Wirth Explores Challenges of Therapy Selection for RAI-Refractory Differentiated Thyroid Cancer

Lori J. Wirth, MD (MODERATOR)

Medical Director, Center for Head and Neck Cancers

Massachusetts General Hospital

Associate Professor in Medicine

Harvard Medical School

Boston, MA

EVENT REGION Nationwide

PARTICIPANT LIST Helen Moon, MD | Peter Oppelt, MD | Amanda Sun, MD | Mohammed Ali, MD | Rabih Fahed, MD | Arun Kumar, MD

MOON: My experience [with lenvatinib] primarily came out of renal cell carcinoma [RCC]…, and my patients with thyroid cancers do much better on it than the patients with RCC. They [require] less dose reduction, in my experience. It may be that the patients with RCC tend to be older; a lot of them may be without one functioning kidney. I’m not sure what it is, but I have been able to put patients on it. The trial data are compelling in the fact that there are not many great drugs in this space, so I accept [the rank-preserving structural failure time–adjusted analysis] to get to the overall survival [benefit; adjusted HR, 0.62; 95% CI, 0.40-1.00].¹ For other [diseases], maybe not, but for thyroid cancer, I think beggars can’t be choosers in that sense.

OPPELT: They are impressive data to review. There were high response rates, and for the patients who respond, the duration of response can be very impressive. For someone who is going to be on this drug for a long time, the toxicity profile is a challenge. It can be something that drags on patients, so a number of patients need to have dose reductions. A lot of them tend to be early on.

WIRTH: I agree. I think that dose reduction is baked into the clinical care for these patients. But I found it’s very interesting that it’s unpredictable. I have younger men who are on 24 mg once a day, and I have older women who also tolerate 24 mg once a day for quite some time. Then [I have] other patients who I’ve got on 10 mg every other day who need to work every day and can’t deal with hand-foot syndrome. I find that we need to personalize the dose for our patients.

SUN: I agree that the adverse event management can be challenging. I have a few patients with thyroid cancer. I have to do dose reduction on all of them. They have a high hypertensive crisis and end up in the emergency department. There are those who are already on antihypertensive drugs and still end up in the emergency department, and diarrhea is common. We do dose reduction for most of the patients with diarrhea issues. I had one with proteinuria of approximately 5 g [per 24 hours]. I haven’t had it in any other patients; it’s probably not the most common. My patients are not tolerating 24 mg, so I start them at 18 mg or 14 mg. Some I have to switch to sorafenib [Nexavar].

WIRTH: Those are all good points, and those adverse events certainly all are issues that we need to contend with when using lenvatinib. One thing that I would say about the hypertension is that we did an analysis of the SELECT trial and found that the patients who were initially randomly assigned to receive lenvatinib who developed treatment-emergent hypertension did have an overall survival benefit compared with those randomly assigned to lenvatinib who didn’t experience treatment-emergent hypertension.² As we’ve seen in other diseases with the VEGF-receptor [VEGFR] multikinase inhibitors, that seems to be a pharmacodynamic marker. My take-home from those data is that if a patient does experience hypertension, we want to try to optimally manage it as much as possible and not stop the therapy because that is a good pharmacodynamic marker. Those patients are more likely to benefit from lenvatinib.

The other thing that I would say is what I’ve learned about blood pressure on lenvatinib is some patients can develop hypertension within just a couple of doses of lenvatinib, so I make sure that patients are normotensive prior to starting therapy. I make sure that they are monitoring their blood pressure before they start taking lenvatinib and that they’ve demonstrated that they can take their blood pressure and keep a log of it. Then I make sure that patients know to call us if they have high blood pressure. Then we see patients [who start] lenvatinib within 2 weeks…to make sure that we’re monitoring their blood pressure and other things carefully.

The other thing you mentioned is the diarrhea. That’s difficult for patients and often leads to the need to dose-reduce lenvatinib. Diarrhea every day can really take a toll on people. Dietary modification can help using loperamide [Imodium], diphenoxylate/atropine [Lomotil]; even DTO [deodorized tincture of opium] can help. But even so, many patients need to have a dose reduction over time.

Because of the proteinuria that can be seen with lenvatinib—and we do monitor [for proteinuria in] patients—I tend to use an ACE [angiotensin-converting enzyme] inhibitor as my first go-to drug because of the concern for proteinuria as well. But we don’t have great data that direct us to the best antihypertensive with VEGFR multikinase inhibitors that I’m aware of. Often patients need to have 2, even 3 drugs. I find that our cardiology colleagues can sometimes be helpful in caring for patients who have particularly refractory hypertension.

DISCUSSION QUESTIONS

• Are there specific patient and/or disease characteristics that would influence you to select certain tyrosine kinase inhibitors (TKIs) over others for the treatment of RAIR-DTC?
  • If so, what factors distinguish these targeted therapies?
• Do you include available local treatments in your algorithm for symptomatic or progressive metastases?
• If, and when, would you combine them with systemic therapy?

WIRTH: Let’s talk a little bit more about specific patient and/or disease characteristics that would influence your decision to select certain TKIs over other forms of treatment for patients with RAI-refractory DTC and what factors might those be, particularly with regard to targeted therapies.

