New treatments, new outcomes for refractory thyroid cancer

Thyroid cancer diagnoses are increasing rapidly in the United States.

But, with an estimated incidence of four cases per million population, thyroid cancer that does not respond to radioactive iodine therapy is rare.

For most of those patients, the prognosis is poor, with a 10-year survival rate of 10% from the time metastatic lesions are detected. Until recently, physicians had little to offer patients in the way of treatment.

That is changing. Today, a patient diagnosed with radioactive iodine-refractory thyroid cancer has several therapeutic options, many of which promise longer PFS and some reduction in tumor size, but rarely complete destruction of the tumor.

Despite these advances, it remains unclear what treatment is best for cases of locally advanced or metastatic thyroid cancer that are refractory to radioactive iodine. At the same time, whom to treat, when to treat and how to treat are all evolving questions.

“A lot of these patients progress so slowly that the disease almost stands still, and you don’t need to treat,” Stephanie L. Lee, MD, PhD, FACE, ECNU, professor of medicine and director of thyroid health in the section of endocrinology, diabetes and nutrition at Boston Medical Center, said in an interview. “That makes a lot of people uncomfortable, and it makes a patient uncomfortable to hear, ‘Oh, yes, your pulmonary nodules are growing, but we’re not going to do anything right now.’ [But,] the adverse effects of treatment and expense of therapy don’t balance the improvement in disease progression.”

HemOnc Today spoke with oncologists and endocrinologists about the new treatment options, the potential role of immunotherapy for refractory thyroid cancer, the challenges in determining which patients should undergo treatment, and what the future of treatment for radioactive iodine-refractory thyroid cancer may look like.

‘Exciting time’

Thyroid cancer is typically treated with surgery, which may be followed by radioactive iodine for certain subtypes, including differentiated thyroid cancer (DTC) at high risk for recurrence. Anaplastic carcinoma — which comprises only 2% of thyroid cancers but is extremely lethal — and medullary thyroid carcinoma are inherently nonsensitive to radioactive iodine treatment.

Finding alternatives to radioactive iodine treatments for radiation-resistant locally advanced or metastatic thyroid tumors has long vexed clinicians.

But, in the past 5 years, new therapeutic agents with molecular targets have emerged as options for this group.

Source: Adolfo Chavez III, Associate Director of Photography, Creative Communications.

“Overall, this is an exciting time,” Naifa Busaidy, MD, FACP, FACE, associate professor in the department of endocrine neoplasia and hormonal disorders at The University of Texas MD Anderson Cancer Center, told HemOnc Today. “There are many more choices than we had 10 years ago, even 5 years ago.”

Sorafenib (Nexavar; Bayer, Onyx Pharmaceuticals), approved in 2013, and lenvatinib (Lenvima, Eisai), approved in 2015, are two tyrosine kinase inhibitors that have been the mainstay of treatment for iodine-refractory DTC.

These TKIs, along with vandetanib (Caprelsa, Sanofi Genzyme) — a kinase inhibitor approved by the FDA for treatment of patients with symptomatic or progressive medullary thyroid cancer who have unresectable locally advanced or metastatic disease — are the only agents that have been evaluated in randomized phase 3 trials vs. placebo for the treatment of refractory thyroid cancer.

In the DECISION trial, researchers randomly assigned 417 treatment-naive patients with radioactive iodine-refractory locally advanced or metastatic DTC that had progressed within the past 14 months to sorafenib 400 mg twice daily or placebo. Sorafenib improved median PFS compared with placebo across subgroups (median, 10.8 months vs. 5.8 months; HR = 0.58; 95% CI, 0.45-0.75). The partial response rate was 12%, and 41.8% of participants achieved stable disease for 6 months or longer.

In the SELECT trial, researchers randomly assigned 392 patients with radioactive iodine-refractory locally advanced or metastatic DTC that had progressed within the past 13 months to lenvatinib 24 mg per day or placebo. Lenvatinib significantly prolonged median PFS compared with placebo (18.3 months vs. 3.6 months; HR = 0.21; 99% CI, 0.14-0.31). The objective response rate was 65%, with complete responses in 2% of patients.

In VERIFY — a randomized controlled trial comparing vandetanib vs. placebo among 238 patients — researchers observed a nonsignificant improvement in median PFS (10 months vs. 5.7 months). Data from the phase 3 ZETA trial presented at European Society for Medical Oncology Congress showed vandetanib induced tumor shrinkage that persisted throughout multiple treatment lines for patients with advanced unresectable medullary thyroid cancer.

