Roundtable Discussion: Treatment Goals for RET-Mutated Lung Cancer

Nicholas J. Vogelzang, MD

During a Targeted Oncology^TM Case-Based Roundtable event, Nicholas J. Vogelzang, MD, chairman, Medical Oncology at the Comprehensive Cancer Centers and clinical professor of Medicine at the University of Nevada, Reno School of Medicine in Las Vegas, NV,, discussed the case of a 59-year-old patient with RET-mutated lung cancer. Vogelzang was joined in his discussion by 9 peers.

VOGELZANG: In my experience, I try to order molecular testing on all patients with lung cancer because you don’t know who’s going to have what. There are 10 separate subtypes, including ALK, ROS1, EGFR, etc. The problem with molecular testing is that it takes time and the pathologists do not do reflex testing. There is also a 14-day rule. You can’t always get them to do it because it’s not reimbursed.

I have to bring the patient in, see the patient, and then I order testing. I use Caris [Life Sciences], and [results take approximately] 4 to 5 weeks to be delivered.

The role of plasma testing is nice, but insurance companies often are not willing to pay for the plasma testing. They’re more willing lately, but still not so readily willing. The issue with the nonbarrier testing is that sometimes the tissue is very small, and even if you wanted to do molecular testing, you can’t get it. Those are some of my barriers.

VICUNA: I agree. The issue is getting the molecular testing. I order NGS panels on my patients with lung cancer and I try to order tissue and liquid at the same time on presentation, but the barriers are the time frame, and when the results are coming back, it can take weeks. While waiting for those test results, the patient may be progressing and symptomatic or they may just be anxious about starting treatment. There is a balance between trying to hold off on waiting for molecular testing to see if there’s a targetable mutation vs treating their physical or emotional symptoms.

VOGELZANG: That delay is, especially for the patients, frustrating.

MUKHERJEE: There are [so] few patients with targeted actionable mutations, but I do order it with every patient, especially the metastatic population. We usually use FoundationOne. Sensitivity is not great, but I’ve had a couple of patients with ROS1 as well as EGFR. I have also run the PD-L1, and I generally don’t do the plasma because of cost issues at the beginning. But when the sensitivity is an issue, then I do go with the plasma testing.

Insufficient tissue is the biggest barrier. It’s more than the cost because sometimes it’s just needle biopsies on certain lesions and they don’t have enough tissue to run all the tests.

VOGELZANG: It’s a challenge, particularly on the transthoracic needle biopsies.

WU: There are barriers with timing issues and also the insufficient specimen. For our patients, we also have another problem with access and insurance issues. We have a large number of patients with Medicare. This testing, particularly for NGS, we have to get through the insurance approval through Quest [Diagnostics] for them to send it out. That’s another issue for Medicare patients.

The timing may be even longer to get results back. This is a problem. Sometimes we send liquid biopsies. Of course, we cannot get enough tissue and the patient is very anxious. In cases where we have cytology from pleural effusions, I sometimes order a liquid biopsy, too.

biopsy came back as adenosquamous. I explained to him I’m going to give him carboplatin/paclitaxel radiotherapy. I said, “I don’t think I’m going to find anything unusual on the molecular testing,” but I warned him. I said, “I’m going to send it off if we can get molecular testing, but meanwhile we’re going to go with radiotherapy and we’ll see what happens.” It’s a challenge all the way around.

The patient wants to start therapy, so do you initiate therapy, or do you normally wait? This patient has brain metastases. It looks [as though] he’s a candidate for chemoimmunotherapy. His PD-L1 staining is high.

ARSLAN: His brain metastases, are they symptomatic or asymptomatic?

VOGELZANG: The brain metastases are asymptomatic, and there are 3 of them. It’s fairly small, and the chemoimmunotherapy option would then cross the blood-brain barrier. Meanwhile, you have to get a consult with your radiotherapist. You’re going to decide if you want to put the patient on steroids.

VOGELZANG: What would you do as a radiation oncologist? Would you recommend that we do brain radiotherapy first?

POMERANTZ: Simply because they’re asymptomatic, I would not choose brain radiotherapy first, but it brings up a good point.

