Anaplastic Thyroid Cancer: Hope Emerges Amid Widening Range of New Therapies
Though scientific advances have been encouraging in the thyroid cancer space, there is much more work to be done to figure out exactly how to tailor the right therapy, or combination of therapies, for individual patients.
Ashok R. Shaha, MD, FACS
Head and Neck Surgeon
Jatin P. Shah Chair in Head and Neck
Surgery and Oncology
Allan H. Selig Chair
Memorial Sloan Kettering Cancer Center
New York, NY
For most of his career, the first thing Ashok R. Shaha, MD, FACS, would do when he had to give a patient a diagnosis of anaplastic thyroid cancer (ATC) was to pick up the phone. Years ago, the purpose of the call was to rally psychological support for the patient because an ATC diagnosis was essentially a death sentence; little could be done, treatment-wise.
But now, with the improvements in ATC treatment options described in this article, numerous phone calls are made to medical professionals to devise and quickly initiate the patient’s treatment plan.
Shaha, a head and neck surgeon at Memorial Sloan Kettering Cancer Center in New York, New York, knew it was going to be a hard conversation with his patients because he knew the prognosis for ATC was almost always dismal.
“Because the tumor grows so fast, most of the time when people present, they present with very advanced local disease,” he said, “and the surgeons cannot operate.”
Back then, about 5% to 10% of patients would receive their diagnosis early enough that surgery was feasible, he said. The rest would be referred for radiotherapy, but most would not survive more than a few months.
However, Shaha said things have changed in recent years. A combination of next-generation sequencing (NGS) and a range of new therapies have created treatment pathways where none previously existed. Multitarget tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs), and experimental combination therapies have sparked hope for patients and led to dramatic improvement in many cases. Yet for all the hope, there are also plenty of questions. Shaha said the scientific advances have been encouraging, but there is much more work to be done to figure out exactly how to tailor the right therapy—or combination of therapies—for individual patients.
The Role of BRAF/MEK Inhibitors
The population of patients with ATC is small, but new therapies have greatly affected the prognosis of those with this rare cancer in recent years, as shown by data from The University of Texas MD Anderson Cancer Center in Houston.
In 2020, the cancer center retroactively analyzed its ATC survival outcomes from the previous 2 decades, which were separated into 3 groups. Each represented a different range of years (2000-2013, 2014-2016, and 2017-2019).1 Whereas the median 1-year overall survival (OS) rate was 35% between 2000 and 2013, by 2017 to 2019, 59% of patients were living for at least 1 year. Similarly, the 2-year OS rate was just 18% between 2000 and 2013. But from 2017 to 2019 it was 42%. Further, the risk for death was reduced by 50% between 2017 to 2019, compared with 2000 to 2013 (HR, 0.50; 95% CI, 0.38-0.67; P < .001).
One of the key reasons for the improvement in outcomes for some patients with ATC is the availability of NGS to identify cases with targetable alterations. At the moment, the most important alterations, Shaha said, are BRAF mutations; in particular, the BRAF V600E point mutation commonly associated with ATC. That is because patients with BRAF-mutant tumors can frequently be treated successfully with the combination of dabrafenib (Tafinlar) and trametinib (Mekinist).
“These are the 2 drugs which have shown remarkable results,” he said. “And the people who respond very well [to these drugs] are [patients whose tumors are] BRAF positive. [Patients whose tumors are] BRAF negative don’t respond to this therapy very well.”
Dabrafenib is a BRAF inhibitor, and trametinib is a MEK inhibitor.1 The FDA approved the combination therapy in 2018 for patients with BRAF V600E–mutated ATC with no satisfactory locoregional treatment options.2
Data from the phase 2 ROAR basket study (NCT02034110) supported the FDA's approval. Updated study data released in 2022 showed an investigator-assessed overall response rate (ORR) of 56% (95% CI, 38.1%-72.1%) at a median follow-up of 11.1 months in a cohort of 36 patients with unresectable or metastatic ATC.3 Patients in the study received a starting dose of dabrafenib 150 mg twice daily plus trametinib 2 mg once daily, and dose adjustments were permitted. Three patients in the study achieved a complete response. The 12-month duration of response rate was 50%, median progression-free survival (PFS) was 6.7 months, and the median OS was 14.5 months.
