Approved Treatments and Decision-Making Considerations for Patients With RET Mutations

Juna Jovani

Hi, Alex. I’m looking forward to talking with you so we can give both a physician assistant perspective and a pharmacist perspective on RET-driven mutations, approved drugs, and treatment decision-making, as well as on the ways that we treat these patients.

To start, can you tell us a little bit about your experience with RET-driven mutations? Could you provide us with some general information about what RET mutations are, the two different types, and RET fusion mutations vs. RET point mutations?

Alex Robinweiler

As an APP, I'm generally managing symptoms and care as opposed to deciding care. I’m also explaining things to the patients, which I think is helpful.

A lot of information was covered in the previous JADPRO Expert Conversations series on RET mutations, so I’ll just provide a basic background here. RET mutations, or driver mutations, are specific mutations involved in the oncogenesis of cancers. Usually, we see these mutations in younger people and non-smokers, as with all driver mutations.

These genetic alterations result in changes to the cell’s mechanisms that regulate proliferation and reproduction. There are two different types of mutations that we're seeing: first are changes in the usual DNA encoding of the gene such as a point mutation, and second are gene fusions, which in essence is an alteration to the gene’s machinery, causing the gene to be always turned on. These are the driving qualities of the cancer, and when we utilize these RET inhibitors, we stop the cancer from utilizing these damaged genes, and thus stop the cancer, which is pretty cool.

Juna Jovani

Yes, it is. We know that it's more common to see RET fusion mutations rather than point mutations in the non-small cell lung space and more common to see RET mutations in thyroid cancer. Based on your experience, do you think there is an impact on the clinical decision-making if the mutation is RET fusion rather than RET point mutation?

Alex Robinweiler

The general sense is that we're trying to use the medications that have the highest potential for the best outcomes. Outside of clinical trials, we generally stick to medications within the FDA-approved indication. And when we're thinking about these two different medications, pralsetinib and selpercatinib, they're very specific as far as what we can use them for. If you were to see a non-small cell lung cancer with a RET mutation, theoretically you might not be able to use certain drugs, rather than if it were a fusion, in which case you could use these certain drugs. I don't think it necessarily changes our practice, because frankly there's just not a lot of flexibility based upon what the FDA approves us to do outside of clinical trials. And we don't do these types of clinical trials at our site.

Juna Jovani

What FDA-approved next-generation sequencing (NGS) have you seen or carry out at your facility for these patients? And how early on do you send tissue samples, whether it’s a tumor sample or a liquid biopsy to next-generation testing for these patients. And how early on in the treatment regimen do you do this?

Alex Robinweiler

We in the cancer field have not always been good about sending out for NGS or immunohistochemical (IHC) staining, or other types of molecular or genetic testing. We’re finding that we need to do those as soon as possible. These days, at least at our center, as soon as somebody is diagnosed, they're sent for some type of genetic testing, some type of molecular testing, so we can look for all types of driver mutations. A patient who has been diagnosed, or even just has symptoms, will get some type of tissue sampling. The tissue sampling can confirm what we're looking for, such as adenocarcinoma for small cell lung cancer rather than thyroid cancer. As soon as that pathology is in process, the NGS is also in process.

Our site typically uses a company called Tempus for NGS. We send samples of the initial biopsy specimen to see if there are any target mutations, any of these driver mutations that we can utilize in treatment.

Some patients who are currently in therapy could potentially benefit from NGS every time they have a relapse. Sending it for NGS after relapse can let us know if they've redeveloped the cancer or potentially find these mutations that were missed previously. It sometimes gives us the chance to challenge somebody with these medications in the second line-setting, which can still be pretty effective.

Juna Jovani

With these RET alteration-detecting mechanisms, do you feel that you've run into issues as far as the sample tumor size? For instance, in the lung cancer space, you may not be able to obtain a big enough sample size for next-generation testing. In that case, do you gravitate toward more of a liquid biopsy, which is a newer approach? Perhaps it’s not as sensitive, but it's still a qualitative test that can help and detect any RET fusion or mutations. What do you gravitate toward, especially those sample sizes that could potentially cause a barrier into finding out what the RET mutation or alteration may be?

Alex Robinweiler

The goal, of course, is to use NGS. But, like you mentioned, occasionally there's just not enough specimen and you run out of tissue. When that happens, you need to consider a liquid biopsy, which has good specificity, but can lack in sensitivity, meaning you trust the findings if they note a mutation, but not necessarily if it's not there. The implication is that if it lacks the mutation, you therefore can't justify treatment with the FDA indication, and would then have to move on to something else. So yes, the goal is always NGS with the actual tissue, using the liquid biopsies as backup. I don't recall the specific example off the top of my head, but in the past I’ve run into some roadblocks with insurance companies where there won’t approve a drug for an indication if that indication was not found using an FDA-approved test, which I recall having been a liquid biopsy.

Juna Jovani

Let's talk a little bit about how the mutated cancers or RET-altered cancers were initially treated. Initially there were broader multikinase inhibitors, which were proven not to be as selective. The inhibitors created more unwanted side effects and toxicities due to their off-target activity. Can you speak to the newer approved drugs or relatively newer approved drugs that are highly specific or highly selective for the RET mutations?

Alex Robinweiler

Regarding those older drugs, such as cabozantinib and sunitinib, if you're using those specifically to target RET mutations, you will see some effect, about an overall response rate of maybe 20 to 40% if that much.¹ There is significantly more potential for side effects because there're going to be much more broad-spectrum inhibitors, which can alter the pathways of healthy genes, thus leading to higher-grade (3 and 4) side effects. Subsequently, you’ll be more likely to have discontinuation of the drug due to intolerability, which increases the chance of treatment failure. However, they may be something to consider with patients in late-stage cancer or those in later lines of therapies.

These newer lines of therapy really haven't been around that long, noting the first one, selpercatinib, was approved in 2022, and the second one, pralsetinib, was approved in 2023. The typical response rates for these two medications are around 70-80%; the data for progression-free survival and overall survivals very compelling compared to what we had before for people with these mutations.²

Juna Jovani

Yes. I think historically we've seen quite a bit of dose reduction with the multikinase inhibitors, and more interruption and discontinuation, which limited the efficacy of these drugs in this population. With the more highly selective drugs, although we potentially may have still some side effects and toxicities, they’re more specific to targeting those particular cancers such as thyroid and lung cancers.

Alex, thanks so much for sharing your knowledge regarding treatments and testing.

Alex Robinweiler

You’re welcome, Juna. I look forward to our future conversations.