Selpercatinib superior to standard MKIs for rare thyroid cancer

Selpercatinib, a highly selective and potent RET inhibitor, trumped two multikinase inhibitors (MKIs) – cabozantinib and vandetanib – for the treatment of advanced, kinase inhibitor-naïve, RET-mutant medullary thyroid cancer (MTC) in the first-line (1L) setting, according to the interim analysis results of the phase III LIBRETTO-531 trial.

After a median follow-up of 12 months, selpercatinib conferred a better progression-free survival (PFS) benefit over cabozantinib or vandetanib (median not estimable [NE] vs 16.8 months; hazard ratio [HR], 0.280; p<0.0001). [ESMO 2023, abstract LBA3]

“The two-sided p-value was below the positivity threshold for this analysis. Therefore, the trial met its primary efficacy endpoint. Selpercatinib demonstrated a statistically and clinically significant PFS improvement vs cabozantinib or vandetanib,” said Dr Julien Hadoux from the Service d’Oncologie Endocrinienne, Gustave Roussy, Villejuif, France, at ESMO 2023.

The benefit was consistent throughout all preplanned subgroups, more so among those with other RET mutations (HR, 0.177). For the other subgroups, HRs ranged between 0.215 and 0.479.

Selpercatinib also trumped cabozantinib or vandetanib in terms of median treatment failure-free survival (NE vs 13.9 months; HR, 0.254; p<0.0001).

The efficacy of selpercatinib was supported by a remarkable clinical activity, with almost 70 percent overall response rate (vs 39 percent with MKIs), including 12 percent complete response (vs 4 percent). “This is exceptional for MTC,” commented discussant Dr Laura Locati from the University of Pavia, Italy.

“Tumour responses were more frequent, profound, and durable with selpercatinib,” said Hadoux.

Overall survival, safety

Positive overall survival (OS) signals were noted with selpercatinib at the time of analysis. About 95 percent of selpercatinib recipients were alive (vs 86 percent in the MKI arm). HR was 0.374 (p=0.0312). However, data were immature due to a censoring rate of 90 percent, noted Hadoux.

Further follow-up will thus be needed to confirm this observation. It was too early to discern any significant difference between arms given the few OS events (n=8 and 10 in the respective selpercatinib and MKI arms), noted Locati.

Selpercatinib was tied to fewer grade 3 adverse events (AEs; 53 percent vs 76 percent), dose reductions due to AEs (39 percent vs 72 percent [vandetanib] and 79 percent [cabozantinib]), and permanent discontinuations (5 percent vs 27 percent).

Potential standard of care

Cabozantinib and vandetanib have been established standards of care for the 1L treatment of advanced MTC. [J Clin Oncol 2013;31:3639-3646; J Clin Oncol 2012;30:134-141] However, they are both limited by toxicities, suboptimal RET inhibition, and long pharmacologic half-lives that confound management. [Cancer Treat Rev 2018;66:64-73; Clin Pharmacokinet 2017;56:477-491; Clin Ther 2012;34:221-237]

Selpercatinib has shown compelling activity in the phase I/II LIBRETTO-001 trial. “We therefore designed LIBRETTO-531 to define the optimal 1L regimen for advanced RET-mutant MTC,” said Hadoux.

A total of 291 patients were randomized 2:1 to selpercatinib 160 mg BID or physician’s choice of cabozantinib 140 mg or vandetanib 300 mg QD. Median age was 56 years in the selpercatinib arm and 54 years in the MKI arm. There were more male patients (60 percent and 70 percent in the respective selpercatinib and MKI arms). Sixty-two percent of patients had the M918T mutation.

“Given the superior efficacy of selpercatinib over MKIs and better safety profile, the results support selpercatinib as 1L standard of care for patients with advanced RET-mutant MTC,” Hadoux said.

“The results provide definitive confirmation that selpercatinib is superior to MKIs from both statistical and clinically relevant perspectives. Tolerability is also better with selpercatinib as shown by the fewer dose reductions and treatment discontinuations,” commented Dr Rocío García-Carbonero from Hospital Universitario 12 de Octubre, Madrid, Spain, in a press release. [dailyreporter.esmo.org/esmo-congress-2023/top-news/first-line-selpercatinib-prolongs-pfs-in-ret-mutated-medullary-thyroid-carcinoma, accessed October 28, 2023]

“LIBRETTO-531 includes a large number of patients considering this is not a common disease. It is now unquestionable that selpercatinib should be the 1L choice for RET-mutated MTC, although I believe many centres are already using it 1L for patients known to be RET-positive,” she added.

“The problem is that RET testing is not routinely performed in all centres. This needs to be addressed … Upfront testing should be routine for all patients before starting therapy so that those with RET mutations can receive selpercatinib,” García-Carbonero added.