Those numbers suggest that combination therapy could significantly improve overall ATC outcomes, given that about half of patients with ATC have BRAF mutations, according to Shaha.3 The exact prevalence of BRAF mutations among patients with ATC is unknown. A 2022 review noted that data from European studies have generally indicated lower rates of BRAF positivity than data from studies in other parts of the world, with results from one European study showing a rate as low as 14%.4
Whatever the exact prevalence, Shaha said NGS has become a critical part of identifying the optimal treatment for patients with this cancer type. He added, however, that time is of the essence. Because the treatment window in ATC is days and weeks rather than months or years, BRAF mutation results are needed as quickly as possible. In an improvement over the turnaround time for targeted NGS, physicians at Memorial Sloan Kettering Cancer Center can perform in-house immunostaining to determine whether a BRAF mutation is present and obtain results within about 48 hours.
“Because if the patient is BRAF positive, the decision-making changes,” he said. “So we try to make all these decisions within 2 to 3 days.”
Multitarget TKIs
BRAF positivity can bring clarity to treatment strategies, but the therapeutic options are not so clear-cut in patients with BRAF-negative tumors, Shaha said. How- ever, a host of newer therapeutic options are being investigated, including TKIs and ICIs.
“These are the new drug treatments, which have shown some remarkable results in select patients,” he said. “So that’s why [The University of Texas] MD Anderson [Cancer Center], Memorial [Sloan Kettering Cancer Center], and [Mass] General [Brigham] are doing prospective studies on these new drugs.”
One of the most closely watched drugs, he noted, is the multitarget TKI lenvatinib (Lenvima). Results from a single-arm, open-label phase 2 study published in 2017 (NCT01728623) showed that patients treated with lenvatinib for ATC (n = 17) had a median PFS of 7.4 months (95% CI, 1.7-12.9) and a median OS of 10.6 months (95% CI, 3.8-19.8).5 The objective response rate was 24% (TABLE 1 5).
Yet a 2022 meta-analysis that included 10 previously published studies, 1 of which was described above, of lenvatinib in patients with ATC found that the pooled median PFS was just 3.16 months (95% CI, 2.18-5.60). The pooled median OS was an identical 3.16 months (95% CI, 2.17-5.64 ).6 In terms of both PFS and OS, the pooled data showed promising outcomes at 3 months, but those quickly faded. Investigators reported the pooled PFS and OS rates at 3, 6, 9, 12, and 15 months (TABLE 2).6 The authors concluded that the therapy led to meaningful antitumor activity but that its clinical efficacy was limited.
Sorafenib (Nexavar), another multitarget TKI, has been studied both as monotherapy and in combination with other treatments.
A 2017 study (NCT02114658) found sorafenib led to a median PFS of 2.8 months (95% CI, 0.7-5.6) and a median OS of 5.0 months (95% CI, 0.7-5.7) in 10 patients with ATC.7 The disease control rate was 40%. However, none of the patients achieved an objective response.
The investigators wrote in the study that “to elucidate the effects of sorafenib on ATC more accurately, a large number of patients, based on a statistical sample calculation, would be required in the future.” A 2010 analysis of another multitarget TKI, imatinib (Gleevec), in patients with ATC and PDGFR overexpression, which is one of imatinib’s targets, found partial responses in 2 and stable disease in 4 of 8 evaluable patients at 8 weeks.8 However, aside from its data showing that the therapy was well tolerated, the study’s numbers were too small to draw wider conclusions, said the authors, but the agent had encouraging antitumor activity in ATC.
Likewise, sunitinib (Sutent) has shown potential benefits in other types of thyroid cancer, but a 2019 review of existing literature found there have not yet been a sufficient number of studies examining this therapy’s efficacy in ATC.9
Vandetanib (Caprelsa), axitinib (Inlyta), and pazopanib (Votrient) are among the other multitarget TKIs proposed to treat ATC. However, clinical trial data have so far been nonexistent, limited by sample size, or have failed to show efficacy, respectively.10
Examining the Role of Immunotherapy
Investigators are also looking at the role of immunotherapy in treating patients with ATC. Potential options include spartalizumab, a monoclonal antibody targeting PD-1.
Results from a 2020 phase 1/2 study of spartalizumab (NCT02404441) involving 42 patients with locally advanced or metastatic ATC included an ORR of 19%, with responses seen in patients who were BRAF-positive and -negative.11 Most (70%) of the patients in the study were positive for tumor PD-L1 expression. The 1-year OS rate of those patients was 52.1%, compared with 40% in the overall cohort. This finding is consistent with research showing superior ICI efficacy in PD-L1–expressing tumors in a wide range of cancer types.
Shaha said another anti–PD-1 therapy that has been the subject of significant study is pembrolizumab (Keytruda). Much of that research has been evaluating combination therapies involving ICIs paired with TKIs.
