Welcome to Multikinase Inhibitors in Radioiodine-Refractory Thyroid Cancer

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Lori J. Wirth, MD

Given that just a short time ago our only treatment option for patients with advanced differentiated thyroid carcinoma was minimally active cytotoxic chemotherapy, these new questions regarding how best to optimize multikinase inhibitor therapy for these patients represent a welcome challenge.

—Lori J. Wirth, MD

In the past 2 decades, the incidence of thyroid cancer has risen steeply, with rates now growing by 5.5% annually.1 In 2014, 62,980 new cases of thyroid cancer were diagnosed in the United States. The good news is that, overall, the prognosis of thyroid cancer remains excellent; 97.8% of patients will survive at least 5 years.

Still, deaths due to thyroid cancer are increasing at a rate of 0.8% each year. While the diagnosis of incidentally found thyroid cancers with minimal clinical significance certainly accounts for the lion’s share of the rise in new cases, the increasing death rate highlights the fact that there is an important subset of patients with aggressive tumors for whom more effective treatments are needed.

The overwhelming majority of thyroid cancer cases falls under the category of differentiated thyroid carcinoma, encompassing a diverse set of tumors, including papillary, follicular, Hürthle cell, and poorly differentiated thyroid carcinomas. Most patients are treated surgically, followed by radioactive iodine. Clinical trials now underway are investigating the optimal surgical approach and impact of foregoing radioactive iodine in carefully defined low-risk thyroid cancer patients.

Refractory Disease

Those patients who respond to radioactive iodine have excellent 10-year survival, at a rate of 92%.1 When patients do not respond to radioactive iodine, 10-year survival is only 19%.

There is no one standardized definition of radioactive iodine–refractory differentiated thyroid carcinoma at present, but there is general agreement that a patient should be considered radioactive iodine–refractory when a known differentiated thyroid carcinoma lesion is present that does not take up radioactive iodine on nuclear imaging or when there is growth of a lesion despite radioactive iodine uptake in the following 6 to 12 months after therapy.

Until recently, there was no good standard of care for patients with radioactive iodine–refractory differentiated thyroid carcinoma beyond the suppression of thyroid-stimulating hormone. Cytotoxic chemotherapy was studied in small, nonrandomized trials 20 years ago, yielding very modest results.2 Now, however, we have entered into a whole new era of more effective multikinase inhibitor therapy for this disease.


DECISION was the first large randomized controlled trial in radioactive iodine–refractory differentiated thyroid carcinoma, investigating sorafenib (Nexavar) compared to placebo in 417 patients who experienced progressive disease within the prior 14 months.3 Patients were treated until disease progression, at which time they were unblinded. Those on placebo were then offered crossover to sorafenib.

The primary endpoint was met, with an improvement in median progression-free survival from 5.8 months with placebo to 10.8 months with sorafenib (hazard ratio [HR] = 0.59, 95% confidence interval [CI] = 0.45–0.76, P < .0001). The overall response rate was 12.2%, with all responses partial. Median overall survival did not differ between the two groups.

Most patients receiving sorafenib experienced adverse events, though most adverse events were grade 1 or 2. The most frequent treatment-emergent adverse events in the sorafenib group were hand-foot skin reaction, diarrhea, alopecia, and rash or desquamation. When possible, adverse events were managed with supportive care, though dose interruptions, reductions, or withdrawals because of adverse events were required in 66.2%, 64.3%, and 18.8%, respectively.

With the success of the ­DECISION trial, a new treatment paradigm emerged for patients with radioactive iodine–refractory differentiated thyroid carcinoma. For patients with symptomatic and/or bulky, rapidly progressive disease, the clear need for better treatment trumps concern for toxicity. On the other hand, many patients have low-volume, slowly progressive, asymptomatic disease. For these patients, concern over the impact of sorafenib toxicity on quality of life has led to the frequent consideration of holding off on treatment until it becomes necessary.


Less than 1 year after DECISION, the SELECT trial, investigating lenvatinib (Levima) in radioactive iodine–refractory differentiated thyroid carcinoma, has now been reported by Schlumberger and colleagues.4 In ­SELECT, as reviewed in this issue of The ASCO Post, 392 patients with progressive disease within the prior 13 months were randomly assigned to lenvatinib vs placebo. Treatment with one prior multikinase inhibitor was allowed, accounting for 25.3% of patients enrolled. Crossover from placebo to lenvatinib was offered to patients after unblinding at the time of progressive disease. 

