Overview of Available Treatment Options for RR DTC

Transcript:

Lori J. Wirth, MD: Ezra, let’s talk a little more about treatment options. Marcia mentioned them. Some patients might have a targetable alteration for frontline therapy. NTRK and RET fusions fall into that category. But there are multiple drugs that are FDA approved for advanced thyroid cancer: sorafenib, lenvatinib, and cabozantinib. What do you think in terms of the treatment selection?

Ezra Cohen, MD, FRCPSC, FASCO: I have a few important points to bring out. First, my conversation with patients starts with, “Unfortunately, you have radioactive iodine–refractory disease with evidence of disease. However, I have nothing that I can cure you with.” I don’t use those words verbatim. But none of these agents is curative yet. Hopefully, we’ll develop those types of therapies in the future. Second, I want to delay as much as possible your exposure to these agents. If you’re feeling well, I can’t make you feel better by starting on 1 of these drugs. Even though we know that the very specific kinase inhibitors are likely to be incredibly well tolerated with very few adverse effects, I’m not going to make an asymptomatic patient feel better by putting them on a drug. Third is that especially for patients who are likely to have a very long natural disease history, I try to minimize exposure to radiographs as much as possible. I utilize ultrasounds and thyroglobulin because some of these patients are going to be alive with their disease for decades. There’s a cumulative dose of radiation exposure that patients can get that can predispose them to secondary malignancies. I try to minimize that as much as possible.

Not knowing about molecular alterations or even in the absence of a targetable molecular alteration, my first choice is lenvatinib. That’s based on the data from the SELECT trial [showing a] high response rate. Let’s not forget that some patients had a complete response, which we don’t see with sorafenib. [I’m thinking of] not only the duration of response but also the median PFS [progression-free survival] in that study. You’re right, Lori: post hoc subgroup analyses demonstrated that patients with lower-volume disease with better performance status did better on lenvatinib. That’s something to keep in mind. If I can’t use lenvatinib, I’ll use sorafenib or cabozantinib. I try to reserve cabozantinib for TKI [tyrosine kinase inhibitor]–refractory patients based on data that Marcia recently published. That was a very nice phase 3 study looking at that patient population. Although biologically cabozantinib and lenvatinib likely have similar activity, I reserve cabozantinib for lenvatinib-refractory patients because there’s level 1 evidence to demonstrate benefit. But most important, I get molecular profiling on all these patients. We have the luxury at our institution [University of California San Diego] to do that. But I get it on all patients because the majority of patients with papillary thyroid cancer will have a targetable molecular alteration. Some of those agents are incredibly effective With TRK inhibitors and RET inhibitors, we’re talking about response rates of 70% or 80% and median durations of response that in some trials haven’t been reached. We’ll have at least a year, probably 18 months. It could even be longer.

Marcia S. Brose, MD, PhD: And even measurable complete responses of 10% to 12%.

Ezra Cohen, MD, FRCPSC, FASCO: That’s a very good point, Marcia. It’s important to know that and detect those because I’ll use them. If there’s an NTRK fusion or a RET fusion—and we’re talking about differentiated thyroid cancer, so we don’t really see RET mutations—I’ll use 1 of those agents first prior to a multikinase inhibitor. Marcia, I completely agree with your approach to BRAF. We have to recognize that V600E is the most common mutation that we’ll see in thyroid cancer. However, thyroid cancer has the second-highest incidence of class 2 BRAF mutations and the third-highest incidence of BRAF fusions in cancer. We also look for those. It’s important. But I completely agree with your point that BRAF inhibitors seem to be less effective than drugs like lenvatinib and cabozantinib. I reserve the BRAF agents when patients become refractory to the TKIs.

Lori J. Wirth, MD: I’m enjoying this program because we all agree on everything. Ezra, will you say 1 more time that a majority of patients with advanced papillary thyroid cancer will have targetable alterations and should have NGS [next-generation sequencing] testing? That’s an important point.

