Selpercatinib benefit for advanced, kinase inhibitor-naïve, RET-mutant medullary thyroid cancer
Dr Julien Hadoux - Institut Gustave Roussy, Villejuif, France
At ESMO 2023 I had the great honour to present the data of the LIBRETTO-531 study which is a randomised phase III study of selpercatinib versus cabozantinib and vandetanib for the treatment of patients with advanced kinase inhibitor naïve RET-mutated medullary thyroid cancer. Medullary thyroid cancer is a rare subtype of thyroid cancer, it accounts for about 5% of the cases. It’s a neo-endocrine tumour on the thyroid gland and it’s driven by a point mutation in the RET oncogene which is found in nearly all hereditary cases and in up to 90% of sporadic cases, especially at the metastatic stage. Up to now, two phase III randomised studies versus placebo have established multi-kinase inhibitors cabozantinib and vandetanib as the standard of care. However, this treatment has a suboptimal RET inhibition activity and a safety profile that leads to frequent treatment discontinuation and dose reduction.
Selpercatinib is a highly selective RET inhibitor with a ten times higher inhibitory activity on RET as compared to the standard of care, cabozantinib and vandetanib. It has demonstrated high clinical efficacy in the phase I/II study. So the LIBRETTO-531 is a randomised study to compare selpercatinib to the standards of care, cabozantinib and vandetanib. So it’s an open label, randomised phase III study with a 2:1 randomisation ratio. The primary endpoint was progression free survival per RECIST 1.1 by blinded independent central review and the secondary endpoints were treatment failure free survival, overall response rate, overall survival and safety.
This international study has enrolled 291 patients from 176 centres in 19 countries. Here at ESMO we presented the interim analysis after 59 PFS events. At the median follow-up of 12 months the median PFS is not reached under selpercatinib while it is 16.8 months in the control arm under cabozantinib or vandetanib. So this corresponds to a 72% reduction of the risk of progression, so a hazard ratio of 0.28, with a two-sided p-value below the positive threshold for this interim analysis. Therefore, this is a positive trial and selpercatinib has demonstrated a PFS advantage over cabozantinib or vandetanib.
The overall response rate under selpercatinib was 69% while it was 38.8% under cabozantinib or vandetanib. There was also a treatment failure free survival which is an endpoint that is defined by the time from randomisation to either progressive disease, treatment discontinuation because of side effects, or death, whichever happens first. The TFFS was not reached in the selpercatinib arm while it was 13.9 months in the control arms. So it’s a hazard ratio of 0.254, so again it is positive on this secondary endpoint.
Finally, if we take about safety, the safety profile of selpercatinib was better than that of these multi-kinase inhibitors. The grade 3 toxicity was lower and this led to fewer drug discontinuations – only 4.7% of the patients discontinued selpercatinib during the trial while it was 28.8% of the patients in the control arm. Almost all the adverse events were more frequent with cabozantinib or vandetanib as compared to selpercatinib except for hypertension and dry mouth. The specific side effects of selpercatinib observed were bilirubin increased, pyrexia, constipation, peripheral oedema and erectile dysfunction.
So, to conclude, this study has demonstrated that selpercatinib prolonged the median progression free survival, provided a higher response rate and a better safety profile as compared to the standard of care, cabozantinib or vandetanib for patients with RET mutant metastatic medullary thyroid cancer. So probably it will become the new standard of care for the first-line treatment of these patients.