“Lenvatinib dominated the market because it gives you a 65% chance of response to PFS but, unfortunately, 75% of patients require a dose reduction,” Krzysztof Misiukiewicz, MD, associate professor of medicine, hematology and medical oncology, and assistant professor of otolaryngology at Icahn School of Medicine at Mount Sinai, told HemOnc Today. “I always counsel my patients that I start high and then de-escalate the treatment if they experience side effects. ... With most of the patients I treat, we can find a dose that is satisfactory for the patient and provides efficacy.”

The FDA approved several new therapies for the treatment of thyroid cancer last year. Although these approvals are not specific to radioactive iodine-refractory disease, they may provide another treatment option for a subset of patients with specific genetic alterations.

In May, the agency approved dabrafenib (Tafinlar, Novartis) and trametinib (Mekinist, Novartis), administered together, for the treatment of anaplastic thyroid cancer with a BRAF V600E mutation, an aggressive type that accounts for just 2% of all thyroid cancers.

Refractory disease is common among patients who harbor BRAF mutations.

“Many patients with BRAF mutations do not respond to any therapy,” Carmelo Nucera, MD, PhD, assistant professor at Harvard Medical School and a principal investigator with the Human Thyroid Cancers Preclinical and Translational Research Program at Beth Israel Deaconess Medical Center, told HemOnc Today. “Others with BRAF mutations respond initially and become refractory, and they start to manipulate the biology of these tumors.”

In November, the FDA granted accelerated approval to larotrectinib (Vitrakvi; Bayer, Loxo Oncology) for adults and children with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation. This marked the second so-called tissue-agnostic FDA approval for the treatment of cancer and offers patients with refractory thyroid cancer a new option, according to Misiukiewicz.

“The vast majority of the patients receiving larotrectinib had thyroid cancer, and the response rate was almost 75%, with some complete responses and with minimal toxicity,” he said. “There was a short follow-up, so we don’t know the long-term data, and this mutation is only seen in about 1% of patients, but I would be inclined to use this drug in this limited population. It’s targeted, the response rate is better numerically, and the side effect profile is much more favorable.”

Routine mutation screening should be performed to determine the best treatment for patients, Busaidy said.

“For patients who have metastatic or advanced disease who need systemic therapy and are resistant to radioactive iodine, I want to see physicians biopsy those tumors and then get those tested to help see what might be different about that tumor and the tumor environment, so we can target the new tumor,” Busaidy said. “We tend to test the primary tumor or the thyroid that came out, which might have been 5 years ago [or] 10 years ago. ... We need to do a new biopsy, educate the patient on why this is important and then test that tumor, because that’s the one affecting them today, not the one they had 10 years ago.”

Immunotherapy options

Alternative treatments, including immunotherapy, are also showing promise, and researchers are looking to new opportunities with combination therapies, according to Nucera.

“The most important new development is in super precision medicine,” Nucera said. “That means that if you have a patient with thyroid cancer ... the most important point is to dissect all possible genomic — either coding or noncoding genes — and epigenetic alterations in the genome of these patients.”

The rise of immunotherapy may further alter the fate of patients with thyroid carcinoma, whether differentiated, medullary or anaplastic.

PD-L1 expression on tumor cells is emerging as a potential predictive biomarker in anti-PD-L1-directed cancer immunotherapy.

In a retrospective study on the overexpression of PD-L1 in papillary thyroid cancers published in Oncotarget, researchers showed that the protein is associated with an increased risk for relapse and is a marker of poor prognosis.

However, researchers agree that immunotherapy therapy is in its infancy with respect to thyroid cancer.

“We do think that immunotherapy will have a role in thyroid cancer, it’s just a question of what that role will be,” Busaidy said. “We haven’t had these magical responses in thyroid that we have seen with melanoma, kidney cancer and bladder cancer.”

Mehnert and colleagues evaluated the anti-PD–1 antibody pembrolizumab (Keytruda, Merck) among 22 patients (median age, 61 years; 59% women) with PD-L1-positive advanced papillary or follicular thyroid cancer enrolled in the phase 1b KEYNOTE-028 trial. Of the patients, 73% had previously received treatment, including 83% who had received iodine.

Results showed an overall response rate of 9% (95% CI, 1-29) and a median PFS of 7 months (95% CI, 2-14).