In the radiotherapy world, you may or may not be familiar with the study that happened. [It investigated] SABR, or stereotactic ablative radiotherapy, for patients who have 5 or fewer metastatic sites of disease.¹ It’s not disease site specific, but it included...3 brain metastases and 2 lung nodules. Outside of a RET discussion, this patient qualifies under our “oligometastatic” disease profile.

To treat all of those in a short hypofractionated way would be reasonable, but I did select that simply because he’s of thin stature. It sounds as though he has some performance status issues just from the lung primary tumor itself. I favored chemoimmunotherapy up front, holding off on molecular analysis and seeing if we can target his therapy better once we know more in a few weeks.

VICUNA: I chose brain radiotherapy first. Even though they are asymptomatic, I would want to wait for molecular testing, at least starting, whether it’s SABR, CyberKnife, or other targeted treatments to the brain lesions. That helps alleviate the patient’s anxiety [without them] being on anything or being treated with anything. At least with the brain radiation, get that taken care of in the next couple of weeks while we’re waiting for molecular testing, and once that’s obtained, then we can move toward systemic treatment.

MUKHERJEE: I also went with the brain radiation therapy because I wasn’t sure about the size. If it was small, then targeted treatment still makes sense. Until the NGS testing comes back, the radiation would afford me the time.

VOGELZANG: With chemoimmunotherapy, there is good evidence that it will get the brain.

GALAMAGA: I don’t necessarily get a 6- to 8-week turnaround. I’m usually getting 10 to 14 days on a lot of that. I wonder [about] using immunotherapy up front—unless there’s a sense of urgency—[does] that affect sensitivity to targeted agents?

VOGELZANG: If you can get Guardant or one of the cell-free DNA [tests], then that’s good. Then I would agree. [I had a patient who was tested with] Guardant and she came back as RET positive in 5 days. I didn’t have to worry about waiting for it, and that’s a big advantage when you get that quick turnaround. In fact, it turned out that she never did get molecular testing because the biopsy was small. It was the cell-free DNA [test] from Guardant.

However, I told the patient I was going to do chemoimmunotherapy, to which she replied that she wanted to wait for the molecular test instead. Then we had an issue of getting her the drug. But at least she got what she wanted, mainly targeted therapy.

WU: I haven’t treated anybody with lung cancer, but I do have a patient with thyroid cancer.

KESHAVA-PRASAD: I have not treated anyone with [RET-targeted] drugs. But there was a patient with renal cell carcinoma. He [had] stage IV [disease], was not very old, but he had metastases everywhere and his overall condition was poor. I was planning to start him on something such as pembrolizumab [Keytruda], but the NGS came back and he had RET fusion. The problem was by that time he was already so ill that he was on a respirator. [He] passed away, unfortunately, before I could treat him.

TARAKJI: I have not treated anybody with RET mutation because it’s rare. I usually run NGS for the patients up front, especially for those [with metastatic disease]. But I haven’t had a patient with RET mutation. I don’t have any experience with it.

GALAMAGA: I have not treated it in the lung, but I have had experience with selpercatinib [Retevmo] for a patient with RET-rearranged thyroid cancer who presented with multiple nodules, probably too numerous to count. He had a really astounding complete response after just a few months on therapy.

VOGELZANG: The answer for these patients is yes: MRI should be done once you know the genetic mutation. Because [as with] ROS1, ALK, and EGFR, they have a higher risk of brain metastases.

VOGELZANG: It’s interesting. A vote came in for cabozantinib [Cabometyx], and cabozantinib is a pretty good drug for these patients. It’s used as second-line oftentimes, not the first line, but it was in the cabozantinib phase 2 [trial] where they began to see unusual activity that led them to do some genetic testing. It was those patients who proved to have RET mutation. Then, of course, cabozantinib has a very good track record in thyroid cancer.…If you’re unable to get the 2 specific RET inhibitors, cabozantinib is a good second choice.

What factors determine your first-line treat-ment approach?

VICUNA: I had 1 patient with lung cancer with RET fusion, and I put him on a trial of selpercatinib.

