Lorch Highlights Ongoing Research at Dana-Farber for Patients With Thyroid Cancer

Jochen H. Lorch, MD

Jochen H. Lorch, MD

Thyroid cancer is very common but is also benign in most cases. The standard treatment for these patients includes surgery followed by a dose of radioactive iodine, with a cure rate over 90%, but there is still a small fraction of patients that still recur.

After recurrence, patients can receive another round of radioactive iodine, but for patients who become refractory to this treatment, a second-line therapy option includes tyrosine kinase inhibitors (TKIs) such as lenvatinib (Lenvima) or sorafenib (Nexavar). These have been tested in numerous phase I and II trials. However, the cancer will return if the patient stops treatment.

MTOR inhibitors offer another option for refractory patients, but physicians still face the challenge of recurrence with these agents. Many clinical trials are currently investigating other treatment options for these patients including newer TKIs, mTOR inhibitors, and immunotherapy combinations.

In an interview withTargeted Oncology, Jochen H. Lorch, MD, a medical oncologist at Dana-Farber Cancer Institute, discussed some of the ongoing trials at his institution across various types of thyroid cancer.

TARGETED ONCOLOGY:You’re involved in a number of clinical trials for patients with thyroid cancer. Can you start by discussing the trial investigating regorafenib (Stivarga) in the second- or third-line setting (NCT02657551)?

Lorch:This is a trial that was originally designed for medullary thyroid cancer (MTC). MTC is a different type of thyroid cancer that is driven not from the malignant cells or produced by the thyroid hormone that is dependent on iodine, but it’s a different hormone called calcitonin and a number of other things. These tumors also respond quite well to these TKIs. In this case, the ones that are FDA approved are cabozantinib (Cabometyx) and vandetanib (Caprelsa). Again, the problem is that eventually these tumors become resistant, so we are looking for another TKI. There is 1 called regorafenib that is primarily for patients who have failed the previous treatments of medullary thyroid cancer.

We have also just opened that up for patients with regular iodine-refractory thyroid cancer, and it’s essentially a variation of these TKIs. There’s vandetanib, there’s cabozantinib, lenvatinib is very closely related, sorafenib is very closely related, and now regorafenib is another member of this family. What you can often do surprisingly is go from 1 drug to another similar drug. You can switch over in the same class of drugs to another member of its family and often still get a response, so people often go from 1 drug to the next to the next to the next. That’s the background for our trial with regorafenib.

It’s FDA approved for colon cancer. It has generally a good track record, but it’s also a relatively tough drug to take just like all the other TKIs. In that respect, it’s unfortunately not very different.

TARGETED ONCOLOGY:Can you also discuss the phase II trial with MLN0128 (NCT02244463)?

Lorch:That is primarily for patients with anaplastic thyroid cancer. We also had that open for DTC. It is an mTOR inhibitor, which is similar to everolimus. It’s a totally different class of drugs targeting a totally different mechanism that’s there: the mTOR PI3-kinase mechanism that is distinct from the other TKIs that we have talked about like lenvatinib, sorafenib, and so on.

As I mentioned, in a phase II study, we have had really good results with everolimus. This is a follow-up study of a next-generation mTOR inhibitor. It actually targets a host of pathways that are inside the cancer cells, but those that are linked to the mTOR pathway. That study is open and accruing. We completed the accrual for patients with iodine-refractory disease, but we are still looking for patients with anaplastic thyroid cancer.

Anaplastic thyroid cancer is one of the worst cancers you can get, period. It also originates from the thyroid gland and often arises from a differentiated, regular thyroid cancer, cancers that frequently affect older people. It’s one of the worst cancers ever, which is surprising because all the other thyroid cancers are generally benign or slow-growing in comparison to lung cancer, colon cancer, or some of the other cancers. This is a different animal. These are people that you could literally watch the tumors grow, and in most cases, people notice a lump in the neck 1 day, and three days later, it’s twice the size. They go to their physician, and by the time they get referred to an oncologist, they can barely breathe within a matter of a couple of weeks. There’s virtually no cure rate. It’s definitely less than 10%. Most people die within half a year or less if they get diagnosed with it.

Also, this poor prognosis doesn’t reflect the staging system. There’s only stage 4. It doesn’t matter, even if it’s localized. You’re automatically stage 4 just because this is such a hyper-aggressive disease. That’s what this is.

That’s primarily what this trial is for with the mTOR inhibitor MLN0128. Because the background here is that frequently there are mutations along this pathway, the PI3K pathway, that affect mTOR, and you are trying to block that. In some cases, it works quite well, but again, these patients require additional interventions.

TARGETED ONCOLOGY:Could you provide some background on the trial with evaluating an immunotherapy combination (NCT03246958)?

Lorch:This is a trial that is totally different using immunotherapy. Nivolumab (Opdivo) is a PD-1 inhibitor, meaning PD-1 is essentially an inhibitor that sends a signal that any cell can use to tell the immune system not to attack. That’s obviously very important, for example, to tell the immune system not to attack the brain, heart, or other vital structures and not cause auto-immune issues. Cancer cells being the body’s own cells as well, they have that program as well. They can make this protein that tells the immune system to stand back, and they do. Otherwise, the immune system would recognize them as unusual and they should be killed, but instead they put out this sign that tells them to let them live, then they survive. That antibody removes the stop sign, if you will, and allows the immune cells to attack and destroy the tumor.

The other drug, called ipilimumab, is targeting a process directly on lymphocytes on certain immune cells. Essentially, it tells them to be a little more active. We’re combining these drugs to make the tumor more visible and to activate the immune system to fight these aggressive cancers. That’s open for patients with all cancer types, including anaplastic thyroid cancers.

The not so exciting part is that somebody published with just 1 drug alone in a small case series, and there, the response was less than 10% in thyroid cancer. Now, that’s not that surprising because compared to other cancers, genetically, thyroid cancers are very bland cancers. There are not a lot of mutations, generally speaking, compared to other cancers where the tumors would produce a lot of unusual proteins and things for the immune system to recognize. These are still relatively normal looking cells for the immune system, and it’s difficult to see it. That’s the reason why we added ipilimumab. We also have, at least when we were planning this, the advantage of working with somebody at MIT who had just developed the world’s first in vitro system where you could test the immune efficacy. We found that CTLA-4 antibody, ipilimumab, conveyed efficacy.

The big promise of immunotherapy is that you see that across all tumor types. The big promise is that for people who respond really well, I have a couple of people with other types of cancer where this happened, where the cancer went away, and we could no longer see it. You treat for 1 or 2 years, then you stop. As I mentioned, with lenvatinib or sorafenib the TKIs, it always comes back. With immunotherapy, in many cases, it doesn’t. Now is that a cure? We don’t know, but it sure looks like one. That’s the hope of immunotherapy. It’s something that no other drug can do. Eventually, for all these other ones, the cancer becomes resistant and continues to grow. With immunotherapy, probably just because it’s using the immune system, it isn’t just introducing 1 block, it’s activating the immune system, a live thing, that sort of moves with the cancer as it tries to escape its fate. I think there is hope that this will lead to some more durable responses that will actually continue after you stop the drugs. This is an ongoing trial so I can’t tell you what we’ve seen, but so far, the results are very encouraging.