Background
Phase I/II single-arm trial (LIBRETTO-001). N=531 patients with RET fusion-positive NSCLC across all lines of therapy. Key cohorts: previously treated (platinum-based chemo ± prior anti-PD-(L)1) and treatment-naive. Patients with CNS metastases were eligible.
Interventions and follow up
Treatment: Selpercatinib 160 mg PO twice daily continuously until progression or unacceptable toxicity (single-arm, no comparator).
Primary endpoint: ORR (per IRC) in previously treated patients
mFollow up: 12.1mo (median, previously treated cohort)
Primary endpoint: ORR (per IRC) in previously treated patients
mFollow up: 12.1mo (median, previously treated cohort)
Results
ORR (previously treated): 64%, 95% CI 54–73
DOR (previously treated): 17.5mo
ORR (treatment-naive): 85%, 95% CI 69–95
CNS ORR (with CNS metastases): 91%
mPFS (previously treated): 16.5mo
DOR (previously treated): 17.5mo
ORR (treatment-naive): 85%, 95% CI 69–95
CNS ORR (with CNS metastases): 91%
mPFS (previously treated): 16.5mo
Adverse events
Overall: grade ≥3 events in 30%; dose reduction 30%; discontinuation due to AEs 2%.
Cardiovascular: hypertension 14%, QT prolongation 6%.
Hepatic: elevated ALT 13%, elevated AST 10%.
Cardiovascular: hypertension 14%, QT prolongation 6%.
Hepatic: elevated ALT 13%, elevated AST 10%.
Conclusions
Selpercatinib demonstrated highly durable responses in RET fusion-positive NSCLC across all prior treatment settings, including robust CNS activity, establishing it as the standard of care for this biomarker-defined population.
Key Limitations
Single-arm design without randomized comparator limits causal inference; ORR as surrogate endpoint requires OS confirmation. Patients were enrolled across multiple lines of therapy with heterogeneous prior treatments. Long-term outcomes from the first-line cohort remain immature. The trial included multiple tumor types; NSCLC-specific survival data were not always separately reported.
Clinical Context
FDA approved selpercatinib for RET fusion-positive NSCLC in May 2020, the first RET-specific inhibitor for this indication. The randomized LIBRETTO-431 trial subsequently confirmed superiority over platinum chemotherapy in the first-line setting. Selpercatinib is the preferred first-line agent per ESMO guidelines for RET fusion+ NSCLC.