- This analysis of LIBRETTO-001, a multicenter, open-label, phase 1/2 trial of selpercatinib, concerns the 162 participants who had RET-altered thyroid cancer
- Approximately 70% of patients with medullary thyroid cancer had deep responses to selpercatinib, regardless of previous treatment with vandetanib, cabozantinib, both or neither
- Activity was also durable, with 86% of those previously treated with vandetanib, cabozantinib or both remaining in response at one year, while 91% of those not previously treated remained in response at one year
- In 19 patients with various subtypes of RET fusion–positive thyroid cancer who were previously treated, the objective response rate was 79%
- Grade 3/4 treatment-related adverse events were infrequent, the most common of which were hypertension (21% of patients), increased alanine aminotransferase level (11%), increased aspartate aminotransferase level (9%), hyponatremia (8%) and diarrhea (6%)
RET mutations, which are associated with aggressive disease, occur in 70% of patients with medullary thyroid cancer. Vandetanib and cabozantinib are approved for this indication, but their safety profile impacts patients' quality of life, and duration of therapy is often short-lived. One main limitation of multikinase inhibitors in treating RET-driven cancers is that these agents inhibit many non-RET kinases that contribute to their toxicity.
Selpercatinib, a highly potent and specific RET kinase inhibitor, was studied in LIBRETTO-001, an open-label phase 1/2 trial involving adolescents and adults with any solid tumor harboring an activating RET alteration. In The New England Journal of Medicine, Lori J. Wirth, MD, medical director of the Center for Head and Neck Cancers at Massachusetts General Hospital, and colleagues report safety and efficacy data that led to FDA approval for selpercatinib for treatment of RET-altered thyroid cancers.
LIBRETTO-001 was conducted at 65 centers in 12 countries. Between May 2017 and June 2019, three cohorts of patients with thyroid cancer were treated:
- 55 patients with RET-mutant medullary thyroid cancer previously treated with vandetanib, cabozantinib or both (cohort 1)
- 88 patients with RET-mutant medullary thyroid cancer not previously treated with vandetanib or cabozantinib (cohort 2)
- 19 patients with RET fusion–positive, previously treated, nonmedullary thyroid cancers (cohort 3)
- Objective response rate—69% (9% complete response; 60% partial response)
- ORR by previous treatment—vandetanib only, 67%; cabozantinib only, 69%; both, 71%
- Ongoing response at 1 year: 86%
- ORR—73% (11% CR; 61% PR)
- Ongoing response at 1 year: 91%
- ORR—79% (11% CR; 61% PR)
- Ongoing response at 1 year: 71%
Treatment-related Adverse Events
Across the cohorts, most TRAEs were grade 1/2. The most common grade 3/4 TRAEs were hypertension (21% of patients), increased alanine aminotransferase level (11%), increased aspartate aminotransferase level (9%), hyponatremia (8%) and diarrhea (6%).
Of all 531 patients treated in LIBRETTO-001, 30% needed dose reduction because of TRAEs and only 2% discontinued therapy because of TRAEs.
The proportion of patients with previously treated RET-mutant medullary thyroid cancer who responded to selpercatinib appears to exceed the percentage who responded to previously approved first-line agents, and selpercatinib potentially offers a better safety profile and therefore improved quality of life.
Screening for RET in all patients with medullary thyroid cancer in need of systemic therapy is essential to identify those who can benefit from selpercatinib.
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