Targeted Therapies Advancing Thyroid Cancer Treatment Paradigm

Lori J. Wirth, MD

Lori J. Wirth, MD

Radioactive iodine therapy remains the standard of care in many types of thyroid cancer, but a subset of patients will still relapse or become iodine-refractory. Therapies targeting alterations such as RET, MEK, and NTRK provide another opportunity to treat these patients.

“I think we have a very compelling argument that doing molecular analyses in these patients with advanced thyroid cancers is really critical to identify these patients that have alterations that are druggable with very active drugs,” said Lori J. Wirth, MD. “If we study the genomics of patients with thyroid cancer, more than half of our patients are going to have druggable alterations found.”

In an interview withTargeted Oncology,Wirth, associate professor of medicine at Harvard Medical School and medical director of the Center for Head and Neck Cancers at Massachusetts General Hospital, discussed the current treatment options for patients with advanced thyroid cancers, in addition to some of the trials that are currently enrolling at her center. She also highlighted early data that have been presented for targeted therapies in these patients.

TARGETED ONCOLOGY:What are some of the recent data we have seen in this patient population that appears promising?

Wirth:One of the big steps forward in thyroid cancer is new treatments for anaplastic thyroid cancer (ATC). This isn’t quite off the presses as the work was published a year ago in theJournal of Clinical Oncology, but it’s still big news, because ATC is a really aggressive disease. Advances in ATC has been very slow, but there was a basket trial with dabrafenib (Tafinlar) and trametinib (Mekinist) forBRAF-mutant cancer that was not melanoma, so there was a basket for patients withBRAF-mutant ATC. About a third of patients with ATC will have aBRAFmutation as a driver mutation in their disease. In that basket, there was about a 65% response rate for those patients, which is really remarkable in ATC. Just recently, the FDA approved dabrafenib and trametinib forBRAF-mutant ATC patients.

In differentiated thyroid cancer (DTC),BRAFmutations are more common, and they are seen in about 60% of patients with papillary thyroid cancer, for example. We have looked at dabrafenib and trametinib in those patients as well, but we didn’t see response rates that were quite as high as in ATC. Still, response rates with either dabrafenib alone or dabrafenib plus trametinib were 50% and 54% in an NCCN-sponsored randomized phase II trial. It looks like dabrafenib plus or minus trametinib will be a new alternative therapy for patients with either iodine-refractory DTC that harbors aBRAFmutation.

TARGETED ONCOLOGY:What kind of impact do these drugs have on these 2 patient populations?

Wirth:For patients with ATC, to have any drug demonstrate any activity at all is just a huge bonus because before the dabrafenib and trametinib data, we really had very few options for patients with ATC. The standard approach is cytotoxic chemotherapy which does bring along its side effects and has modest to very little activity at best in ATC. For the subset of patients who haveBRAFmutations in ATC, to have this combination of targeted therapy is a huge leap forward, basically taking them from having no good treatment alternatives to having at least 1 good treatment alternative.

There is some other progress in ATC worth noting. We did an expansion cohort of the PD-L1 antibody made by Novartis called spartalizumab (PDR001) and treated more than 40 patients with ATC with spartalizumab. That was presented at ASCO last year, and we saw a 20% overall response rate (ORR) with spartalizumab in patients with ATC that wasn’t genotype specific. It’s notable, too, that some of the patients that had responses seemed to have very durable responses, which has been discoursed in other solid tumors. It does look like the checkpoint inhibitors have pretty good activity for patients with ATC.

TARGETED ONCOLOGY:Are there any other recent updates in the field that you think are important?

Wirth:For patients that have DTC that is iodine-refractory, as I mentioned,BRAFmutations are seen in 60% of patients with papillary thyroid cancers. That is the most common driver mutation that is seen. However, we also see fusions in DTC that are actionable. In fact, DTC has the highest rate of actionable oncogenic fusions seen across solid tumors, so 12% of all thyroid cancers harbor highly-actionable fusion alteration. Two of those driver fusion kinases that have now been studied in terms of targeted therapy are NTRK and also RET. Both NTRK fusions and RET fusions are seen in a subset of patients with iodine-refractory DTC.

With NTRK, both larotrectinib (Vitrakvi) and entrectinib (Ignyta) have been studied in patients with NTRK fusion-driven iodine-refractory DTC. Both of those drugs have also been shown to have remarkable activity in patients with NTRK-fusion thyroid cancer. Overall, with larotrectinib, there was an 80% response rate in NTRK-fusion tumors, and that activity across different tumor types led to the first tumor agnostic FDA approval in oncology just this year. There will be a subset of patients with thyroid cancer that will be benefiting from that drug now being on the market. Similarly, entrectinib is a multikinase inhibitor that blocks TRK as well as other kinases and entrectinib has been studied in NTRK fusion thyroid cancer as well with similar degrees of very solid activity.

About 10% of DTC will harbor RET fusions, and then a very large percentage with medullary thyroid cancer (MTC), which is a different type of thyroid cancer, will have activating point mutations in RET, which is a kinase that is considered a driver alteration in those cancers as well as a subset of patients with non—small cell lung cancer. Two new drugs that are now in phase II trials that are potent specific inhibitors of RET are LOXO-292 and BLU-667. The data in thyroid cancers have been presented for both of the 2 drugs at the American Thyroid Association meeting in October of this year, and both of those 2 drugs have a very high ORR in RET-altered thyroid cancers, both the RET fusion in DTC and RET mutant MTC.

