First-line Selpercatinib: a new standard of care for RET-positive medullary thyroid cancer?

Sepretinib/serpatinib compared with cabozantinib or vandetinib in patients with multikinase inhibitor-naïve, RET-mutated advanced or metastatic medullary thyroid carcinoma style="font-family:宋体;font-size:12pt;">(Selpercatinib)First-line treatment achieved statistically significant improvements in progression-free survival and overall response rate. At a median follow-up of 12 months, septinibThe median progression-free survival was not reached, compared with 16.8 months in the control group (cabozantinib or vandetanib), which reduced the risk of disease progression or death by 72% (P<0.0001).

Compared with multikinase inhibitors, Seputinib is an effective and selective RET inhibitor that can prolong progression-free survival, treatment failure-free survival, higher overall response rate and good safety. It is used for the first-line treatment of patients with RET-mutant medullary thyroid cancer. These results emphasize the importance of RET selectivity and timely implementation of biomarker testing in patients with metastatic medullary thyroid cancer and supportSeputinibas a new first-line standard of care for patients with advanced RET-mutated medullary thyroid cancer.

The phase III LIBRETTO-531 trial is designed to determine the optimal first-line treatment for patients with advanced RET-mutant medullary thyroid cancer. Eligible patients had unresectable locally advanced or metastatic RET-mutant medullary thyroid cancer within 14 months prior to enrollment. The patient received kinase inhibitor therapy for the first time. A total of 291 patients with advanced RET-mutated medullary thyroid cancer were randomly assigned in a 2:1 ratio to receive first-line treatment with 160 mg of seputinib twice daily (n = 193) or physician's choice of 140 mg of cabozantinib daily or 300 mg of vandetanib daily (n = 98). Patients were recruited between February 2020 and March 2023 at 176 centers in 19 countries.

The primary endpoint was progression-free survival based on Response Evaluation Criteria in Solid Tumors reviewed by a blinded independent committee. Secondary endpoints included treatment failure based on blinded independent committee review and investigator-progression-free survival, investigator-assessed progression-free survival, blinded independent committee review and investigator-assessed overall survival, and safety. A total of 18 patients discontinued seputinib, and 58 patients discontinued cabozantinib or vandetanib. Among 58 patients, 24 patients entered the seputinib group. Baseline characteristics were comparable between the two treatment groups. The median patient age is approximately 55 years old, and approximately 25% of patients are 65 years or older. About two-thirds were male and 68.7% were white. A total of 62.5% of patients had the RET M918T mutation. The median time from diagnosis to study enrollment was 42.7 months in the seprotinib group and 61.6 months in the control group.

According to the researchers' assessment, the progression-free survival benefit of seputinib was also seen, with progression-free survival improved by 72% (P<0.0001). Improved progression-free survival with seputinib was observed in all prespecified subgroups, particularly those with RET co-mutations in addition to M918T. At a median follow-up of 15 months, 8 deaths occurred in the seputinib group and 10 deaths occurred in the control group; at the time of the ESMO Congress, 94.8% and 85.7% of patients in each group were alive, respectively. Survival data are still immature. Of the 24 patients who received seputinib, 19 were still receiving treatment as of the data cutoff date.

Septinib treatment failure-significant improvement in free survival compared with control treatment (P<0.0001), based on blinded independent committee review and investigator assessment. The overall effective rate in the seplutenib group was 69.4%, compared with 38.8% in the control group. The complete response rate was 11.9% in the seputinib group compared with 4.1% in the control group. The median duration of response was not reached with seputinib and 16.6 months with cabozantinib or vandetanib.

Seputinib was associated with fewer treatment-related adverse events thancabozantinib or vandetinib. The incidence of grade 3 or higher treatment-related adverse events was 52.8% for seputinib and 76.3% for cabozantinib or vandetanib. Dose reductions due to adverse events were reported in 38.9%, 79.2%, and 71.0% of patients receiving seputinib, cabozantinib, and vandetanib, respectively. 4.7% and 26.8% of patients discontinued treatment due to adverse events, respectively. There were 4 deaths due to adverse events in the seputinib group and 2 deaths in the control group.