RET mutations occur in 70% of medullary thyroid cancers and RET fusions occur rarely in other thyroid cancers. The LIBRETTO-001 study investigators reported on 27 August 2020 in The New England Journal of Medicine that a response to selpercatinib, a novel selective RET inhibitor, occurred in 69% of previously treated patients with vandetanib, cabozantinib, or both and in 73% of previously untreated patients with medullary thyroid cancer and RET mutations. Activity was also seen in a small series of patients with RET fusion–positive previously treated thyroid cancer from whom 79% achieved response. The responses were durable with mainly low-grade side effects.
Germline RET mutations result in hereditary multiple endocrine neoplasia. These hereditary syndromes account for 25% of all diagnosed cases of medullary thyroid cancer. Of the remaining 75% of cases with sporadic medullary thyroid cancer, approximately 60% harbour somatic RET mutations. RET mutations are associated with more aggressive disease in medullary thyroid cancer. Majority of patients with metastatic medullary thyroid cancer harbour RET mutations.
In non-medullary thyroid cancers that arise from follicular cells of the gland, including papillary, poorly differentiated, anaplastic, and Hürthle-cell thyroid cancer, RET fusions are found in less than 10% of differentiated thyroid cancers and are even more uncommon in anaplastic carcinomas. The incidence of RET fusions is higher in thyroid cancers diagnosed in children and young adults than in those diagnosed in older persons. The incidence of RET fusions is also increased in patients with cases related to environmental radiation exposure.
The authors wrote in the study background that safety and durability of responses to multitargeted kinase inhibitors in thyroid cancer are at least partially limited by side effects. Selpercatinib is a novel, ATP-competitive, highly selective, small-molecule RET kinase inhibitor. Its safety and efficacy were evaluated in LIBRETTO-001, a phase I/II clinical trial involving adolescent and adult patients with any solid tumour type harbouring an activating RET alteration.
The cohort of patients with thyroid cancer consisted of patients with RET-mutated medullary thyroid cancer who were or not previously treated with vandetanib or cabozantinib, as well as those with previously treated RET fusion–positive thyroid cancer. The study primary endpoint was an objective response (a complete or partial response), as determined by an independent review committee. Secondary endpoints included the duration of response, progression-free survival (PFS) and safety.
Among first 55 consecutively enrolled patients with RET-mutated medullary thyroid cancer who were previously treated with vandetanib, cabozantinib, or both, the response was 69% (95% confidence interval [CI], 55 to 81). One-year PFS was 82% (95% CI, 69 to 90).
In 88 patients with RET-mutated medullary thyroid cancer who had not previously received vandetanib or cabozantinib, the response was 73% (95% CI, 62 to 82). One-year PFS was 92% (95% CI, 82 to 97).
In 19 patients with previously treated RET fusion–positive thyroid cancer, the response was 79% (95% CI, 54 to 94). One-year PFS was 64% (95% CI, 37 to 82).
Most related side effects were of grade 1 or 2, dose reductions were relatively uncommon, and treatment discontinuation due to treatment-related side effects occurred in only 2% of the patients. The most common side effects of grade 3 or higher were hypertension in 21% of the patients, increased alanine aminotransferase in 11%, increased aspartate aminotransferase in 9%, hyponatremia in 8% and diarrhoea in 6%.
The authors concluded that activity of selpercatinib in the LIBRETTO-001 was seen across all RET alterations and histologic types of thyroid cancer. They underlined that implementation of effective molecular screening strategies for patients with either germline or somatic RET mutation in non-familial medullary thyroid cancer will be essential in identifying patients who may benefit from RET inhibition.
Razelle Kurzrock of the Moores Cancer Center, University of California in San Diego, CA, US, who commented the study findings, wrote in an accompanied editorial that selpercatinib showed in the LIBRETTO-001 study marked and durable antitumour activity in most patients with RET-altered thyroid cancer and non-small cell lung cancer (NSCLC). RET abnormalities now join the genomic alterations such as NTRK fusions, tumour mutation burden, and deficient mismatch-repair genes across cancers and ALK, BRAF, EGFR, MET, and ROS1 alterations in NSCLC that warrant molecular screening strategies.
The LIBRETTO-001 study was supported by Loxo Oncology, a wholly owned subsidiary of Eli Lilly, and by grants from the National Institutes of Health and the University of Texas M.D. Anderson Cancer Center.
References
- Wirth LJ, Sherman E, Robinson B, et al. Efficacy of Selpercatinib in RET-Altered Thyroid Cancers. N Engl J Med 2020; 383:825-835. DOI: 10.1056/NEJMoa2005651.
- Kurzrock R. Selpercatinib Aimed at RET-Altered Cancers. N Engl J Med 2020; 383:868-869. DOI: 10.1056/NEJMe2024831.