For example, a retrospective analysis that included 6 heavily pretreated patients with metastatic ATC who were treated with lenvatinib plus pembrolizumab found that 4 of the patients achieved complete responses, 1 had stable disease, and the other patient’s disease progressed.12 The median PFS was 16.5 months, and treatment duration was between 1 month and 40 months.
In a review published last year, David Delarbre, MD, of University Military Hospital Sainte-Anne in Toulon, France, and colleagues, argued that combining an ICI such as pembrolizumab with lenvatinib could lead to synergistic benefits.13
The authors contended that the tumor microenvironment, elevated tumor mutational burden (TMB), and microsatellite instability that are characteristic of ATC are all factors associated with ICI success in other cancers. This points to pembrolizumab as a reasonable treatment option.
“Unfortunately, studies evaluating immunotherapy alone in ATC are disappointing,” they wrote.
Moreover, the antitumor effects of lenvatinib monotherapy are offset by the limited survival benefit so far observed, they noted.
“Nevertheless, lenvatinib’s immunomodulatory activity provides [a] mechanistic rationale for a lenvatinib combination with anti–PD-1 therapy,” they concluded.
Delarbre and colleagues added that high TMB or PD-L1 expression (a tumor proportion score above 50%) might be reasonable biomarkers to predict the efficacy of the combination.
Adverse Events
One important caveat in the discussion of new therapies is the high prevalence of adverse events in the literature. Recently reported results from a study (NCT02657369) of lenvatinib monotherapy in ATC showed that 56% of patients experienced treatment-related hypertension, and 29% of patients reported each of the following treatment-related reactions: decreased appetite, fatigue, and stomatitis.14 This trial was halted for futility. In the 2017 sorafenib study discussed above, 72% of patients experienced drug-related palmar-plantar erythrodysesthesia, 56% reported alopecia, and another 56% reported hypertension.7
“All…these drug therapies have [adverse] effects,” Shaha said.
He noted that hypertension is both common and problematic in patients receiving therapy for ATC, adding that endocrinologists need to be vigilant and monitor patients closely for hypertension.
“They have the know-how, and they know how to manage that,” he said. “But they have to titrate and make sure they’re not going overboard.”
He said patients also commonly develop anemia and low white blood cell counts, putting them at significant risk of infections.
Many Questions Remain
Although Shaha and others point to tremendous progress in the treatment of patients with ATC, they also acknowledge that the remaining questions outnumber the clear answers. In other words, a wide range of therapies show potential, but it is not always clear which therapy will work best for which patient, particularly in BRAF-negative cases.
In one recently reported case, clinicians used the anti–PD-1 antibody camrelizumab (AiRuiKa) in combination with the multitarget TKI famitinib to treat a patient who had unresectable ATC, as reported in trial NCT04521348.15 The treatment shrank the tumor to the point where it could be surgically removed. The patient then received adjuvant radiotherapy with subsequent maintenance immunotherapy. Two years after the diagnosis, the patient was alive and reported being able to carry out his normal daily activities. Researchers noted that this is the first report describing the use of famitinib and camrelizumab as a neoadjuvant treatment for ATC in patients with wild-type BRAF.
Given all the changes in ATC care, Shaha said he takes a number of factors into consideration as he works with patients on treatment plans. If the tumor happens to be caught early enough, and while small enough, surgery might still be the first-line therapy, he said.
“But that’s a rarity,” he noted, given the aggressiveness of the cancer type.
Testing for BRAF mutations is essential in patients with ATC, he said, because there is a straightforward option if the tumor is BRAF positive.
If the patient’s tumor does not have a BRAF mutation, TKI monotherapy is typically the standard treatment, Shaha said. If that does not work, or if the tumor is progressing to the point where it is causing airway distress or obstruction, then he suggests immunotherapy. However, he said individual medical centers will make different choices based on their own experiences, adding that some institutions will use chemotherapy in combination with other ATC therapies.
He outlined 2 major questions he hopes can be answered in the coming years. First and foremost, he said, is the question of which combination therapies are the least toxic and most efficient. Beyond that, he is curious to see whether surgery might someday become optional for certain patients who respond well to their initial therapy.
“Can they bypass surgery and go to radiation therapy?” he asked. “We don’t have the right answers because nobody has a huge amount of experience.”
However, Shaha said he is optimistic about the current research taking place at academic medical centers like his own.
“I think we should get good answers in the next 5 to 10 years because a lot of institutions are doing prospective studies,” he said. “I think we have all learned a lot about this disease.”
