Molecular Testing Moves in Front of Systemic Treatment for Certain Thyroid Cancers

Marcia Brose, MD, PhD

Marcia Brose, MD, PhD

Upfront biomarker testing is now recommended for patients with differentiated thyroid cancer (DTC) or medullary thyroid cancer (MTC) since targeted therapies that are highly tolerable and also effective have been introduced, said Marcia Brose, MD, PhD. This is causing a shift in the role of immunotherapeutic agents for the management of the disease.

“It looks like we're now going to be in a situation in which we can do molecular testing upfront for any patients that are going to head toward systemic therapy,” Brose stated.

In the past, agents like sorafenib (Nexavar), lenvatinib (Lenvima), were beneficial to all patients and, therefore, biomarkers were not necessary before first-line treatment. Once patients did undergo testing after or during their first-line treatment, ifBRAFmutations were found, physicians knew that BRAF inhibitors were the ideal second-line treatment.

Now, oncologists are studying potential options for patients withRETfusions andRETmutations. In thephase I LIBRETTO-001 study, for example, patients with papillary thyroid cancer and other thyroid cancers withRETfusions, or non—small cell lung cancer, and patients withRET-mutated MTC were given selpercatinib (LOXO-292), a RET inhibitor, at the maximum tolerated dose (MTD) for 28-day cycles. The study assessed MTD, recommended phase II dose, and objective response rate (ORR) as primary endpoints.

Patients withRET-mutant who had no previous treatment with vandetanib (Caprelsa) or cabozantinib (Cabometyx), (n = 76), had an of 59% after treatment with selpercatinib (95% CI, 47%-70%), and 1% complete response (CR). No patients were reported as having progressed during the study at 5.5 median follow-up. The duration of response (DoR) endpoint was not reached.

Among pretreated patients withRETfusions-positive thyroid cancer (n = 26), the overall response rate was 62% (95% CI, 41%-80%). No CRs were seen in this group and the DoR was also not reached.

In terms of safety, the 531 patients in the study across all cancers and dose levels tolerated selpercatinib well. The most common all-grade treatment-emergent adverse events were dry mouth (27%), increased aspartate aminotransferase (22%), and increased alanine aminotransferase (21%). Grade 3 and 4 TEAEs were also observed with the most common being hypertension (9%), increased aspartate aminotransferase (7%), and increased alanine aminotransferase (5%).

The LIBRETTO-001 study demonstrated the potential of novel therapies to safety drive patient responses. There are also studies looking at options for patients withTRKfusions, Brose mentioned.

In an interview withTargeted Oncology, at the 2019 Chemotherapy Foundation Symposium (CFS), Brose, associate professor, University of Pennsylvania School of Medicine, and director of the institution’s Thyroid Cancer Therapeutics Program and Center for Rare Cancers and Personalized Therapy, discussed the cases of thyroid cancer in which molecular testing can be initiated upfront to aid in the treatment decisions of oncologists. She also advised physicians on how to decide when to test patients with the disease.

TARGETED ONCOLOGY: Can you provide an overview of your presentation on at the 2019 CFS?

Brose: I talked about the evolving role of new agents in thyroid cancer. It's been an amazing 10 years for thyroid cancer because we've had multiple FDA approvals, mostly with targeted therapies. After that, we also need additional therapies because when those agents stop working patients need other options.

The big story in thyroid cancer is also a big story in other cancers. First, TRK inhibitors play a role in thyroid cancer, and it may be more significant than in other cancers becauseTRKfusion cancers are found in [around] 5% of DTC in patients who are refractory to radioactive iodine. When TRK inhibitors got approved, it actually had a positive impact on our patients because now we have options that give patients therapeutic responses and have a good [safety] profile.

[The other 2 types of drugs that] have come down the pike are the second generation RET inhibitors, which have also shown a lot of activity with good [toxicity] profiles. These are now in clinical trials that are showing [promising] data. Some of these data were presented at 2019 European Society for Medical Oncology (ESMO) Annual Meeting, recently. These are forRETfusion-positive cancers within DTC.

It's interesting because it looks like we will be in a situation where we can do molecular testing upfront for any patients that are going to head toward systemic therapy. In the past, we used to treat patients with sorafenib or lenvatinib, and these drugs benefitted all of our patients. We knew that we could use BRAF inhibitors next if the patients wereBRAF-positive. We didn't necessarily move our testing forward, but we often do genetic and genomic testing after patients completed their first-line therapy or during therapy. Given the amazing side effect profiles of these new agents, we can now argue that we need to do molecular testing upfront for any patient that is going to head towards systemic therapy.

Can you discuss the LIBRETTO 001 study, which you mentioned during your presentation?

