What APs Need to Know: An Overview of RET+ Mutations

Megan May

Hi Kate, thanks for agreeing to talk with me about RET gene fusion. RET driver alterations are predominantly mutually exclusive from other oncogenic drivers and they occur in about 1%-2% of non-small cell lung cancers.¹ These patients are typically younger, non-smokers, and have a tumor histology of adenocarcinoma. At diagnosis, 25% of patients with stage IV non-small cell lung cancer with a RET mutation have brain metastases² and RET mutations are also present in less than 10% of papillary thyroid cancers.¹ This is such an important topic to cover because, as APPs, we make sure we’re providing the best care to this patient population with a poorer prognosis. What other general information do you have to share on RET gene fusions?

Kate Taucher

There are two main types of RET genetic alterations, or errors in the gene. One is called RET point mutations. You can think of that as places where the DNA is misspelled. Those are often found in medullary thyroid cancer. The other is called a RET rearrangement or gene fusion. That’s when a piece of DNA joins with another gene and creates a fusion. This fusion leads to uncontrolled cell growth and cancer. This is the most common RET gene error in lung cancer and in papillary thyroid cancer.³

Megan May

So, RET mutations can occur within non-small cell lung and thyroid cancers. Do you know of any other tumor types with a RET mutation that have shown response in clinical trials?

Kate Taucher

Yes, actually. Other solid tumors such as pancreatic, colorectal, sarcoma, ovarian, breast, and salivary all have a prevalence of less than 1% with RET mutations.⁴

Megan May

Due to the prevalence of these mutations and now that we have targeted treatment options for these patients, NCCN Guidelines recommend testing for RET alterations in appropriate patients with advanced and metastatic non-small cell lung cancer and thyroid carcinoma to determine if they’re eligible for RET inhibitors.^5,6 Do you know if there’s a specific FDA-approved companion diagnostic that’s needed to detect one of these mutations, Kate?

Kate Taucher

The gold standard is still to get a tissue biopsy for next-generation sequencing, or NGS. There may be some situations though where a patient can’t undergo the biopsy needed to perform NGS, and so a liquid biopsy is recommended.

Megan May

We also struggle sometimes with not having enough tissue at my institution. It’s so great that we have targeted therapy options available for patients with this mutation. Can you share a little about the mechanism of action of the medications that are used when a patient has a RET driver mutation?

Kate Taucher

Selpercatinib and pralsetinib are highly selective anti-RET kinase inhibitors. RET stands for “REarranged during Transfection.” Both of these agents also targeted several other mutation domains. Certain point mutations in RET or chromosomal rearrangements involving in-frame fusions of RET can result in constitutively activated chimeric RET fusion proteins, which may act as oncogenic drivers, promoting tumor cell line proliferation. Selpercatinib and pralsetinib have demonstrated anti-tumor activity in cells harboring constitutive activation of RET proteins resulting from gene fusions and mutations. Selpercatinib also crosses the blood-brain barrier and has shown anti-tumor activity in mice intracranially implanted with a patient-derived RET fusion-positive tumor.⁷

Megan May

That's great news. So, we currently have these two RET inhibitors available, selpercatinib or pralsetinib and both of them are approved for RET fusion-positive non-small cell lung cancer, papillary thyroid cancer, and medullary thyroid cancer. Selpercatinib also has a pan-tumor approval for RET fusion-positive solid tumors. Kate, what do you see that’s similar about these two medications? And in what ways are they different from each other?

Kate Taucher

Well, selpercatinib is available as 40 and 80mg capsules. The dosing of selpercatinib is weight-based. It should be taken twice a day about 12 hours apart. If a patient has preexisting severe hepatic impairment, then the starting dose of selpercatinib will have to be reduced. Both selpercatinib and pralsetinib are taken until the patient has disease progression or if the patient has toxicities we’re unable to manage. Selpercatinib can be taking with or without food unless it’s given with a proton pump inhibitor, like omeprazole. If taken with a PPI, then the patient should take selpercatinib with food. It’s also best to separate selpercatinib from any antacid, including locally acting antacids. Pralsetinib is a flat dose of 400 mg and is only once a day. It’s really important to tell patients that pralsetinib needs to be taken on an empty stomach at least one hour before or two hours after food.

Megan May

That’s a great point about patients having to take pralsetinib on an empty stomach. I know during my education sessions with patients, I go ahead and discuss specifically when the patient will take pralsetinib. I find it’s easier for patients if we can plan out a schedule and have a plan together prior to them starting the medication. I’m always evaluating how compliant a patient will be. Since both of these RET inhibitors are oral agents, like you discussed, adherence is a must. With selpercatinib being dosed twice daily and pralsetinib being once a day, I want to make sure taking the medication can fit within the patient’s lifestyle and daily routine. When I’m working with my providers to decide which specific treatment to use on a patient, I also take into consideration the safety profile of each medication. Selpercatinib and pralsetinib are associated with similar toxicities, including hypertension, but subtle differences between the safety profiles do exist. For example, selpercatinib appears to cause more QT interval changes compared to pralsetinib.⁸ Kate, how do you decide which agent a specific patient should receive?

Kate Taucher

Deciding between agents will be a patient-centered decision. Given the similar toxicity profiles, understanding the patient’s ability to fit these agents into their daily routines, either once daily or twice daily, like you discussed Megan, will be an important factor. Also, we need to consider what other medications they’re currently taking to assess for drug interactions or needed dose reductions, such as PPIs. With these being oral medications, the patient’s prescription insurance coverage and patient responsibility is also often a decision point. We help patients with obtaining authorization through their insurance, as well as financial assistance or prescription assistance (aka “free drug”) when it’s required.

Megan May

Thanks Kate, this has been a great conversation. One last question. What information would you like to make sure APs know about RET?

Kate Taucher

It’s important for APs to understand that we have targeted therapies for RET mutations and fusions and that we should be testing and treating appropriately based on the genetic testing results. I think this is a great role for APs to play in a patient’s treatment plan–to assess the patient’s diagnosis and need for testing. If a patient hasn’t had testing, that can be ordered to better direct the patients care. What about you, Megan?

Megan May

My last bit of advice is when using these targeted agents, we need to make sure we’re providing good initial education to the patient. We also need to make sure we’re addressing adherence regularly. At my institution, our patient care coordinators call the patients every cycle while taking selpercatinib or pralsetinib to check on adherence, new toxicity concerns, or determine if a patient has started any new medications. If any of these factors have changed then the concern is escalated to the pharmacists to investigate further. We also need to mention financial toxicity. Since these are oral agents, we do have to evaluate the out-of-pocket cost to the patient. This is a role for our patient care coordinators and pharmacists to assist the patient in making the cost as low as possible, so hopefully the cost is one less thing for our patients to worry about. Kate, thanks for this great conversation about RET fusion-targeted therapies.

Kate Taucher

Thanks, Megan. I really enjoyed getting a chance to talk about this.