Ezra Cohen, MD, FRCPSC, FASCO: Fortunately, we live in a rich country where most patients have access to these high-quality tests that also look at DNA and RNA. It makes a difference. It’s truly lifesaving for some patients. Quality of life with some of these agents is going to be far superior. It’s important to get [NGS] on every patient.

Francis P. Worden, MD: Absolutely.

Lori J. Wirth, MD: I agree. We pretty much all agree that for patients who don’t have an NTRK fusion or a RET fusion and who needs therapy, lenvatinib is our first-line therapy of choice unless there’s a reason not to use lenvatinib.

Ezra Cohen, MD, FRCPSC, FASCO: I cheat a little because there’s a low incidence of ALK fusions in these patients.

Lori J. Wirth, MD: I agree.

Ezra Cohen, MD, FRCPSC, FASCO: I’ll use an ALK inhibitor there. I cheat a little bit there, even though it’s obviously not approved.

Lori J. Wirth, MD: There are a few more case reports in the literature, fortunately. If anybody has trouble getting insurance approval, at least now we have a few case reports to lean on.

Francis P. Worden, MD: There’s 1, so you’re right. That’s important.

Lori J. Wirth, MD: In terms of dose, we’re all in agreement that the default first dose is 24 mg of lenvatinib. But that has to be individualized and doesn’t apply to every patient who walks through the door. Is there anything else we need to talk about with lenvatinib while we’re on the subject?

Marcia S. Brose, MD, PhD: We should put the numbers out there. We’re comparing the TRK and RET inhibitors, which have response rates of over 70% or 80%, with lenvatinib, which has response rates around 60%, and sorafenib, which has response rates in phase 3 of 12%. The response rates for vemurafenib and dabrafenib were around 30%. Those numbers tell the story behind Ezra’s choice of sequencing. That’s where a lot of us are coming down. You could argue that if there was a lower response with a miracle drug, like drinking water, you might consider putting that ahead. But we don’t have that. BRAF inhibitors aren’t without adverse effects. They’re not so superior to lenvatinib that I’m willing to give up half the response rate because of it. It’s good to a face on the opinions and why we come up with that.

Francis P. Worden, MD: The only reason I might consider a BRAF up front is if I’m worried about some a catastrophic bleeding event. Then I’ll take that into consideration. But otherwise…

Marcia S. Brose, MD, PhD: The generic all comers are where we start. I often like to say with all these things that we do—for instance, not going over 600 mCi with radioactive iodine, not treating patients with lenvatinib at a top dose, and not treating patients with lenvatinib in the first line—are all general rules. But if you’re going to break the rule, make sure you have a reason. In general, you should follow these general guidelines. But if you don’t, have a reason why [you aren’t]. The occasional patient has had 200 mCi every 6 or 7 years, and it seems to control their disease well. That might be the person whoends up going to 800 mCi. I’m not going to argue with them because there’s a clinical benefit in that patient. We all know the data show that that’s extremely rare. Unless you can point to a reason for breaking that rule, you’re not doing anybody any favors.

The other point is that for the patients who’ve really had documented radioactive iodine–refractory disease and clear progressions after they had their dose, the average radioactive iodine that they got was 400 mCi. It puts into context the doses that we’re talking about and why we say what we do. We’re used to talking about issues, but it’s good to point out the numbers behind the opinions you’re hearing here.

Francis P. Worden, MD: Another point I’d like to bring up about the BRAF inhibitors is that we have an agnostic approval for dabrafenib and trametinib in patients with BRAF V600Emutations in all cancers. That’s not a license to say, “This is a cancer that has this mutation. Therefore, we should offer it up front.” It’s important that we understand the data that lenvatinib should be tried first because of the response and the data we’ve been discussing. An agnostic indication doesn’t mean it should be given up upfront.

Marcia S. Brose, MD, PhD: You don’t ignore it.

Lori J. Wirth, MD: That’s a great point. But the approval is when there’s no other acceptable treatment alternative, lenvatinib applies.

Transcript edited for clarity.