Developments and Directions in Thyroid Cancer
PracticeUpdate: Dr. Sherman, will you give us a brief background on thyroid cancer, and where we are right now?
Dr. Sherman: Of course. Thyroid cancer is a very prevalent malignancy, and this year, it will be the fifth most common cancer diagnosed in women. Over 6% of all women who survive cancer are survivors of thyroid cancer. Most people with the disease live long enough to die from something else, and since these patients don’t require traditional medical oncologic treatment, oncologists rarely get involved.
The primary treatment for virtually all of these patients is surgical, and the extent of the surgery, and whether any additional treatment follows, depends on the type of thyroid cancer. Most patients have what is termed differentiated thyroid cancer, which is either papillary or follicular, or variants of those. And most patients present with very small-volume disease, which is picked up incidentally on ultrasound or another type of imaging, and they are effectively treated, and probably cured, with surgery alone. Patients who are at intermediate or high risk for recurrence generally receive adjuvant radioactive iodine, which is the first treatment to consider for patients who actually have distant metastatic disease following initial surgery—about 1 out of 7. So, the combination of surgery and radioactive iodine effectively deals with differentiated disease for most patients. If the cancer recurs, it is still most likely to recur in the neck, and then additional surgery becomes the primary option.
A subset of patients has a different histology. They have the neuroendocrine tumor— medullary thyroid cancer—and surgery is the mainstay and only curative intervention we have. It is not a disease treated with radioactive iodine.
The problem in both histologies is that, historically, the traditional cytotoxic chemotherapies were pretty ineffective and, therefore, rarely used, even in patients with progressing metastatic cancer that didn’t respond—at least the differentiated form didn’t—to radioactive iodine. And the reality is that more than half of patients with distant metastases from differentiated cancer don’t benefit from radioactive iodine treatment, but we had nothing else to give. So, we followed the traditional approach which was to give radioactive iodine, and, if it didn’t work, we kept giving more. Again, medical oncologists weren’t involved; the radioactive iodine was usually provided by endocrinologists and nuclear medicine physicians. Until about 10 years ago, there really were no viable systemic treatment options.
The recognition that some of the emerging targeted therapies—tyrosine kinase inhibitors (TKIs)—potentially had a role changed things. Initially, it was thought that one of the kinases inhibited by the TKIs was an oncogene associated with the development of thyroid cancer. It turns out that this particular oncogene, RET/PTC, is rarely involved in metastatic differentiated disease, and wasn’t likely to be a relevant target. A related oncogene—the RET oncogene—turned out to be critically important in medullary cancer, and it may well be an important target. However, all of those early agents were primarily of interest because they targeted angiogenesis, and the VEGF receptor in particular; therefore, the first clinical trials were done with multi-targeted TKIs, all of which were very good inhibitors of angiogenesis.
Now, drugs like sorafenib, sunitinib, and pazopanib are widely used in metastatic differentiated thyroid cancer. Sorafenib has been tested in a large multi-center phase III trial, and results will be presented at ASCO, although the pharmaceutical company indicated in a press release several months ago that the primary endpoint of improvement in progression-free survival was achieved. I think there is a possibility that sorafenib could become the first proven effective chemotherapy to be approved by the FDA for treating metastatic differentiated thyroid cancer.
Two agents—vandetanib and cabozantinib—have already been through phase III trials and have been approved for treatment of medullary cancer. We’ve seen a very rapid growth in options, including off-label use of several agents, and an increase in the number of clinical trials, and, now, we have agents that are, and potentially could be, approved.
PracticeUpdate: How do you determine whether to use vandetanib or cabozantinib?
