Alterations in the RET gene are involved in the pathogenesis of around 2% of cancers. The common alterations that lead to RET tyrosine kinase activation are mutations (around 37%) and gene fusions (around 31%). RET mutations have been found in most patients with sporadic medullary thyroid carcinoma (MTC) and are commonly associated with multiple endocrine neoplasia (MEN) and familial MTC. RET fusions are oncogenic drivers in a variety of cancers, including 10 – 20% of papillary thyroid cancers, 1 – 2% of non-small cell lung cancers (NSCLC), and in small subgroups of colorectal, breast and other cancers. Until recently, only multikinase inhibitors with non-selective RET inhibitory activity (vandetanib and cabozantinib) have been available for select patients with RET-altered cancers. However, the efficacy of these agents is modest, and their use is limited because of their off-target side effects. Conversely, next generation RET inhibitors such as selpercatinib and pralsetinib have been found to be highly potent and selective for RET with favorable toxicity profile.

The efficacy and safety of selpercatinib in patients with solid tumors harboring an activating RET alteration is evaluated in an international, open-label, phase I/II LIBRETTO-001 trial. Preliminary data from 162 patients with thyroid cancer, and 144 patients with NSCLC, were recently reported in the New England Journal of Medicine. The primary endpoint of the trial is objective response rate (ORR) per independent review committee; secondary endpoints include duration of response (DOR), progression-free survival (PFS), and safety. In patients with RET-mutant MTC, who had previously received vandetanib and/or cabozantinib, the ORR was 69% and 1-year PFS was 82%; among treatment-naive patients, the ORR was 73% and 1-year PFS was 92%. In patients who had previously treated RET fusion-positive thyroid cancer, the ORR was 79% and 1-year PFS was 64%. Patients with RET fusion-positive NSCLC who had previously received at least platinum-based chemotherapy had an ORR of 64% and DOR was 17.5 months; the 1-year PFS was 66% with a median PFS of 16.5 months. Furthermore, among previously treated patients who had measurable central nervous system (CNS) metastasis at enrolment, the objective intracranial response rate was 91%. In treatment-naive patients with RET fusion-positive NSCLC, the ORR was 85%, and 90% of the responses were ongoing at 6 months; neither median DOR nor median PFS had been reached at a median follow-up of 7.4 months and 9.2 months, respectively. The adverse events profile of selpercatinib was broadly similar across all patients, the most common grade 3/4 adverse events were hypertension, increased level of aminotransferases, hyponatremia and lymphopenia. Discontinuation of selpercatinib due to drug-related adverse events occurred in 12% of patients with thyroid cancer and 2% of patients with NSCLC.

Data from the LIBRETTO-001 trial demonstrate that selpercatinib has durable efficacy and mainly low-grade toxicity in patients with RET-mutant MTC, and RET fusion-positive thyroid cancer and NSCLC, including those with CNS metastasis. Detecting RET alterations is therefore vital for identifying patients who may benefit from selpercatinib treatment. Based on these impressive results, the US Food and Drug Administration (FDA) approved selpercatinib for the treatment of RET-altered thyroid cancer and NSCLC (see details in ACE OncoBlog 12 June 2020). In an editorial accompanying the LIBRETTO-001 trial results, Dr. Razelle Kurzrock (Moores Cancer Center, University of California, San Diego, USA) concluded that “RET abnormalities now join other genomic alterations such as NTRK fusions, tumor mutational burden, and deficient mismatch repair genes across cancers and ALK, BRAF, EGFR, MET, and ROS1 alterations in NSCLC that warrant molecular screening strategies”.

References

Wirth LJ, et al. N Engl J Med.2020;383:825-35.

Drilon A, et al. N Engl J Med. 2020;383:813-24.

Kurzrock R. N Engl J Med. 2020;383:868-869.