Roundtable Discussion: Brose and Participants Review NTRK Inhibitors vs Other Therapies for Advanced Thyroid Cancer

Marcia S. Brose, MD, PhD (Moderator)

Vice Chair of Medical Oncology

SKCC Regional Chief of Cancer Services Sidney Kimmel Cancer Center – Jefferson Health

Philadelphia, PA

CASE SUMMARY

A 67-year-old woman presented with a painless lump on her neck. Physical exam results showed a palpable, nontender, solitary, right-of-the-midline neck mass. Exam results were otherwise unremarkable. Laboratory results, including thyroid-stimulating hormone (TSH) level, were within normal limits. An ultrasound of the neck revealed a 3.6-cm suspicious mass arising from the right thyroid and 3 suspicious supraclavicular lymph nodes (LNs), the largest being 2.0 cm. An ultrasound-guided fine-needle aspiration biopsy of the thyroid mass and the largest LN confirmed a diagnosis of papillary thyroid carcinoma.

The patient underwent total thyroidectomy with central compartment and right selective neck dissection. Pathology showed a 3.6-cm papillary thyroid cancer arising in the right lobe of the thyroid, tall-cell features, extrathyroidal extension present; 2 of 6 positive central compartment LNs, largest 1.6 cm, no extranodal extension; 3 of 13 right lateral compartment LNs, largest 2 cm, positive extranodal extension. Her disease staging was T2N1bMX and her ECOG performance status was 0.

She was treated with radioactive iodine 150 mCi. Whole-body scan results showed uptake in the neck only, consistent with thyroid remnant. At 6-month follow-up, the TSH level was 0.1 mU/L and thyroglobulin was 24 ng/mL (negative for antithyroglobulin antibodies). A chest CT scan showed approximately 10 small bilateral lung nodules, the largest being 1.1 cm. Follow-up CT neck and chest scans 3 months later were notable for a 1- to 2-mm growth in several lung nodules and 2 new, distinct 8-mm lung nodules.

Next-generation sequencing showed an NTRK1 gene fusion.

BROSE: [In thyroid cancer], sorafenib [Nexavar] and lenvatinib [Lenvima], 2 multikinase inhibitors, are approved in the first-line setting. Cabozantinib [Cometriq] is approved in the second-line setting.¹ There are NTRK and RET [inhibitors] approved across the board. Immune checkpoint inhibitors have the tumor agnostic indication. Two-thirds of participants [chose] an NTRK inhibitor and one-third [chose] the VEGF receptor inhibitor. There are no data to say one is right and the other is wrong. Lenvatinib has been the go-to for many years now for most patients in the first-line setting. [One] would not get it wrong by choosing lenvatinib or sorafenib. However, I think the thing that’s differentiating the NTRK inhibitors is the adverse event [AE] profile. I don’t think we’re going to get a head-to-head [comparison trial] because NTRK gene fusions are so rare.

DISCUSSION QUESTIONS

• What triggers warrant a change/addition of therapy?
• How do you decide what treatment to use?
• What factors related to this case drive your selection?

BROSE: When you’re thinking about up-front treatment options available for RAI [radioactive iodine]-refractory DTC [differentiated thyroid cancer], what kind of triggers warrant a change or addition of another therapy, and how much treatment would you use? It’s a solid tumor like everything else. What’s your general rule if the patient is on an oral therapy and it’s working? Even for lung cancer or other cancers, what do you usually do? Do you stop at a certain point or do you continue? And what usually prompts you to change?

FAROUN: The No. 1 [reason to change therapies] is if the patient is progressing.

BROSE: If a patient is progressing, that usually makes us change. I had 2 patients whom I didn’t test until later because they were doing great, and then they started progressing on lenvatinib. This was before cabozantinib was approved, so I did the testing at that point because they hadn’t had testing. I didn’t want to put them through a bronchoscopy and I didn’t have any other tissue. Remember, tissue…is a problem if you’re doing RNA-based testing. For a sample that’s older than 2 years, sometimes the RNA is not viable.

