Dabrafenib + Trametinib (Anaplastic Thyroid Cancer)
Posted: Tuesday, April 28, 2020
Well-differentiated papillary and follicular thyroid cancers are among the most treatable, even curable, malignancies. In 2019, 52,070 new cases of thyroid cancer were reported in the United States, and 98.2% of such patients survive for 5 years.1 However, poorly differentiated and undifferentiated thyroid cancers, such as anaplastic thyroid cancer, are less common, aggressive, metastasize early, and have a poorer prognosis.2 Unlike the well-differentiated subtypes, anaplastic thyroid cancer is not responsive to iodine I-131 therapy and is generally difficult to manage. In some early-stage cases, surgery or external-beam radiation therapy may be effective, but until 2018, few medical options existed for treatment of more advanced disease.
A ‘Comparatively Bland’ Genomic Landscape
A large percentage of papillary and follicular thyroid cancers, perhaps 60%, are positive for BRAF mutations (the vast majority of which are V600E).3 Most of these well-differentiated tumors can be cured with surgery, with or without radioactive iodine, explained Jochen Lorch, MD, MSc, Director of the Thyroid Cancer Center at the Dana-Farber Cancer Institute and Associate Professor of Medicine at Harvard Medical School, Boston.
“Only a small minority of these cases go on to develop recurrence, and an even smaller percentage develop iodine refractoriness requiring systemic treatment,” Dr. Lorch told JNCCN 360. Noting that another 15% to 20% of cases are positive for RAS mutations, he emphasized “there is no overlap between BRAF and RAS mutations. A tumor will not be positive for both mutations.” Although a few other mutations, such as PI3K, mTOR, and p53, have also been identified, “compared with other tumor types (colorectal, lung, and breast), the genomic landscape in thyroid cancer, even in anaplastic thyroid cancer, is comparatively bland,” he noted.
Anaplastic Thyroid Cancer
Anaplastic thyroid cancer is uncommon, perhaps in 1% to 2% of all thyroid cancers, although it accounts for 30% to 50% of thyroid-related mortality,4 Dr. Lorch pointed out. It is extremely aggressive, with a median survival of 4 to 6 months,5 “usually presenting as metastatic disease, even if the primary tumor in the neck is resectable. Patients go from being completely healthy to having a lump in the neck that’s going to suffocate them within a few days or weeks. It’s one of the worst malignancies.” Nonetheless, he characterized the genomic landscape of anaplastic thyroid cancer—compared with other highly aggressive tumor types as relatively bland.
BRAF Mutation–Positive Anaplastic Thyroid Cancer
BRAF V600E mutation occurs in approximately 45% of all anaplastic thyroid cancer cases.6,7 In addition, other mutations, such as PI3K, were sometimes observed as overlapping with either the BRAF or RAS mutation.
“Genomically, there’s more going on with anaplastic thyroid cancer than with differentiated tumors such as papillary thyroid cancer,” Dr. Lorch said. “Nonetheless, compared with other aggressive tumor types, there appear to be fewer of these genomic alterations in these anaplastic tumors. The other surprising feature of these tumors is that when you examine clonal evolution, despite their aggressiveness, the tumors are genomically stable. Phylogenetic trees drawn for anaplastic thyroid tumors—on which each branch represents a new mutation—are fairly simple, indicating the tumors are genomically stable, and DNA repair seems rather intact,” he explained.
Targeted Combination Treatment: Dabrafenib + Trametinib
The combination therapy of dabrafenib plus trametinib has been approved for these BRAF mutation–positive anaplastic thyroid tumors8 on the basis of results from a 16-patient subset of a larger basket trial looking at a variety of tumors with BRAF V600E mutations.9 Because of its aggressiveness and poor prognosis, all patients diagnosed with anaplastic thyroid cancer and a BRAF mutation should be given the opportunity for treatment with dabrafenib and trametinib, Dr. Lorch emphasized.
