Selpercatinib (Retevmo) becomes the first targeted therapy to be approved by the US Food and Drug Administration (FDA) for use in patients with cancer who have certain tumors that have an alteration (mutation or fusion) in the RET gene.
The drug is indicated for use in RET-positive tumors found in the following:
- Non–small cell lung cancer (NSCLC) that has spread in adult patients
- Advanced medullary thyroid cancer (MTC) or MTC that has spread in adult and pediatric patients (older than 12 years) who require systemic therapy
- Thyroid cancer that requires systemic therapy and that has stopped responding to or is not appropriate for radioactive iodine therapy in adult and pediatric (older than 12 years) patients.
Before initiating treatment, a RET gene alteration must be determined via laboratory testing, the FDA emphasized. However, no FDA-approved test is currently available for detecting RET fusions/mutations.
Approval based on responses in open-label trial
This was an accelerated approval based on the overall response rate (ORR) and duration of response (DOR) seen in an open-label clinical trial (the phase 1/2 LIBRETTO-001 study), which involved patients with each of the three types of tumors.
All patients received selpercatinib 160 mg orally twice daily until disease progression or unacceptable toxicity occurred.
For this trial, identification of a RET gene alteration was prospectively determined in plasma or tumor tissue by local laboratories using next-generation sequencing, polymerase chain reaction testing, or fluorescence in situ hybridization, according to Eli Lilly, the company marketing selpercatinib. Immunohistochemistry was not used in the clinical trial.
Efficacy for NSCLC was evaluated in 105 adult patients with RET fusion-positive NSCLC who were previously treated with platinum chemotherapy. The ORR was 64%.
Efficacy was also evaluated in 39 patients with RET fusion-positive NSCLC who had not received any previous treatment. The ORR for these patients was 84%.
For both groups, among patients who responded to treatment, the response lasted more than 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,” LIBRETTO-001 lead investigator Alexander Drilon, MD, of Memorial Sloan Kettering Cancer Center in New York, N.Y., said in an Eli Lilly press release.
“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,” Dr. Drilon added.
About 1% to 2% of NSCLC tumors are thought to have a.
The same trial also included patients with thyroid cancer.
Efficacy for MTC was evaluated in 55 adult and pediatric (older than 12 years) patients with advanced or metastatic RET-mutant MTC who had previously been treated with cabozantinib, vandetanib, or both. The ORR in these patients was 69%.
In addition, selpercatinib was evaluated in 88 patients with advanced or metastatic RET-mutant MTC who had not received prior treatment with cabozantinib or vandetanib. The ORR for these patients was 73%.
The trial also enrolled 19 patients with RET-positive thyroid cancer whose condition was refractory to radioactive iodine (RAI) treatment and who had received another prior systemic treatment. The ORR was 79%. Eight patients had received only RAI. The ORR for these patients was 100%.
In all the cases of thyroid cancer and lung cancer, among the patients who responded to treatment, the response lasted longer than 6 months.
“RET alterations account for the majority of medullary thyroid cancers and a meaningful percentage of other thyroid cancers,” Lori J. Wirth, MD, of Massachusetts General Hospital Cancer Center in Boston, noted in the company release.
Afrom Eli Lilly notes that RET mutations are found in about 60% of sporadic MTC cases and in over 90% of familial MTC cases, and that RET fusions are found in approximately 10% to 20% of papillary 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,” Dr. Wirth commented. “Based on the published data for this new medicine, as well as my personal experience treating patients, this may be a good treatment option.”
In the LIBRETTO-001 trial, the rate of discontinuations because of adverse reactions (ARs) was 5%, the company reported. The most common ARs, including laboratory abnormalities (≥25%), were increased aspartate aminotransferase level, increased alanine aminotransferase level, increased glucose level, decreased leukocyte count, decreased albumin level, decreased calcium level, dry mouth, diarrhea, increased creatinine level, increased alkaline phosphatase level, hypertension, fatigue, edema, decreased platelet count, increased total cholesterol level, rash, decreased sodium levels, and constipation. The most frequent serious AR (≥2%) was pneumonia.
The FDA warned that selpercatinib can cause hepatotoxicity, elevation in blood pressure, QT prolongation, bleeding, and allergic reactions. It may also be toxic to a fetus or newborn baby so should not be taken by pregnant or breastfeeding women.
Selpercatinib is currently being assessed in two phase 3 confirmatory trials. LIBRETTO-431 will test the drug in previously untreated patients with RET-positive NSCLC. LIBRETTO-531 involves treatment-naive patients with RET-positive MTC.
The company that developed selpercaptinib, Loxo Oncology, was acquired by Eli Lilly last year in an. This drug was billed as the most promising asset in that deal, alongside oral BTK inhibitor LOXO-305, according to in Pharmaphorum.
Loxo developed Vitrakvi (larotrectinib), the first TRK inhibitor to reach the market, as well as the follow-up drug LOXO-195. Both were acquired by Bayer ahead of the Lilly takeover, that report notes.
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