Real-world external control arm for the single-arm LIBRETTO-001 trial of selpercatinib in RET-mutation-positive...

The single-arm phase I/II LIBRETTO-001 trial demonstrated durable efficacy with selpercatinib in patients with rearranged during transfection (RET)-mutation-positive medullary thyroid cancer (MTC). RECALIB-RET compared effectiveness outcomes using a real-world external control (EC) arm of patients with RET-mutation-positive MTC treated with standard of care (SoC) versus selpercatinib (LIBRETTO-001).

In this retrospective study, the selpercatinib arm comprised first-line (1L) or second-and-later-line (≥2L) patients from LIBRETTO-001. The EC arm comprised SoC-treated patients, pooled across (i) the French ENDOCAN-TUTHYREF (Refractory Thyroid Tumours) database (1L and ≥2L); (ii) a chart review of European patient medical records (1L and ≥2L) and (iii) a published United States chart review (≥2L). Index treatment was cabozantinib or vandetanib (1L) and any SoC (≥2L; including multikinase inhibitor, chemotherapy or immunotherapy). The primary endpoint was progression-free survival (PFS). The safety profile of SoC in the EC arm was a secondary endpoint. Propensity score matching (PSM) balanced baseline characteristics between treatment arms.

Baseline characteristics of the 1L selpercatinib (n = 116) and EC (n = 107) arms were balanced; PSM reduced the sample size by <30% across arms (n = 84 per arm after PSM). 1L selpercatinib conferred statistically significant PFS benefit over SoC both pre-PSM [median: not reached (NR) versus 24.0 months; P < 0.001] and post-PSM (median: NR versus 26.1 months; P < 0.001). In ≥2L (selpercatinib, n = 179; EC, n = 51), PSM increased attrition, reducing sample sizes by 78.8% (selpercatinib) and 25.5% (EC), to n = 38 per arm. The unadjusted median PFS was significantly longer with ≥2L selpercatinib versus SoC (35.6 months versus 11.6 months; P = 0.005); the difference did not reach significance after PSM. Safety findings were consistent with previously reported findings for SoC.

Selpercatinib conferred significant PFS benefit over SoC in treatment-naïve (1L) patients with RET-mutation-positive MTC, with inconclusive results in the ≥2L setting. Matching retrospective real-world data to prospective trial data is feasible. EC arms to single-arm trials may provide evidence supporting the evaluation of comparative effectiveness.