LIBRETTO-531
A Multicenter, Randomized, Open-label, Phase 3 Trial Comparing Selpercatinib to Physicians Choice of Cabozantinib or Vandetanib in Patients With Progressive, Advanced, Kinase Inhibitor Naive, RET-Mutant Medullary Thyroid Cancer (LIBRETTO-531)
Phase 3N = 291NCT04211337
- Population
- Advanced, progressive, kinase inhibitor-naive RET-mutant medullary thyroid cancer
- Design
- Randomised, open-label (per the registry title) phase 3 trial comparing selpercatinib first line with the physician's choice of cabozantinib or vandetanib. Eligible patients had progressive disease documented within 14 months before enrolment. Primary endpoint in the protocol-specified interim efficacy analysis: progression-free survival by blinded independent central review. Crossover to selpercatinib was permitted in the control group after progression. Treatment failure-free survival (blinded independent central review) was a secondary, alpha-controlled endpoint tested only if PFS was significant.
- Primary endpoint
- PFS
- Arms
- Physician's choice: cabozantinib or vandetanib (control): Cabozantinib or vandetanib at the physician's choice
- Selpercatinib (experimental): Selpercatinib
- People
- Hadoux J, senior author Wirth LJ
PFSHR 0.28 (95% CI 0.16–0.48)Δ 12-month PFS+21.1 pointsTFFSHR 0.25 (95% CI 0.15–0.42)Δ 12-month TFFS+24.1 pointsΔ ORR+30.6 points
Show the numbers
| Endpoint | Analysis | Selpercatinib | Physician's choice: cabozantinib or vandetanib | Effect |
|---|---|---|---|---|
| PFSRandomised patients (291), protocol-specified interim efficacy analysis; the abstract does not name the analysis population | interimmedian follow-up 12 monthsHadoux 2023 | 86.8% at 12 mo (79.8–91.6%) | median 16.8 months (12.2–25.1); 65.7% at 12 mo (51.9–76.4%) | HR 0.28 (95% CI 0.16–0.48)P<0.001Median PFS by blinded independent central review was not reached in the selpercatinib group. Hazard ratio for disease progression or death. Arm sizes are not stated in the abstract. |
| TFFSRandomised patients (291), protocol-specified interim efficacy analysis | interimmedian follow-up 12 monthsHadoux 2023 | 86.2% at 12 mo (79.1–91.0%) | median 13.9 months; 62.1% at 12 mo (48.9–72.8%) | HR 0.25 (95% CI 0.15–0.42)P<0.001Hazard ratio for disease progression, discontinuation due to treatment-related adverse events, or death. Median treatment failure-free survival was not reached in the selpercatinib group. |
| ORRRandomised patients (291), protocol-specified interim efficacy analysis | interimmedian follow-up 12 monthsHadoux 2023 | 69.4% (62.4–75.8%) | 38.8% (29.1–49.2%) | Overall response. Adverse events led to dose reduction in 38.9% of the selpercatinib group and 77.3% of the control group, and to treatment discontinuation in 4.7% and 26.8% respectively. |
| Endpoint | Analysis | Selpercatinib | Physician's choice: cabozantinib or vandetanib | Effect |
|---|---|---|---|---|
| PFSRandomised patients (291), protocol-specified interim efficacy analysis; the abstract does not name the analysis population | interimmedian follow-up 12 monthsHadoux 2023 | 86.8% at 12 mo (79.8–91.6%) | median 16.8 months (12.2–25.1); 65.7% at 12 mo (51.9–76.4%) | HR 0.28 (95% CI 0.16–0.48)P<0.001Median PFS by blinded independent central review was not reached in the selpercatinib group. Hazard ratio for disease progression or death. Arm sizes are not stated in the abstract. |
| TFFSRandomised patients (291), protocol-specified interim efficacy analysis | interimmedian follow-up 12 monthsHadoux 2023 | 86.2% at 12 mo (79.1–91.0%) | median 13.9 months; 62.1% at 12 mo (48.9–72.8%) | HR 0.25 (95% CI 0.15–0.42)P<0.001Hazard ratio for disease progression, discontinuation due to treatment-related adverse events, or death. Median treatment failure-free survival was not reached in the selpercatinib group. |
| ORRRandomised patients (291), protocol-specified interim efficacy analysis | interimmedian follow-up 12 monthsHadoux 2023 | 69.4% (62.4–75.8%) | 38.8% (29.1–49.2%) | Overall response. Adverse events led to dose reduction in 38.9% of the selpercatinib group and 77.3% of the control group, and to treatment discontinuation in 4.7% and 26.8% respectively. |
Data table
| Endpoint | HR | 95% CI |
|---|---|---|
| PFS | 0.28 | 0.16–0.48 |
| TFFS | 0.25 | 0.15–0.42 |
- Physician's choice: cabozantinib or vandetanib (control)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | Physician's choice: cabozantinib or vandetanib |
|---|---|
| 0 | 100.0% |
| 11 | 63.5% |
| 21 | 42.0% |
| 32 | 26.7% |
| 42 | 17.7% |
- Physician's choice: cabozantinib or vandetanib (control)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | Physician's choice: cabozantinib or vandetanib |
|---|---|
| 0 | 100.0% |
| 9 | 63.8% |
| 17 | 42.8% |
| 26 | 27.3% |
| 35 | 17.5% |