We participated in the LIBRETTO study that was presented at ESMO. This was a basket trial that [enrolled] all patients who had eitherRET-mutated cancers, which were usually MTC or lung cancer. These were patients who had never been treated with vandetanib or cabozantinib.

RETmutations are often found in both lung and thyroid cancers, and, interestingly,RETfusions are also found in a significant number of patients with RAI-refractory DTC. [For patients with thyroid cancer in this trial], we win in 2 ways because MTC is often associated withRETpoint mutations, and RET fusions are found in DTC.

What biomarkers are typically used in thyroid cancer?

The first thyroid cancer drugs did not require biomarkers. They were good in all-comers. The next biomarkers we look at areBRAFin DTC becauseBRAFmutations are prevalent in 50% - 60%. In 2012, we showed that vemurafenib (Zelboraf), a BRAF inhibitor, works. More recently, we saw that dabrafenib (Tafinlar) also works in DTC.

We then look at the things that are being approved across tumor types. There's no question that patients who have MSI-high are eligible for immunotherapy, like pembrolizumab (Keytruda) or nivolumab (Opdivo). We don't see a lot of MSI-high patients, but we do see some. That would be an option for those patients. However, the TRK story is more important because that is FDA approved, and we can get that done. The molecular markers, for the most part, are genetic and they areTRKfusions,RETfusions,RETpoint mutation, andBRAFpoint mutations, such as V600E.

What type of testing do you recommend physicians do and at what point in treatment to you recommend testing?

In thyroid cancer, we have now moved our biomarker testing up from being in the second-line setting to the first-line setting. That is mostly because several of these agents, primarily the TRK inhibitors and RET inhibitors, have such good safety profiles, so we want to know about this from the start. Given the [manageable toxicities], we are now recommending that all patients have point mutation testing and fusion testing upfront. You have to make sure that you get both because some of the panels are not complete. At the University of Pennsylvania, we have in-house testing, so I know that we are testing for all fusions and point mutations.

[It's important to understand] that 80% to 90% of patients are going to be cured. We're talking about testing patients with RAI-refractory disease that's progressing or MTC that's metastatic or recurrent. People who are a candidate for systemic treatment should now be tested before starting systemic therapy so that you know what their options are.

How do the option differentiate based on what is found in the testing?

The options for all-comers in DTC will always be sorafenib and lenvatinib, and in medullary thyroid cancer, it's going to be vandetanib and cabozantinib in all-comers. What it does is it takes out the subgroups that have these mutations. You have to understand that they are a vast majority, and altogether they may not represent more than 10% in DTC because the toxicity profile is so good, you would never want to miss them.

In MTC, it a little bit different because you have the multi kinase inhibitors like vandetanib and cabozantinib that you can give to everybody, butRETis significant in over 5% of patients with MTC. The other thing that's important for people to know is that the testing in MTC is different. Many people will know that you should test all patients with MTC for germline mutations, and 10% of the patients will have germline mutations. However, if you go to people who have metastatic disease, half of them will have germline mutations inRET. Another 25% of them might have somatic mutations.

In my clinic, if I'm faced with a patient who's going to need treatment, I do the somatic testing first, and if they have the mutation, I know what to do for that patient. Then, I'll send off the blood tests because half of those patients will have the germline. It does depend on age. If the patient is younger, it's more likely, and if they're older, it's less likely.

What is the key takeaway from your presentation?

There is now a subgroup of patients in both DTC and MTC that have excellent new treatment options with low toxicities and good response rates. While this will not apply to the majority of patients, it is a significant enough proportion of patients that we now need to do testing upfront, and we now need to find a way to offer these patients the new agents. Sometimes we need to offer these agents ahead of first-line multi kinase inhibitors.

What advice would you give to an oncologist treating these 2 patient populations with the agents available in the current landscape?

I can't emphasize enough how important it is to know how to manage side effects.

While we have these great new targeted therapies that can benefit a minority of people and have good toxicity profiles, the other agents are also good. Lenvatinib is excellent for patients and sorafenib, cabozantinib, and vandetanib can treat patients for a couple of years. The patients who do the best are the patients who are treated by a physician who knows thyroid cancer, knows the safety profiles, and works with their patients. Patients can have long-term responses for up to 8 years.

If physicians are not managing these adverse events well, patients are never going to get those great responses.

Reference:

Wirth LJ, Sherman E, Drilon A, et al. Registrational results of LIBRETTO-001: A phase 1/2 trial of selpercatinib (LOXO-292) in patients with RET-altered thyroid cancers. Presented at ESMO Congress 2019; September 27-October 1, 2019; Barcelona, Spain. Abstract LBA93.