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Introduction
In recent decades, the incidence of thyroid cancer has increased significantly worldwide, which is partially caused by an increase in early tumor detection due to excessive diagnosis and increased diagnosis rate. Rapid increases were mainly observed for papillary thyroid cancer (PTC). PTC also showed the largest geographical variation, with the highest rates recorded in some high-income countries [1,2]. Differentiated thyroid carcinomas (DTCs) are derived from follicular epithelial cells and include PTC and follicular thyroid carcinomas. Of 63,324 patients diagnosed with thyroid carcinoma between 2011 and 2015, 89.8% had PTC, 4.5% had follicular carcinoma, 1.8% had oncocytic carcinoma of the thyroid, 1.6% had medullary carcinoma, and 0.8% had anaplastic carcinoma [3,4].
DTCs are usually successfully treated with surgical excision and/or radioactive iodine therapy (RAI). Total lobectomy is recommended over total thyroidectomy for patients with incidental small-volume pathological N1a metastases [5]. However, up to 30% of patients with DTC experience tumor recurrence over several decades. Distant metastases are the sites of recurrence in approximately 20% of patients, and 50% of patients with distant metastases die of cancer [6-8]. In particular, anaplastic thyroid carcinoma (ATC) is rare but is the most aggressive type, often accompanied by locoregional invasion, with distant metastasis in approximately 15%-20% of patients [8,9]. Because the prognosis of ATC is dismal compared to that of DTC, the American Joint Committee on Cancer Staging Manual classifies all ATC cases as stage IV [8]. Most ATCs do not respond well to RAI because iodine uptake is absent [10,11]. PTC can progress to poorly differentiated thyroid cancer or ATC in several decades [12].
Systemic treatment is required for patients with diseaserelated symptoms that are difficult to manage with local treatment. Lenvatinib and sorafenib have been recommended as category 1 drugs in the National Comprehensive Cancer Network guidelines for patients with progressive or symptomatic RAI-refractory DTC in two pivotal phase 3, randomized studies [13,14].
The most commonly identified mutation in PTC is BRAFV600E [10,15]. The mitogen-activated protein kinase pathway is a group of signal transducer kinases that promote cell growth, proliferation, and the inhibition of apoptosis. Activation of BRAF activates a second protein kinase called mitogen-activated extracellular signal-regulated kinase (MEK). MEK causes the phosphorylation and activation of extracellular signal-regulated kinase (ERK), which leads to gene expression. Patients with thyroid cancer with BRAF mutations are activated by the V600E mutation in the BRAF oncogene, which leads to uncontrolled cell cycle progression and tumor growth [16,17].
Dabrafenib is a competitive, reversible, selective BRAF inhibitor that binds to ATP pockets. Trametinib is a reversible, selective inhibitor of MEK1/MEK2 activation and kinase activity [18,19]. The combination of dabrafenib and trametinib was found to have antitumor activity in patients with metastatic melanoma, non-small cell lung cancer, and ATC harboring the BRAFV600E mutation [20-25]. The combination of dabrafenib and trametinib in patients with BRAFV600E mutation-positive DTC deserves further exploration or study.
Therefore, this study aimed to assess the real-world efficacy and safety of dabrafenib plus trametinib in pretreated patients with metastatic BRAFV600E mutation-positive PTC or PTC with anaplastic transformation who participated in the Managed Access Program (MAP) of Novatis at the Samsung Medical Center, Korea.
Materials and Methods
1. Study subjects and data collection
The MAP of dabrafenib plus trametinib initiated on February 2, 2021, to enable early access to dabrafenib plus trametinib in patients with BRAFV600E-mutated PTC or anaplastic transformation who were unable to participate in clinical studies. We retrospectively analyzed the efficacy and safety of dabrafenib plus trametinib in patients with BRAFV600E-mutated PTC or anaplastic transformation enrolled in the MAP of dabrafenib plus trametinib at Samsung Medical Center, Korea. We included patients aged 18 years or older with a symptomatic disease that had progressed less than 12 months before treatment. There were no limitations on the quantity or type of prior systemic treatments. Patients who received dabrafenib plus trametinib before the initiation of MAP were also included.
The patient received an initial dose of dabrafenib 150 mg twice daily and trametinib 2 mg once daily. The patients were treated with dabrafenib plus trametinib for 28 days until disease progression, unacceptable toxicity, withdrawal of consent, or death. Dose reduction and temporary interruption were permitted based on the physician’s judgment.
Baseline neck and chest contrast computed tomography were performed within 4 weeks before starting the first dose of dabrafenib plus trametinib. Disease progression was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) ver. 1.1. Treatment-related adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) ver. 5.0. The baseline characteristics, treatment history, efficacy, and safety outcomes were evaluated.
We evaluated progression-free survival (PFS), the investigator-assessed objective response rate (ORR), overall survival (OS), and safety profiles.
