What APs Need to Know: RET-Mutated Non-Small Cell Lung Cancer

Megan May

Thanks for joining me today, Beth. I'm excited to talk more about metastatic RET+ non-small cell lung cancer. RET rearrangements are typically observed in about 1-2% of patients with non-small cell lung cancer. And now we have selpercatinib and pralsetinib, which are FDA-approved for the treatment of advanced RET+ non-small cell lung cancer, regardless of the previous lines of treatment.¹ Beth, when you see patients with these RET+ mutations, do they have specific characteristics that are similar?

Beth Sandy

Thanks for talking with me about this today. The average age of a patient with lung cancer is around 69 or 70 years old.² What we have often observed is that patients with RET fusions in non-small cell lung cancer tend to be a little bit younger on average. They tend to be non-smokers or distant smokers, and they have brain metastases more frequently than patients with run-of-the-mill non-small cell lung cancer.³

Megan May

Beth, how do you test to find this mutation in these patients? How do you know what to look for?

Beth Sandy

I think RET is one that is unique because of how it presents as a fusion gene, similar to what we see with ALK and ROS1, which are also fusions. We do next-generation sequencing testing, of course, which is what we should really be doing in all patients with non-small cell lung cancer who have adenocarcinoma, regardless of whether they're a smoker or not. Even though this one is more common in patients who haven't smoked, we should be doing this biomarker testing as a next gen sequencing panel for everyone.

That being said, most are complex DNA testing platforms and can absolutely find a RET-fusion gene. However, there's a newer technology now that we've been using the past couple years called RNA sequencing. There was a study out of Memorial Sloan Kettering that showed that if an actionable gene fusion wasn’t found in that original next gen sequencing panel, they would reflex that to look at an RNA-sequencing panel or an RNA-fusion panel. When they did that, they found several fusion genes such as ALK, ROS1, RET, MET and NTRK in those patients, and so it's a much more sensitive platform to detect some of these fusion genes.⁴ So, I think it's important to do that when you're doing next gen sequencing panels so that we’re making sure we're not missing any of these fusions.

Speaking of adenocarcinoma, I'd also like to add that we typically find these RET fusions in patients with adenocarcinoma,¹ the most common type of non-small cell lung cancer that we see. It would be uncommon to find this in a patient with a squamous cell of the lung. Typically, in lung cancer, we use chemotherapy, immunotherapy in our patients without biomarker positive disease or mutations. For patients with RET+, a lot of times we will use one of these inhibitors frontline. There’s a lot of data looking at using it either frontline or in the second-line setting. So, what have you observed as far as efficacy for these RET inhibitors?

Megan May

I think you bring up a good point about the brain metastasis with these patients because when I was looking at the trials for these inhibitors, the one thing that kept standing out to me is how well they are responding in patients that already have brain metastasis. The phase 1/2 Libretto 001 trial evaluated selpercatinib in a subpopulation of non-small cell lung cancer and included patients that were treatment naive and patients who had received prior platinum treatment.⁵

For the patients who previously received treatment, the overall response rate was 61% and the median progression-free survival was 24.9 months. And then when you look at the patients who were treatment-naive, their overall response rate was 84% and their median progression-free survival was 22 months. In terms of the brain metastasis, 26 patients who were enrolled did have brain metastasis and the objective intracranial response was 85%. This included 27% of these patients who had intracranial complete responses.

The median duration of response for these patients was 9.4 months.⁵ This is showing some really remarkable intracranial activity, which is exciting for our patients. The ARROW trial looked at pralsetinib, our other RET inhibitor. This also had patients that were treatment naive and patients that had previously received platinum-based treatment. The overall response rate for patients with previous treatment was 61%, and the median progression-free survival was 17.1 months. In the treatment naive population, the overall response rate was 70%, and the median progression-free survival was 9.1 months. Pralsetinib demonstrated intracranial activity with an intracranial overall response rate of 56%, including three patients with a complete response.⁶

Because of this data, you can use pralsetinib and selpercatinib as first-line treatment in patients with RET-fusion non-small cell lung cancer. And we saw that this targeted therapy is good for CNS control, especially in the patients with asymptomatic brain metastasis.

So, looking at all this great data, Beth, what do you normally see within a toxicity profile in these patients?

