The FDA has greenlighted selpercatinib, the first targeted therapy for RET-altered non–small cell lung cancer (NSCLC) and certain types of thyroid cancer. Another RET inhibitor, pralsetinib, has been submitted for approval to treat NSCLC. Both drugs have shown effectiveness in treating brain metastases.

The FDA has greenlighted the first targeted therapy for RET-driven non–small cell lung cancer (NSCLC) and certain types of thyroid cancer, selpercatinib (LOXO-292; Retevmo; Eli Lilly). The drug, along with another RET inhibitor, pralsetinib (BLU-667; Blueprint Medicines), also attacks brain metastases, according to data presented at the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting, May 29–31.

Selpercatinib's accelerated approval was based on results of the phase I/II LIBRETTO trial, which showed positive, durable responses and low toxicity in most patients. Specifically, selpercatinib can be used to treat metastatic RET fusion–positive NSCLC in adults and advanced or metastatic RET-mutant medullary thyroid cancer (MTC) and RET fusion–positive thyroid cancers in patients age 12 and older who require systemic therapy. In the trial, the drug produced overall response rates (ORR) in previously treated and treatment-naïve patients ranging from 64% to 84% for NSCLC; 69% to 73% for advanced or metastatic MTC; and 79% to 100% for RET fusion–positive thyroid cancer in patients whose tumors had stopped responding to or were not appropriate for radioactive iodine therapy.

“This approval is an important milestone in the treatment of RET-altered cancers,” said Yasir Elamin, MD, of The University of Texas MD Anderson Cancer Center in Houston, who was not involved in the research. “It clearly gives patients an important option that is effective with an acceptable toxicity profile when compared to the currently available standard-of-care options, such as platinum-based chemotherapy and multikinase inhibitors.”

RET alterations occur in approximately 2% of NSCLCs but are common in thyroid cancers—an estimated 90% of patients with advanced MTC carry them. Patients are typically treated with multikinase inhibitors, including cabozantinib (Cabometyx; Exelixis), vandetanib (Caprelsa; Sanofi), lenvatinib (Lenvima; Eisai), and sorafenib (Nexavar; Bayer).

However, “the side effects of multikinase inhibitors have been a huge problem, and few patients can tolerate the full dose,” said Jochen Lorch, MD, of Dana-Farber/Brigham and Women's Cancer Center in Boston, MA, who wasn't involved in the research. “RET inhibitors are changing that in a dramatic way, producing high response rates with fewer side effects.”

Early reports from LIBRETTO and ARROW, a phase I/II trial of pralsetinib, indicated that both drugs had promising central nervous system (CNS) activity. Researchers have further assessed the potency of both inhibitors in treating CNS metastases in patients with NSCLC, reporting their findings during the ASCO meeting. For selpercatinib, the ORR was 81.8% (18 of 22 patients with measurable CNS tumors), with a median duration of response of 9.4 months. The ORR for nine patients with CNS metastases who received pralsetinib was 56%; three patients had a complete response.

Given the small number of patients receiving the RET inhibitors and the caveats that come with cross-trial comparisons, researchers cannot say whether selpercatinib's ORR makes it the superior agent. No head-to-head comparisons have been done, said Vivek Subbiah, MD, also of MD Anderson, who has participated in both trials.

How treatment resistance should be handled is another open question. “These two drugs are chemically similar so likely will have similar resistance mechanisms,” said Lorch. “RET inhibitors are a huge step forward in treatment but they do not solve the problem of resistance, which will eventually emerge in most patients.”

Although the ARROW trial continues to enroll patients, Subbiah noted that pralsetinib has been submitted for FDA approval to treat advanced RET fusion–positive NSCLC, and that Blueprint plans to seek approval later this year for RET-mutant MTC. Additionally, the phase III AcceleRET trial, which is testing pralsetinib in patients with newly diagnosed RET-altered NSCLC, is under way. –Janet Colwell