The study was powered to detect a 75% improvement in progression-free survival with lenvatinib vs placebo, from 8 months with placebo to 14 months with lenvatinib. Final results were striking; median progression-free survival improved by almost 15 months, from 3.6 months with placebo to 18.3 months with lenvatinib (HR = 0.21, 95% CI = 0.14–0.31, P < .001). The progression-free survival benefit was seen in all subgroups analyzed, including histologic subtype and prior multikinase inhibitor therapy.

While the difference in overall survival was not significant (HR for death = 0.73, 95% CI = 0.50–1.07, P = .10), the numerical difference became larger when crossover bias was taken into account using the bootstrap method (rank-preserving structural failure time [RPSFT] model HR = 0.62, 95% CI = 0.40–1.00, P = .05). Surprising activity was also seen in the response rates; the overall response rate was 64.8%, and while most responses were partial, four patients did experience a durable complete response.

As in DECISION, grade 1 and 2 adverse events were seen in most patients. Hypertension was encountered more frequently in SELECT, whereas hand-foot reaction and other dermatologic adverse events were less common. Similarly to DECISION, dose interruption, reduction, and discontinuation were necessary in 82.4%, 67.8%, and 14.2% patients, respectively.

New Dilemma

With the success of two back-to-back studies demonstrating activity of multikinase inhibitors in patients with progressive radioactive iodine–refractory differentiated thyroid carcinoma, leading to the U.S. Food and Drug Administration (FDA) approval of both sorafenib and lenvatinib for this disease, effective treatment is now available for a group of patients who previously had no good treatment options.

Providers who previously had little to offer their patients with advanced differentiated thyroid carcinoma now have a new dilemma. Rather than trying to come up with any therapy at all, the question now is, “Which treatment should be started first?” Should sorafenib with a longer track record be used first, especially since lenvatinib does have second-line activity? Or should we take advantage of the drug with the higher overall response rate and longer progression-free survival benefit first?

In the absence of a randomized comparative trial, a definitive answer is simply not available. Still, clinical decisions must and will be made and can be guided by consideration of the efficacy and toxicity data available.

Another key question to revisit is “When should multikinase inhibitor therapy begin?” For those patients with low-volume, slowly growing asymptomatic disease, is holding off on multikinase inhibitor therapy as long as possible truly the best approach, especially now that we have therapy offering a 65% overall response rate and 14.7-month progression-free survival benefit? More data are ultimately needed to address this critical question.

Adverse Event Profiles

Lastly, the adverse event profiles of multikinase inhibitor therapy, as well as the duration of treatment, call attention to the need to get dosing and toxicity management right. For example, in SELECT, the starting dose was 24 mg by mouth daily. Is this the best dose outside of the clinical trial setting? At present, the available evidence suggests that the answer is “yes.” In SELECT, the median time to first dose reduction was 3 months, while the median time to objective response was only 2 months, indicating that most responses were first experienced at full dose, before dose reduction occurred.

If it is indeed important to maintain dose intensity, adverse event management is critical. When considering the list of common adverse effects, including hypertension, diarrhea, anorexia, weight loss, and rash, a comprehensive team approach to address the multiplicity of adverse events may be optimal. Hypertension can occur early in treatment. Thus, home monitoring with nursing follow-up may help avoid the sequelae of uncontrolled hypertension.

Likewise, the gastrointestinal adverse events pose challenges. High-fat foods and milk products that are often recommended to stave off weight loss in oncology patients may aggravate drug-induced diarrhea, suggesting that nutrition consultation may be an integral part of the team approach to caring for patients on multikinase inhibitor therapy.

Given that just a short time ago our only treatment option for patients with advanced differentiated thyroid carcinoma was minimally active cytotoxic chemotherapy, these new questions regarding how best to optimize multikinase inhibitor therapy for these patients represent a welcome challenge. ■

Disclosure: Dr. Wirth has served as a consultant for Ashion, AstraZeneca, Eisai, and Loxo.


1. Durante C, Haddy N, Baudin E, et al: Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: Benefits and limits of radioiodine therapy. J Clin Endocrinol Metab 91:2892-2899, 2006.

2. Pacini F, Ito Y, Luster M, et al: Radioactive iodine-refractory differentiated thyroid cancer: Unmet needs and future directions. Expert Rev Endocrinol Metab 7:541-554, 2012.

3. Brose MS, Nutting CM, Jarzab B, et al: Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: A randomised, double-blind, phase 3 trial. Lancet 384:319-328, 2014.

4. Schlumberger M, Tahara M, Wirth LJ, et al: Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med 372:621-630, 2015.

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