Dr. Sherman: That’s a good question. Since vandetanib was approved first, we have about 12 to 18 months worth of experience with it. The two drugs are difficult to compare in terms of effectiveness because the phase III trials were designed differently, with significant differences in the patient cohorts. The vandetanib phase III trial essentially took all comers with metastatic disease. But, in both medullary and differentiated cancer, patients often have stable or very indolent metastases, which do not particularly grow over a period of months or years of follow-up. You see a very long time to growth in the absence of any therapy at all. In the placebo arm of the vandetanib study, the median progression-free survival was 19 months. However, in the vandetanib arm, progression-free survival was significantly improved to 30 months—readily meeting the study’s primary endpoint.1
The cabozantinib clinical trial was designed with the recognition that a large population of patients arguably did not need treatment because they had stable disease, even if it was metastatic and measurable. So, the study was limited to patients who had documented progressive disease over a specified timeframe. The median progression-free survival in the placebo arm was only 4 months, and it improved to about 11 months in the cabozantinib arm.2
The comparison based on side effects is difficult as well because the cohort of patients in the cabozantinib study had more advanced disease at the outset. The placebo group in the cabozantinib trial had a much higher level of adverse events than the placebo group in vandetanib study. Without a head-to-head trial, we really can’t compare the two drugs directly.
As far as I am concerned, cabozantinib has two advantages. It appears to lack the effect on cardiac conduction as well as the significant prolongation of the QT interval seen with vandetanib. So, cabozantinib may have a bit of a safety advantage and it’s easier to use as a result since the safety monitoring of patients is easier. The other advantage is that the level of evidence documenting its benefit in patients with progressive disease is stronger because that was the group specifically recruited for the trial. However—a caveat—I have a conflict of interest, or dualities of interest, having been the lead investigator on the cabozantinib study, and I have had consulting relationships with both of the pharmaceutical companies as well.
PracticeUpdate: How are you approaching all of this new data, and where do you see us going in the future in thyroid cancer?
Dr. Sherman: A lot of the most exciting data are not immediately clinically relevant because we’re talking about drugs that are not commercially available. And, unfortunately, the clinical trials following up on these results are limited right now as well. The data are very intriguing in that they are helping us learn about mechanisms of the disease and they point us in a direction; but, none of this can be translated into clinical practice at this point.
What has emerged is that there is a very centrally important pathway in the most common differentiated cancer— papillary cancer—involving MAP kinase signaling. The most common oncogenic mutation is an activating mutation of BRAF, and there is a spectrum of BRAF mutations similar to those seen in melanoma and colon cancer. Of course, the effectiveness of BRAF inhibitors in melanoma and colon cancer differs between the two. There is a very clear, very high rate of response in melanoma, but a low rate of response in BRAF-mutated colon cancer. We’re beginning to understand some of the tissue-specific differences between how the cancer cell responds to a BRAF inhibitor; and how a melanoma cell responds is, in fact, different from how a colon cancer cell responds. And that yields different mechanisms of resistance, either primary or acquired.
We have some early evidence that BRAF inhibitors can be valuable in treating papillary thyroid cancer. The combined published phase I data for the two BRAF inhibitors—vemurafenib and dabrafenib— that are most studied in this situation show about a one-third response rate in papillary cancer with the BRAF mutation. So, the response is somewhere between that of colon cancer and melanoma. From the melanoma experience, one would expect that a MEK inhibitor would be effective in BRAF-mutated cancer. One published phase II trial of a MEK inhibitor (selumetinib) was rather disappointing, but it wasn’t specific for BRAF-mutated tumors, which may be why there was a rather high rate of progression.3 That is what we know so far. There are a lot of in vitro data suggesting that MEK inhibition would be helpful and that MEK combined with BRAF inhibition could be potentially beneficial. Most of it is following the melanoma model as well.
A randomized phase II trial is starting, funded through the National Comprehensive Cancer Network (NCCN). A randomized phase II trial of the BRAF inhibitor dabrafenib vs dabrafenib combined with the MEK inhibitor trametinib is getting underway in four sites, (Ohio State, MD Anderson, Massachusetts General Hospital, and Johns Hopkins). The hypothesis that a MEK inhibitor in combination with BRAF inhibitor maybe more effective and yield less resistance than a BRAF inhibitor alone will be directly tested.
