Roundtable Discussion: Brose Reviews Data for Using Lenvatinib in Everyday Practice

During a Targeted Oncology^TM Case-Based Roundtable event, Marcia S. Brose, MD, PhD, director, Center for Rare Cancers and Personalized Therapy, director, Thyroid Cancer Therapeutics Program, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania in Philadelphia, PA, discussed the case of a 67-year-old woman with thyroid cancer.

BROSE: What are the upfront treatments that are available for radioactive-refractory differentiated thyroid cancer [RR-DTC]? At this point, I’m glad nobody put doxorubicin [Adriamycin], because it is no longer indicated.

The data for doxorubicin predated CT scans, so it was approved based on x-rays when you couldn’t see anything, so this is no longer something that we would recommend. [For those of you who voted lenvatinib (Lenvima)], what made you think of starting lenvatinib? [Why] did you choose [it]? Lenvatinib, sorafenib [Nexavar], and pembrolizumab [Keytruda]—provided that patients have microsatellite instability [MSI]-high disease—would have been all FDA approved in this [setting].

MITA: Lenvatinib is my preferred first-line treatment. In my experience, I had a little bit less toxicity with lenvatinib and it was more manageable compared with sorafenib. I’m not aware [of] any direct comparison between the 2, and it’s always dangerous to compare across trials, but…I had better luck with lenvatinib and I stick with it. In the absence of other factors to indicate another treatment, if patients have an activating agent or MSI-high disease, anything like that, lenvatinib is my preferred first line.

I’m using 20 mg [of lenvatinib]. I don’t start at 24 mg. I think lenvatinib is one of those drugs that was approved with too high a dose for most patients, and I start at 20 mg. I try to avoid starting at 18 mg because there was that trial [whose data] failed to show noninferiority of 18 compared with 24 mg, so I’m trying to be not too toxic but not too low.¹

BROSE: In addition to the fact that 18 mg was not noninferior, it also, interestingly, showed that it had the same number of grade 3 serious adverse events and the same quality-of-life factors…. I was also doing the lower [dose], but it shows that the higher dose is superior but the quality of life and the safety are the same.²

MITA: I have not seen that.

KHASAWNEH: There were some data in kidney cancer with everolimus and lenvatinib comparing 18 with 14 mg. The efficacy was better and the quality of life was worse on the 14 mg compared with 18 mg of lenvatinib when you gave it with everolimus.³

BROSE: That’s a very different question of doing the combination. I’m talking about single-agent lenvatinib, which was in a blinded, randomized trial. In other words, people didn’t know which dose they were getting, so they couldn’t [become] biased by their physician or by themselves to think, “Oh, I’m going to have more toxicity,” and interestingly, I did not expect these data. I have to tell you, I was shocked.

But the quality of life was virtually superimposable and the safety was superimposable, so what that says is, when you start with lenvatinib, you have to pay attention to your patient.2 If you pay attention to your patient you’ll do the right things, whether it means stopping the drug, pausing the drug, or treating their blood pressure, but as long as you do that, they will get the same quality of life and safety [and]…a better overall response. I know people are nervous about it.

MITA: I was not aware of the data and I would like to see how the data came [out] because they are surprising, as you said. In my…experience, when you reduce the dose from 24 to 20 mg, [patients] do better. I don’t understand how the results came [out] that way.

BROSE: That paper you referred to was accepted by the Journal of Clinical Endocrinology and Metabolism, so in the original study that has the safety and the dose, the efficacy is there.1 There’s a second paper on the quality of life that was presented at the European Society for Medical Oncology [meeting].2 I will leave that there, but just wanted to say that [the results] surprised me. I am like you, I didn’t expect it, but I have to pay attention to these data because the trial was done the right way, so it would be interesting to see.

BROSE: Lenvatinib, I think, is most people’s first choice. But I agree, you can’t do head-to-head comparisons. Interestingly, a lot of people stay away from sorafenib because patients have a skin reaction. A lot of people don’t realize that if you treat this with ibuprofen and keep the hands and skin well hydrated, patients acclimate to it, if you can get them over the first 4 to 6 months. I’ve had patients stay on sorafenib for 8 years. I’m not saying that I do that first, [but] there are some patients where I do do it first.

