FIRST therapy for RET mutations seen in lung and thyroid cancers receives FDA approval: selpercatinib

On 8 May 2020, the United States Food and Drug Administration (FDA) approved treatment for patients with a RET genetic alteration (mutation or fusion) in their tumors, covering non-small-cell lung cancer, medullary thyroid cancer and other types of thyroid cancer. Treatment of these three tumor types with selpercatinib (Retevmo) capsules received accelerated approval. Selpercatinib is the first treatment specifically approved for cancer patients with RET gene alterations.

Innovations in treatments targeting specific gene alterations that trigger cancer and cause it to spread — which we call smart cancer drugs — continue to enter oncology practice rapidly.

The cancers for which selpercatinib has received FDA approval include:

• Advanced RET fusion-positive non-small-cell lung cancer (NSCLC),
• Advanced RET mutation-positive medullary thyroid cancer requiring systemic treatment in patients aged 12 and older, and
• Radioactive iodine treatment-resistant or radioactive iodine-ineligible advanced RET fusion-positive thyroid cancer requiring systemic treatment in patients aged 12 and older.

Selpercatinib is a kinase inhibitor: it blocks a type of enzyme called a kinase and helps prevent cancer cells from growing. Before treatment begins, a RET gene alteration must be identified using a laboratory test.

The RET gene is a proto-oncogene and encodes the RET receptor, a tyrosine kinase cell-surface receptor. Both loss of function, for example in Hirschsprung disease, and excessive or incorrect activation, for example in cancers, of this gene cause various diseases.

Below are the types of RET genetic alterations and their frequencies in these 3 cancer types and in other cancers.

The clinical trial that led to FDA approval of selpercatinib (Retevmo): LIBRETTO-001

The FDA approved Retevmo based on the results of the phase I/II LIBRETTO-001 study, a clinical trial that included each of the three tumor types. During the trial, patients took 160 mg selpercatinib capsules twice daily until disease progression or unacceptable adverse effects. The main efficacy outcome measures were the overall response rate, reflecting the percentage of patients with a certain amount of tumor shrinkage, and the duration of response.

Previously, platinum-based chemotherapy had been given to 105 adults with RET fusion-positive non-small-cell lung cancer (NSCLC), in whom the efficacy of selpercatinib was evaluated. For these 105 patients, the overall response rate was 64%. Among those who responded to treatment, 81% of patients had responses lasting at least 6 months. Efficacy was also evaluated in 39 patients with RET fusion-positive NSCLC who had never received treatment. For these patients, the overall response rate was 84%. For 58% of patients who responded to treatment, responses lasted at least six months.

The efficacy of selpercatinib in adult and pediatric medullary thyroid cancer (MTC) was evaluated in patients with RET mutations aged 12 and older. The trial included patients previously treated with cabozantinib, vandetanib or both who had advanced or metastatic RET-mutant MTC: 143 patients, as well as patients with advanced or metastatic RET-mutant MTC who had not previously received cabozantinib or vandetanib. For the 55 previously treated patients, the overall response rate was 69%. Among patients who responded to treatment, 76% had responses lasting at least 6 months. For the 88 previously untreated patients, the overall response rate was 73%. Among those who responded to treatment, 61% had responses lasting at least 6 months.

The efficacy of selpercatinib for RET fusion-positive thyroid cancer was evaluated in adult and pediatric patients aged 12 and older. The trial enrolled 19 patients with radioactive iodine (RAI)-resistant RET fusion-positive thyroid cancer who had previously received another systemic treatment, and 8 patients with radioactive iodine-resistant RET fusion-positive thyroid cancer who had not previously received another systemic treatment. For the 19 previously treated patients, the overall response rate was 79%. Among those who responded to treatment, 87% of patients had responses lasting at least 6 months. Among those who had received no treatment other than RAI, the 8 patients had an overall response rate of 100%. Among those who responded to treatment, 75% had responses lasting at least 6 months.

The most common adverse effects reported with selpercatinib are increased liver enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT), increased blood sugar, decreased white blood cell count, decreased blood albumin, decreased blood calcium, dry mouth, diarrhea, increased creatinine (a measure of kidney function), increased alkaline phosphatase (an enzyme found in the liver and bones), hypertension, fatigue, swelling of the body or limbs, low blood platelet count, increased cholesterol, rash, constipation and decreased blood sodium.

Selpercatinib can cause serious adverse effects such as hepatotoxicity (liver damage), high blood pressure, QT prolongation on an ECG heart tracing (the heart muscle takes longer than normal to recharge between beats), bleeding and allergic reactions. If a patient develops hepatotoxicity, the selpercatinib dose should be reduced or treatment permanently discontinued. Drugs in the selpercatinib group can cause serious delays in wound healing, so treatment should be planned carefully before and after surgery.

Selpercatinib can harm a developing fetus or newborn baby. Healthcare professionals should advise pregnant women about this risk and advise both women of reproductive potential and men with female partners of reproductive potential to use effective contraception during selpercatinib treatment and for one week after the last dose. Women should also not breastfeed while taking selpercatinib.

Selpercatinib (Retevmo) was approved under the FDA's "Accelerated Approval" pathway, which enables approval of drugs treating serious or life-threatening diseases and generally providing a meaningful advantage over existing treatments. Retevmo had also received "Orphan Drug" designation, which provides incentives to help and encourage development of drugs for rare diseases.

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