PracticeUpdate: Where do you see selumetinib coming into play? How do you see its role as a radiosensitizer?
Dr. Sherman: It will be very interesting. The data published made a very strong case for a short course of an MEK inhibitor as potentially allowing successful radioactive iodine treatment of patients with disease previously refractory to radioactive iodine.4 This is not necessarily novel; people have been pursuing different drugs, including retinoids, to try to do the same thing for several decades. What was different, beside the fact that the study was very well designed, was the results demonstrated that the subsequent treatment with radioactive iodine actually induced radiographic responses. That is something that we had not seen before, even though we thought that we could enhance radioiodine uptake.
Now, where is this headed? Well, the obvious next step would be to replicate those data in a much larger cohort of patients, and, perhaps, focus particularly on the subgroup of patients with RAS—not BRAF— mutations who, in that single paper, were much more likely to benefit from the combination of selumetinib and radioactive iodine. Another approach would be to give selumetinib along with radioiodine at the time of first treatment to try to improve the remission rate with that first therapy. This would not be patients with known metastatic disease; the treatment would be given to patients at intermediate to high risk for recurrence or metastasis to try to prevent the initial treatment from failing.
PracticeUpdate: Are there any other new developments in thyroid cancer?
Dr. Sherman: An extremely important development is the creation of a cooperative group specifically focused on thyroid cancer. It is notable that none of the trials focused on these new agents since the first—almost 10 years ago—has come out of the National Cancer Institute (NCI) cooperative group system. Some of them have come out of phase II studies supported by the NCI. Some were conducted because of pharmaceutical company interests, which had to be coaxed since pharma did not have background in thyroid cancer either. In an effort to try to provide an organizing structure for thyroid cancer trials, and to enhance the ability to perform better science by merging philanthropic support for translational studies and broader clinical trials with support from either industry or the NCI, we created an organization now called the International Thyroid Oncology Group (ITOG). ITOG is an independent, not-for-profit cooperative group involving a broad multidisciplinary collection of the leading investigators in thyroid cancer research in the US, Canada, Europe, and Australia. ITOG’s primary focus is to promote opportunities for prospective clinical trials, and to ensure that these trials are optimally designed to yield the largest amount of scientific information.
We recently finalized an agreement with Academic and Community Cancer Research United (ACCRU), a cancer research group based at the Mayo Clinic, to serve as the research-coordinating center for ITOG clinical trials. The first ITOG clinical trial in partnership with ACCRU will be starting in the next month or two. It is an NCI-supported trial of cabozantinib as second-line therapy in patients with differentiated thyroid cancer. Other trials of more novel study concepts and drug combinations are in development through ITOG as well.
We certainly want community physicians to be aware that ITOG exists, and our new website, which will be online within the next few weeks, will provide information about thyroid cancer and thyroid cancer research, including trial-related information, and how patients can be directed to ITOG clinical trials.
References
- Wells SA, Robinson BG, Gagel RF, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012;30(2):134-141.
- Schoffski P, Elisei R, Müller S, et al: An international double-blind, randomized, placebo-controlled phase III (EXAM) of cabozantinib (XL184) in medullary thyroid cancer patients with documented RECIST progression at baseline. Paper presented at: 2012 ASCO Annual Meeting; June 1-5, 2012; Chicago, IL. Abstract 5508.
- Kirkwood JM, Bastholt L, Robert C, et al. Phase II, open-label, randomized trial of the MEK1/2 inhibitor selumetinib as monotherapy versus temozolomide in patients with advanced melanoma. Clin Cancer Res. 2012;18(2):555-567.
- Ho AL, Grewal RK, Leboeuf R, et al. Selumetinib-Enhanced Radioiodine Uptake in Advanced Thyroid Cancer. N Engl J Med. 2013;368:623-632.
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