The safety and durability of responses to multitargeted inhibitors in thyroid cancer are at least partially limited by side effects. In all, 70% of patients with medullary thyroid cancer carry the RET mutation; RET fusions are rare in other types of thyroid cancer. The efficacy and safety of selective RET inhibition in patients with RET-altered thyroid cancer is unknown.
In a new phase 1-2 clinical trial, LIBRETTO-001, researchers evaluated the safety and efficacy of selpercatinib (Retevmo) in patients with medullary thyroid cancer and RET mutation or thyroid cancer and RET fusions (Wirth LJ, et al. N Engl J Med. 2020;383:825-835).
Selpercatinib is an ATP-competitive, highly selective, small-molecule RET-related kinase inhibitor, and is the first therapy that was recently approved by the FDA for the treatment of 3 types of cancer associated with RET alterations, including advanced or metastatic medullary thyroid cancer and advanced thyroid cancer with RET fusion (in addition to lung cancer with RET mutation).
LIBRETTO-001 was an open-label study with a total of 162 adolescent and adult patients with any solid tumor type harboring an activating RET alteration. The cohort of patients with thyroid cancer included patients with medullary thyroid cancer and RET mutation who had previously received vandetanib (Caprelsa), cabozantinib (Cabometyx), or both; those who did not receive either of these therapies, and patients with thyroid cancer and RET fusion who had previously received treatment.
Selpercatinib was administered orally in 28-day cycles until disease progression, death, unacceptable adverse effects, or patient withdrawal from the study. Patients who were enrolled in the phase 1 dose-escalation portion of the study received selpercatinib ranging from 20 mg once daily to 240 mg twice daily. All patients enrolled in the phase 2 portion of the study received the recommended dose of 160 mg twice daily.
The primary end point was the objective response rate (ORR), including complete or partial response. Secondary end points included the duration of response, progression-free survival (PFS), and safety.
The ORR was 69% among the 55 patients with medullary thyroid cancer and RET mutation who had previously received vandetanib, cabozantinib, or both. Overall, 9% of patients had a complete response and 60% of patients had a partial response. The 1-year PFS was 82% in that subset of patients.
In the 88 patients with medullary thyroid cancer and RET mutation who had not received previous therapy with vandetanib or cabozantinib, the ORR was 73%, including 11% complete responses and 61% partial responses. In this subset, the 1-year PFS was 92%.
Finally, among the smaller cohort of 19 patients with RET fusion–positive thyroid cancer who had previously received treatment, the ORR was 79%, including 5% complete responses and 14% partial responses. The 1-year PFS was 64% in this group.
Selpercatinib was generally well-tolerated, and the majority of the adverse events were low-grade. The most common grade ≥3 adverse events were hypertension (21%), increased alanine aminotransferase (11%), increased aspartate aminotransferase (9%), hyponatremia (8%), and diarrhea (6%).
The researchers concluded that the activity of selpercatinib was observed across all RET alterations and histologic types of thyroid cancer. They underscored that “the implementation of effective molecular screening strategies for patients with either germline or somatic RET mutation in nonfamilial medullary thyroid cancer will be essential in identifying patients who may benefit from RET inhibition.”
