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New FDA Approval for RET Positive Medullary Thyroid Cancer

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Published on December 2, 2020

Pralsetinib (Gavreto) Approved for RET Mutation-Positive Thyroid Cancer

Pralsetinib (Gavreto) recently received FDA approval for use by medullary thyroid cancer patients who tested positive for the RET (rearranged during transfection) gene mutation. Studies showed promising results in disease control without the severe side effects that often accompany current frontline thyroid treatment.

Dr. Vivek Subbiah, clinical trials and Physician Investigator at MD Anderson Cancer Center, joins Patient Power Co-Founder Andrew Schorr to discuss the results of the clinical trial that resulted in the approval of pralsetinib (Gavreto) and what this new drug means for thyroid cancers with the RET gene mutation.

This program is sponsored by Blueprint Medicines. This organization has no editorial control. It is produced by Patient Power. Patient Power is solely responsible for program content.

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Transcript | New FDA Approval for RET Positive Medullary Thyroid Cancer

Andrew Schorr: Hello, and welcome to Patient Power. I'm Andrew Schorr in California and joining me from MD Anderson Cancer Center in Houston is a noted clinical investigator, Dr. Vivek Subbiah. Dr. Subbiah, we have a new drug approved for medullary thyroid cancer. Let me see if I'd get it right, pralsetinib (Gavreto). So, help us understand thyroid cancer and where this drug could make a difference. We have, I think, more than 50,000 people in the U.S. diagnosed each year with thyroid cancer.

Dr. Subbiah: Thank you, Andrew, for the wonderful opportunity for me to share my insights on updates on thyroid cancer and this new drug.

What Are the Different Types of Thyroid Cancer?

Andrew Schorr: What are the different types of thyroid cancer?

Dr. Subbiah: Thyroid cancer is of different types as we all know; medullary thyroid cancer, differentiated thyroid cancer, anaplastic thyroid cancer, and papillary thyroid cancer. The majority of patients with thyroid cancer are not going to need any systemic therapy. And specifically, medullary thyroid cancer, almost 90% of the patients with advanced medullary thyroid cancer have their cancer driven by this gene called RET, R-E-T.

Andrew Schorr: For medullary thyroid cancer, patients who test positive for the RET gene, the first line TKIs are cabozantinib (Cometriq) and vandetanib (Caprelsa).

Dr. Subbiah: The challenge with treating thyroid cancer with these multi-kinase inhibitors like vandetanib and cabozantinib has been the off-target side effects and toxicity potential like diarrhea, rash. So that led to physicians and patients that using the drug and that led to a lot of drug discontinuation. So, with the advent of selective RET inhibitors like pralsetinib, we can overcome the off-target toxicities of these multi-kinase inhibitors.

Andrew Schorr: Pralsetinib entered clinical trials in 2017. Clinical trial candidates included medullary thyroid cancer patients whose cancer had the RET mutation and were previously treated with cabozantinib and vandetanib and patients who had not received systemic treatment at all.

Dr. Subbiah: Again, all patients receive this drug pralsetinib, also known as Gavreto, at a starting dose of 400 milligrams once a day. It's once a day convenient dosing.

Andrew Schorr: It's a pill, right?

Dr. Subbiah: Yeah. It's a pill. It's a once-a-day pill and patients can take it at their convenience. So, what we saw in the data is that in the 53 patients who were treated with cabozantinib or vandetanib, that for the prior FDA approved drugs for medullary thyroid cancer and who received pralsetinib, the overall objective response rate was 60% with one response pending at the time of confirmation. The disease control rate - I think this is very important. The disease control rate was 96%. So in almost 96% of the patients, the disease was controlled.

And because the study is ongoing, because we have most of the patients responding, the median duration of response is not reached. Even the median progression-free survival because these drugs are new, and patients are doing very well. The median progression-free survival has not been reached in patients previously treated with cabozantinib or vandetanib.

Interestingly, we had 19 patients who were treatment-naive, meaning those patients that had advanced systemic medullary thyroid cancer who are not candidates for surgery and who are not eligible for standard of care therapies like cabozantinib or vandetanib. They were enrolled on this study. In these patients, the objective response rate was 74%. And you know what the disease control rate was? 100%.

So, almost all the patients benefited from this treatment and these patients are special because this was the first-ever treatment they receive. An oral pill, once a day, 400 milligrams. Interestingly, as with the treated patients before, the median duration of response was not reached and 93% of the responders remain on treatment as of date.

Andrew Schorr: Now with a new drug, Doctor, we always need to ask you about side effects. We understand there are off-target side effects of some of the previously approved medicines, but now we have a new one. What about side effects for that?

What Side Effects Did Patients Experience During the Trial?

Dr. Subbiah: The most common treatment-related adverse events as reported by investigators, which were collected was over 15%: increasing in the liver function test. Liver function test meaning that aspartate aminotransferase, the alanine aminotransferase and some patients reported anemia. There was some hypotension and constipation. In fact, medullary thyroid cancer patients, as you know, suffer from diarrhea chronically because of the paraneoplastic syndrome and diarrhea.

So, once they start this drug, we've seen that patients stop having diarrhea within a week or two, and they switched from a diarrhea mode to a constipation mode, and we've had to give some drugs to help patients with their constipation. The drug discontinuation rate from the previous multi-kinase inhibitors, it was in the order of 12-16%. But in the same whole data set of pralsetinib, the drug discontinuation rate due to the treatment was 4%.

Andrew Schorr: Patients with thyroid cancer. At what point, based on a new medicine that targets a gene that could be active, the RET fusion, when should they have genomic testing?

When Should a Thyroid Cancer Patient Discuss Genomic Testing with Their Doctor?

Dr. Subbiah: My personal pitch is that for a bad cancer like thyroid cancer, it should be a part of the diagnosis. It does not have just diagnostic impact. It has therapeutic impact and prognostic impact.

Andrew Schorr: Dr. Subbiah, you study drugs at the earliest phase and there's been an unmet need for some patients with thyroid cancer where surgery and radioactive iodine wasn't going to cut it, or the drugs had previously been approved for more advanced thyroid cancer had off-target side effects, or people would become resistant, the drugs would no longer work. How excited are you to have this new drug based on the data you've seen with patients who needed it?

Dr. Subbiah: Oh, absolutely. It is so rewarding as an early phase clinical trial investigator to do clinical trials and give the gift of time to these patients, especially with these fantastic drugs that work in patients. And every time in our clinic, when we see a patient responding, it gives us the positive energy and positive motivation for us to wake up in the morning and go to clinic. This is what keeps us going.

Andrew Schorr: So, to sum up for patients who are watching, genomic testing early to understand your personal thyroid cancer situation, and to understand now that there's an approved drug that can make a difference, all the difference, perhaps.

Dr. Subbiah: Absolutely.

Andrew Schorr: Better than the therapies that have existed before. Dr. Vivek Subbiah, thank you so much for being with us and also helping pioneer, really, testing that's driven by an understanding of the genes that maybe have gone awry and where there are therapies that you're helping develop that can correct that problem. Thank you so much for being with us from MD Anderson.

Dr. Subbiah: Thank you so much. Thank you for the wonderful opportunity for me to share with thyroid patients, thank you.

Andrew Schorr: Alright. I'm Andrew Schorr. Remember, knowledge and getting the right personalized treatment can be the best medicine of all.

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