PFS was defined as the time from the first dose of dabrafenib plus trametinib to the first occurrence of disease progression or death. Patients who had not experienced treatment discontinuation at the analysis cutoff date were censored at the analysis cutoff date. The investigator-assessed ORR per RECIST ver. 1.1. ORR was defined as the proportion of patients with a confirmed complete response and partial response (PR) according to RECIST ver. 1.1. The OS is the time between the start of dabrafenib plus trametinib treatment and the occurrence of death from any cause. We censored patients who were alive at the time of the last data cutoff and the last follow-up.
2. Statistical analysis
The all-data cut-off date for the analyses was August 27, 2023. Statistical analysis was performed using SPSS software ver. 27.0 (IBM Corp., Armonk, NY) and MedCalc software version 22.006. Median PFS and OS were estimated from Kaplan-Meier curves. The log-rank test was used to compare the subgroups. The statistical significance level was set at p < 0.05 for all tests.
Results
1. Study population and clinical characteristics
Between December 2019 and January 2022, 27 metastatic BRAFV600E mutation–positive PTC patients including eight with poorly differentiated or anaplastic transformation, signed an informed consent form and received dabrafenib and trametinib. Three patients started treatment with dabrafenib plus trametinib before starting the MAP and were subsequently enrolled in the MAP. Data were collected between December 2019 and August 27, 2023. At the time of data lock, among the 15 deceased patients, 13 passed away due to progression of thyroid cancer, while two succumbed to sepsis—one as a result of urinary tract infection, and the other due to acute cholecystitis.
Table 1 presents the baseline characteristics of 27 patients. The median age was 73 years (range, 24 to 84 years), and 74.1% of the patients were female. 96.3% of the patients had a Eastern Cooperative Oncology Group performance status of 0-1. The sites of distant metastases were the lungs (n=23), brain (n=3), bones (n=3), and liver (n=1). A total of 24 patients underwent total thyroidectomy or hemithyroidectomy. The remaining three patients had distant metastases at the time of diagnosis but refused initial surgery. BRAFV600E mutation was identified in nine patients through real-time polymerase chain reaction, while 18 patients were confirmed through next generation sequencing (TruSight Oncology 500 [Illumina] in three cases, CancerSCAN ver. 2 [GENINUS] in 2 cases). Seventeen patients (63.0%) were treated with a combination of dabrafenib and trametinib as first-line therapy. However, 10 patients (37.0%) were receiving palliative chemotherapy prior to the dabrafenib plus trametinib. Out of these 10 patients, six received lenvatinib treatment, one received a combination of lenvatinib and pembrolizumab, and three were administered sorafenib.
2. Treatment outcomes of dabrafenib and trametinib
With a median follow-up period of 19.8 months (95% confidence interval [CI], 16.7 to 22.9), the median number of cycles of dabrafenib and trametinib was 13 (range, 1 to 46). The ORR was 73.1% and the disease control rate (DCR) was 92.3% (Table 2). Fig. 1 shows the largest percentage change from baseline in the sum of the longest target tumor lesion diameters per patient. At the time of data lock, nine patients (33.3%) were still receiving dabrafenib plus trametinib with PR or stable disease. The median duration of response was 21.5 months (95% CI, 13.5 to 29.5) (S1 Fig.).
The median PFS was 21.7 months (95% CI, 15.3 to 31.3) (Fig. 2A), and the median OS was 21.7 months (95% CI, 11.5 to 31.9) (Fig. 3A). In the cancer-specific mortality group, the median OS was 31.5 months (95% CI, 15.0 to 48.0) (S2 Fig.). There was no significant difference in PFS and OS between the first-line and second-line treatment groups of dabrafenib and trametinib (Figs. 2B and 3B). The median PFS was 23.3 months (95% CI, 3.7 to 42.8) in the first-line treatment group and 16.9 months (95% CI, 2.6 to 31.2) in the second-line treatment group (p=0.353). The median OS was 31.5 months (95% CI, 19.8 to 43.2) in the first-line treatment group and 19.3 months (95% CI, 4.8 to 33.8) in the second-line treatment group (p=0.190). There was a tendency for PFS and OS to be longer in the PTC group than in the PTC with poorly differentiated or anaplastic transformation group, but there was no significant difference (Figs. 2C and 3C). The median PFS was 23.3 months (95% CI, 15.3 to 31.3) for PTC and 5.6 months (95% CI, 0.5 to 10.7) for PTC with poorly differentiated or anaplastic transformation (p=0.101). The median OS was 28.8 months (95% CI, 16.9 to 40.7) for PTC and 7.5 months (95% CI, 0.0 to 17.8) for PTC with poorly differentiated or anaplastic transformation (p=0.441).