ALI: I think having a target is very important, and [I would] look at the target and [use the] therapy that is most effective.

WIRTH: So if there’s a target, you would use a target-specific therapy first.

FAHED: It depends on the type of mutation. If I have NTRK or RET, that would be my first line…. But if I have a BRAF mutation, I would leave the combination for third line.

WIRTH: I agree with you. I’m anxious to see the results of the second-line trial [NCT04940052] of dabrafenib [Tafinlar] and trametinib [Mekinist], and we’ll have some solid data. But based on the response rates that we see with lenvatinib and the long progression-free survival, it’s hard to beat.

What if the patient with bone metastases was on lenvatinib, and she developed some pain in the cervical spine area but not significant tumor growth there. What might your thoughts be about combining external beam radiation therapy for palliation of pain? What would you consider doing with the lenvatinib? Would you continue it, hold it, or stop it altogether?

ALI: I would continue the medication and use bone-modifying agents.…

WIRTH: I agree that bone-modifying agents are useful in this setting, though there haven’t been specific trials in patients with thyroid cancer with the bone-modifying agents. But that’s never going to happen, so we have to certainly use our best clinical judgment. To my mind, if there’s some change in symptoms but there isn’t growth of lesions that are RECIST measurable, then that doesn’t qualify as disease progression. Especially if a patient like this has had progressive disease and then is doing well on lenvatinib for a long time, there’s probably a chance for further benefit. So taking an oligofocal approach to treating a lesion that’s bothersome and then continuing an effective therapy seems to make sense to me.

KUMAR: It would not be wrong to hold the lenvatinib while the patient is getting the radiation. It’s already too toxic. I would hold it temporarily while they’re finishing the radiation.

WIRTH: That’s a very good point, and it also depends on how the radiation is being done and the anatomic location as well. For example, if there’s going to be bowel in the area, because of the diarrhea concerns with lenvatinib, I wouldn’t consider continuing it. In general, patients can use a drug holiday to reset when on lenvatinib for a long period of time. Doing a drug holiday during a short course of palliative radiation is not necessarily a bad thing at all.

DISCUSSION QUESTIONS

• In your opinion, when is the optimal time to introduce lenvatinib in the treatment of DTC?
• Are the lung metastases data clinically meaningful to you?

OPPELT: The subgroup analysis [from the SELECT trial] looking at the size of the burden of disease is interesting. Those are small thresholds. I picture a lot of patients who may have just a few lung nodules who may have been inching along. Was that a large percentage of the patients, or was that a pretty small subgroup who had a small burden of disease?

WIRTH: It shows the split between [tumors of] 4 cm or less or more than 4 cm.³ Approximately one-third of the patients had 4 cm or less. But you also have to think about how RECIST 1.1 tumor measurements are done, so you will generally pick 1 target lesion in each of the organs that best represents the measurable lesion and best represents the disease. You can have a bunch of small lung nodules and still have a RECIST baseline measurement of less than 4 cm. This is a fraught analysis in terms of what the overall tumor burden is; it is perhaps more [showing] the size of the most representative target lesions—[whether they are] relatively big lesions or relatively small lesions.

I have to say that I changed my thoughts on when to best initiate therapy or at least how I discuss this with patients in clinic after we did see the [post hoc lung metastasis] data. When there is overall survival benefit in patients who have lung metastases that are as small as 1 cm [From the Data⁴], despite the fact that most patients did cross over and receive lenvatinib at a median of just 4 months, this is some information that I incorporate into my discussion with patients.

Does anybody else feel that they might change how they think about the data based on those lung metastases data or other particularly difficult clinical challenges that you encounter?

FAHED: It’s a very difficult decision. On one hand, you have to subject the patient to an extra year or two of toxicity for a small, minimally growing [nodule]. If a lung nodule is 1 cm [and grows] to 1.2 cm in 1 year, do you need 1 year of lenvatinib? At the same time, it’s hard to argue with the improved survival in that setting. My experience with lenvatinib is that nobody can stay on it…permanently. It’s on-off treatment. You do it for a few months, you take a break—or the patient forces you to take a break—and go back on it. I might do it, but probably…not at 1 cm.

WIRTH: I hear you, and I struggle with these decisions all the time. I discuss it with the patients. We make a team decision, what makes most sense for the patients.

FAHED: Is there a lead-time bias that led to that conclusion of better survival?

WIRTH: Because of the randomization to placebo, that does away with the lead-time bias. If we were comparing how patients did with 1-cm lung nodules compared with [larger] than that, then that would give you a lead-time bias. That is what’s powerful about that subset analysis. But it was a post hoc subset analysis, and those always need to be interpreted with caution.

REFERENCES:

1. 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

2. 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

3. Kiyota N, Tahara M, Robinson B, et al. Impact of baseline tumor burden on overall survival in patients with radioiodine-refractory differentiated thyroid cancer treated with lenvatinib in the SELECT global phase 3 trial. Cancer. 2022;128(12):2281-2287. doi:10.1002/cncr.34181

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