Importance of Multidisciplinary Care
Although much has been learned about ATC, Shaha said it remains a rare malignancy. For that reason, he suggests quickly referring patients with suspected ATC to academic medical centers with experience treating this cancer type.
“They need to go to a center of excellence,” he explained. “They need to go to a center where there is a true multidisciplinary team available—where the surgeon is there, the endocrinologist is there, the medical oncologist is there.”
Many changes have taken place in ATC treatment in recent years, but Shaha said he still responds to a diagnosis of ATC by quickly picking up the phone—or perhaps checking his email.
“The minute we see the patient, there is a flurry of emails reaching out to the multidisciplinary team,” he said. “Patients’ appointments are not ‘next available’; their appointment is either today or tomorrow. That’s the way we look at it.”
REFERENCES:
1. Maniakas A, Dadu R, Busaidy NL, et al. Evaluation of overall survival in patients with anaplastic thyroid carcinoma, 2000-2019. JAMA Oncol. 2020;6(9):1397-1404. doi:10.1001/ jamaoncol.2020.3362
2. FDA approves dabrafenib plus trametinib for anaplastic thyroid cancer with BRAF V600E mutation. FDA. May 4, 2018. Accessed April 20, 2023. https://bit.ly/3AcplOV
3. Subbiah V, Kreitman RJ, Wainberg ZA, et al. Dabrafenib plus trametinib in patients with BRAF V600E–mutant anaplastic thyroid cancer: updated analysis from the phase II ROAR basket study. Ann Oncol. 2022;33(4):406-415. doi:10.1016/j.annonc.2021.12.014
4. Jannin A, Escande A, Al Ghuzlan A, et al. Anaplastic thyroid carcinoma: an update. Cancers (Basel). 2022;14(4):1061. doi:10.3390/cancers14041061
5. Tahara M, Kiyota N, Yamazaki T, et al. Lenvatinib for anaplastic thyroid cancer. Front Oncol. 2017;7:25. doi:10.3389/ fonc.2017.00025
6. Huang D, Zhang J, Zheng X, Gao M. Efficacy and safety of lenvatinib in anaplastic thyroid carcinoma: a meta-analysis. Front Endocrinol (Lausanne). 2022;13:920857. doi:10.3389/ fendo.2022.920857
7. Ito Y, Onoda N, Ito KI, et al. Sorafenib in Japanese patients with locally advanced or metastatic medullary thyroid carcinoma and anaplastic thyroid carcinoma. Thyroid. 2017;27(9):1142-1148. doi:10.1089/thy.2016.0621
8. Ha HT, Lee JS, Urba S, et al. A phase II study of imatinib in patients with advanced anaplastic thyroid cancer. Thyroid. 2010;20(9):975-980. doi:10.1089/thy.2010.0057
9. Ferrari SM, Centanni M, Virili C, et al. Sunitinib in the treatment of thyroid cancer. Curr Med Chem. 2019;26(6):963-972. doi:10.2174/0929867324666171006165942
10. De Leo S, Trevisan M, Fugazzola L. Recent advances in the management of anaplastic thyroid cancer. Thyroid Res. 2020;13(1):17. doi:10.1186/s13044-020-00091-w
11. Capdevila J, Wirth LJ, Ernst T, et al. PD-1 blockade in anaplastic thyroid carcinoma. J Clin Oncol. 2020;38(23):26202627. doi:10.1200/JCO.19.02727
12. Dierks C, Seufert J, Aumann K, et al. Combination of lenvatinib and pembrolizumab is an effective treatment option for anaplastic and poorly differentiated thyroid carcinoma. Thyroid. 2021;31(7):1076-1085. doi:10.1089/thy.2020.0322
13. Boudin L, Morvan JB, Thariat J, Métivier D, Marcy PY, Delarbre D. Rationale efficacy and safety evidence of lenvatinib and pembrolizumab association in anaplastic thyroid carcinoma. Curr Oncol. 2022;29(10):7718-7731. doi:10.3390/ curroncol29100610
14. Wirth LJ, Brose MS, Sherman EJ, et al. Open-label, single-arm, multicenter, phase II trial of lenvatinib for the treatment of patients with anaplastic thyroid cancer. J Clin Oncol. 2021;39(21):2359-2366. doi:10.1200/JCO.20.03093
15. Yang S, Ji D, Xue F, Chen T, Wang Y, Ji Q. Neoadjuvant famitinib and camrelizumab, a new combined therapy allowing surgical resection of the primary site for anaplastic thyroid carcinoma. Cancer Rep (Hoboken). 2023;6(1):e1770. doi:10.1002/cnr2.1770
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