Antitumor Activity Seen with Selpercatinib in RET-Mutant MTC in Chinese Patients


Selpercatinib is a promising treatment option for Chinese patients with RET-altered thyroid cancer, according to LIBRETTO-321 results.

Selpercatinib (Retevmo) showed durable antitumor activity in Chinese patients with advanced rearranged during transfection (RET)-mutant medullary thyroid cancer (MTC). These findings were presented in a poster at the European Society for Medical Oncology Targeted Anticancer Therapies Congress 2022.1 Selpercatinib is a first-in-class, potent inhibitor of the RET kinase with central nervous system (CNS) activity.

Patients in the primary analysis set (PAS) with RET-mutant MTC (n=26) had an objective response rate (ORR) of 57.7% (95% CI, 36.9%-76.6%) measured by an independent review committee (IRC). The 9-month duration of response (DOR) rate was 90.9 % (95% CI, 50.8%-98.7%).

All patients with RET-mutant MTC (n=29) had an IRC-assessed ORR of 58.6% (95% CI, 38.9%-76.5%), and the 9-month DOR rate was 92.3% (95% CI, 56.6%-98.9%).

The LIBRETTO-321 (NCT04280081) trial evaluated the efficacy and safety of selpercatinib in 77 patients with solid tumors harboring an activating RET alteration. This ongoing, open-label, multicenter, phase 2 study, enrolling patients 18 years or older with treatment-naïve or pretreated, locally advanced, or metastatic tumors, had 3 cohorts. Cohort 1 (n=30) consisted of patients with advanced RET-fusion solid tumors who progressed on or were intolerant to at least 1 prior standard first-line therapy, or of patients who declined or were unsuitable for standard first-line therapy in the investigator’s opinion. In cohort 1, only 1 patient had RET-fusion TC, which was confirmed by a central laboratory. This patient displayed an ICR-assessed partial response (PR), and a rapid response by week 8. This patient’s treatment and response were ongoing at 23.4 weeks.

Cohort 2 (n=26) included patients with advanced RET-mutant MTC with or without prior systemic therapy. These 26 patients made up the PAS MTC group. Cohort 3 (n=21) consisted of patients with advanced RET-altered solid tumors without measurable disease and no known presence of cell-free DNA in the tumor. Within cohort 3, there were 3 patients who had RET-mutant MTC. These 3 patients were added to the PAS MTC group to create the All MTC group.

Patients received oral selpercatinib at 160 mg twice a day in 28-day cycles until progressive disease, unacceptable toxicity, withdrawal of consent, or death. Treatment beyond progression was permitted with continued benefit. The primary end point of the study was ORR per RECIST v1.1 by IRC. The secondary end points were ORR per RECIST v1.1 by investigator assessment, DOR, CNS ORR,CNS DOR, clinical benefit rate, time to response (TTR), time to best response (TTBR), progression-free survival, overall survival, pharmacokinetics, and safety. The exploratory end point was biochemical response, defined as normalization or 50% or greater decrease in calcitonin or carcinoembryonic antigen (CEA) levels from baseline sustained for 4 or more weeks.

In thePAS MTC group, 2 patients had a complete response (CR), 13 patients had PR, and 10 patients had stable disease (SD), with 1 patient having SD for at least 16 weeks. In the All MTC group, 3 patients had CR, 14 had PR, and 11 had SD.

In the 15 patients who experienced a CR or PR in the PAS MTC group, the median DOR was not reached (NR). After a median follow-up of 8.7 months, 93.3% of responses are ongoing. Investigators found the median TTR to be 1.87 months (range, 0.89-5.52) and the median TTBR to be 1.94 months (range, 0.89-5.52) in these patients. Among the 17 patients who experienced a confirmed response in the All MTC group, the median DOR was NR. At a median follow-up of 9.0 months, 94.1% of the responses were ongoing. The TTR and the TTBR for patients in the All MTC group were 1.84 months and 1.87 months, respectively.

Patients in the PAS MTC group experienced a biochemical ORR of 92% (95% CI, 74.0%-99.0%) for the 25 patients who had a decrease in calcitonin levels. The biochemical ORR for patients who had decreased CEA levels (n=23) was 87% (95% CI, 66.4%-97.2%).

Of the 29 patients in the All MTC group, 20.7% were female. The median age was 46 years (range, 23-70). More patients had an ECOG performance score of 0 (58.6%) than 1 (41.4%). Seven patients (24.1%) had a multikinase inhibitor, 17 patients (58.6%) were treatment naïve, and 27 patients (93.1%) had measurable disease by investigator assessment.

Among all 77 patients who received selpercatinib, the most common any grade treatment emergent adverse events (TEAEs) included increased alanine aminotransferase (64.9%), increased aspartate aminotransferase (61.0%), increased blood bilirubin (39.0%), and thrombocytopenia (39.0%). TEAEs led to treatment discontinuation in 5.2% of patients and dose reduction in 32.5% of patients. However, 3.9% of patients discontinued treatment because of treatment-related AEs. One patient died because of a TEAE, but investigators deemed it unrelated to selpercatinib treatment.

The durable antitumor activity and the manageable safety profile results remained consistent with previous data with selpercatinib and suggest selpercatinib is a promising treatment option for Chinese patients with RET-altered TC. LIBRETTO-531 (NCT04211337), a phase 3 trial of selpercatinib vs physician’s choice of cabozantinib (Cabometyx) or vandetanib (Caprelsa) in patients with kinase inhibitor-naïve, progressive advanced, or metastatic RET-mutant MTC, is under way.


Zheng X, Ji Q, Sun Y, et al. LIBRETTO 321, a phase 2 study of the efficacy and safety of selpercatinib in Chinese patients with advanced RET-altered thyroid cancer. Poster presented at: ESMO Targeted Anticancer Therapies Congress (Virtual) 2022; March 7-9, 2022; Lugano, Switzerland. Accessed March 29, 2022.

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