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Second Potent Agent for RAI-Refractory Differentiated Thyroid Cancer

Carlson, Robert H.

doi: 10.1097/


CHICAGO—Until very recently, patients with radioactive iodine (RAI)-refractory, differentiated thyroid cancer, a subgroup not cured by surgery and RAI, had no therapies whatsoever. Then last November, the Food and Drug Administration approved sorafenib to treat this patient population, following positive results of the Phase III DECISION trial, now available online ahead of print in The Lancet (doi:10.1016/S0140-6736[14]60421-9).

Now a second, very active drug has come on the horizon. As reported here at the American Society of Clinical Oncology Annual Meeting, the Phase III SELECT trial has shown very impressive response and survival rates for the experimental targeted agent lenvatinib (Abstract LBA6008).

Treatment with oral lenvatinib delayed disease progression 14.7 months longer than use of placebo, and nearly two thirds of patients experienced tumor shrinkage, and median overall survival has not been reached, said lead study author Martin Schlumberger, MD, Professor of Medicine at Institut Gustave Roussy and University Paris-Sud in Villejuif, France, reporting the results in an oral session.



“We are confident that, based on our findings, lenvatinib will eventually become a standard treatment for radioiodine-resistant thyroid cancer. As little as a year ago, this group of patients had no effective treatment options. It's remarkable that we now have two active drugs in this setting, both of them tyrosine-kinase inhibitors [TKIs].”

Differentiated thyroid cancer is generally curable with surgery and radioiodine therapy, but approximately 15 percent of patients develop radioiodine resistance.

Lenvatinib is an oral TKI that blocks VEGFR1–3, FGFR 1–4, PDGFR-β, KIT, and RET, among other targets. It is being explored in Phase II and III clinical trials in liver, lung, and kidney cancers.

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Study Details

In SELECT, which was supported by Eisai, 392 patients with advanced, RAI-resistant differentiated thyroid cancer that had progressed within a year were randomly assigned to treatment with either lenvatinib or placebo. The patients' median age was 63, and 51.0 percent were male.

Patients on the placebo arm of the study were allowed to cross over to the lenvatinib arm upon disease progression.

The response rates were 63.2 percent for patients receiving lenvatinib versus 1.5 percent for those on placebo. The majority of responses occurred within two months of starting treatment, Schlumberger reported.

Median progression-free survival was 18.3 months in the lenvatinib arm versus 3.6 months for placebo. Median overall survival has not been reached.

Median progression-free survival times for patients with prior versus no prior VEGF therapy were 15.1 and 18.7 months, respectively.



The dose was reduced in 78.5 percent of patients and discontinued due to adverse events in 14.2 percent, he said, but the benefit of lenvatinib persisted even with decreased dose.

Treatment-related adverse events of any grade included hypertension (68%), diarrhea (59%), decreased appetite (50%), weight loss (46%), and nausea (41%).

Grade 3/4 treatment-related adverse events included hypertension (42%), proteinuria (10%), weight loss (10%), diarrhea (8%), and decreased appetite (5%).

Mortality was not insignificant: 71 patients (27%) in the lenvatinib arm died, versus 47 patients (36%) for placebo.

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Impressive Hazard Ratio

ASCO 2013–2014 President Clifford Hudis, MD, Chief of the Breast Cancer Medicine Service at Memorial Sloan Kettering Cancer Center, commented that thyroid cancer has undergone a revolution in recent years. “Iodine-131 is the traditional treatment, but when cancer is refractory to that, a defensible standard historically was to do nothing.”

Progression-free survival in SELECT had a hazard ratio of 0.21 in favor of lenvatinib, he noted—“that's impressive.”

Another of the SELECT coauthors, Marcia S. Brose, MD, PhD, Director of the Thyroid Cancer Therapeutics Program at the Abramson Cancer Center of the University of Pennsylvania, was also lead author on DECISION and commented on both in an interview for this article.

Until sorafenib was approved for patients with RAI-refractory, differentiated thyroid cancer, she noted, the only drug for such patients that was FDA approved was doxorubicin (approved in 1974), and that was subsequently deemed ineffective and highly toxic.

“Since then, the only option had been palliative care for this devastating disease,” Brose said. “Patients were told ‘go home and call us when you have a problem,’ and every time they had a problem we would ‘spot cure’ them to death, trying surgery and trying radiation. There was incredible morbidity with that approach because you're never treating the disease; you're just trying to catch up to it when it causes problems.”

What the DECISION trial showed was that the first TKI therapy to complete a randomized Phase III trial, sorafenib, could increase progression-free survival in patients to 10.8 months, versus 5.8 months for placebo. “Having a period when we could tell patients ‘you're not going to progress’ was incredibly meaningful to patients who would have been sent home with no hope,” Brose said.



Lenvatinib has a role, she explained, because even though patients may survive a year or a year and a half on sorafenib, they will subsequently progress and need new therapies. “I suspect almost all of my patients will receive both of these agents sequentially in the course of their disease,” she said.

This scenario follows in some respects the experience in renal cell carcinoma where several kinase inhibitors were developed at once. “Any one of the studies doesn't necessarily show overall survival, but I suspect that the impact of this class of drugs will lead to overall survival improvements in these patients.”

Brose speculated that while sorafenib and lenvatinib would not likely be given concurrently because of overlapping toxicities, there is a potential for sequential use, and also for combinations with other targeted agents—for example, Phase II trials of sorafenib plus mTOR inhibitors are underway based on complementary mechanisms, she said.

“I want to stress that many of these [thyroid] patients are asymptomatic and living full lives in spite of the fact that their disease is progressing. Making sure that you don't ruin their quality of life is important, so when we do these sequential therapies we have to take into account the toxicities.”

It may be important to start off with agents that are more gentle and easier to manage, and then later come on to the stronger agents that have more toxicities as secondary therapies, she said.

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‘A Good Problem to Have’

Another author on the SELECT trial, Lori J. Wirth, MD, Medical Director of the Head and Neck Program at Massachusetts General Hospital, was asked which drug she might use first, lenvatinib or sorafenib, if and when lenvatinib is approved for these patients: “That's a great question, and I look forward to having that problem; it's an incredible problem to have,” she said. “Five years ago I had nothing and now, hopefully, I will have to decide which to use first.”



But because DECISION showed significant improvement in progression-free survival but not in overall survival—i.e, not yet reached—and because side effects were very frequent with sorafenib, especially hand and foot skin reaction, she said these considerations might point her toward lenvatinib as the “go-to drug” if it is approved.

© 2014 by Lippincott Williams & Wilkins, Inc.
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