The Future of RAI-Refractory DTC Management

Lori J. Wirth, MD: Now that we have drugs that have great efficacy and a better adverse effect profile, are you starting to think about treating people earlier in the course of the illness? Especially after the DECISION trial, where we saw the sorafenib data that showed modest activity and moderate toxicity, the pendulum swung away from treating people when they walked through the door with radioactive iodine-refractory differentiated thyroid cancer [RAI-refractory DTC], to the end of the spectrum to hold off as long as possible before starting a multikinase inhibitor. I have had my pendulum swing back since the SELECT data became available because it showed a similar toxicity profile, but lenvatinib works better. There have been some emerging data that suggest that you get more benefit if you start earlier rather than waiting until there’s a significant disease burden. 

There are very few other settings in oncology where we follow people with known metastatic disease and keep their TSH [thyroid stimulating hormone] suppressed, but otherwise don’t do anything about it. With a patient who is RET fusion-positive or NTRK fusion-positive, where do you think things are going to be heading? 

Frank Worden, MD: It’s a good question. I think some of the issues that come into play are that the numbers are smaller here, as we said earlier, less than 10% in many of these cases, so we don’t see a lot of these patients. We do not have a lot of anecdotal experience treating patients, even though when we do treat them, we see good responses. I believe if I have a patient who has, in fact, I do have a lady with an NTRK fusion. She has miliary disease, and her largest tumor in the lungs is around 0.4, 0.5 cm, so she doesn’t meet eligibility for a clinical trial if one were available. The disease has been growing slowly, so she is someone who is a late comer in terms of genetic testing. I had more of an idea about her progression of disease or her doubling of disease without evidence of what was available.  

I stop and think about this, and since progression was relatively slow, I probably would have continued to observe this patient. I don’t want to say that just because someone has a particular fusion or mutation that they automatically need to be treated because there are adverse effects associated with the drugs. However, when we didn’t have such data, when we were watching patients and they would inch along, I’d say, “Well, OK, it’s a little bit bigger this time, it’s a little bit bigger this time.” But now since these drugs are available, I’m quicker to start therapy when I know these drugs are available and we can start treatment.  

I agree with what you said about data supporting starting earlier instead of waiting until they get overwhelming disease burden or are so symptomatic. The answer is to your question is really yes. I would still observe a number of these patients, especially if they are asymptomatic, but I would observe them closely and my activation would come more quickly. 

Lori J. Wirth, MD: I have the same thoughts there. What else do you think of in terms of promising developments that we’re looking forward to in the not-too-distant future?

Frank Worden, MD: A couple of things. You and I are both ITOG [International Thyroid Oncology Group] members, and we have presented our data on the use of immunotherapy with lenvatinib. Up front there are some patients who have gained responses. I have had patients who are on the immunotherapy for 2 years and stopped, which is great. At the beginning of the study we were hoping for complete responses in some of these patients and didn’t see that, so the primary end point wasn’t met. But in the second group of patients we studied, where we added pembrolizumab when patients progressed on lenvatinib instead of treating up front with lenvatinib and pembrolizumab, that showed some interesting data. The patients in the second group were progressing, and now the median progression-free survival is maybe 12 months or so. It’s still a little early, but that’s great because here we have patients who are on a dose and are tolerating that dose, progressing, and now perhaps are garnering a benefit with immunotherapy. That definitely needs to be explored.

There are other tumor types—hepatocellular carcinoma, renal cell carcinoma—where those data seem to be playing out, and they’re similar glandular-type tumors. That’s one thing I think we need to continue to look at and explore. I’m excited that we completed that study relatively quickly, and I was happy to be part of it. Eric Sherman, MD, brought up on an NCI [National Cancer Institute] conference call that BRAF inhibition will upregulate ERBB3, so using drugs like lenvatinib in combination with BRAF inhibitors, which is a great idea to look at, especially in a population such as the tall cells and these papillary cancers in general that have BRAF expression more so than some of these other targeted mutations that we’ve discussed today. I think those are areas that need to be looked at as we move forward. 

Something that hasn’t been discussed so much compared to renal cancer and some of the others is sequencing. We have second-line data with lenvatinib from SELECT, but that’s the only study where we do have data. We do say that we would give somebody else a multikinase inhibitor when they fail, outside of having a targeted mutation, but we don’t know what the exact sequencing is. Maybe it is the use of things like immunotherapy, but sequencing is an area that should be explored, so that we can set up options for patients instead of using what we think is the right regimen.

We didn’t really talk about cabozantinib today, but that shows some promising data in the second-line setting, too. There’s an ongoing study of cabozantinib in the second-line setting, so there's a lot of exciting things that still need to be done. Again, looking at starting and stopping these TKIs [tyrosine kinase inhibitors] and then seeing what breaks we can take to make patients feel better without losing efficacy would be something else I think we need to explore. Those are some of the things that come to mind when I think about that question.

Lori J. Wirth, MD: I’m glad that you commented on Eric Sherman’s interest in studying BRAF and ERBB3, especially because BRAF is the most common driver alteration that we see in thyroid cancer. We can do better than dabrafenib plus or minus trametinib, or vemurafenib plus or minus cobimetinib in patients with thyroid cancer. For whatever reason, they just don’t do as well as the patients with melanoma, yet that alteration is there. The other major unmet need is approaching the patients who have RAS-driven tumors. Again, it should be druggable.

Frank Worden, MD: I know. Well, at our center there’s a medical therapeutic study that’s opening for RAS, HRAS, and some of the other drivers. I’m excited to see if we can see something in a patient who has a KRAS or NRAS mutation. 

Lori J. Wirth, MD: Great. Well, if you do let me know. I want to open a trial, too.