On May 8, 2020, the FDA accelerated the approval of a new kinase inhibitor, selpercatinib (Retevmo; Loxo Oncology) capsules, for the treatment of 3 types of cancer—metastatic non–small-cell lung cancer (NSCLC), metastatic medullary thyroid cancer, and other types of thyroid cancer—that are associated with RET gene mutations or fusions, as determined by an FDA-approved test. Selpercatinib is the first therapy approved specifically for the treatment of patients with cancer that is linked to RET mutations or fusions. The FDA granted selpercatinib breakthrough therapy and orphan drug designations.
“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,” said Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence. “The FDA is committed to reviewing treatments like Retevmo that are targeted to specific subsets of patients with cancer.”
Specifically, selpercatinib is indicated for the treatment of (1) metastatic NSCLC with RET fusions in adults, (2) advanced or metastatic medullary thyroid cancer with RET mutations in patients aged ≥12 years who require systemic therapy, and (3) advanced thyroid cancer with RET gene fusion in patients aged ≥12 years who require systemic therapy and cannot use, or their cancer has stopped responding to, radioactive iodine therapy.
The FDA approved selpercatinib based on a clinical trial of patients who had 1 of the 3 types of tumors associated with RET mutations or fusions. All patients received 160 mg of selpercatinib twice daily until disease progression or unacceptable toxicity. The major efficacy outcome measures were overall response rate (ORR) and duration of response.
The efficacy of selpercatinib for NSCLC was evaluated in 105 adults with NSCLC and RET fusion who had previously received platinum chemotherapy. The ORR was 64% in these patients, and the response lasted ≥6 months in 81% of the patients whose tumor responded to treatment. The efficacy in NSCLC and RET fusion was also evaluated in 39 treatment-naïve patients, resulting in an ORR of 84%; and in 58% of the patients whose cancer responded to treatment, the response lasted ≥6 months.
In addition, the study included 143 patients aged ≥12 years with advanced or metastatic medullary thyroid cancer and RET mutations, including 55 patients who had received previous chemotherapy with cabozantinib, vandetanib, or both, as well as 88 treatment-naïve patients. The ORR for the patients who had received previous therapy was 69%, and the response lasted ≥6 months in 76% of the patients who had a response to treatment. Among the 88 treatment-naïve patients, the ORR was 73%, and the response lasted ≥6 months in 61% of the patients whose cancer responded to treatment.
The study also evaluated the efficacy of selpercatinib in 19 patients aged ≥12 years with thyroid cancer and RET fusion whose disease was refractory to radioactive iodine and who had previously received another systemic treatment, as well as 8 treatment-naïve patients with this cancer. The ORR was 79% among the 19 patients who had received previous therapy, with 87% of responses lasting ≥6 months. Of the 8 treatment-naïve patients, the ORR was 100%, with 75% of responses lasting ≥6 months.
The most common side effects with selpercatinib were increased AST, ALT, and blood glucose levels; decreased white blood cell count, albumin, and calcium levels; dry mouth; diarrhea; increased creatinine, alkaline phosphatase, and hypertension; fatigue; swelling in the body or limbs; low platelet count; increased cholesterol; rash; constipation; and decreased sodium levels.
The serious side effects with selpercatinib include hepatotoxicity, elevated blood pressure, QT prolongation, bleeding, and allergic reactions. Selpercatinib should be withheld, dose reduced, or discontinued permanently in patients with hepatotoxicity.