When you’re thinking about choosing between different types of treatments, for any cancer, what are the factors that affect you the most? There are a handful of factors: age, comorbidities, toxicity, need for response, survival benefit, NCCN [National Comprehensive Cancer] guidelines, and ATA [American Thyroid Association] guidelines.^1,2 What are your top 3 factors for picking a therapy?

RIZVI: Generally the survival benefit, No. 1. Toxicity, No. 2. The third one would be comorbidities.

FAROUN: I think because we don’t treat a lot of thyroid cancer, I follow the NCCN guidelines. Toxicity is important because a lot of tyrosine kinase inhibitors are not tolerated at the recommended dose. And I consider survival benefit.

BROSE: Of course, the situation that we’re talking about is in a patient [with metastases]. I think that those numbers might change if we were talking about adjuvant therapy, or we’re going for a cure. You might accept a little bit more toxicity if you had a better chance at a cure; at least, that’s one of the things that might change it.

DISCUSSION QUESTIONS

• How do you counsel the patient about what to expect, and what are the goals of therapy?

BROSE: What’s your approach? A generic patient comes in. Let’s say they’re eligible for a bunch of oral therapies, not necessarily chemotherapy, as a choice. How do you usually approach educating patients, talking to them about whether or not they want to do it?

NATHAN: Usually I discuss treatment options. What are their expectations? What is important to them? [And] quality of life [and] how [adherent] they are with taking the medications. I also discuss the comorbid conditions that they have and how this treatment will affect them. Then we’ll have a conversation and pick the one that is best for them.

BROSE: I think it’s important [to note that] most of these therapies are not curative. That’s one of the first things that we have to let the patients know, [regarding] their expectations. I even have patients with metastatic disease who are still hoping for a cure. So I have to explain to them that many times it shrinks quite a bit, but often doesn’t go away, and that this is going to be a long-term therapy. I think that brings up the point that Dr Rizvi said, which is that toxicity and quality of life start to become more important. And of course, talking about goals of therapy, especially with regard to quality of life, maintaining lifestyle and things like that, is important.

I also have a long conversation with my patients about— and this is regardless of the therapy—how once they start, our relationship changes in a way, from me being just the doctor to being a kind of coach. They will run into problems and issues, and then they have to discuss them with me if I’m going to help them mitigate some of them, because I think mitigating any AEs, whether it’s a more active drug with more or fewer AEs, is an important part of that question—especially with oral therapies, where they go on and on and [adherence] can be an issue.

DISCUSSION QUESTIONS

• What should influence the recommendation of the NTRK inhibitor?
• Which end points from the studies of these agents are most important to you?

BROSE: What should influence the recommendation of the NTRK inhibitor for a patient like this? The fact that they have a [certain] site of disease? Is it their mutational profile, convenience, quality of life, patient satisfaction, financial toxicity, or other patient factors? What are the top factors that would influence you to recommend NTRK inhibitors to a patient like this?

BURKI: First is their mutational profile. That is important. Also, from what I’ve heard—I’ve never personally used them—it’s not hard to tolerate these agents, so I think that goes a long way, especially when we’re trying to maintain quality of life. Then, the ease and convenience of taking it.

BROSE: There’s something [advantageous] about an oral therapy that they can just stop the day before if they need to have a surgery or something like that. I’ve almost exclusively been dealing with oral therapies my whole career; it’s been a nice thing, and definitely good for the patients. That affects quality of life, as well as convenience. It all goes together.

Which end points do you think are the most convincing? Would it be a good progression-free survival [PFS], objective response rate, time to response, duration of response [DOR], or other? Dr Rizvi said he likes [overall] survival [OS].

SILVA: I think PFS is probably very acceptable in a situation like this. Especially with this disease, considering it is not as fast-growing as many other tumors. You have an opportunity to try something else. Going back to the issue, in terms of the factors, I also suspect the NTRK agents are more tolerable than the VEGF agents.

BROSE: The point is well taken that PFS is the primary end point that we have, especially because with all the crossover it’s hard to show in any of these studies that there’s OS [benefit]. However, the VEGF receptor [inhibitors] have shown OS, interestingly, especially in patients over age 65. Lenvatinib has an OS benefit. Cabozantinib has an OS benefit in medullary thyroid cancer, but not without a cost.

