The FDA has approved selpercatinib (RetevmoTM, Eli Lilly), for adult patients with metastatic RET-fusion—positive NSCLC, adult and pediatric patients 12 years of age or older with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy, and adult and pediatric patients 12 years of age or older with advanced or metastatic RET-fusion—positive thyroid cancer who require systemic therapy and are refractory to radioactive iodine. Selpercatinib is the first treatment specifically approved for patients with RET gene alterations.
The approval was based on LIBRETTO-001, a multicohort phase 1/2 clinical trial which enrolled patients with the three tumor types. Identification of RET alterations was performed using next generation sequencing, polymerase chain reaction, or fluorescence in situ hybridization. The study's primary end points were overall response rate and duration of response.
In 105 adult patients with RET fusion-positive NSCLC previously treated with platinum chemotherapy, selpercatinib produced an overall response rate of 64%, with 81% of responses lasting at least six months. Among 39 patients with NSCLC who had not received prior treatment, selpercatinib produced an overall response rate of 85%, with 58% of responses lasting at least six months.
In 143 adult and pediatric patients with RET-mutant MTC, selpercatinib produced an overall response rate of 69% in 55 patients previously treated with cabozantinib, vandetanib, or both and an overall response rate of 73% in 88 patients who had not received previous treatment. Responses lasting at least six months were seen in 76% of previously treated patients and in 61% of patients with no prior treatment.
In 27 adult and pediatric patients with RET fusion-positive thyroid cancer, selpercatinib produced an overall response rate of 79% in 19 radioactive iodine-refractory patients who had received another prior systemic therapy and an overall response rate of 100% in 8 radioactive iodine-refractory patients who had not received another systemic therapy. Responses lasting at least six months were experienced by 87% and 75% of patients with and without prior systemic therapy, respectively.
Adverse events experienced by at least 25% of patients included increased aspartate aminotransferase/alanine aminotransferase (AST/ALT) enzymes, elevated blood sugar, decreased white blood cells, decreased albumin and calcium, dry mouth, diarrhea, increased creatinine and alkaline phosphatase, hypertension, fatigue, swelling in the body or limbs, decreased platelet counts, increased cholesterol, rash, constipation, and decreased sodium. Serious adverse events can include hepatotoxicity, elevated blood pressure, QT prolongation, bleeding, and allergic reactions.
"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," commented 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. "The FDA is committed to reviewing treatments like selpercatinib that are targeted to specific subsets of patients with cancer."
The recommended dose of selpercatinib is 120 mg for patients weighing less than 50 kg and 160 mg for patients weighing 50 kg or greater. Selpercatinib should be taken orally twice daily with or without food; it should be taken with food when co-administered with a proton pump inhibitor.
For More Information
Clinicaltrials.gov (2020). Phase 1/2 study of LOXO-292 in patients with advanced solid tumors, RET fusion-positive solid tumors, and medullary thyroid cancer (LIBRETTO-001). NLM identifier: NCT03157128.
Wirth LJ, Sherman E, Drilon A, et al (2019). Registrational results of LOXO-292 in patients with RET-altered thyroid cancers. Ann Oncol (ESMO Congress Abstracts), 30(suppl_5): v851-v934. Abstract LBA93. DOI:10.1093/annonc/mdz394
US Food and Drug Administration (2020). FDA approves selpercatinib for lung and thyroid cancers with RET gene mutations or fusions. Available at: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-selpercatinib-lung-and-thyroid-cancers-ret-gene-mutations-or-fusions
Image credit: Nephron. Licensed under CC BY-SA 3.0