“Prior to the approval of this targeted regimen, we had the option of doxorubicin, which was minimally effective,” he explained. “Combinations of doxorubicin with a platinum yielded a slightly higher response rate but with an unclear effect on overall survival. Essentially, there was no standard of care for these cases with a poor prognosis.” [Editor’s Note: The NCCN Clinical Practice Guidelines in Oncology for Thyroid Carcinoma10 list several systemic chemotherapy regimens for patients with metastatic anaplastic thyroid cancer, irrespective of BRAF mutation status. They include paclitaxel/carboplatin, docetaxel/doxorubicin, paclitaxel, and doxorubicin.]
Dabrafenib and trametinib are tyrosine kinase inhibitors: Dabrafenib targets the BRAF mutation and trametinib targets MEK, which are two components of the same pathway.11 Surprisingly, there was an almost 70% response rate in the patient cohort studied in the basket trial.9 “Perhaps even more astounding,” Dr. Lorch said, “at least some of the responses seemed to be durable. Of the 16 patients, 11 had a confirmed response, and 7 patients still had a confirmed response at 1 year. In anaplastic thyroid cancer, that’s quite spectacular.”
Very Small Data Set
Although there are some patients who achieve durable responses with this regimen, there are also many cases in which tumors become quickly resistant and recur within weeks to months. Because of the small number of patients in the published trial, “I remain a bit skeptical about a 70% response with durability but optimistic in general about the activity of this regimen,” Dr. Lorch told JNCCN 360. He pointed out that some of the responses might have been in patients with poorly differentiated thyroid cancer rather than in true anaplastic disease.
“Keeping in mind there was no central pathology review in the basket trial, the distinction between anaplastic and poorly differentiated thyroid cancers is not trivial. We know the prognosis for those with poorly differentiated thyroid cancer is good, and the response to any BRAF-inhibiting strategy or to other tyrosine kinase inhibitors (such as lenvatinib or sorafenib) is also good.12 In practice, the dabrafenib [plus] trametinib regimen might not achieve a 70% response rate, although it is clearly of value in some patients.”
With regard to the use of BRAF inhibition in other subtypes of thyroid cancer, Dr. Lorch noted that “a few patients with well-differentiated thyroid cancers that involve BRAF mutations will develop recurrent iodine-refractory disease. Although dabrafenib and trametinib have not been studied in this setting, vemurafenib has been explored in a phase II trial13 of about 50 patients.”
Although anaplastic thyroid cancer is rare, clinicians in academic centers generally see more cases than those in the community. “The vast majority of patients with thyroid cancer are treated with surgery and perhaps radioactive iodine, and they do very well,” Tura R. Coombs, RN, a nurse navigator with the Head & Neck Cancer Treatment Center and Thyroid Cancer Center at the Dana-Farber Cancer Institute told JNCCN 360. Nevertheless, she acknowledged that she and her colleagues commonly see patients with advanced anaplastic disease. “Patients often come to us [a specialized thyroid cancer center] when treatment hasn’t worked or the disease is progressing rapidly.”
Oral Therapy for Patients With Swallowing Difficulties
Clinically, some of these patients are hoarse and/or have difficulty swallowing from an enlarged tumor, which complicates or even obviates the ability to ingest oral medications. Fatigue is often also part of the overall picture, Ms. Coombs said.
“Some patients have a feeding tube,” she noted. “We defer to the oncologists and pharmacists if we want to try to administer the medication that way [through the tube].”
Asked about patients who have major problems with swallowing due to a growing neck tumor, Dr. Lorch said, “There is no instruction about opening the capsule and administering the powder medication via feeding tube in the prescribing information for dabrafenib.14 We have done that successfully,” he said. “However, there is no liquid formulation, nor are there any data about whether the dosage is equivalent when compared with oral ingestion.”
Patient education is a team effort and involves several reinforcing layers. When a decision is made to treat, “we contact our oral chemotherapy teaching group, which comprises pharmacists,” Ms. Coombs said. “They reach out to the patient, obtain necessary assessments, and initiate education about the regimen, advising about red flags and how to manage common, mild side effects.” The nurse navigator then follows up with an “oral chemotherapy adherence call” to review and ensure that all questions are addressed. This allows patients time to absorb information and several opportunities to clarify any remaining issues.
