Medical Treatment Horizons for Metastatic Differentiated and Medullary Thyroid Cancer

Introduction to Chapter 52, Medical Treatment Horizons for Metastatic Differentiated and Medullary Thyroid Cancer.

Introduction

Metastatic differentiated thyroid cancer (DTC) and medullary thyroid cancer (MTC) are rare tumors with limited treatment options and an overall poor response to cytotoxic chemotherapy. Oral small molecule inhibitors targeting several different oncogenic pathways relevant to thyroid cancers have emerged over the past decade. Development of such kinase inhibitors has revolutionized the treatment of DTC and MTC, leading to sorafenib, lenvatinib, vandetanib, and cabozantinib becoming new standard therapies in advanced thyroid cancer. However, these multikinase inhibitors have off-target side effects that can take a toll on the patient’s quality of life (QoL). Thus the overall benefits must be weighed against the potential downsides in therapeutic decision making. The advent of genomic analysis and identification of specific driver alterations have spurred the study of more potent and highly selective therapies intended to treat subgroups of patients harboring targetable alterations more effectively and with less drug-related adverse events.

Differentiated Thyroid Cancer Subtypes

Who and When to Treat With Systemic Therapy

Metastatic DTC often presents as a relatively slow-growing and asymptomatic cancer. As long as there is response to radioactive iodine (RAI), these malignancies carry a good prognosis even when metastatic disease is present. Tumors that have de novo resistance to RAI or become RAI-refractory have a considerably worse prognosis.

In general, locoregional therapy, such as surgery and external beam radiation, is considered for localized tumor burden, whereas systemic treatments are reserved for more widespread metastatic disease, especially when disease progression occurs. Because kinase inhibitors are not curative and can cause side effects that affect QoL, deciding when to initiate therapy can be challenging. Factors to be taken into account include the pace of tumor growth and symptoms. Thyroid cancers that progress slowly over time, are asymptomatic, and of a low burden may be appropriately followed under active surveillance, whereas systemic treatment should be considered in progressive disease, especially if bulky or symptoms are thought to be imminent. Other factors to consider when deciding on systemic treatment initiation include the anatomic location of the disease (such as brain, proximity to airway, spinal cord, or risk for pathologic fracture from bone metastasis), side effects from systemic therapies, the patient’s performance status and comorbidities, and the patient’s desire for treatment after discussion and risk-benefit assessment.

RAI-Refractory DTC

Patients with RAI-refractory DTC fall into four categories: (1) those with malignant disease that has never concentrated RAI, (2) patients with tumors with prior RAI uptake that subsequently lost the ability to concentrate RAI, (3) patients with RAI uptake in some but not all sites of disease, and (4) disease progression despite RAI uptake.

Current Standard of Care

In RAI-refractory progressive DTC, lenvatinib and sorafenib are the current standard of care therapies approved by regulatory bodies.

Lenvatinib

Lenvatinib is an oral multikinase inhibitor that blocks vascular endothelial growth factor receptors (VEGFR) 1-3, fibroblast growth factor receptors (FGFR) 1-4, platelet-derived growth factor receptor alpha (PDGFR-α), KIT, and RET. Lenvatinib became an established standard treatment for locally recurrent unresectable and/or metastatic, progressive, RAI-refractory DTC based on the Study of E7080 (Lenvatinib) in Differentiated Cancer of the Thyroid (SELECT). This was a phase 3, randomized, double-blind, multicenter international study of lenvatinib versus placebo. 261 patients were randomized to receive lenvatinib (at a dose of 24 mg daily in 28-day cycles), and 131 patients to placebo. Progression-free survival (PFS) was the primary endpoint of this study, and secondary endpoints included response rate (RR), overall survival (OS), and safety. At the time of disease progression, patients were unblinded, and those found to have been initially randomized to placebo were offered crossover to open-label lenvatinib. The median PFS was 19.4 months in the lenvatinib group and 3.6 months in the placebo group (hazard ratio [HR] for progression or death, 0.21; 99% confidence interval [CI], 0.14 to 0.31; P < 0.001). 65% of the patients in the lenvatinib group had a response, of which 4 cases were complete responses, and responses were durable, lasting a median of 30 months. The median OS could not be reached by the time of data cutoff as more than 50% of patients remained alive in both arms, though the study’s crossover design can make detection of an OS benefit impossible. Indeed, 88% of patients on placebo did cross over to receive open-label lenvatinib after disease progression on placebo. Updated analysis of the elderly patient population enrolled in SELECT did, however, show that patients greater than 65 years of age did experience an OS benefit with lenvatinib compared with placebo. In additional subgroup analyses, all subgroups of patients had a PFS benefit with lenvatinib compared with placebo, including patients who had received a prior VEGF-targeted therapy, patients with all histologic subtypes, and all anatomic sites of metastasis, including bone. Treatment-related side effects related to lenvatinib were seen frequently, including hypertension in 68% of patients, diarrhea in 59%, fatigue in 59%, anorexia in 50%, weight loss in 46%, and nausea in 41%. Side effects were generally manageable with supportive care, dose holds, and dose reductions, but lenvatinib was discontinued due to toxicity in 37 patients (14%). Two percent of deaths out of the 261 patients who received lenvatinib were attributed to treatment by the investigator, though it is important to note that the rate of death on study was significantly higher in the placebo arm, and the majority of deaths were due to disease progression.

