CHICAGO—A subset of patients with radioiodine-resistant BRAF-mutant papillary thyroid cancer can be made to have new iodine uptake following treatment with dabrafenib, according to the results of a pilot study reported at the American Society of Clinical Oncology Annual Meeting (Abstract 6025).
“Resistance to radioactive iodine is a leading cause of mortality in differentiated thyroid carcinoma,” noted S. Michael Rothenberg, MD, a medical oncologist at Massachusetts General Hospital Cancer Center for Head and Neck Cancers. “The mitogen-activated protein kinase (MAPK) pathway is a major determinant of iodine uptake into thyroid carcinoma cells, and mutations in BRAF activate this pathway, resulting in resistance to radioiodine uptake in preclinical cell line and mouse tumor models.”
Selective BRAF inhibitors have potent activity in BRAF-mutant melanomas, although their activity as single agents in BRAF-mutant colon and thyroid cancer preclinical models is modest, he explained.
A pilot study using the MEK1/2 inhibitor selumetinib showed increased radioiodine uptake in a subset of thyroid cancers, particularly those harboring RAS mutations, and led to tumor responses following administration of treatment doses of radioactive iodine (RAI).
The single-institution, single-arm study he reported was conducted to investigate the potential of four weeks of the BRAF-inhibitor dabrafenib to induce radioiodine uptake in patients with metastatic, BRAF-mutant, radioiodine-refractory papillary thyroid carcinoma.
The primary endpoint of the study was increased radioiodine uptake on low-dose 131-I whole body scan. Patients who did then have increased uptake received 14 additional days of dabrafenib, followed by treatment with 150mCi 131-I. Secondary endpoints were safety and tolerability and clinical benefit as measured by decreases in serum thyroglobulin and objective response rate per modified Response Evaluation Criteria in Solid Tumors.
All of the nine patients enrolled in the study had negative 131-I scans within 14 months, with measureable structural disease, and five of nine patients demonstrated new radioiodine-avid uptake after 28 days of dabrafenib, including new radioiodine-avid lesions in three of five patients after receiving a therapeutic dose of 131-I on day 42, Rothenberg reported.
“One-third of patients with 131-I uptake who were evaluated for tumor response demonstrated a complete response. Two-thirds of patients had stable disease.”
“These results are similar to those observed in patients with BRAF-V600E papillary thyroid cancer treated with selumetinib. In the four patients without new 131-I uptake following dabrafenib, it is possible that BRAF inhibition was incomplete and determinants other than BRAF mutation status contributed to radioiodine sensitivity.”
The toxicities were moderate and manageable, he said, and no dose adjustments for toxicity have been needed. One patient developed reversible hypophosphatemia and a second developed a benign skin lesion.
In conclusion, Rothenberg said, “These preliminary results warrant further study of dabrafenib in iodine-refractory BRAF-V600E papillary thyroid cancer, possibly in combination with additional targeted agents. Reuptake may correlate with increases in thyroglobulin, suggestive of re-differentiation.”
It is not yet known, though, whether increased uptake of radioactive iodine will translate into a radiographic response, he said.
The Discussant for the study, Vassiliki Papdimitrakopoulou, MD, Professor in the Department of Thoracic/Head and Neck Medical Oncology at the University of Texas MD Anderson Cancer Center, noted that BRAF mutations are associated with multiple negative prognostic indicators and that point mutations are seen in 40 to 45 percent of papillary thyroid cancers.
“Upregulation of matrix metalloproteinases and vascular endothelial growth factor leads to invasion and angiogenesis, and the silencing of tumor suppressive genes involves iodine transport,” she explained.
S. MICHAEL ROTHENBERG, MD
Studies that have selectively targeted MEK 1/2 in papillary thyroid cancer have shown this pathway to be critical to the molecular pathophysiology of thyroid cancer tumorigenesis and is a major determinant of iodine uptake into thyroid cancer cells.
She said that the patients in Rothenberg's study who failed to convert may have had incomplete BRAF inhibition, and she agreed with the conclusion that combination strategies may be useful.
“RAI-refractory thyroid cancer may harbor second mutations in the PI3K/AKT/mTOR pathway, and therefore, blockade of both pathways may be synergistic. We have proof that both MEK and BRAF inhibitors can induce iodine uptake. There may be an advantage to short courses of tyrosine kinase inhibitors [TKIs] followed by RAI.”
Published studies of TKIs in thyroid cancer show a clinical benefit that ranges from 57 to 76 percent, she continued. “These are small studies, and interpretation of the differences is hard because of heterogeneous populations,” she said. “Patients with longer distance from the original diagnosis may fare worse. Selumetinib has lower clinical potency, and alternate inhibitors of MEK or BRAF may be more effective.”
Information about the degree of progression prior to entry in clinical trials with TKIs is important since RAI- refractory patients can have disease progression at very slow rates, making toxicity unacceptable, Papdimitrakopoulou said.
“Patients who progress rapidly may define a population with greater responses due to increased dependence on angiogenesis that is blocked by multi-kinase inhibitors. Genotype-driven clinical trials with homogeneous patient populations that include profiling of resistance are needed. A re-differentiation strategy in RAI-refractory thyroid cancer may spare patients unnecessary toxicity.”