","sponsor":"Eli Lilly","result":"PFS HR 0.46.","started":"2020-02-17","startedType":"actual","yearReported":2023,"enrolled":261,"enrolledBasis":"registry","outcomes":[{"endpoint":"Progression-free survival (BICR), ITT-pembrolizumab population","primary":true,"unit":"months","arms":[{"name":"Selpercatinib","n":129,"value":24.8},{"name":"Platinum-pemetrexed ± pembrolizumab","n":83,"value":11.2}],"hr":0.46,"ci":[0.31,0.7],"p":"<0.001","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2309457"}],"replication":"Consistent with the single-arm LIBRETTO-001 (ORR 84% treatment-naive); pralsetinib (ARROW) supports the RET class."},"route":"/trials/libretto-431/","neighbours":{"cancer":[{"id":"lung-cancer","kind":"cancer","name":"Lung cancer (all types)","route":"/cancers/lung-cancer/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"},{"id":"ret-fusion-nsclc","kind":"cancer","name":"RET fusion-positive non-small-cell lung cancer","route":"/cancers/ret-fusion-nsclc/"}],"technology":[{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}],"target":[{"id":"ret","kind":"target","name":"RET","route":"/targets/ret/"}],"drug":[{"id":"selpercatinib","kind":"drug","name":"Selpercatinib","route":"/drugs/selpercatinib/"}],"company":[{"id":"eli-lilly","kind":"company","name":"Eli Lilly (incl. Loxo)","route":"/companies/eli-lilly/"}],"paper":[{"id":"paper-libretto-431-nejm-2023","kind":"paper","name":"LIBRETTO-431: first-line selpercatinib versus chemotherapy with or without pembrolizumab in RET fusion-positive lung cancer","route":"/key-papers/paper-libretto-431-nejm-2023/"}],"pairing":[{"id":"targeted-before-io-nsclc","kind":"pairing","name":"Sequence: targeted therapy before immunotherapy in driver-positive NSCLC","route":"/pairings/targeted-before-io-nsclc/"}],"trial":[{"id":"nct03157128","kind":"trial","name":"A Study of Selpercatinib (LOXO-292) in Participants With Advanced Solid Tumors, RET Fusion-Positive Solid Tumors, and Medullary Thyroid Cancer (LIBRET","route":"/trials/nct03157128/"},{"id":"arrow-thyroid","kind":"trial","name":"ARROW (thyroid cohorts)","route":"/trials/arrow-thyroid/"},{"id":"libretto-531","kind":"trial","name":"LIBRETTO-531","route":"/trials/libretto-531/"}],"roadmap":[{"id":"targeted-therapy-roadmap","kind":"roadmap","name":"Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall","route":"/roadmaps/targeted-therapy-roadmap/"}]}}