“Most patients do well in terms of adhering properly to the schedule by using pill boxes, charts, and medication diaries,” Ms. Coombs continued. Use of a simple tool is encouraged because the regimen consists of two medications, taken either 1 hour before or 2 hours after meals, and one is taken twice daily, whereas the other is taken once daily. “It is not a terribly complicated regimen, nor is it the simplest,” she noted. It is critical for the team to check in with patients frequently and to note anything that seems unusual compared with baseline, added Ms. Coombs.
Adverse Events and Management Strategies
Although the adverse effects of tyrosine kinase inhibitors are “considered by many to be relatively benign [compared with those of infusional chemotherapy], they are not necessarily benign, especially with respect to trametinib,” according to Dr. Lorch. Patients can develop severe pyrexia with trametinib, which manifests as high fever and extreme fatigue. “They develop a systemic inflammatory response and feel really sick,” he said. “I’ve had patients admitted to the hospital with these sepsis-like syndromes, which were clearly drug-related, because there was never any infection.”
Patients can develop severe pyrexia with trametinib, which manifests as high fever and extreme fatigue.
According to Dr. Lorch, acetaminophen or nonsteroidal anti-inflammatory drugs are not prescribed prophylactically. “However, we have a low threshold if a patient reports fever. Unfortunately, these fevers do not seem to be very responsive to standard interventions, such as these over-the-counter medications.”
Other side effects include lack of appetite, rash, and hypertension. “Patients sometimes report relatively minor symptoms, such as itching, but if something more serious comes up, we usually manage it by altering the regimen in some way, ie, reducing or holding the dose, before the side effect becomes more severe,” Ms. Coombs said. Whether both drugs are modified or paused, or only one of them, depends on the symptoms and how severe they are, she explained.
Our rationale is that we want patients to call us if they are having a symptom, rather than trying to treat themselves alone at home.
Many patients are already on stool softeners to prevent or manage constipation, Ms. Coombs remarked, and “we advise them to hydrate at home. If they are unable to hydrate enough on their own, we can set up hydration at our infusion center.” Patients usually are not given prophylactic prescriptions to have on hand, but “we can promptly call any medications into the pharmacy, if needed,” she said. “For nausea, we might prescribe ondansetron or metoclopramide, for instance. Our rationale is that we want patients to call us if they are having a symptom, rather than trying to treat themselves alone at home. This way, we can assess the severity and seriousness of the situation.”
The most challenging adverse effects, Dr. Lorch repeated, however, are pyrexia and fatigue. It is sometimes necessary to continue treatment with just one drug, usually dabrafenib, while holding trametinib. “We need to be aware of an increased risk of cutaneous cancers when dabrafenib is used alone. Because such lesions on the skin grow slowly and may be well managed with removal by dermatology colleagues, awareness is usually a sufficient precaution,” he observed.
We need to be aware of an increased risk of cutaneous cancers when dabrafenib is used alone.
The Thyroid Cancer Center team sees patients with anaplastic thyroid cancer who are receiving dabrafenib plus trametinib weekly or every other week, Ms. Coombs commented. “We always ask about any changes in their health status, whether it is the appearance of a rash or changes in their vision, she said. “I am the point person for patient contact whenever there is an issue. I give them my card, the on-call pager number. They can call us for anything. Primarily, we tell patients to call if there is any new onset of symptoms, such as pain, nausea/vomiting, or fever (≥ 100.4°F). We also want to hear if they vomited their medication, damaged it, or lost it.”
Future directions for patients with anaplastic thyroid cancer include the use of mTOR inhibitors, such as everolimus,15 “especially when there are mutations along the PI3K/mTOR axis,” Dr. Lorch observed. In addition, he noted that some emerging data suggest immunotherapy (eg, combination of nivolumab plus ipilimumab) may be effective (ClinicalTrials.gov identifier: NCT03246958). Other approaches include neoadjuvant treatment16 or combinations of BRAF inhibitors plus immunotherapy.17 All such research is ongoing, however, and is being conducted with small numbers of patients.
Dr. Lorch urged community endocrinologists to immediately refer patients with anaplastic thyroid cancer to oncology colleagues, “preferably at an academic center where a BRAF mutation panel can be ordered quickly. Time is of the essence in these cases, as tumor growth is rapid,” he emphasized.