Beth Sandy

Something that I have seen the most is hypertension, which is so disruptive to their life. If you look at the rates of this in clinical trials, all grades hypertension in the selpercatinib trial was 35% and 29% in the pralsetinib trial. If you look at grades 3/4 hypertension, it's pretty high, 14% in the pralsetinib trial and 17% in the selpercatinib trial.^5,6 I just want to remind everybody what grades 3/4 hypertension is. According to the National Cancer Institute Common Terminology Criteria for Adverse Events, grade 3 hypertension means that their systolic blood pressure is over 160 and their diastolic blood pressure is over 100. Medical intervention is indicated, and more than one drug or more intensive therapy than previously used is now indicated. Grade 4 is always life-threatening.⁷ These are pretty high blood pressures which is why a lot of the time I end up having to hold the drug and potentially dose reduce.

Other things that I've seen with RET therapy is the lowering of blood counts. We typically think of these targeted therapies, especially the orals, as drugs that do not lower blood counts like we see with chemotherapy, but that's something that you really have to be looking out for. You should be bringing these patients back and checking their labs. In a recent meta-analysis looking at 11 different trials of re-inhibitors in non-small cell lung cancer, the rate of grades 3/4 anemia and neutropenia was 13%.⁸ That's pretty high. Remember, a grades 3/4 neutropenia is an ANC of less than 1,000. So again, these are reasons that sometimes we may need to hold or dose reduce.

Hepatic toxicity can be common with a lot of the oral TKI therapy that we use in lung cancer. In the studies, the rates of elevated transaminases like AST and ALT were 69% in pralsetinib and 51% in selpercatinib. But if you looked at grades 3/4, it was pretty high, in the range of 7- 8% in one study and 11-12% in another study, so you may need to dose reduce.^5,6  It's just really important to bring patients back and check their labs every 2-3 weeks, especially in the first few months that they're on therapy.

Megan, the other thing I've seen is QT interval prolongation. Do you want to talk at all about that and have you seen that much?

Megan May

Oh yes. For selpercatinib, we’re checking upfront for QT prolongation, especially in the beginning. We'll do it about 2-3 times throughout the treatment just to make sure that patients are tolerating it okay. One thing I'm always looking for are any drug-drug interactions that also cause QT prolongation. We might need to monitor those patients even more if there is an interaction. With pralsetinib we do not monitor QT prolongation proactively with an EKG unless we are concerned. The risk with QT prolongation with pralsetinib is not an issue like with selpercatinib.

One good point you brought up was needing to either hold treatment or do dose adjustments because of these toxicities. In the ARROW trial, 38% of the patients had to have a dose adjustment, but there have been studies showing that once you dose reduce, the outcomes are still similar. So I think we should all feel comfortable knowing that we might have to dose adjust in order to keep patients on this treatment. Of the participants, 6% of the patients had to discontinue pralsetinib due to treatment-related adverse events.⁶  In the Libretto study, 41% of the patients had a dose adjust and 8% of the patients discontinued use due to those treatment-related adverse events.⁵

Beth, do you have any examples of real-world experiences that you've had with patients and how you were able to keep them on treatment in order to have the best outcomes as possible?

Beth Sandy

Yes I do. We had a patient who was on selpercatinib, and she had a pretty severe reaction. Nosebleeds and bruising were her main complaints. But when we took her blood pressure, it was 204/127, so there’s your grade 3 hypertension, and her platelet count was only 20, and this was after two weeks being on the drug. She ended up having to be admitted for hypertensive crisis and bleeding, of course. This was pretty severe, and for her, we permanently discontinued based on how severe the reaction was.

Within two weeks, we switched drugs and restarted her on pralsetinib, but at a very low dose. We started and worked our way up. She’s currently still on it, but only on 200 mg, so she really hasn’t even gotten up to what the actual recommended dose of pralsetinib is, which is 400 mg. She’s responding, so we’ve kept her there because we’re too worried about the side effects that she had with the selpercatinib. We have to really watch a patient’s labs very closely and certainly their blood pressure. It’s really important to bring them back at that two-week mark just to make sure that their labs are okay, their blood pressure's okay.

The other thing we should talk about is edema, which some of these patients have. In fact, I have one patient right now who has upper extremity edema. Not lower extremity, but upper extremity edema for whatever reason. The rates in the clinical trials of any grade were around 30%. Rarely did they have grades ¾ edema.^5,6  That was very uncommon, but some get it, so he’s staying on the drug. It’s an annoyance to him and while we didn’t dose reduce him, we gave him a drug holiday. It did subside during that couple-week drug holiday, but then we restarted him. That’s one of the side effects that may not be life-threatening, such as something like a hypertensive crisis, but something that you have to manage for the patient’s lifestyle.