SILVA: My more extended experience with lenvatinib is in other diseases, especially endometrial cancer. It’s a very hard drug for patients to take at the full dose.

BROSE: Are you talking about giving it with pembrolizumab [Keytruda] or do you give it as a single agent?

SILVA: With pembrolizumab, yes.

BROSE: Pembrolizumab has overlapping toxicity [with lenvatinib]. In general, my experience with the combination is that getting over [lenvatinib] 14 mg is rare.

SILVA: Fatigue is the issue that patients complain about the most. I’m not so sure how much the pembrolizumab contributes to that. I have used [lenvatinib] a couple of times in other cancers, including [as a single agent] in hepatocellular carcinoma [HCC], and back before the combination was used in [renal cell carcinoma]. Even as a single agent, it’s a harsh drug to take at more than 14 mg.

BROSE: There are interesting data in thyroid cancer, because that is where [lenvatinib] started. The starting dose was 24 mg, which is hefty, and you had high grade 3 toxicity, mostly hypertension. That was the limiting dose.

What was also interesting is that there was a randomized, placebo-controlled, double-blind trial [with] between 18 mg and 24 mg as a starting dose.³ It showed that the 24-mg dose was more efficacious, and at the end of the day, there were the same number of grade 3 [AEs] and same quality of life detriment. You could only do that with a blinded unbiased trial.

What that implies, at least in thyroid cancer, is that you [may want] to start at the higher dose. By starting at the higher dose, you’re going to get a better efficacy without sacrificing much in [tolerability and quality of life]. When you change the dose as needed, the patients do just as well, whether they start on a higher dose or a lower dose.

SILVA: I got scared with that drug at a bigger dose when I tried it in a patient who was relatively young and healthy with HCC. The patient was responding beautifully to the drug and HCC doses are smaller.

He was taking 10 mg or 12 mg. I thought he was responding well. He developed a very florid case of heart failure, so I had to stop the drug and send him to [the] cardio-oncology [department]. By the time I was able to resume the drug at a lower dose, his disease had taken over.

BROSE: I’ve [treated] several hundred patients with thyroid cancer and they didn’t have that. That probably had more to do with the physiology of HCC.

[There] are AEs you have to manage, and I’d say hypertension is No. 1 in thyroid cancer. The nice thing about [patients with] thyroid cancer is, in general, they’re healthy patients. But toxicity and safety are at the top of my mind and I think that’s exactly why a lot of oncologists are preferring to [target] the NTRK fusions, if you know about them.^5,6 But in order to know about them, you have to test up front and some physicians hadn’t been doing that; so [this is] another reason to do that, in that order.

DISCUSSION QUESTIONS

• What are your reactions to the NTRK inhibitor data?
• From your perspective, what are the similarities and differences between larotrectinib (Vitrakvi) and entrectinib (Rozlytrek) in terms of efficacy, safety, and convenience?

BROSE: From your perspective, what are the similarities and differences between larotrectinib and entrectinib in terms of efficacy, safety, and convenience?

FAROUN: If you have a patient with an NTRK fusion mutation, you have to go right away to an NTRK inhibitor, instead of lenvatinib, in my opinion. There is a higher objective response rate [ORR], [86%], for larotrectinib [in papillary and follicular thyroid cancer], and DOR up to 39 months [with a median DOR of 24 months], so you can’t beat that.^6,7 That’s my drug of choice.

BROSE: [Would you choose] that over entrectinib?

FAROUN: [Entrectinib had] a 62% ORR in patients with thyroid cancer.⁸ I don’t know if the patient progresses on the first agent…[whether they] would respond to a second agent. I don’t know, but I still believe that larotrectinib is the first choice for me.

BROSE: It turns out that it’s not so great to [sequence one after the other]. There are second-generation [NTRK inhibitors] out there that address the gatekeeper mutations in the most common resistance. But for each other, there is some cross resistance because they’re a bit too similar.