“Just a few years ago,” Dr. Lorch concluded, “I attended a panel discussion about anaplastic thyroid cases at an oncology conference. Almost universally, the recommendation was for hospice. This is changing rapidly, and such nihilism is no longer justified.” As already observed, the “genomics of this disease are relatively simple. Once we identify treatments that work, they can work for a surprisingly long time. Some of these cases are potentially treatable and even curable, particularly as current research evolves and new findings emerge.”
Jochen Lorch, MD, MSc, has served on advisory boards for Genentech, Bayer, and Novartis. He has received research support from Bayer, Bristol-Myers Squibb, Takeda, and Novartis.
Tura R. Coombs, RN, reported no conflicts of interest.
- National Cancer Institutes. Thyroid Cancer Treatment (Adult) (PDQ). Health Professional Version. Available at https://www.cancer.gov/types/thyroid/hp/thyroid-treatment-pdq#cit/section_7.8. Accessed April 21, 2020.
- Saini S, Tulla K, Maker AV, et al. Therapeutic advances in anaplastic thyroid cancer: a current perspective. Mol Cancer 2018;17:154.
- Tafinlar (dabrafenib). Full prescribing information. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202806s012lbl.pdf. Accessed April 21, 2020.
- Nagaiah G, Hossain A, Mooney CJ, et al. Anaplastic thyroid cancer: a review of epidemiology, pathogenesis, and treatment. J Oncol 2011;2011:542358.
- Lin B, Ma H, Ma M, et al. The incidence and survival analysis for anaplastic thyroid cancer: a SEER database analysis. Am J Transl Res 2019;11:5888–5896.
- Landa I, Ibrahimpasic T, Boucai L, et al. Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers. J Clin Invest 2016;126:1052–1066.
- Forbes SA, Beare D, Boutselakis H, et al. COSMIC: somatic cancer genetics at high-resolution. Nucleic Acids Res 2017;45:D777–D783.
- U.S. Food and Drug Administration. FDA approves dabrafenib plus trametinib for anaplastic thyroid cancer with BRAF V600E mutation. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-dabrafenib-plus-trametinib-anaplastic-thyroid-cancer-braf-v600e-mutation. Accessed April 21, 2020.
- Subbiah V, Kreitman RJ, Wainberg ZA, et al. Dabrafenib and trametinib treatment in patients with locally advanced or metastatic BRAF V600-mutant anaplastic thyroid cancer. J Clin Oncol 2018;36:7–13.
- Haddad RI, Bischoff L, Busaidy NL, et al. NCCN Clinical Practice Guidelines in Oncology: Thyroid Carcinoma. Version 2.2019. Accessed April 21, 2020. For the most recent version of these guidelines, visit NCCN.org.
- Oikonomou E, Koustas E, Goulielmaki M, et al. BRAF vs RAS oncogenes: are mutations of the same pathway equal? differential signaling and therapeutic implications. Oncotarget 2014;5:11752–11777.
- Crispo F, Notarangelo T, Pietrafesa M, et al. BRAF inhibitors in thyroid cancer: clinical impact, mechanisms of resistance and future perspectives. Cancers 2019;11:E1388.
- Brose MS, Cabanillas ME, Cohen EE, et al. Vemurafenib in patients with BRAF(V600E)-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised multicentre, open-label, phase 2 trial. Lancet Oncol 2016;17:1272–1282.
- Tafinlar (dabrafenib). Full prescribing information. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202806s012lbl.pdf. Accessed April 21, 2020.
- Harris EJ, Hanna GJ, Chau N, et al. Everolimus in anaplastic thyroid cancer: a case series. Front Oncol 2019;9:106.
- Wang JR, Zafereo ME, Dadu R, et al. Complete surgical resection following neoadjuvant dabrafenib plus trametinib in BRAFV600E-mutated anaplastic thyroid carcinoma. Thyroid 2019;29:1036–1043.
- Cabanillas ME, Ferrarotto R, Garden AS, et al. Neoadjuvant BRAF- and immune-directed therapy for anaplastic thyroid carcinoma. Thyroid 2018;28:945–951.