ONCAlert | Upfront Therapy for mRCC

Dirty Kinases in TRK-Fusion Malignancies

Targeted Oncology
Published Online:12:34 PM, Mon August 26, 2019

David Hong, MD: Before the era of targeted therapy, before we had all these new drugs now, what was the standard of care after radioactive iodine? Was it docetaxel?

Marcia Brose, MD, PhD: Actually, it wasn’t docetaxel. Adriamycin was the only approved drug in 1974. Even though it was FDA approved, once we had CAT [computerized axial tomography] scans, it turned out they weren’t responding. We had an FDA-approved drug that was not causing responses, so it was actually supportive care. This is really amazing. I mean, in our generation where there was nothing, and now all of a sudden, this is an agent.

David Hong, MD: When you look at lenvatinib compared with larotrectinib—I mean adverse-effect-wise, profile-wise—how do you see that in comparison?

Marcia Brose, MD, PhD: As you know, larotrectinib is very well tolerated, with dizziness being 1 of the primary issues. We do actually have patients who get myalgia, and it’s not just if they don’t take their drug on time. Unfortunately, it’s sort of anticipatory, so we’re going to have to work that out. I think that can be worked out by dosing, so we’re going to probably learn how to adjust for that. In general, larotrectinib is very, very well tolerated. And even the dizziness in our patients—even though it didn’t go away, some people say it gets better with longer treatment. In the patients for whom it didn’t, 1 single-dose reduction and they still have a complete response. So it may not be that we need to have dizziness, and we can probably treat around that.

The other drugs can cause quite a bit of morbidity, like hand-foot skin reaction. With lenvatinib, there’s a lot of hypertension. That’s actually the No. 1 issue we have to manage. And that’s not just grade 1; it’s a significant proportion of grade 3. So hand-foot skin reaction with sorafenib and hypertension with lenvatinib, and then diarrhea in both cases—these impact people. Initially, we were thrilled, of course, to have drugs that are so effective. But I think toxicity profile does matter, especially because these patients live a long time now with their disease.

David Hong, MD: Marcia, you’ve now treated probably many, many patients with NTRK fusions in thyroid. When you look at the data sets and your own experience, what is the overall response in thyroid, in papillary thyroid, in some patients even anaplastic thyroid cancer?

Marcia Brose, MD, PhD: There actually haven’t been that many. There have been about 7 patients, and 1 of them was anaplastic. And they did very well compared with anaplastic. Their progression-free survival, I think, lasted on the drug about 6 months before they had some progression. Of course, that’s a BRAF wild-type patient who then got tested. That 6 months in anaplastic, for anybody who treats anaplastic thyroid cancer, it turns out to be a good number because these patients on the other kinase inhibitors will progress by their first assessment. So it’s probably active in anaplastic. I definitely would be testing every patient who has anaplastic thyroid cancer without a BRAF mutation.

Interestingly, in the differentiated, there have been about 5 or 6, and their responses have been great. Just as you’ve seen across the board, we’re talking a very high rate—60% to 70%—and we’re talking deep responses. We’re talking 80%. I think you point out it was ones on the phase I, a complete response. These are really amazing.

The 1 thing I actually would like to point out about thyroid cancer is that we have a new adolescent thyroid cancer program, and it turns out there are a growing number—well, not a growing number, we’re just more aware of them now—of adolescents who have RAI-refractory thyroid cancer. Almost all those patients have ETV6 and NTRK3. I think that we don’t have a lot of experience with them. I have 3 or 4 patients in my clinic who don’t need systemic therapy yet. But as soon as it starts to grow, this will be a great drug for them, because they’ll be able to go to school and have a great quality of life. I might really go to larotrectinib before going to the other FDA-approved drugs, just because adverse-effect profiles in kids is really going to make a difference.

I will say that among the patients, adolescents who have had lenvatinib have done well. So it’s not that we don’t use them, but I think adverse-effect profiles do count. It’s an interesting cadre of patients who I think have been underdiscussed, and we’ll be having more data on that soon.

David Hong, MD: Thank you, Dr Brose and Dr Langer, for this insightful discussion. And thank you to our audience for watching this Targeted Oncology™ presentation on Precision Medicine.