Another thing I think about when I’m starting patients is, in this case, I was one of the people who [voted for] active surveillance because they’re definitely going in that direction. I’m now having that conversation with a patient: “You’re going to probably be on this in the next 3 to 6 months. What weddings do you have to go to? What trips do you have planned? What do you have going on in the next 3 months? Let’s make sure we get you through those things,” because usually it’s not an emergency.

This patient’s [disease] is going to keep growing, but they’re not right now in imminent risk of harm. That’s not true if 1 of these nodules or a 1-cm nodule is on the pleura and they could suddenly overnight develop a huge pleural effusion.

So I look at 5 criteria: rate of progression, location, the size of the largest nodules, the overall tumor burden, and [lastly] symptoms. If they have symptoms, I feel like I’ve missed the boat. I really want to [treat] them before they have symptoms, so those are things I throw out there as things that you want to be looking for in these patients.

You never do that with lung cancer. [With] lung cancer and a 2-cm nodule, you’re going to treat them no matter what. But [with] thyroid cancer, you have a little bit of room, and you can really work with a patient to have a good quality of life when they start these therapies.

BROSE: An older-aged patient is interesting…. We worry a little bit more about blood pressure and things like that. There were data, interestingly, that said with lenvatinib, if patients are over 65 years old, they had an overall survival benefit.4 That was another shocker, and that’s probably because older people don’t tolerate progression the way somebody who’s younger does. Somebody who’s younger might manage better if they have some growth; people who are older are more likely to have an event that will lead to their demise, so it turned out that age was the opposite of what I expected.

We do look at comorbidities and toxicities. Which of these factors drive your selection? When you’re talking to your patients, for instance, you know you have sorafenib and lenvatinib; how do you bring that up when you’re talking to them, because there’s more than 1 choice? Most people picked lenvatinib. How do you have those discussions with them before they start?

BENDANDI: I think that sometimes the most important thing for the patient is [talking about the] chemotherapy, which is a tough question. I explain that if they mean old-fashioned chemotherapy, no, it’s not [that], but it is chemotherapy.

BROSE: You have to really give them some good education about what to expect. My patients get the number of the nurse navigator and I have them text their blood pressures every day for that first week. I have prescriptions—thank goodness for e-scribing¾because I will often get them on blood pressure medicines right away, so if it does start to shoot up we’re on top of that.

It’s also good to have the blood pressure well controlled before you start, of course. Do you ever tell patients that they have a choice between sorafenib and lenvatinib, or do you just say lenvatinib is the one?

MITA: I tell them. I don’t want the burden on them to make them feel that they have [to make] the choice. I tell them their 2 options and…this is what I prefer. [So they know] they don’t have to be treating themselves.

BROSE: I do think that as an oncologist you’re obligated to weigh the data for them.

MITA: I tell them that that’s what I would take for myself.

BROSE: The other thing I would point out is, sometimes, if lenvatinib stops working and you go through your other options, and you don’t have any other options, they might end up on sorafenib. [Additionally], you have to be a little careful not to shoot yourself in the foot and say this one is really great and this one sucks, because if they end up on the one later, you’re going to have to convince them to take that because that might be their only option down the line. So do remember that there are a limited number of options and be a little bit delicate with how you’re presenting [them]….

Our goals of therapy [are that] you explain to them we’re not curing people. They understand this is going to be long term; we’re doing a marathon here, not a sprint.

The National Comprehensive Cancer Network guidelines talks about using larotrectinib [Vitrakvi] or entrectinib [Rozlytrek] if they have an NTRK fusion.5 The larotrectinib data look a little bit better for toxicity and efficacy, so I usually choose larotrectinib over entrectinib. Selpercatinib [Retevmo] and pralsetinib [Gavreto] are also approved for RET fusion.

Pembrolizumab is approved, but there aren’t really good data for that in thyroid cancer. The No. 1 and 2 are lenvatinib and sorafenib.

