Selumetinib: No Benefit Boosting RAI for High Risk Thyroid Cancer

Nancy A Melville

October 16, 2018

WASHINGTON, DC — The addition of the oral MEK 1/2 inhibitor selumetinib (AstraZeneca) to adjunctive radioactive iodine (RAI) therapy has shown no substantial benefit in improving complete remission (CR) rates of patients with differentiated thyroid cancer (DTC), contrary to expectations, in the phase 3 ASTRA trial.

"On the one hand, it is disappointing that the study's primary endpoint wasn't reached, but what will be helpful will be breaking down the subanalyses to see what aspects of the trial can be optimized in the future," lead investigator Alan L. Ho, MD, PhD, a medical oncologist at Memorial Sloan Kettering Cancer Center and New York Presbyterian/Weill-Cornell Medical Center, told Medscape Medical News.

Studies have shown that activation of the RAF/MEK/ERK pathway has the effect of downregulating thyroid gene expression and consequently compromising the uptake of RAI in patients with DTC. Meanwhile, as many as 70% of patients with DTC have mutations in the RET, NTRK, RAS, and BRAF genes, which stimulate those pathways.

In exploring this, Ho and colleagues showed in previous research (N Engl J Med. 2013;368:623-632), as reported by Medscape Medical News, that selumetinib, with its highly selective inhibition of MEK1/2, successfully restored RAI reuptake in 12 of 20 patients with thyroid cancer that was refractory to RAI.

With that in mind, the multicenter phase 3 ASTRA study, presented here at the 2018 Annual Meeting of the American Thyroid Association (ATA), was designed to determine if a short course of selumetinib could give a boost to adjunctive RAI and help achieve CR responses in a larger group of patients with DTC.

Commenting on the study, Mabel Ryder, MD, an endocrinologist with the Mayo Clinic, Rochester, Minnesota, and cochair of the meeting program committee, agreed that the lack of benefit with the addition of selumetinib was unexpected.

"The results are a surprise, as decreased recurrences for higher risk patients in the context of selumetinib were expected," she told Medscape Medical News.

ASTRA Study: Selumetinib Fails to Meet Primary Endpoint

In the ASTRA study, 233 patients with nonmetastatic DTC determined to be at high risk of primary treatment failure following total thyroidectomy were randomized (2:1) to selumetinib 75 mg twice daily (n = 155) or placebo (n = 78), initiated approximately 4 weeks prior to RAI therapy and continuing through 5 days after treatment with 3.7 GBq RAI.

There were no significant differences between the groups, with the primary tumor class of T3 or higher found in about 80% of patients in each group, and 56.1% of patients in the selumetinib group and 59% in the placebo group had involvement of five or more lymph nodes, with at least one lymph node larger than 1 cm.

In terms of the primary endpoint of CR at 18 months, 40% of patients in the selumetinib group (n = 62) achieved CR, yet the rate was nearly as high, 38.5%, in the placebo group (n = 30) (odds ratio [OR], 1.07; P = .82), for a difference that was well below the primary goal of 20% greater improvement in CR.

Subanalyses of 142 (61%) patients with BRAF/NRAS mutations showed CR rates of 37.4% (n = 34) with adjunctive selumetinib, compared to 41.2% (n = 21) with placebo (OR, 0.85; P = .65). Of patients without detected BRAF/NRAS mutations (n = 61), the CR rate was 44.4% (n = 20) with selumetinib and 31.3% (n = 5) in the placebo group (OR, 1.76; P = .35).

Adverse events were more common in the selumetinib group (98%) compared with placebo (75%), including grade 3 or higher adverse events, which occurred in 18% of the selumetinib group versus 1% of patients in the placebo group; these included dermatitis acneiform (11 cases), headache (1), blood creatinine phosphokinase increases (5), hypertension (2), and headache (1).

Eighteen patients taking selumetinib discontinued treatment because of adverse events.

The most common adverse events of all grades included dermatitis acneiform (44.8%), diarrhea (44.2%), and fatigue (28.6%).

Important Insights Gained, Despite Lack of Efficacy of Selumetinib

Ho noted that the study is the first of its kind to evaluate the efficacy of adjuvant therapy for improving the CR rate in patients with DTC, and in that regard, important insights were gained, despite not reaching the primary endpoint.

"The placebo group established that a 38.5% CR rate is achieved with standard RAI alone in high risk patients, suggesting the need for improved therapeutic approaches," he explained.

Among important factors that could have played a role in the results were deviations from the study's protocol — rates of patients with at least one important deviation were 35.5% in the selumetinib group and 33.3% in the placebo group, Ho noted.  

A subanalysis of patients who were treatment-compliant and received full doses of selumetinib or placebo in the 7 days preceding RAI, on the day of RAI, and for 5 days after RAI did show a slightly higher CR rate for patients treated with selumetinib of 46.7% (n = 120) versus a rate of 37.5% in the placebo group (n = 72), however the difference still was not significant (P = .21).

"I think in order to maintain the potent and durable inhibition of the pathway to get therapeutic effects, we have to make drugs more tolerable," Ho observed.

He also noted that some promising outcomes were seen in further subanalyses according to BRAF mutational status, and "beyond MEK inhibition, targeting BRAF may be more efficacious for this."

Little Evidence RAI Is the Right Treatment in High-Risk DTC

Ryder says evidence is lacking regarding any advantages of RAI (without selumetinib) in high-risk DTC. "There are very limited data on whether adjuvant RAI for high risk disease is of benefit," she explained.

"Adjuvant RAI is done routinely for such patients based on the idea that the RAI can ablate microscopic foci of disease and prevent recurrences. There is no randomized trial to demonstrate this rational approach, however."

But she agreed that a variety of factors could have undermined the outcome in the ASTRA trial.

"There are multiple caveats," she said. "The genomics of the disease may have influenced the results; the dose of iodine may have been insufficient; and there were several protocol 'violations' among the enrolled patients, all of which may impact the results."

The rapid advancement of precision medicine could yet hold clues to patients who could most benefit from the therapy, Ryder noted.

"Clearly genomic analyses may impact the findings and future studies," she concluded.

The study received funding from AstraZeneca. Ho has received research funding from and/or been a consultant for AstraZeneca, Kolltan Pharmaceuticals, Lilly, Bayer, TRM Oncology, Sun Pharmaceuticals, Merck, Eisai, Sanofi Aventis, Regeneron, Ayala Pharmaceuticals, Genzyme, Novartis, Bristol-Myers Squibb, Genentech, Novartis, Janssen, Hai-ll, Ignyta, and Kura Oncology. Ryder has reported no relevant financial relationships.

2018 Annual Meeting of the American Thyroid Association. October 6, 2018; Washington, DC. Abstract Short Call Oral 8.

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