Transcript edited for clarity.

David Hong, MD: Before the era of targeted therapy, before we had all these new drugs now, what was the standard of care after radioactive iodine? Was it docetaxel?

Marcia Brose, MD, PhD: Actually, it wasn’t docetaxel. Adriamycin was the only approved drug in 1974. Even though it was FDA approved, once we had CAT [computerized axial tomography] scans, it turned out they weren’t responding. We had an FDA-approved drug that was not causing responses, so it was actually supportive care. This is really amazing. I mean, in our generation where there was nothing, and now all of a sudden, this is an agent.

David Hong, MD: When you look at lenvatinib compared with larotrectinib—I mean adverse-effect-wise, profile-wise—how do you see that in comparison?

Marcia Brose, MD, PhD: As you know, larotrectinib is very well tolerated, with dizziness being 1 of the primary issues. We do actually have patients who get myalgia, and it’s not just if they don’t take their drug on time. Unfortunately, it’s sort of anticipatory, so we’re going to have to work that out. I think that can be worked out by dosing, so we’re going to probably learn how to adjust for that. In general, larotrectinib is very, very well tolerated. And even the dizziness in our patients—even though it didn’t go away, some people say it gets better with longer treatment. In the patients for whom it didn’t, 1 single-dose reduction and they still have a complete response. So it may not be that we need to have dizziness, and we can probably treat around that.

The other drugs can cause quite a bit of morbidity, like hand-foot skin reaction. With lenvatinib, there’s a lot of hypertension. That’s actually the No. 1 issue we have to manage. And that’s not just grade 1; it’s a significant proportion of grade 3. So hand-foot skin reaction with sorafenib and hypertension with lenvatinib, and then diarrhea in both cases—these impact people. Initially, we were thrilled, of course, to have drugs that are so effective. But I think toxicity profile does matter, especially because these patients live a long time now with their disease.

David Hong, MD: Marcia, you’ve now treated probably many, many patients with NTRK fusions in thyroid. When you look at the data sets and your own experience, what is the overall response in thyroid, in papillary thyroid, in some patients even anaplastic thyroid cancer?

Marcia Brose, MD, PhD: There actually haven’t been that many. There have been about 7 patients, and 1 of them was anaplastic. And they did very well compared with anaplastic. Their progression-free survival, I think, lasted on the drug about 6 months before they had some progression. Of course, that’s a BRAF wild-type patient who then got tested. That 6 months in anaplastic, for anybody who treats anaplastic thyroid cancer, it turns out to be a good number because these patients on the other kinase inhibitors will progress by their first assessment. So it’s probably active in anaplastic. I definitely would be testing every patient who has anaplastic thyroid cancer without a BRAF mutation.

Interestingly, in the differentiated, there have been about 5 or 6, and their responses have been great. Just as you’ve seen across the board, we’re talking a very high rate—60% to 70%—and we’re talking deep responses. We’re talking 80%. I think you point out it was ones on the phase I, a complete response. These are really amazing.

The 1 thing I actually would like to point out about thyroid cancer is that we have a new adolescent thyroid cancer program, and it turns out there are a growing number—well, not a growing number, we’re just more aware of them now—of adolescents who have RAI-refractory thyroid cancer. Almost all those patients have ETV6 and NTRK3. I think that we don’t have a lot of experience with them. I have 3 or 4 patients in my clinic who don’t need systemic therapy yet. But as soon as it starts to grow, this will be a great drug for them, because they’ll be able to go to school and have a great quality of life. I might really go to larotrectinib before going to the other FDA-approved drugs, just because adverse-effect profiles in kids is really going to make a difference.

I will say that among the patients, adolescents who have had lenvatinib have done well. So it’s not that we don’t use them, but I think adverse-effect profiles do count. It’s an interesting cadre of patients who I think have been underdiscussed, and we’ll be having more data on that soon.

David Hong, MD: Thank you, Dr Brose and Dr Langer, for this insightful discussion. And thank you to our audience for watching this Targeted Oncology™ presentation on Precision Medicine.

Transcript edited for clarity.
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