RET inhibitors: a treatment for any RET-altered cancer

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

“A few years ago, we started testing these drugs, and now they’re giving patients more time,” says Dr. Vivek Subbiah. Under Subbiah’s direction, the Phase I/II ARROW and Phase I/II LIBRETTO-001 open clinical trials in md anderson in 2017 to investigate the RET inhibitors pralsetinib and selpercatinib for the first time in patients. The results of clinical trials led to accelerated approval by the Food and Drug Administration (FDA) just 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. Since then, selpercatinib has been approved to treat any cancer caused 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 various health conditions, including cancer. These genetic abnormalities can be classified into two categories: RET mutations and RET fusions.

When an abnormality occurs within the RET gene, it is known as a RET mutation. It can cause an overactive protein called an enzyme that causes the cell to grow out of control. Some people are born with a RET mutation, and it has been linked to an inherited syndrome called multiple endocrine neoplasia type 2. The syndrome can lead to the formation of both cancerous and benign tumors that usually 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 does not change. Instead, the gene’s DNA fuses with a different gene, activating an enzyme that sends a continuous signal to the cell, telling it to grow. This abnormal growth of cells can develop into a tumor.

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

Subbiah points out that RET mutations and RET fusions are not the same thing. “This distinction can mean a lot in 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 caused by a RET fusion. “No matter where in the body a tumor is, if it’s due to a RET gene rearrangement, selpercatinib can be used,” says Subbiah.

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 are also found in other types of cancer.

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

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 pulling a needle out of a haystack, but we’ve shown that the benefit has been dramatic for these patients,” says Subbiah.

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 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 a DNA-altered RET gene spilling into the bloodstream,” says Subbiah.

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

RET inhibitors are convenient and effective

Compared to other cancer therapies, such as chemotherapy, immunotherapy, and multikinase inhibitors, RET inhibitors are accurate, safe, and convenient. Pralsetinib and selpercatinib are taken as a pill once or twice a day, depending on the medicine prescribed. Since they are prescribed for patients whose cancers are due to RET abnormalities, patients experience fewer side effects with better outcomes.

“These drugs represent a game changer in cancer therapeutics and a huge step forward for precision medicine,” says Subbiah.

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