Still Perfecting Radioiodine in Thyroid Cancer, After All These Years Free

Since the first use of therapeutic radioiodine in the 1940s, radioiodine has remained a mainstay of thyroid cancer treatment (1, 2). Although recent efforts have focused on limiting exposure to radioiodine in patients with differentiated thyroid cancer (DTC) who have low-risk disease, radioiodine remains a critical aspect of treatment of other patients with DTC, including patients with metastases that take up and respond to radioiodine (3). Patients with DTC who have metastatic disease and respond to radioiodine can live for decades, whereas patients with unresectable recurrent/metastatic radioiodine-refractory DTC have a 10-year survival rate of only 10%. Advances in angiogenesis multikinase inhibitor therapy have led to a new standard of care for this subset of patients, but these gains have come at a cost, with treatment-associated side effects that can affect quality of life (4, 5). As a result, multikinase inhibitors are often reserved for patients with radioiodine-refractory DTC who have clinically meaningful disease progression. Patients with radioiodine-refractory DTC who are asymptomatic and have a low burden of slowly progressive disease are often followed with active surveillance alone. Although these patients may enjoy a long asymptomatic period of slow tumor growth, their disease-specific survival is not favorable, and an effective, appropriate treatment approach that would be more effective than active surveillance is clearly needed.

In this issue of JCEM, Dunn et al. (6) from Memorial Sloan-Kettering Cancer Center report the results of a feasibility study of the BRAF inhibitor, vemurafenib, for redifferentiation in BRAF-mutant radioiodine-refractory DTC. BRAF^V600E is the most common driver molecular alteration in thyroid cancer. Thyroid cancers harboring BRAF^V600E are less likely to concentrate radioiodine at least part due directly to mutant BRAF resulting in constitutive activation of the MAPK pathway. The Memorial Sloan-Kettering Cancer Center group has shown in preclinical studies that MAPK pathway activation downregulates expression of the Na⁺/I⁻ symporter and suppresses other mediators of thyroid cell iodide uptake (7, 8). These data led to their first clinical redifferentiation study investigating the MEK inhibitor, selumetinib, as pretreatment with radioiodine to elicit thyroid cancer reprogramming and iodide sensitivity (9). This was achieved in all five patients enrolled in the trial with NRAS-mutant DTC, whereas only one of nine patients with BRAF^V600E-mutant DTC responded. Thus, the group hypothesized that in BRAF^V600E-mutant tumors, preradioiodine treatment by a more robust MAPK inhibitor such as the BRAF inhibitor, vemurafenib, may be needed to effectively induce redifferentiation and radioiodine uptake.

In this feasibility study, 12 patients with BRAF^V600E-mutant radioiodine-refractory DTC were enrolled, and 10 were evaluable. During the fourth week of vemurafenib treatment, patients underwent I-124 positron emission tomography/CT imaging. Those with lesional dosimetry reaching a prespecified threshold of at least 2000 cGy with I-131 of 300 mCi or less, considered sufficient to warrant treatment with I-131, remained on vemurafenib until Thyrogen-stimulated therapeutic I-131 by dosimetry was administered. I-131–treated patients were then followed 6 months for response by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Of the 10 evaluable patients, 4 were I-124 responders and received I-131 therapy. Of these, three experienced a post-I-131 decrease in tumor measurements, two of whom met the criteria for partial response by RECIST v1.1. Two of the I-131–treated patients went on to require subsequent thyroid cancer treatment at 9 and 18 months, whereas the other two patients have not required further therapy at 22 and 33 months, respectively. Overall, this feasibility study suggests that vemurafenib for redifferentiation in BRAF^V600E-mutant radioiodine-refractory DTC is a strategy that may offer a moderate degree of clinical benefit, which appears similar to activity seen in an earlier feasibility study of another BRAF inhibitor, dabrafenib, as pretreatment with I-131 in a similar BRAF^V600E-mutant radioiodine-refractory patient population (10). With dabrafenib, 6 of 10 patients converted to iodine uptake positive disease and received therapeutic I-131. Of these six patients, two experienced a partial response by RECIST v1.1.

In addition to these feasibility studies in patients with unresectable recurrent/metastatic DTC, results from the landmark Comparing Complete Remission After Treatment With Selumetinib/Placebo in Patients With Differential Thyroid Cancer (ASTRA) trial, which studied selumetinib compared with placebo prior to adjuvant I-131 treatment in postoperative patients with DTC who are at high risk for primary treatment failure, have now been presented (11). The ASTRA trial, the first of its kind in studying redifferentiation to improve the long-term cure rates of patients with thyroid cancer, unfortunately did not meet its primary end point of improved complete remission at 18 months with selumetinib/I-131 compared with placebo/I-131. Although these final results are disappointing, there was still a suggestion of activity; when the analysis was limited to patients taking selumetinib or placebo in the critical period before and immediately after I-131 dosing, there was a numerical improvement in complete remission, with 46.7% of patients on selumetinib remaining in remission at 18 months compared with 37.5% of patients on placebo (OR = 1.46; 95% CI, 0.81 to 2.67; P = 0.2131).

In this era of precision oncology, in which potent inhibition of driver molecular alterations has led to great treatment successes across multiple tumor types, these latest thyroid cancer redifferentiation efforts have not clearly hit the ball out of the park. Why? In the vemurafenib trial, Dunn et al. (6) performed pre- and on-treatment biopsies in three patients to interrogate MAPK pathway activity, BRAF/RAS score, and enhanced Thyroid Differentiation Score. On treatment, a decrease in the MAPK pathway transcriptional output was seen in all three cases, demonstrating target engagement. Moreover, an increase in both the BRAF/RAS and enhanced Thyroid Differentiation Scores was seen in all three cases, consistent with at least some success in the desired pharmacologic reprogramming and redifferentiation effects. Although correlative studies in such a small number of patients may not have the power to uncover the mechanisms behind activity of and resistance to a particular therapy, if carried out in the setting of a larger trial, correlative studies as elegant as these performed by Dunn et al. (6) hold great promise for optimizing a novel precision approach to redifferentiation in radioiodine-refractory DTC.

It is remarkable that, more than 75 years after radioiodine was first introduced into clinical thyroidology, we are still working to perfect its use. These early redifferentiation studies along with the emerging correlative data are encouraging. Ongoing efforts to achieve successful redifferentiation in patients with radioiodine-refractory DTC in need of better treatment options than our current standard of care should not be abandoned.

Abbreviations:

Abbreviations:
 
• DTC

  differentiated thyroid cancer

 
• RECIST

  Response Evaluation Criteria in Solid Tumors.

Acknowledgments

Disclosure Summary: L.J.W. has served on advisory boards and/or performed consulting for Ayala, Bayer, Eisai, Loxo, and Merck.

References