Background
LIBRETTO-001 thyroid cancer cohorts — Phase I/II open-label basket trial. Multiple cohorts; thyroid cancer data reported by Wirth LJ et al, JCO 2024. Selpercatinib (LOXO-292) is a highly selective, potent oral RET kinase inhibitor with CNS penetration. RET alterations drive oncogenesis in RET-mutant MTC (hereditary and ~50% sporadic) and RET fusion-positive DTC/ATC. Phase II primary cohorts in thyroid cancer: (1) RET-mutant MTC previously treated with cabozantinib and/or vandetanib; (2) treatment-naive RET-mutant MTC; (3) RET fusion-positive thyroid cancer (DTC or ATC). Trial registered NCT03157128.
Interventions and follow up
Regimen: Selpercatinib 160 mg PO BID until progression; thyroid cohorts: RET-mutant MTC previously treated (n=143); cabozantinib/vandetanib-naive RET-mutant MTC (n=152); RET fusion-positive DTC ± prior therapy (n=41)
Primary endpoint: ORR (masked independent central review)
mFollow up: Cohort-dependent; 12.1–33.1 month
Primary endpoint: ORR (masked independent central review)
mFollow up: Cohort-dependent; 12.1–33.1 month
Results
RET-mutant MTC (prior cab/van): ORR 69% (95% CI 55–81%), DoR ≥6 months 76%
RET-mutant MTC (treatment-naive): ORR 73% (95% CI 55–87%)
RET fusion-positive DTC: ORR 79% (95% CI 62–91%)
mDuration of response: Not reached across cohorts
CNS responses: Observed in patients with brain metastases
RET-mutant MTC (treatment-naive): ORR 73% (95% CI 55–87%)
RET fusion-positive DTC: ORR 79% (95% CI 62–91%)
mDuration of response: Not reached across cohorts
CNS responses: Observed in patients with brain metastases
Adverse events
Main adverse events: Grade ≥3 treatment-related AEs: 30.2%. Most common: hypertension (13%), increased ALT (12%), increased AST (9%), QT prolongation (5%). AE-related dose reductions: 32%; discontinuations: 2.3%. Well tolerated relative to cabozantinib/vandetanib.
Conclusions
Selpercatinib achieved ORRs of 69–79% across RET-mutant MTC and RET fusion-positive thyroid cancer — substantially higher than vandetanib (45%) or cabozantinib (28%) — with durable responses and manageable toxicity. These data established selpercatinib as the preferred treatment for RET-altered thyroid cancers.
Key Limitations
Single-arm basket trial; no randomized comparator. Response rates are based on radiologic assessment without OS data mature. Long-term durability and resistance mechanisms are being defined. RET testing required — only ~1–2% of DTC harbors RET fusions; RET mutations occur in ~25% hereditary MTC (RET M918T = highest risk) and ~50% sporadic MTC. The distinct LIBRETTO-001 lung cohort (PMID 39094065 is thyroid — confirmed distinct) provides data on RET fusion NSCLC separately.
Clinical Context
FDA approved selpercatinib for RET-mutant MTC (any line) and RET fusion-positive thyroid cancer in May 2020 — the first approval based on a tumor-agnostic RET biomarker selection. NCCN lists selpercatinib (and pralsetinib/ARROW) as preferred first-line treatment for RET-mutant MTC and RET fusion-positive thyroid cancer. RET testing (FISH, NGS, or RT-PCR) is now recommended in all MTC and DTC/ATC at diagnosis. Selpercatinib has replaced vandetanib and cabozantinib as the preferred agent in RET-mutant MTC due to superior ORR and tolerability.