Megan May

For that patient that had a hypertensive crisis, did she call in with symptoms or was she just coming to see you for a normal follow-up?

Beth Sandy

No, she had not checked her blood pressure at home. Her only complaint to us when she got there was that she had bruising and what she thought was a rash, which really ended up being petechiae, and nosebleeds. So, she really wasn't feeling that hypertension. Now, it’s hard for me to know how long that had been going on. That was two weeks after starting the drug. I don't know if that had started within seven days, and so it wasn't enough time for her to experience any kind of cognitive side effects. Oftentimes these patients would have headaches, lightheadedness, blurred vision, things like that, but she had not started experiencing any of that. So, I'm glad we caught it when we did. I think that was important.

Megan May

Yes, I'm glad that you brought her back in so soon after starting it in order to evaluate for those toxicities that can happen quickly when they start taking it. I know for blood pressure management here, we provide our patients with a log and encourage them to check it regularly at home if possible. Some pharmaceutical companies provide coupons for patients so they can order a blood pressure cuff at a discounted price. This is a nice offering for those patients with financial barriers.

Beth Sandy

So, Megan, as a pharmacist working in oncology, do you have any pearls for adherence as these medications are oral and the dosing is a little bit different. I know that selpercatinib is twice a day with or without food, but pralsetinib is once a day and supposed to be taken on an empty stomach. How do you counsel patients when they're being started on this medication?

Megan May

Educating patients is so important because they need to take the medication in order for it to have an effect, right? Part of our job is making sure that when we're educating them, we work to incorporate taking the medication into the patient's daily routine, asking them “When is a time you can take this when you haven't just eaten? Can you take it first thing in the morning and then eat your breakfast, or could you eat dinner and then take it at bedtime just to make sure you have an empty stomach?”

And with the medication that’s twice a day, one thing we do is give out personalized calendars with little check boxes so a patient can check it off, because sometimes it can be hard to remember if you took your medication in the morning. We want to make sure they're not doubling up ever with these medications.

For our program, we consider an adherence rate of 80% as adherent. If it's less than 80%, we need to get more involved; a pharmacist calls the patient more regularly to make sure they are being adherent and to provide any tools we can to them. We also have patient care coordinators who call patients every month before we fill the RET inhibitors for them. One of the things the coordinators check for is adherence and toxicity and any other issues that can come up in the meantime. These touchpoints we have with patients really help them stay adherent and allow an easy connection to the patient, so they’re more likely to call us if they're having any problems with it.

What about you all? Do you do anything different with encouraging adherence from your patients?

Beth Sandy

I like the cell phone alarms, especially for the daily medications. Our pharmacists, as you do, also make  calendars with check boxes for them, which I think is really important. Adherence can be tough, especially when patients are travelling. One of my patients went on a trip to Europe for two weeks and he really wanted to consolidate his meds so he didn’t have to bring all these bottles with him. He poured two weeks of medications, which is about eight different meds, including his targeted therapy, into one big bottle. And then when he got on vacation, he couldn't remember which was which.

Now I know that if I have a patient going on vacation, I remind them not to pour everything in one unmarked bottle because then they’ll have a really hard time remembering which is which. Like you said, if it's an allergy medication, it might not be a big deal, but with a cancer medication, you definitely don't want a patient taking more than they're supposed to. That can have serious adverse reactions. So, that's something that I've picked up from that patient's experience.

Megan May

That’s a great story. Some of the things we hear when we're in clinic can be surprising, right? Beth, do you have any last tips for our APPs about these RET inhibitors or the fusion with lung cancer?

Beth Sandy

My take-home messages are, number one, make sure you're testing and using a platform with the RNA-sequencing panel, because you're going to find more of these fusions by using that. Understanding the toxicity profile of these RET inhibitors is important, especially with the hypertension and the lowering of blood counts, which are things that we're not always used to thinking about with targeted therapies. And then making sure that the patient is following up with the NP or PA in the clinic. Schedule a follow-up visit to make sure that you're assessing for both adherence and these toxicities and do that regularly, especially early on to make sure the blood counts are not dropping. Megan, do you have any take-home messages from a clinical pharmacy role?

Megan May

We just need to make sure we're thoroughly educating these patients, because like we've said, there can be serious toxicities associated with the drugs and we want to make sure we're catching those quickly in these patients.

Thanks so much, Beth. I appreciate you joining us today. This was really informative.

Beth Sandy

Thank you for having me, Megan.