The FDA has approved selpercatinib (LOXO-292) for the treatment of patients with advanced RET fusion–positive non–small cell lung cancer, RET-mutant medullary thyroid cancer, and RET fusion–positive thyroid cancer.
The FDA has granted an accelerated approval to selpercatinib (LOXO-292; Retevmo) for the treatment of patients with RET alteration—positive non–small cell lung cancer (NSCLC), medullary thyroid cancer (MTC), and other thyroid cancers.1
Specifically, the approval is for the treatment of adult patients with metastatic RET fusion—positive NSCLC; adult and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy; and adult and pediatric patients 12 years of age and older with advanced or metastatic RET fusion—positive thyroid cancer who require systemic therapy and who are radioactive iodine (RAI)-refractory (if RAI is appropriate).
The NSCLC cohort included 105 adult patients with RET fusion—positive NSCLC who had received prior platinum-based chemotherapy. In these patients, the ORR was 64%, including a response lasting ≥6 months among 81% of the responders. Among 39 treatment-naïve patients, the ORR was 84% and 58% of the responders had a response ≥6 months.
"In the clinical trial, we observed that the majority of metastatic lung cancer patients experienced clinically meaningful responses when treated with selpercatinib, including responses in difficult-to-treat brain metastases," Alexander Drilon, MD, lead investigator for LIBRETTO-001 and acting chief of early drug development at Memorial Sloan Kettering Cancer Center, stated in a press release.2 "The approval of selpercatinib marks an important milestone in the treatment of NSCLC, making RET-driven cancers now specifically targetable in the same manner as cancers with activating EGFR and ALK alterations, across all lines of therapy. I am pleased that patients with these RET-driven cancers have this newly approved option."
The MTC population included adult and pediatric patients aged ≥12 years with advanced or metastatic RET­ mutation—positive disease. The MTC population comprised 143 patients who had either received prior cabozantinib (Cometriq), vandetanib (Caprelsa), or both, or who had not received prior treatment with either of these agents. Among the 55 patients treated with cabozantinib and/or vandetanib, the ORR was 69%, and 76% of responders had a response ≥6 months. In the 88 patients who had not received cabozantinib or vandetanib, the ORR was 73%, and 61% of responders had a response ≥6 months.
The efficacy cohort for RET fusion—positive thyroid cancer comprised adult and pediatric patients aged ≥12 years. The cohort included 19 patients with RET fusion—positive thyroid cancer who were RAI-refractory and had received another prior systemic treatment, and 8 patients with RET fusion—positive thyroid cancer who were RAI-refractory and had not received any additional therapy. Among the 19 patients with prior systemic therapy, the ORR was 79% and 87% of responders had a response ≥6 months. In the 8 patients who only received prior RAI, the ORR was 100% and 75% of responders had a response ≥6 months.
"RET alterations account for the majority of medullary thyroid cancers and a meaningful percentage of other thyroid cancers. For patients living with these cancers, the approval of selpercatinib means they now have a treatment option that selectively and potently inhibits RET," Lori J. Wirth, MD, medical director of head and neck cancers, Massachusetts General Hospital Cancer Center, stated in a press release. "Based on the published data for this new medicine, as well as my personal experience treating patients, this may be a good treatment option."
According to the FDA, the most common side effects with selpercatinib were “increased AST and ALT, increased blood sugar, decreased white blood cell count, decreased albumin in the blood, decreased calcium in the blood, dry mouth, diarrhea, increased creatinine, increased alkaline phosphatase, hypertension, fatigue, swelling in the body or limbs, low blood platelet count, increased cholesterol, rash, constipation, and decreased sodium in the blood.”
The agency also noted that selpercatinib “can cause serious side effects including hepatotoxicity, elevated blood pressure, QT prolongation, bleeding, and allergic reactions."
Selpercatinib is a highly selective and potent, oral investigational agent for the treatment of patients with cancers that harbor abnormalities in the RET kinase; RET fusions and mutations occur across multiple malignancies with varying frequency. Additionally, selpercatinib is designed to inhibit native RET signaling and anticipated acquired resistance mechanisms.
“Innovations in gene-specific therapies continue to advance the practice of medicine at a rapid pace and offer options to patients who previously had few,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, said in a press release. “The FDA is committed to reviewing treatments like Retevmo that are targeted to specific subsets of patients with cancer.”
The accelerated approval of selpercatinib is contingent on the results of a confirmatory trial. The confirmatory phase 3 LIBRETTO-431 trial (NCT04194944) is evaluating selpercatinib in patients with advanced or metastatic RET fusion—positive NSCLC, while the confirmatory LIBRETTO-531 study (NCT04211337) is exploring the agent in patients with RET-mutant MTC. Both studies will enroll 400 patients.
Selpercatinib is the first therapy that the FDA approved specifically for patients with cancer whose tumors harbor RET gene alterations. The approval is based on findings from the phase 1/2 LIBRETTO-001 trial, which evaluated selpercatinib in RET-altered NSCLC and thyroid cancers. Overall response rate (ORR) and duration of response were the primary outcome measures.