Roundtable Discussion: Rodriguez Discusses the Differences in RET+ Lung Cancer Treatment

Estelamari Rodriguez, MD, MPH (Moderator)

Associate Director of Community Outreach, Thoracic Oncology

Sylvester Comprehensive Cancer Center

University of Miami Health System

Miami, FL

AGALIOTIS: We tend to use liquid biopsy at the same time as tumor tissue to get as many tumor markers available as possible. I don’t know whether other colleagues do the same thing, but I’m trying to do that now, at least for labs that do both like Guardant360; they do liquid biopsy and the histology.

Now, PD-L1, yes, it comes fast, but PD-L1 is not reliable in the liquid biopsy, so if you have enough material to run it on the tumors [that] is best, and then do the rest of the test in liquid, and if you have enough material [then test] the histological specimen. That’s what I’m trying to apply to my patients, and I would prefer to test, test, test and do most of the available markers that we can from the lab that you’re using.

RODRIGUEZ: Are you doing testing now on patients who are surgical cases, resected cases—are you doing full testing?

AGALIOTIS: Yes, and for solid tumors, we use minimal residual disease as well, to make sure that this remains negative—again, if there’s enough material to do the original tumor or circulating DNA.

RODRIGUEZ: That’s interesting. I haven’t done that. Have you been able to detect these rarer fusions in liquid biopsies consistently, or have you had panel discrepancy between NGS and tumor or liquid?

CARTWRIGHT: Maybe a few years ago there seemed to be more discrepancy, but now if you do foundation liquid and tissue testing or Guardant, there seems to be a pretty good correlation. RET is 1% or 2%, so if [you] missed something, I don’t think you would know it, but I think if you order them both from the same company, there seems to be pretty good correlation, and I think it’s better the last few years rather than 5 years ago.

RODRIGUEZ: Some companies out there are doing RNA-based testing, so they have more sensitivity for some of these fusions but I think the technology has gotten better.

RODRIGUEZ: I heard Dr Agaliotis mentioning that he does liquid biopsy and NGS at the same time, which we do [as well]. I think most of us do that, and I think we probably do that more routinely because we like to get the information as fast as we can. What about the question of communicating with the interventionalist? Do you make a phone call? Or [are] most interventionalists in your area aware that we need enough tissue for testing?

CARTWRIGHT: Sometimes it’s difficult [to get enough tissue], but [one should] routinely order liquid and tissue at the same time, next generation, because I think they are complementary. You don’t want to do one and then wait another 2 weeks or so, and so the liquid sometimes comes back quicker but I think the radiologists do the best they can to get the most tissue.

PARAS: I send in both for NGS and liquid biopsy. I think sometimes they don’t have enough specimens, so they would ask what’s my priority. Sometimes I’m not able to order the MET or the RET, because by the time they will run the test, they will not have enough samples. Usually, I end up just getting the EGFR, ALK, ROS1, PD-L1 TPS, and then I order the liquid biopsy just to supplement.

RODRIGUEZ: The National Comprehensive Cancer Network [NCCN] recommendations added KRAS as part of the recommended testings.¹ Now we have EGFR, ALK, ROS1, BRAF, NTRK1/2/3, RET, and KRAS. Then testing should be conducted, as part of a broad molecular testing, which I think is opening the door for full NGS instead of hot spot testing. I think that as a field, there have been more data that if we do broader testing we get more information, because a lot of these options are coming at us fast.

So, the recommendation is if you do broader testing, you will minimize tissue waste, and you identify rare mutations, and there are trials. We have one of those trials at the University of Miami, the NCI-MATCH trial [NCT02465060] and the [American Society of Clinical Oncology] TAPUR trial [NCT02693535]; those are trials where if you find rare mutations in one of these NGS reports, you can potentially put a patient in a basket trial.^2,3 It is important to get all the information up front for patient care. If there is insufficient tissue to allow testing and KRAS, are they recommending that a repeat biopsy or plasma testing should be done?¹

AGALIOTIS: So for squamous you don’t do all this, or you do? What do you do for squamous?

RODRIGUEZ: That’s a great question, and we’re covering nonsquamous [lung cancer], but for squamous, you do have KRAS and MET exon 14 skip mutation, so we do test for squamous as well, because we believe that’s important for patient care. You’re not going to get as much information, you don’t have as many targeted options, you have only 2, and you have some rare mixed tumors that may have EGFR. For the most part, the recommendation for squamous is to do PD-L1, and NGS testing is still recommended.

The recommendation is the same: that although PD-L1 expression can be elevated with an oncogenic driver, targeted therapy for the driver should take precedence. This patient had an 80% PD-L1 expression, but these patients will do well with targeted treatment, and we’ve seen that at different stages of disease. In the recent PACIFIC trial [NCT02125461], they looked at patients who had EGFR and ALK, and they found that they didn’t have a lot of benefit from consolidation immunotherapy, so the driver mutations don’t do as well with immunotherapy.^3,4 Patients with metastatic cancer and PD-L1 more than 1 should have 1 line of targeted therapy and should not have first-line immunotherapy alone.

