RET inhibitors: A treatment for any RET-altered cancer

Cancer research is advancing rapidly, and patients are benefitting from new therapies faster than ever. One example is a type of targeted therapy known as a RET inhibitor.

“A few years ago, we were starting to test these drugs, and now they’re giving patients more time,” says Vivek Subbiah, M.D. Under Subbiah’s direction, the Phase I/II ARROW and the Phase I/II LIBRETTO-001 clinical trials opened at MD Anderson in 2017 to investigate the RET inhibitors pralsetinib and selpercatinib for the first time in patients. The clinical trials’ results led to accelerated approval by the Food and Drug Administration (FDA) only three years later.

Pralsetinib and selpercatinib are approved to treat patients with RET fusion-positive non-small cell lung cancer, RET fusion-positive papillary thyroid cancer and RET mutation-positive medullary thyroid cancer. Selpercatinib has since been approved to treat any cancer driven by a RET fusion.

RET mutations are different from RET fusions

The RET gene is vital in tissue development. As with any gene, when there are irregular changes, cells can develop into several health conditions, including cancer. These genetic abnormalities can fall into two categories: RET mutations and RET fusions.

When an abnormality occurs within the RET gene, it’s known as a RET mutation. It can cause an overactive protein called an enzyme that triggers the cell to grow uncontrollably. Some people are born with a RET mutation, and it’s been linked to a hereditary syndrome called multiple endocrine neoplasia type 2. The syndrome can lead to the formation of both cancerous and benign tumors that typically involve the body's hormone-producing glands. Examples include neuroendocrine tumors and pheochromocytoma, which is a tumor of the adrenal gland.

RET fusions, also known as RET gene rearrangements, differ from RET mutations in that the gene isn’t changed. Instead, the gene’s DNA fuses with a different gene, which activates an enzyme that sends a continuous signal to the cell, telling it to grow. This abnormal growth of the cells can develop into a tumor.

Pralsetinib and selpercatinib work to treat RET-altered cancers by targeting the enzyme that causes the cancer cells to grow.

Subbiah notes that RET mutations and RET fusions aren’t the same things. “This distinction can mean the world when knowing which RET inhibitor is available to you,” he says.

Pralsetinib and selpercatinib are approved to treat RET mutation-positive medullary thyroid cancer as well as RET fusion-positive non-small lung cancer and thyroid cancers. However, the FDA has approved selpercatinib to treat any cancer driven by a RET fusion. “No matter where a tumor is located in the body, if it’s driven by a rearrangement of the RET gene, selpercatinib can be used,” Subbiah says.

RET fusions can occur in a wide range of tumors

RET fusions are found in 2% of non-small cell lung cancers and 20% of thyroid cancers. Unlike RET mutations, they’re also found in other types of cancer.

While enrolling patients in the clinical trials, Subbiah and his team found RET fusions in patients with pancreatic cancer, colorectal cancer, sarcomas and many other cancers.

Although RET fusions are found in less than 1% of all tumor types, they can be found in difficult-to-treat tumor types. “It’s like picking a needle out of a haystack, but we’ve shown the benefit has been dramatic for these patients,” Subbiah says.

Next-generation sequencing and liquid biopsies detect RET alterations

RET mutations and RET fusions are detected with next-generation sequencing. The test is performed on a sample of tumor tissue that is removed by an interventional radiologist or by a surgeon.

However, Subbiah says that RET fusions can also be found using a newer approach known as liquid biopsy. “It’s an amazing technology that can detect an altered RET gene by the DNA shed into the bloodstream,” Subbiah says.

Although the liquid biopsy is specific, it’s not sensitive, Subbiah says. If a RET mutation or RET fusion is detected with a liquid biopsy, the results are reliable. But if it’s not detected, comprehensive molecular testing on tumor tissue is still necessary to rule out the genetic abnormality.

RET inhibitors are convenient and effective

When compared with other cancer therapies such as chemotherapy, immunotherapy and multikinase inhibitors, RET inhibitors are precise, safe and convenient. Pralsetinib and selpercatinib are taken as a pill once or twice a day, depending on which medication is prescribed. Since they are prescribed to patients whose cancers are fueled by RET alterations, patients experience fewer side effects with better results.

“These drugs represent a big shift in cancer therapeutics and a big step forward for precision medicine,” Subbiah says.

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