FDA Approves RET Inhibitor RETEVMO for Patients Living With Certain Thyroid and Lung Cancers

Retevmo is the first FDA-approved drug that effectively treats lung and thyroid cancer patients with RET

With Richard Pazdur MD and Nisha Jayani MD

On May 8, 2020, the U.S. Food and Drug Administration  (FDA) approved a new drug, Retevmo to Loxo Oncology, Inc., which is a subsidiary of Eli Lilly and Company.

Retevmo is the first gene-specific therapy approved specifically for cancer patients with RET (otherwise known as rearranged during transfection) gene mutations or fusions.

“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, M.D., 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 statement issued by the FDA this week. “The FDA is committed to reviewing treatments like Retevmo that are targeted to specific subsets of patients with cancer,” he says.

Retevmo is the first FDA-approved drug for RET kinase, although other drugs like it do exist. “It is not necessarily a replacement for other drugs, but is now one of three options for systemic therapy of medullary thyroid cancer or thyroid follicular epithelial-derived cancers,” says Paloma Health’s Dr. Nisha Jayani, who is board-certified in Diabetes, Metabolism, and Endocrinology. “The other two FDA-approved options are vandetanib and cabozantinib. Both are also tyrosine kinase inhibitors, but they also target other receptors. Retevmo specifically targets only RET kinase.”

Understanding RET

According to the U.S. National Library of Medicine, the RET gene provides instructions for producing a protein that is involved in signaling within cells. It is essential for developing some nerve cells, and for the normal development of some functions in the nervous system. It also has a role in kidney and sperm development and production, respectively. Unfortunately, RET gene mutations and fusions can cause health conditions and cancers.

Retevmo is being hailed as an innovation in gene-specific therapies for those cancers – an important advance for patients who didn’t previously have a targeted treatment option for RET cancers. It is a selective RET kinase inhibitor. The generic name is selpercatinib and it was known previously as LOXO-292.

A selective RET kinase inhibitor works by blocking kinase, an enzyme; this can help to stop the growth of cancer cells. “Retevmo received accelerated approval (formal title of "Breakthrough Designation”) from the FDA based on the results of its phase one and two trials. The endpoints of these trials were objective response rate and duration of response. The approval is contingent upon the results of confirmatory trials. There are currently two of these phase three trials that are enrolling patients,” Dr. Jayani says.

Retevmo is approved by the FDA to treat a few types of cancers. These include:

  • Non-small cell lung cancer (NSCLC) that has spread in adult patients
  • Advanced medullary thyroid cancer (MTC) or MTC that has spread in patients who are 12 years or older and who also require systemic treatment, rather than a specific or targeted treatment.
  • Advanced RET fusion-positive thyroid cancer in patients who are 12 and older and who also require systemic therapy which has not responded to radioactive iodine therapy or for whom radioactive iodine therapy is not appropriate.

Using Retevmo

“Taking the drug is an easy process,” Dr. Jayani says. “It is a capsule that is taken twice daily with or without food.” This drug is not chemotherapy, immunotherapy, or radiation therapy, according to its makers. It is a take-at-home treatment.

The recommended dosage in both adults and patients 12 years of age or older is based on weight. If the patient is less than 50 kg (or x pounds) they should be given 120 mg twice per day. If they are over 50 kg, they should be giving 160 mg twice per day. In patients with hepatic impairment (or disease of the liver), reduce the dose. Note that clinical trials had patients take 160 mg Retevmo twice per day, orally, until disease progression or unacceptable toxicity occurred.

Before your patients can begin utilizing the drug, however, you must have evidence of RET gene alteration via a laboratory biomarker test. In trials, all patients were determined to have RET gene alteration by plasma or tumor tissue lab testing.

A look at the efficacy results of Retevmo for non-small cell lung cancer

  • A trial with 105 adult patients who were given platinum chemotherapy previously showed an overall response rate of 64 percent.
  • 81 percent of patients saw a response that lasted six months, at least.
  • For 39 of the 105 patients who had never received prior treatment, the drug was effective at 84 percent — with 58 percent efficacy lasting six months or more.

A look at the efficacy results of Retevmo for advanced medullary thyroid cancer in patients 12 years of age or older

  • The study included 143 patients with advanced or metastatic RET-mutant MTC who also had previous treatment with vandetanib, cabozantinib (or both) as well as patients with advanced or metastatic RET-mutant MTC who had never received treatment with either cabozantinib or vandetanib.
  • The overall response rate was 6 percent for the 55 patients who were previously treated. 76 percent of those saw efficacy for at least six months. 
  • 88 patients who never had previous treatment saw an overall response rate of 73 percent. Of that 76 percent, 61 percent saw efficacy that lasted six or more months.

A look at the efficacy results of Retevmo for RET fusion-positive thyroid cancer in patients 12 years of age and older

  • The study included 19 patients with RET fusion-positive thyroid cancer who were radioactive iodine-refractory and previously received a systemic treatment, as well as eight patients who had received a previous systemic treatment, and another eight patients who had not received any previous therapy and who were radioactive iodine-refractory.
  • The 19 patients in the first group saw an efficacy rate was 79 percent. 87 percent of those of patients saw efficacy for six months at least.
  • There was 100 percent efficacy in the eight patients who had no prior treatment.

What you should know about Retevmo’s side effects and potential complications

According to the FDA, the most common side effects included:

  • High blood sugar
  • Lowered white blood cell count
  • Dry mouth
  • Hypertension
  • Fatigue
  • Swelling in the limbs
  • Low blood platelet count
  • Rash
  • Constipation
  • Decreased sodium in the blood
  • Increased aspartate aminotransferase (AST) enzymes in the liver
  • Increased alanine aminotransferase (ALT) enzymes in the liver

Make sure you speak to your patients to confirm whether they are undergoing surgery (the drug can alter wound healing) and if they are pregnant (the drug can cause development problems for a fetus or infant). Patients — both male and female — should use contraception during treatment for at least one week before and after use of the drug.  There is currently no data around breastfeeding or breast milk.

You should know that this drug also has the potential to cause allergic reactions, bleeding, increased blood pressure, QT prolongation, and hepatotoxicity (liver damage or injury). If the latter is experienced, do not let the patient resume course with Retevmo or reduce the dosage.

“It has not been studied for use with other drugs yet,” Dr. Jayani says.

How Retevmo compares to other drugs

As for how it compares to vandetanib and cabozantinib, “Retevmo does not seem to have fewer side effects than vandetanib or cabozantinib,” Dr. Jayani says. “The most common adverse events were reported in >/= 25% of patients. With vandetanib the most common adverse events were reported in >/= 20% of patients and >/= 25% with cabozantinib.”

Dr. Jayani continues, “The head-to-head trial of Retevmo vs vandetanib or cabozantinib will help clarify whether it is a better therapy option, since it did show promising objective response rates in its Phase I and II trials.”

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