When I read this…it makes sense to me, but when some of the companies have published real-world data, you’ll be surprised by how many patients have had pembrolizumab [Keytruda], for example, without any testing out there. There are probably other reasons for that, like patients who are too ill—and doctors, patients want immunotherapy, they don’t have tissue for biopsy, and they feel like that’s the only thing the patient can tolerate. But it’s not an insignificant number of patients who go through immunotherapy before having PD-L1 testing, so I just wanted to highlight that.

CARTWRIGHT: I know patients who have thyroid or lung [cancer] have a high response to these drugs. What about some of those other cancers; are there any data?

RODRIGUEZ: In the basket trial, it was predominantly non– small cell and medullary thyroid, so I don’t know about the esophageal responses.

CARTWRIGHT: Yeah, I just wondered if you did NGS on, say, a colon cancer, [and] it came back having a RET mutation, would you treat the patient? I guess there are just no data for something like that.

RODRIGUEZ: There are data from the lung space and medullary thyroid that you get first-line responses that are better than the standard, and there are no published [data] for RET fusions in these other tumors that are better than your standard. I would reserve those options in some cases for patients who have failed the first line, at least, of treatment, but that is a great question. I think we don’t have enough data to answer it well right now.

RODRIGUEZ: Is this patient typical in what proportion of patients with RET-rearranged lung cancer have brain involvement at diagnosis? How many do you think develop brain metastases at some point or in the course of the disease, and what is your general approach for patients with brain metastases that have a targeted therapy option? Are these patients you’re referring to radiation; are you doing treatment up front? I would like to get comments… if you choose not to treat the patient, send the patient to a radiation oncologist, how closely do you follow the brain metastases, for example?

LUKE: If there is a target, a patient who is not symptomatic, then I’ll wait, use the targeted drug, and see whether you get a response. If the patient is symptomatic, enlarged tumors, we either resect it or go with the radiation therapy.

RODRIGUEZ: You base it on symptoms? Do you do baseline MRI screening on all patients regardless of symptoms?

LUKE: [For] all patients who are metastatic we do MRIs, whether they have symptoms or not.

RODRIGUEZ: I guess that way, you don’t have any surprises. We enroll patients in phase 1 clinical trials, and [in] some of these trials, you only need an MRI [if the patient is] symptomatic or [has already] shown progression. But I agree with you [on] testing up front and doing an MRI. What I sometimes struggle with is, how often do you monitor the response before you decide on radiation? In some cases [where] I’m very concerned, I will do another MRI in 6 to 8 weeks, but that might be a bit excessive.

If patients are not symptomatic, you probably have more time to evaluate response. We are fortunate at the university that we have neuro-oncologists.

When I was at a prior practice, we didn’t have neuro-oncologists to run this by. Some patients who have multiple brain metastases, who are very young, can be very challenging to know what to treat and when to treat, and to minimize toxicity. I think we all have moved away from whole brain radiation as a field, which is a good thing for patients.

RODRIGUEZ: Once you knew the patient had RET-rearranged lung cancer, would you still do chemoimmunotherapy up front? What drives your selection of RET inhibitors in the front line vs immunotherapy?

CARTWRIGHT: I think it’s the high response rate. I don’t remember exactly, but I think the response rate is 70% to 80% in brain metastases and progression-free survival is close to 2 years. The problem I have with brain metastases is the radiation therapists find out about it, they start the patients on radiation therapy that day, and it’s hard to talk them out of it. What do you do; are the radiation therapists not quite so aggressive?

RODRIGUEZ: I don’t know. I guess our radiation oncology team is so busy that I haven’t encountered a case that they have seen before I’ve seen.

AMIN: When they have small tumors and they have a target, they’ve been very willing to allow me to treat them first, and ask how quickly [they respond]. I mean, I think in general, when [patients] have mutations, you’ll see a response within 6 weeks, when you repeat the MRI. So they’ve been very… OK with letting us treat first on a mutation, especially with a drug that you know has CNS penetration. Like osimertinib [Tagrisso], you see a lot of CNS penetration, and obviously there are RET inhibitors that have CNS penetration, so I think they’re starting to, at least at our university, allow us to do treatment first and avoid radiation.

RODRIGUEZ: I mean, there are some gray areas.

CARTWRIGHT: I think the problem is that sometimes, the primary care or the pulmonologist [sees] brain metastases and sends them to radiation immediately before you even have a chance to do the testing.

NGUYEN: But for patients with just a few brain metastases, they’re candidates for stereotactic body radiation therapy [SBRT]; there’s no harm in giving them SBRT, right?