For example, with the LOXO-292 trial, overall in the RET-mutant MTC, there was a 59% ORR with responses we are seeing that are very durable. Also, what’s really great is that both of the 2 drugs are very well tolerated. They are very potent to specific RET inhibitors that off-target the side effect profile which is really minimized with that potent strategy. Drugs are really much better tolerated from what I can tell in my clinic. The drugs for MTC that are now FDA approved are cabozantinib (Cabometyx) and vandetanib (Caprelsa).

TARGETED ONCOLOGY:How do you see this field evolving going forward?

Wirth:The standard of care for iodine-refractory thyroid cancer that is progressive with a VEGFR multikinase inhibitor is either lenvatinib (Lenvima) or sorafenib (Nexavar). Both of those 2 drugs are approved. I think the drug that I use in the first-line is lenvatinib because it has a very significant 15-month progression-free survival (PFS) benefit, and the ORR is 65%. That’s actually a pretty good first-line drug, so it’s hard to beat an ORR at 65% and median PFS of 19 months. We will have to see what happens with new drugs coming online. There will probably be a number of drugs that will be used in the second-line after a drug like lenvatinib. For example,BRAF-mutant iodine-refractory PTC dabrafenib plus/minus trametinib has a response rate of about 50%, so in my own practice I use lenvatinib first, but I’ve got a great second-line alternative, though it is off-label at this point with dabrafenib plus/minus trametinib for those patients.

Whereas I think with the activity we are seeing in the very potent and specific inhibitors like larotrectinib and entrectinib for NTRK fusion thyroid cancers and thinking ahead with LOXO-292 and BLU-667 for RET-driven cancers, those drugs look like they have very high response rates that are very durable and also have very favorable side effect profiles. What I think we will be doing in the future is using those drugs in the subset of patients whose tumors harbor those alterations as first-line therapy, then using a drug like lenvatinib in the second-line.

TARGETED ONCOLOGY:What questions still need to be answered in thyroid cancer?

Wirth:One of the big questions is how we can improve on lenvatinib as first-line therapy, because when patients aren’t cured and have metastatic disease and even if you’ve got a good first-line therapy, there is always room for improvement. One of the strategies that I think is very promising and is being studied now is the combination of checkpoint inhibitor with a VEGFR multikinase inhibitor, so we have seen activity across several different combinations and tumor types, for example, with axitinib (Inlyta) and pembrolizumab (Keytruda) in renal cell carcinoma or the combination of lenvatinib and pembrolizumab which has been studied in several phase I/II trials in several different tumor types that have shown the combination has promising activity. We are now conducting a clinical trial investigating pembrolizumab and lenvatinib in patients with iodine-refractory DTC hoping that we can get even better responses and more durable responses with that combination. That trial is being conducted as a multicenter trial in the US at about 10 different centers by the International Thyroid Oncology Group (ITOG).

TARGETED ONCOLOGY:What ongoing trials do you have available at your center?

Wirth:One of them is the pembrolizumab/lenvatinib trial that I mentioned. That study is enrolling now, and enrollment will be complete soon, sometime, I think this year, so we should expect to see data from that study in 2020, I would hope. Another trial that we are a part of, again through ITOG, is with a drug called selumetinib (AZD6244), a MEK inhibitor. That trial is looking at the potential for selumetinib to reverse the resistance to radioactive iodine in a subset of patients with iodine-refractory thyroid cancer. Based on work that was done by Memorial Sloan Kettering and published in theNew England Journalseveral years ago showing that if you pretreat patients with selumetinib, you can trick thyroid cancers into taking a pre-active iodine. The study that ITOG is doing a follow-up from that initial feasibility trial randomizing patients to selumetinib versus placebo, and then pretreating them prior to giving a course of radioactive iodine, then following the patients to see if patients pretreated with selumetinib will have better responses to the radiative iodine. That’s a really interesting and important trial.

One of the things that is of a lot of interest in the thyroid cancer community is figuring out how to take advantage of radioactive iodine for more patients. It’s interesting with radioactive iodine, which was first used in the 1940s, was really the first targeted therapy in oncology. Now, decades later, we are still figuring out how to optimally use it. We do think that by blocking the pathways that down-regulates, thyroid cancer cells can concentrate on iodine. We can enhance the overall treatment effect of radioactive iodine.

TARGETED ONCOLOGY:Are there other trials at your center that you can highlight for these patients?

Wirth:I think it is really important to highlight the LOXO-292 trial and also the BLU-667 trial, both of which are the RET inhibitors that I mentioned. Both of those 2 drugs are now in phase II studies at multiple centers across the US and also worldwide. The trials are both open to enrollment. The early data that had been reported so far are really very promising. Neither one of the drugs is FDA approved yet, but hopefully we will be seeing these become standard of care options for patients with RET-driven thyroid cancers in the future. I think over the next 5 years, we will be thinking about how to really utilize these really promising and well-tolerated therapies optimally in patients. Should we be using them earlier in the course of disease? For example, I think there is a wealth of future studies that we will be seeing with the RET inhibitors, I hope.

The other thing that I think is really important to emphasize is that doing genomic or molecular characterization of advanced thyroid cancer is something that hasn’t really been a routine part of the standard of care for these patients. Now, with all of the advances that I just mentioned, I think we have a very compelling argument that doing molecular analysis in these patients with advanced thyroid cancer is really critical to identify those patients that have alterations that are druggable with very active drugs. If we study the genomics of patients with thyroid cancer, more than half of our patients are going to have druggable alterations found, so I really think that we need to consider this kind of testing as the standard of care. It is now, for example, incorporated into the NCCN guidelines for the treatment of advanced thyroid cancer.