VOGELZANG: I tried to get my patient on it and the trial was closed, so I couldn’t do that. Selpercatinib is the one that I’ve used.

KESHAVA-PRASAD: [Because of] comorbid conditions, there might be a preference for 1 RET inhibitor over another I heard. I don’t have that experience, but they said that selpercatinib can cause QT prolongations and cardiac issues, then pralsetinib [Gavreto] can cause interstitial lung disease [ILD]. If anybody has preexisting lung disease, you should avoid that.

VICUNA: When my patients with lung cancer have repository issues, I don’t like pralsetinib because of the potential ILD toxicity. I don’t want to complicate them with breathing issues. I don’t know if it’s progression or if it’s from cancer or if is it ILD. I tend to use selpercatinib.

VOGELZANG: I put one patient on selpercatinib because she had fairly significant respiratory symptoms and I didn’t want to do anything to complicate the clinical picture.

WU: The response in metastases to CNS disease: If a patient has a mutation of adenocarcinoma of the lung with metastases in the brain, that’s definitely the first choice even though the patient was a PD-L1 overexpression.

TARAKJI: I think targeted therapy [is] well tolerated. I think it would be a good option for anybody who has the [RET] mutation rather than giving them just the chemotherapy. There are much fewer adverse events and higher efficacy.

VOGELZANG: How would you handle this? Would you recommend they start the drug and still get radiotherapy? Would you delay radiotherapy? How would you handle a patient such as this?

POMERANTZ: I would think [about] a couple things: Are the brain metastases symptomatic? I think it goes back to the timing. Are we waiting for this? While we’re sitting and waiting, at least we’re doing something. I’m not opposed to starting radiotherapy, but my inclination is, if at all possible, to hold it and, hopefully, we can push down the line. Maybe we wouldn’t need to treat all the initial presenting diseases. Hopefully, we’ll treat less.

I’d say wait, if at all possible, but I understand the emotional component. I think 25% of these patients with RET fusion or rearrangements have brain metastases and, ultimately, I think [approximately] 50% will have those.

VOGELZANG: You’re still not going to be able to fully avoid radiotherapy, so the question always is, “Should they get stereotactic when their tumors have shrunk?” Now, that might be the time to obliterate the brain metastases.

ARSLAND: I think the response rate is high. I think it provides durability. I also think if the patient is asymptomatic in the brain, we can avoid brain radiation and just give them this targeted treatment.

VOGELZANG: I agree. Although you don’t see the eradication of the brain metastases, you’re going to need to radiate them probably down the line, and the timing of that is still as important. You don’t have a cure in the brain.

SANGAVE: I’m a radiation oncologist as well, and I would agree with my colleagues. I think usually we’re following these patients with brain metastases with MRI post surveillance, so I don’t think we’re losing a whole lot in just delaying treatment if they’re asymptomatic.

VOGELZANG: I do worry about the future. You have a great drug, but it doesn’t last forever and you’re still going to have to face things [down the line].

MUKHERJEE: The good part is these drugs are so well tolerated and...with these tyrosine kinase inhibitors, we’re gaining experience. We’re also able to handle the adverse events much better. I think these are great tools, especially if [a patient has] the targeted mutation.

VOGELZANG: Dr Keshava, you brought up pneumonitis. Does that change your feelings about these drugs?

KESHAVA-PRASAD: If the patients don’t have any preexisting lung disease, it works. Either drug is good. I think it comes down to whichever you’re familiar with and whichever you have more experience with.

VOGELZANG: It also may be ease of access. My patient received selpercatinib. She had a response in 24 hours. She said she was feeling better within 24 hours. It’s dramatic. But one of the reasons it took so long for me to get the drug was that I went to get her either drug and it was a matter of who could deliver it sooner. She received selpercatinib. [To me, it is] a matter of what drug can the patient afford and also what drug the insurance will cover.

_REFERENCE:

_{Palma DA, Olson R, Harrow S, et al. Stereotactic ablative radiotherapy for the comprehensive treatment of oligometastatic cancers: long-term results of the SABR-COMET phase II randomized trial. J Clin Oncol. 2020;38(25):2830-2838. doi:10.1200/JCO.20.00818}