RODRIGUEZ: No, there’s no harm, except that after treating some of these patients who have done well for years with tyrosine kinase inhibitors [TKIs], radiation necrosis…impacts things down the line. However, I agree…if the patient is in front of you and you can do SBRT, there’s nothing wrong with that. I think that when the patient comes to you and they already have seen a radiation oncologist, it’s sometimes hard to get that train back, but I guess you can contribute some of the data, and I think as the radiation oncologists see [that] these patients do well, they also are more willing to wait.

When I graduated from fellowship and started becoming an attending [physician], I would go always to the guidelines to see what to do, and then I would encounter all these things with category 1 recommendation, or many options that didn’t help you make decisions. But they do, here at least, prefer selpercatinib [Retevmo] and pralsetinib [Gavreto] based on the data.

Previous to that, we had data for cabozantinib [Cabometyx] and vandetanib [Caprelsa], but that’s category 2B at this point, and then there are options.¹ Basically, other patients can get chemotherapy, if need be, so that’s still included in the NCCN guidelines. If you discover the RET rearrangement during first-line therapy, the recommendation is that you complete your planned systemic therapy, so if you were doing carboplatin and pembrolizumab [or just pembrolizumab] you would complete the planned systemic therapy, including maintenance, followed by a TKI, so that has a category 2B recommendation. I wanted to know from the group, when you encounter that situation, do you complete your plan and then move to a TKI, or do you go to a TKI directly?

NEGRET: I tend to switch them to an oral-directed therapy. I think when you go over it with the patient, and you tell them the information and data, a lot of them choose to reserve the chemotherapy and immunotherapy for the second line, and are willing to switch over to a targeted therapy, you know? In general, I try to switch them over to a targeted therapy.

RODRIGUEZ: The other concern is that getting the TKI to the patient can take time in some cases.

NEGRET: The exceptions would be [individuals] whom you’re going to give osimertinib, but I don’t think that has been shown as much with the [patients with] RET mutations who don’t get pneumonitis.

RODRIGUEZ: They haven’t shown it, and I think some [individuals], what they have done for caution is take a break from the immunotherapy for at least 3 months before you give people a TKI, at least for osimertinib. However, for selpercatinib and pralsetinib, that hasn’t been shown, so I think I probably will be more conservative and move over.

NGUYEN: I think it’s overall a small number for CNS control; just about 50%, right?

RODRIGUEZ: Yes, and there were only 8 patients on whom they presented data. We would like to see more patients, obviously.

CARTWRIGHT: How do you manage the hypertension?

RODRIGUEZ: I think if a patient comes to me and they already have 3 hypertension medications, and I am going to start this drug, I want to involve the primary care doctor and the team that has been managing the blood pressure. After they’re already on 3 or 2 drugs, I think I need help, but for the most part this is manageable.

I do have patients who get very obsessive about it. Every time they come to see us, they get white coat hypertension, it gets worse, and then at home it’s not that bad. For the most part, it’s a real thing, but it’s not that it’s happening in front of you. If you ask them to check at home, they will have hypertension, and a lot of them will need treatment.

CARTWRIGHT: Yeah, probably 10 or 15 years ago, I was asked to write a review article on management of hypertension with VEGF drugs. I wrote the article, and the reviewers hated it. They said, “This is just anecdotes, there’s no evidence; it’s just your opinion, but there wasn’t any evidence.” You know, just recommended [angiotensin-converting enzyme] inhibitors and diuretics and occasional calcium [channel blockers], but that was 15 years ago, and I don’t think there are still any data out.

RODRIGUEZ: We have some guidelines for immunotherapy-related adverse events, and some toxicities, but we don’t have good guidance for hypertension. Some of the clinical trials recommend amlodipine [Norvasc] but they give you an option [of a] β-blocker. You have a lot of options up front; whatever it’s easier to do with the patient.

_REFERENCES

_{1. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 3.2022. Accessed March 7, 2022. https://www.nccn.org/professionals/physician_ gls/pdf/nscl.pdf}

_{2. Targeted therapy directed by genetic testing in treating patients with advanced refractory solid tumors, lymphomas, or multiple myeloma (the MATCH screening trial). ClinicalTrials.gov. Updated March 3, 2022. Accessed March 8, 2022. https://clinicaltrials.gov/ct2/show/NCT02465060}

_{3. TAPUR: testing the use of Food and Drug Administration (FDA) approved drugs that target a specific abnormality in a tumor gene in people with advanced stage cancer (TAPUR). ClinicalTrials.gov. Updated March 17, 2022. Accessed March 17, 2022. https://clinicaltrials.gov/ct2/show/NCT02693535}

_{4. Antonia SJ, Villegas A, Daniel D, et al; PACIFIC Investigators. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017;377(20):1919- 1929. doi:10.1056/NEJMoa1709937}

_{5. Antonia SJ, Villegas A, Daniel D, et al; PACIFIC Investigators. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018;379(24):2342-2350. doi:10.1056/NEJMoa1809697}