LIBRETTO-431

Background

Phase III, open-label RCT (LIBRETTO-431). 212 patients with previously untreated RET fusion-positive advanced/metastatic NSCLC. Asymptomatic/treated CNS metastases eligible; prior systemic therapy for metastatic disease excluded.

Interventions and follow up

Arm A: Selpercatinib 160 mg PO BID continuously.
Arm B: Investigator's choice platinum chemotherapy (carboplatin or cisplatin + pemetrexed) ± pembrolizumab; crossover to selpercatinib permitted at progression.
Primary endpoint: PFS (IRC, RECIST 1.1)
mFollow up: 15.0mo

Results

mPFS: NR vs 11.2mo, HR 0.46, 95% CI 0.31–0.70, P<.001
ORR: 84% vs 65%, P<.001
CNS PFS (CNS mets subgroup): HR 0.36
OS: Immature, HR 0.96 (NS; confounded by ~75% crossover)

Adverse events

Overall: Grade ≥3 events 58% vs 65%. Discontinuation 8% vs 9%.
Cardiovascular: Hypertension grade ≥3 19%; QT prolongation 3%.
Hepatic: Elevated ALT grade ≥3 10%; elevated AST 7%.

Conclusions

Selpercatinib significantly prolonged PFS and improved ORR vs platinum chemotherapy ± pembrolizumab in first-line RET fusion-positive NSCLC, confirming it as preferred frontline therapy for this biomarker-defined population.

Key Limitations

OS uninterpretable due to ~75% crossover. PFS is a surrogate; mPFS not reached in selpercatinib arm limits HR precision. Open-label design risks performance bias. Heterogeneous comparator (chemo ± pembrolizumab).

Clinical Context

FDA approved selpercatinib first-line for RET fusion+ NSCLC (2024) based on LIBRETTO-431. Confirms RET-directed therapy superior to chemo ± IO, analogous to EGFR/ALK paradigms. Selpercatinib is the preferred first-line option; testing for RET fusion required before therapy selection.

References