PROOTHI: The efficacy is definitely better with the larotrectinib [in terms of] ORR and DOR. So I think there’s a winner, even though it’s not a head-to-head study. The toxicity is not much different.

BROSE: [Toxicity] may be a little better with larotrectinib when you’re actually giving it. Those are good observations.

Obviously, they’re both indicated.^9,10 There’s a little bit more JAK2 activity with entrectinib. That’s why patients are having a little bit more toxicity, as [well as] the ROS1 activity. Unfortunately, some of those are the activities that are causing more toxicity in the entrectinib. That’s great if you want to target ROS1 or ALK, but it’s not so good if you don’t want to target those.

DISCUSSION QUESTION

• Are there any adverse reactions for larotrectinib or entrectinib that stood out to you? How would you manage them?

BROSE: Give me an example of how you would manage an oral therapy with this kind of a toxicity profile.

FAROUN: Fluid retention in entrectinib. This is weight gain. I don’t know if they respond to furosemide [Lasix], or any diuretics, or even steroids.

BROSE: Interestingly, the weight gain seems to be real weight. All my female patients get quite despondent about this. Some of the mechanisms in the central nervous system might be the cause, but it is probably from ingesting increased calories.

It is good to warn patients up front that they may [have a greater appetite], and if they don’t want to gain weight, they’ll probably have to pay attention, because many of my patients come in 10 lbs heavier, pretty quickly, if they’re not tracking it, so it’s a good thing to know. I do have them come in every 2 weeks for the first month just to make sure everything’s OK, and then I spread it out pretty quickly as long as they’re doing well. I think that’s a good way to monitor.

_REFERENCES

_{1. NCCN. Clinical Practice Guidelines in Oncology. Thyroid carcinoma, version 3.2022. Accessed January 31, 2023. https://bit.ly/3HI5FXG}

_{2. Bible KC, Kebebew E, Brierley J, et al. 2021 American Thyroid Association guidelines for management of patients with anaplastic thyroid cancer. Thyroid. 2021;31(3):337-386. doi:10.1089/thy.2020.0944}

_{3. Brose MS, Panaseykin Y, Konda B, et al. A randomized study of lenvatinib 18 mg vs 24 mg in patients with radioiodine-refractory differentiated thyroid cancer. J Clin Endocrinol Metab. 2022;107(3):776-787. doi:10.1210/clinem/dgab731}

_{4. Tahara M, Kiyota N, Hoff AO, et al. Impact of lung metastases on overall survival in the phase 3 SELECT study of lenvatinib in patients with radioiodine-refractory differentiated thyroid cancer. Eur J Cancer. 2021;147:51-57. doi:10.1016/j.ejca.2020.12.032}

_{5. Schlumberger M, Elisei R, Müller S, et al. Overall survival analysis of EXAM, a phase III trial of cabozantinib in patients with radiographically progressive medullary thyroid carcinoma. Ann Oncol. 2017;28(11):2813-2819. doi:10.1093/annonc/mdx479}

_{6. Waguespack SG, Drilon A, Lin JJ, et al. Efficacy and safety of larotrectinib in patients with TRK fusion-positive thyroid carcinoma. Eur J Endocrinol. 2022;186(6):631-643. doi:10.1530/EJE-21-1259}

_{7. Hong DS, DuBois SG, Kummar S, et al. Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol. 2020;21(4):531-540. doi:10.1016/S1470-2045(19)30856-3}

_{8. Demetri GD, De Braud F, Drilon A, et al. Updated integrated analysis of the efficacy and safety of entrectinib in patients with NTRK fusion-positive solid tumors. Clin Cancer Res. 2022;28(7):1302-1312. doi:10.1158/1078-0432.CCR-21-3597}

_{9. Vitrakvi. Prescribing information. Bayer HealthCare Pharmaceuticals Inc; 2021. Accessed January 31, 2023. https://bit.ly/3WQK7wj}

_{10. Rozlytrek. Prescribing information. Genentech, Inc; 2019. Accessed January 31, 2023. https://bit.ly/40jCUaU}