“If you look at all cancers across the board, about 30% of the time, cancers will disappear [with immunotherapy],” Busaidy said. “One of the trials that looked at pembrolizumab was disappointing. We cannot just give immunotherapy by itself, but we’re looking at trials combining it with some of these targeted therapies — let’s attack the blood supply, let’s attack the abnormal proteins. Whether we do it sequentially or in combination is not known.”

As with other thyroid cancer treatments, Busaidy said, the problem is determining who is an ideal candidate for immunotherapy.

“Is it the type of tumor, the environment or a combination of the two that helps make that determination?” Busaidy said. “These drugs are not without their side effects, so it’s important that we figure this out.”

Whom to treat

Because thyroid cancer can be slow to progress, whether to treat patients and expose them to side effects of therapy is an important clinical decision.

Francis P. Worden, MD, medical oncologist at University of Michigan Health System Comprehensive Cancer Center and professor in the department of internal medicine at University of Michigan, said the question of whom to treat — and when — is somewhat complex once DTCs fail to respond to radioactive iodine.

“When people come into the clinic with such diagnoses, and they are iodine refractory, it’s not necessarily a knee-jerk reaction to treat everybody,” Worden told HemOnc Today.

“Think about it as four boxes,” Worden added. “In the top right quadrant, you have people with rapidly progressing disease with a large burden of disease. Those people in all likelihood need to be treated. Take the opposite quadrant — a small amount of disease, but disease that is really not growing. Those patients can be observed with serial imaging.”

The “tricky” part, Worden said, is deciding what to do with the patients in the other two quadrants: those with a large amount of disease that is not changing quickly and those with a small amount of disease that is growing rapidly.

“Those are the patients we need to watch more closely and have meaningful discussions with about treatment and risk-vs.-benefit profiles,” he said. “Additionally, we may offer some of these patients focal treatments with radiation or perhaps surgery for disease that may be growing in one particular area, causing symptoms such as dysphagia or difficulty breathing. Furthermore, multikinase inhibitors used to treat disseminated disease have toxicity profiles that can certainly alter a patient’s quality of life.”

Misiukiewicz said he keeps several criteria in mind when evaluating treatment options for a cancer that is radioiodine refractory.

“One is whether the patient has symptoms,” Misiukiewicz said. “If the patient has symptoms, I would be inclined to treat to help the patient feel better. Second is the location of the lesion. If it is located next to a vital organ, that by allowing this lesion to grow there is possible damage to the organ, I would be inclined to treat.”

The third criterion, Misiukiewicz said, is progression.

“If we have a rapid progression — and we don’t have strict definition of ‘rapid’ — I would say if there is more than a 20% increase in the size in the lesions, I would be inclined to treat,” he said.

Lee agreed.

“Once a tumor gets [larger than] 1.5 cm, I will usually treat,” Lee said. “[American Thyroid Association] guidelines say the patient has to be symptomatic, but you can get 2- to 4-cm lung metastases and not be symptomatic, so I don’t think that is the answer. It has to be a combination of where the tumor is — TKIs work best with lung nodules and lymph nodes and less with bone metastases — and size, and also the rapidity of progression.”

Additionally, Lee said, patients with progressive, unresponsive cancer often experience a very slow rise in serum thyroglobulin. The beginning of that rise can indicate rapid growth of the tumor.

“What you want to do, ideally, is to figure out when that ‘takeoff’ in [thyroglobulin] occurs and start the TKI then, and not wait until they’ve gone way up on the curve,” Lee said.

Whatever path is chosen, Worden noted, the treating clinician must have meaningful discussions with the patient regarding when to start treatment.

“We have a study where we are looking at patients who were radioactive iodine refractory and when they first started a TKI, trying to determine what the median time is between refractoriness and the start of initial treatment,” Worden said. “The idea behind this is to get an idea of what time frame we’re looking at in such patients. We have drugs that are helpful; however, just because we have these drugs does not mean we should be using them.”

‘Keeping my eyes open’

Incorporating these new treatments will require oncologists and endocrinologists to become adept at managing their effects.

In clinical trials with TKIs, participants reported multiple adverse events that ultimately led to dose reduction or withdrawal for some patients, ranging from hand-foot skin reactions to a marked increase in hypertension.

In the DECISION trial, sorafenib exhibited the expected safety profile, but researchers observed a higher incidence of adverse events than seen in patients with other cancer types. The most common adverse events were hand-foot skin reactions (76%), diarrhea (69%), alopecia (67%) and rash/desquamation (50%). Toxicities led to a dose reduction for 64% of participants and to drug withdrawal for 19%.

