# LIBRETTO-431

Source: https://onco.cc/trials/libretto-431/  
OnCo record `libretto-431` (Trial). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Trial
- Status: positive
- Last checked: 2026-09-06
- Registry id: NCT04194944
- Phase: 3
- Setting: First-line RET-fusion advanced NSCLC: selpercatinib vs platinum-pemetrexed ± pembrolizumab
- Sponsor: Eli Lilly
- Enrolled: 261
- Result: PFS HR 0.46.
- Outcomes: Progression-free survival (BICR), ITT-pembrolizumab population: Selpercatinib 24.8 months vs Platinum-pemetrexed ± pembrolizumab 11.2 months, HR 0.46
- Replication: Consistent with the single-arm LIBRETTO-001 (ORR 84% treatment-naive); pralsetinib (ARROW) supports the RET class.

## Sources

- ClinicalTrials.gov NCT04194944: https://clinicaltrials.gov/study/NCT04194944

## Connected records

- cancers: [Lung cancer (all types)](https://onco.cc/cancers/lung-cancer/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/), [RET fusion-positive non-small-cell lung cancer](https://onco.cc/cancers/ret-fusion-nsclc/)
- technologies: [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/)
- targets: [RET](https://onco.cc/targets/ret/)
- drugs: [Selpercatinib](https://onco.cc/drugs/selpercatinib/)
- companies: [Eli Lilly (incl. Loxo)](https://onco.cc/companies/eli-lilly/)
- key papers: [LIBRETTO-431: first-line selpercatinib versus chemotherapy with or without pembrolizumab in RET fusion-positive lung cancer](https://onco.cc/key-papers/paper-libretto-431-nejm-2023/)
- pairings: [Sequence: targeted therapy before immunotherapy in driver-positive NSCLC](https://onco.cc/pairings/targeted-before-io-nsclc/)
- trials: [A Study of Selpercatinib (LOXO-292) in Participants With Advanced Solid Tumors, RET Fusion-Positive Solid Tumors, and Medullary Thyroid Cancer (LIBRET](https://onco.cc/trials/nct03157128/), [ARROW (thyroid cohorts)](https://onco.cc/trials/arrow-thyroid/), [LIBRETTO-531](https://onco.cc/trials/libretto-531/)
- roadmaps: [Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall](https://onco.cc/roadmaps/targeted-therapy-roadmap/)

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