HAO: I have a question about patients with BRAF V600E [mutations]. I have 1 patient who had a FoundationOne CDx panel and it showed BRAF V600E. I believe the recommendation is still always lenvatinib. My question is, where do you put that anti-BRAF treatment in [sequencing]?

BROSE: I put it third or fourth line. The data for the BRAF mutations are phase 2…[for] vemurafenib [Zelboraf] from 2012, as well as dabrafenib [Tafinlar] about a year or 2 ago. When you compare them with 65% response rates with lenvatinib, I don’t think there’s really any discussion.6 There are people who will say that [vemurafenib or dabrafenib are] more tolerable. I think lenvatinib can be managed if you’re on top of it.

BRAF inhibitors, in my opinion, go after lenvatinib––certainly after cabozantinib [Cabometyx]. So we’re looking at 2 agents at least that would be ahead. If they have a BRAF mutation, they’re going to have lenvatinib, sorafenib, cabozantinib, and a BRAF inhibitor [as options], so my word would be lenvatinib, cabozantinib, and then maybe I’d hit the BRAF inhibitor to give a VEGF receptor inhibitor break, and then maybe I’d use sorafenib in the fourth line. But they’re going to be on this [for about] 10 years; by the time you get to number 3 and 4, hopefully you might even have some better options.

SEMENIUK: Can you comment on the combination of lenvatinib and pembrolizumab for patients?

BROSE: Up front, I don’t think the data are very good. It doesn’t compare well to lenvatinib [monotherapy]. The reason for that is when you combine pembrolizumab and lenvatinib, you’re committing yourself to a lenvatinib dose of 14 mg because in general the colitis is overlapping toxicity, so it’s very rare that you might start them at 18 mg. A lot of the starting doses are at 18 mg, but no one really—in my experience, and I was on all these trials—tolerated more than 14 mg.

So now you have something that you know is dose dependent. We know from the data that higher lenvatinib dosing works better and now you’re taking a lower dose. So even if pembrolizumab is adding something in, it’s adding more toxicity and it’s decreasing the effectiveness of something that we know works. So in the upfront setting, lenvatinib is the one to go with. I do not think the data support the combination.

There are data [where investigators examined the use of pembrolizumab] at the time of progression on lenvatinib. At the time of progression, they added in pembrolizumab and found they could get another 6 to 9 months.7 That might be good. But if you’re measuring by RECIST criteria, if they’re progressing it might have taken them that long to progress anyway, so I would say there are little data there to suggest it; it’s still pretty weak.

SEMENIUK: So generally, when you start lenvatinib you start it at the 18-mg dose and then you [monitor for] toxicity, or do you start low and go high?

BROSE: The data say that you should start at the 24-mg dose. Extremely rarely I will not do that, and it usually is in people who have been on other kinase inhibitors for years. I’ve had some people who weren’t on lenvatinib and then get on lenvatinib later, and I know they’re not going to tolerate [anything] but that’s because of a prior experience with kinase inhibtors.

For brand-new thyroid cancer, [if they] have not had anything else, I will do everything I can to start them at 24 mg of lenvatinib and I will only do a lower dose if I can’t manage adverse events that I know. And that’s part of the trial; you were allowed to drop the dose if you really felt that you couldn’t manage it. We know that the dose intensity is still higher even with those dose drops and we also know that it seems, even if they only get 2 months at that higher dose, that 2 months might be enough to give an extra punch to the cancer. And that might be why they have better efficacy than if you just started at 18 mg to start with.

SEMENIUK: Are you seeing a correlation between hypertension and response?

BROSE: We tried to show that. Lori Wirth, MD, has a paper [on it].8 I would argue the data were not good for that—not because it hasn’t been shown, it’s just that the way the study was done; it was [vastly different] how people were treating the blood pressure. So collecting that blood pressure data was very problematic in the study [and] we do not have [definitive] data.

I’ve been looking for that since 2012 and I’ve tried [looking for correlation] multiple times. I think it just is the way thyroid cancer is.