In the SELECT trial, treatment-related adverse events were reported among all participants in the lenvatinib group and included hypertension (68%), fatigue (64%), diarrhea (59%) and decreased appetite, among others.

However, overall, Busaidy said, available thyroid cancer therapies are well-tolerated, and a clinician should not be afraid to prescribe them.

“Some clinicians will say, ‘You have thyroid cancer, but this drug that is available is worse than your disease.’ Not necessarily,” Busaidy said.

Most of the adverse events are manageable, Lee said.

“A lot of endocrine doctors are afraid to manage patients with TKIs because they don’t know what to expect, but the reality is that side effects are medical conditions like hypertension and rash that we already know how to manage,” Lee said. “We endocrinologists need to get out of our comfort zone to manage these patients on targeted therapy.”

Moving forward, Nucera said, dissecting tumors to determine specific genetic alterations and clonal evolution will allow clinicians to design a “cocktail” of therapeutics, combined therapies, to offer patients a chance at better outcomes while considering toxicity, dosage and safety.

“Radioiodine can do a good job ... but it isn’t working if you have a complex genetic alteration with heterogenous tumor cell clusters,” Nucera said. “Through super precision medicine, you might or might not use radioactive iodine. You need to stratify and categorize with each patient, case by case. You need to find the ‘personality’ of the tumor in this way. Once you know the tumor personality, you can develop a good strategy.”

Misiukiewicz said the current landscape is much different from when he was at ASCO Annual Meeting years ago and there was a lack of interest in thyroid cancer.

“It’s pretty exciting that we are seeing more and more medications being approved for thyroid cancer,” he said. “Anaplastic thyroid cancer, one of the most aggressive cancers we see in oncology, suddenly has a treatment. Most of the time, we had nothing to offer them. These patients were going to die in weeks. Now, it’s an exciting time, so I’m keeping my eyes open.” – by Regina Schaffer

Click here to read the , “Should lenvatinib be used as first-line therapy for slowly progressing radioiodine-refractory thyroid carcinoma?”

References:

Berdelou A, et al. Endocr Relat Cancer. 2018;doi:10.1530/ERC-17-0542.

Chowdhury S, et al. Oncotarget. 2016;doi:10.18632/oncotarget.8698.

Cubera JH, et al. Abstract 1329P. Presented at: European Society for Medical Oncology Congress; Oct. 19-23, 2018; Munich.

Faugeras L, et al. Ther Adv Med Oncol. 2018;doi:10.1177/1758834017752853.

Mehnert JM, et al. BMC Cancer. 2019;doi:10.1186/s12885-019-5380-3.

Nucera C. Aging. 2016;doi:10.18632/aging.101030.

Schlumberger M, et al. N Eng J Med. 2015;doi:10.1056/NEJMoa1406470.

Worden F. Ther Adv Med Oncol. 2014;doi:10.1177/1758834014548188.

For more information:

Naifa Busaidy, MD, FACP, FACE, can be reached at The University of Texas MD Anderson Cancer Center, Department of Endocrine Neoplasia and Hormonal Disorders, 1400 Pressler Road, Unit 1461, Houston, TX 77030; email: nbusaidy@mdanderson.org.

Stephanie L. Lee, MD, PhD, FACE, ECNU, can be reached at Boston Medical Center, 88 E. Newton St., Boston, MA 02118; email: stephanie.lee@bmc.org.

Krzysztof Misiukiewicz, MD, can be reached at Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, Box 1055, New York, NY 10029; email: krzysztof.misiukiewicz@mssm.edu.

Carmelo Nucera, MD, PhD, can be reached at Beth Israel Deaconess Medical Center, 99 Brookline Ave., Office Room RN270G, Boston, MA 02215; email: cnucera@bidmc.harvard.edu.

Francis P. Worden, MD, can be reached at University of Michigan Health System Comprehensive Cancer Center, Floor B1, Reception A, 1500 E. Medical Center Drive, SPC 5911, Ann Arbor, MI 48109; email: fworden@med.umich.edu.

Disclosures: Busaidy reports consultant fees from Eisai and Loxo Oncology and research funding from Novartis. Misiukiewicz reports speaking fees from Eisai. Nucera reports an advisory board role with Loxo Oncology for therapeutics development not reported in this article. Worden reports consultant fees from Bayer and research funding from Eisai. Lee reports no relevant financial disclosures.