Sorafenib

Sorafenib is another oral multikinase inhibitor that targets VEGFR 1-3, RET, RAF, and PDGFR-β and has been established in the treatment of progressive RAI-refractory DTC based on the DECISION trial. This was a phase 3, international multicenter, randomized, double-blind, placebo-controlled trial that investigated sorafenib versus placebo, also with a crossover design and PFS as the primary endpoint. 417 patients were enrolled. 207 were randomized to sorafenib (400 mg twice a day) and 210 to placebo. The median PFS was 10.8 months on sorafenib versus 5.8 months on placebo (HR 0.59; 95% CI, 0.45 to 7.6; p < 0.0001). Twelve percent of patients on sorafenib responded, with a median duration of response lasting 10.2 months. Ninety-nine percent of patients receiving sorafenib had adverse events, most of which were grade 1 or 2. The most common adverse events seen in the sorafenib group included hand-foot syndrome (76%), diarrhea (69%), alopecia (67%), and desquamation or rash (50%). One death was attributed to sorafenib (myocardial infarction). At the time of analysis, median OS could not be reached by the time of data cutoff as more than 50% of patients remained alive in both arms, though no separation of survival curves was seen.

QoL was also studied in the DECISION trial using the Functional Assessment of Cancer Therapy General Survey, which considers physical, social, familial, emotional, and functional well-being of individuals receiving cancer treatment. The results of this survey indicated that patients in the sorafenib group had an overall lower QoL compared with those who received placebo, especially early on in therapy. In light of the potential effect on QoL, a discussion addressing potential side effects and the benefits of therapy must take place before starting any therapy.

BRAF-MEK Targeted Therapies

The BRAF V600E mutation is present in approximately 58% of all papillary thyroid cancers (PTCs), whereas 40% to 50% of follicular thyroid cancers (FTCs) harbor N or H RAS mutations. BRAF is a serine-threonine kinase that binds to RAS and triggers downstream activation of the MAP kinase signaling cascade. RAS -mutated thyroid cancers are prone to distant metastases to lung and bone. Given the limited therapeutic options for RAI-refractory DTC, the identification of BRAF and RAS as potential therapeutic targets has been of interest.

Vemurafenib

Vemurafenib is a kinase inhibitor initially designed as a specific inhibitor of the mutated BRAF kinase frequently present in melanoma. A retrospective analysis of the efficacy and tolerability of vemurafenib in patients with advanced BRAF V600E mutated PTC showed efficacy and tolerability. Of the 17 patients identified, 7 had a partial response and 8 had stable disease. Duration of response was more than 6 months, and the median time to treatment failure was 13 months. Vemurafenib was also studied in a phase 2, open-label, clinical trial for patients with RAI-refractory recurrent and/or metastatic PTC harboring a BRAF V600E mutation. Participants were enrolled into two cohorts, one treatment-naïve, and the other for patients who had received one prior VEGFR multikinase inhibitor. In the first cohort 10 of 26 patients (38%) experienced a partial response, a median PFS of 18.2 months, and a median duration of response of 16.5 months. In the second cohort 6 is the actual number instead of 10, hence 27% is correct 10 of 22 patients (27%) had a partial response, with a median PFS of 8.9 months and median duration of response of 7.4 months. The most commonly reported adverse events included rash, fatigue, weight loss, taste alteration, and alopecia. Seventeen patients in each cohort had grade 3 to 4 side effects, including cutaneous squamous cell carcinoma, keratoacanthoma, dyspnea, pneumonia, and hypotension.

Dabrafenib

Dabrafenib and trametinib combination.

Dabrafenib is a BRAF inhibitor and trametinib inhibits MEK. BRAF and MEK are components in the same signaling pathway that ultimately activate tumor proliferation and growth. In a phase 1 study of dabrafenib in patients with solid tumors, 3 of the 9 evaluable patients achieved a partial response. Subsequently, the combination of dabrafenib and trametinib compared with dabrafenib monotherapy was studied in patients with RAI-refractory PTC. This randomized phase 2 study enrolled 53 patients, of whom 25% had received 1 to 3 prior multikinase inhibitors. Patients in arm A (N = 26) were treated with dabrafenib monotherapy (150 mg twice a day), and those in arm B (N = 27) received combined dabrafenib and trametinib (dabrafenib 150 mg orally twice a day plus trametinib 2 mg orally daily). Preliminary data analysis showed an overall response rate (ORR) of 50% for arm A and 54% for arm B, median PFS was 11.4 months and 15.1 months, respectively, and median duration of response was 15.6 months and 13.3 months, respectively. Unlike in melanoma, in which combined BRAF plus MEK inhibition is both better tolerated and has greater activity than treatment with BRAF-directed monotherapy, this study showed no statistically significant difference in ORR, median PFS, or duration of response between the two arms; however, monotherapy and combination therapy were both tolerable.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here