MITA: Do you ever use a stop-and-go approach because the toxicity is cumulative, both the hand-foot syndrome, the fatigue, and others? I’ve done it with a few patients where I’d give them 3 or 4 weeks on and 1 week off without cutting the dose further because of what we just discussed and the dose dependency.

BROSE: I think staying at a high dose is absolutely important. I don’t do a scheduled thing like you’re talking about because of dose intensity. If they’re tolerating it, I don’t give them a break, but I do give them a break if they have what I call the dwindles; if a patient has been totally fine and then all of a sudden they lose 8 lbs, I’m going to give them a 2-week break. Many times, their gastrointestinal tract needs to be reset and then I start them back on the same dose. So I do use holidays but I wouldn’t call it intermittent dosing in the scheduled way that you’re talking [about] because I would go a lot longer than 4 weeks. Maybe at the very end, if they’ve been on it for a few years and now they need that [break], maybe. But I definitely don’t do that to start with.

MITA: No, I misspoke. I don’t do it upfront but when I see that they have recurrent toxicity and every 4 to 6 weeks they start having this, then I change the schedule instead of reducing the dose.

BROSE: Yes, and I do it, but I do it based on the symptoms, not so much on the schedule. But it probably ends up pretty close. I might just get an extra week here and there because I wait for the symptom, but patients get really good at it. They know when the symptoms are coming and they’ll often let me know. They’ll text me and say, “Hey, I think I need a break,” and I’ll say, “Take a break.”

I also plan breaks. And if somebody is going to have the holidays—Thanksgiving, for example––if they’ve been doing really well for a long time, I might [give them a break]. But [when] I know they’re not eating a lot, I’ll say, “Stop on the Monday before Thanksgiving so you can have a good Thanksgiving.” So I will also do that because quality of life does matter, but I want to do things that won’t also get in the way of their outcome. So not dropping the dose, I think, is more important than giving them a week, [unless] I think I can give them a week and not have that be a big problem.

_REFERENCES

_{1. 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. Published online October 19, 2021. doi:10.1210/clinem/dgab731}

_{2. Taylor MH, Leboulleux S, Panaseykin Y, et al. Health-related quality-of-life (HRQoL) analyses from study 211: a phase 2 study in patients (pts) with radioiodine-refractory differentiated thyroid cancer (RR-DTC) treated with 2 starting doses of lenvatinib (LEN). Ann Oncol. 2021;32(suppl 5):S1205. doi:10.1016/j.annonc.2021.08.892}

_{3. Eisai announces new investigational data evaluating TKI-MTOR inhibitor regimen Lenvima (lenvatinib) plus everolimus in advanced renal cell carcinoma (RCC) at IKCS 2020. News release. Eisai. November 7, 2020. Accessed January 12, 2022. https://bit.ly/3A0NBlV}

<sub>4. Brose MS, Worden FP, Newbold KL, Guo M, Hurria A. Effect of age on the efficacy and safety of lenvatinib in radioiodine-refractory differentiated thyroid cancer in the phase III SELECT trial. J Clin Oncol. 2017;35(23):2692-2699. doi:10.1200/JCO.2016.71.6472

5. NCCN. Clinical Practice Guidelines in Oncology. Thyroid carcinoma, version 3.2021. Accessed April 9, 2021. https://bit.ly/2TCNGIq</sub>

_{6. Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015;372(7):621-630. doi:10.1056/NEJMoa1406470}

_{7. Haugen B, French JD, Worden F, et al. Pembrolizumab salvage add-on therapy in patients with radioiodine-refractory (RAIR), progressive differentiated thyroid cancer (DTC) progressing on lenvatinib: results of a multicenter phase II International Thyroid Oncology Group Trial. Ann Oncol. 2020;31(suppl 4):S1086-S1087. doi:10.1016/j.annonc.2020.08.1405}

_{8. Wirth LJ, Tahara M, Robinson B, et al. Treatment-emergent hypertension and efficacy in the phase 3 study of (E7080) lenvatinib in differentiated cancer of the thyroid (SELECT). Cancer. 2018;124(11):2365-2372. doi:10.1002/cncr.31344}