3. Safety profile
All patients who received at least one dose of dabrafenib or trametinib were evaluated for safety. The most common nonhematological treatment-related adverse events (TRAEs) of any grade were alkaline phosphatase elevation (n=17, 61.5%), and aspartate aminotransferase elevation (n=12, 42.3%) and general weakness (n=8, 29.6%). The most common over grade 3 non-hematological TRAEs were general weakness (n=6, 22.2%), fever (n=3, 11.1%), and rash (n=2, 7.4%). The most common hematologic adverse events of any grade were anemia (n=21, 76.9%), neutropenia (n=6, 23.1%), and thrombocytopenia (n=4, 15.4%). Hematologic TRAEs of grade 3 or higher were reported in 19.2% of the patients (Table 3). There were no fatalities attributed to TRAEs.
Temporary interruptions and dose reduction occurred in 13 patients (48.1%) and 22 patients (81.5%), respectively. The dabrafenib dose was reduced to 75 mg twice daily in 20 patients, and 75 mg once daily in two patients. The trametinib dose was reduced to 1 mg once daily in one patient. Four patients (14.8%) discontinued the treatment because of adverse events. Three patients experienced grade 3 generalized weakness and one had a progression of heart failure.
Discussion
Based on several clinical trials, the U.S. Food and Drug Administration recently approved the use of dabrafenib and trametinib in unresectable or metastatic solid tumors with BRAFV600E mutation. In light of this development, it seems pertinent to evaluate the real-world efficacy and safety of dabrafenib and trametinib in advanced BRAFV600E-mutated PTC. This study demonstrated the promising efficacy of dabrafenib and trametinib combination therapy in patients with metastatic BRAFV600E-mutated PTC. The ORR of the combination of dabrafenib and trametinib was 73.1%, and the DCR was 92.3%. The median PFS was 21.7 months in all patients, and the median PFS was 23.3 months in the first-line treatment group. In patients who experienced disease progression with other tyrosine kinase inhibitors (TKIs) (secondline treatment group), the median PFS was 16.9 months. Nevertheless, temporary interruptions and dose reduction occurred in 48.1% and 81.5%, respectively. Four patients (14.8%) discontinued the treatment because of TRAEs.
In the phase 3 SELECT trial, the median PFS was 18.3 months in the lenvatinib group, while 3.6 months in the placebo group with a hazard ratio (HR) of 0.21. Hypertension (67.8%), diarrhea (59.4%), and fatigue/asthenia (59.0%) were the most prevalent TRAEs in the lenvatinib group. Lenvatinib discontinuation due to TRAEs occurred in 14.2% of patients, and six of 20 deaths during the treatment period were considered drug-related [13]. In the phase 3 DECISION trial, patients with RAI-refractory locally advanced or metastatic DTC that had progressed within the past 14 months were randomized on a 1:1 basis to sorafenib or placebo groups. The median PFS was 10.8 months in the sorafenib group and 5.8 months in the placebo group with an HR of 0.59. Adverse events occurred in 98.6% of patients in the sorafenib group. Hand-foot reactions (76.3%), diarrhea (68.6%), and alopecia (67.1%) were common [14]. As a first-line therapy, compared to previous PFS data of the lenvatinib or sorafenib, the combination of dabrafenib and trametinib showed superior PFS data in our study (10.8-18.3 vs. 23.3 months). In the phase 2 trial comparing dabrafenib to the combination of dabrafenib and trametinib, the ORR was 42% for dabrafenib alone and 48% for the combination therapy. The median PFS was 15.1 months in the combination therapy. Notably, previous study had a median age of 60 years, and more than 90% of the patients were either white or African American. In contrast, the current study featured a median age of 73 years, with an exclusively Asian patient population [26].
This study had several limitations. As this was a retrospective study, there might have been a potential bias in evaluating the efficacy and adverse events. The median age was 73 years, which was comparatively older than that of dabrafenib and trametinib for other solid tumors such as lung cancer or melanoma. Given the greater susceptibility of elderly patients to the adverse events of dabrafenib and trametinib, more attention should be paid to adverse event management including more generous and early dose reduction [21,22]. Temporary interruptions and dose reduction occurred in 13 patients (48.1%) and 22 patients (81.5%), respectively. In this study, three patients (11.1%) died within three months of the first drug administration. One patient with a poor performance status was unable to continue the prescribed two-week course of dabrafenib and trametinib and subsequently passed away. Additionally, two patients died of sepsis: a 76-year-old male patient with a urinary tract infection and a 71-year-old male patient with acute cholecystitis. Owing to the wide spectrum of the disease course of thyroid cancer, well-defined indications for starting first-line TKIs should be established. The median time from distant metastasis to first-line therapy was 24.2 months in our study. Considering the small number of patients in this single institute, further large-scale prospective studies are warranted to validate the efficacy and safety of this treatment.
This study demonstrated the efficacy and safety of a combination of dabrafenib and trametinib in patients with advanced BRAFV600E-mutated PTC regardless of prior TKIs therapy. Notably, the combination of dabrafenib and trametinib as a first-line therapy demonstrated a promising ORR and PFS. Nevertheless, cautious dose reduction and management of TRAEs are required in most patients.
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