Thyroid cancer represents the most common endocrine malignancy, with papillary thyroid cancer (PTC) accounting for approximately 85% of cases (1, 2). While most PTCs have an excellent prognosis, a subset of patients develop aggressive, treatment-refractory disease. At the other end of the spectrum, anaplastic thyroid cancer (ATC) stands as one of the most lethal human malignancies, with a historical median survival of only 3–5 months (3, 4).

The somatic BRAFV600E mutation is present in 37%–60% of PTC, particularly among the tall-cell variants, and to a similar extent in ATC (1–3). The presence of BRAFV600E mutation is linked to dysregulation of the sodium-iodide symporter, reducing the capacity of tumor cells to absorb radioiodine (RAI) and consequently, leading to RAI resistance (4). Patients with BRAFV600E-positive tumors are more likely to exhibit a more aggressive tumor behavior and potentially higher cancer-related mortality, requiring systemic therapies for recurrent or metastatic disease (5, 6).

Recent advances in molecular profiling have revolutionized our understanding of thyroid cancer biology and opened new avenues for targeted therapies (5–7). The identification of driver mutations, particularly the BRAF V600E mutation, has led to the development of targeted tyrosine kinase inhibitors with a promising therapeutic potential in both differentiated and anaplastic thyroid cancers (7–9), extending the overall survival in ATC to 80% at 12 months (8).

To date, the only BRAF/MEK inhibitor regimen approved by the U.S. Food and Drug Administration (FDA) for the treatment of ATC is the combination of dabrafenib and trametinib (10). This approval was initially based on findings from the phase II ROAR basket trial, which demonstrated promising clinical activity, with subsequent research further supporting its efficacy (11, 12). Despite these encouraging results, dabrafenib and trametinib remain the sole labeled combination approved for ATC, in contrast to melanoma treatment, where other BRAF and MEK inhibitor combinations, such as vemurafenib–cobimetinib and encorafenib–binimetinib, are available (13–15). These alternative regimens exhibit slightly different side-effect profiles, which may enable clinicians to modify therapy in the presence of severe adverse events, potentially reducing the need for dose reductions or treatment discontinuation.

These cases illustrate the complexity of managing advanced thyroid cancer in the era of precision medicine, emphasizing both the benefits and challenges of targeted therapies (13, 16–18). Prior treatments, tumor mutation profiles, and outcomes compared with previously reported cohorts are summarized in Table 1, and sequential therapeutic strategies are outlined in Figure 1. This series highlights the real-world use of BRAF and MEK inhibitors, management of treatment-related toxicities, and the need for ongoing research to optimize personalized care and improve patient outcomes (14, 23).

This case series presents four patients with advanced thyroid cancer: three with PTC and one with ATC, all harboring the BRAF V600E mutation diagnosed using next-generation sequencing (NGS) by The Ion Torrent™ Oncomine™ Dx Express Test in all cases but case 2 in which FoundationOne^®CDx was used.

Disease progression was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) ver. 1.1 (15). Treatment-related adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) ver. 5.0 (24). The baseline characteristics, treatment history, efficacy, and safety outcomes were evaluated. The study was approved by the local IRB (TLV-0197-25) and conducted in accordance with the Declaration of Helsinki, with informed consent waived due to its retrospective design.

Here, we presented four cases of thyroid cancer, three PTC and one ATC, which highlight the complex nature of managing advanced thyroid cancers, particularly those with BRAF V600E mutations. All patients received standard-of-care treatments, including surgery, radiation, radioactive iodine, and multikinase inhibitors. For progressive locoregional disease, various BRAF–MEK inhibitors were used as personalized salvage therapy to delay progression and improve quality of life, obtained through individual insurance approvals since they are not included in standard protocols.

The BRAF V600E mutation constitutively activates the mitogen-activated protein kinase (MAPK) pathway by promoting ligand-independent phosphorylation of downstream kinases MEK and ERK (9, 13). This dysregulation promotes uncontrolled cell growth and differentiation, contributing to oncogenesis of tumor cells (16, 17). Targeted inhibition of BRAF and MEK interrupts this signaling cascade and has demonstrated clinical benefit across several BRAFV600E-mutated solid tumors (Figure 4) (18).

The identification of BRAF V600E mutations in these cases underscores the critical role of molecular profiling in guiding treatment decisions (23), particularly in heavily pretreated patients. BRAF V600E is a known driver of thyroid cancer progression and a target for therapy (5, 26, 27). BRAF and MEK inhibitor combinations such as dabrafenib–trametinib, encorafenib–binimetinib, and vemurafenib–cobimetinib exemplify the transition toward personalized medicine in advanced thyroid cancer (14, 23).

While multiple BRAF–MEK combinations are approved for melanoma, with comparable efficacy and slightly differing toxicity profiles, approval in thyroid cancer remains more limited (28). As of 2025, dabrafenib plus trametinib is the only FDA-approved targeted regimen for unresectable or metastatic BRAF V600E-mutant ATC, based on the ROAR trial, which demonstrated a 61% response rate (10–12). This combination later received tumor-agnostic approval for BRAF V600E-mutant solid tumors and is recommended by ESMO as standard therapy for eligible ATC patients (10, 12, 18, 29).

Earlier ATA guidelines (2015) recommended kinase inhibitors for progressive, symptomatic, radioiodine-refractory differentiated thyroid cancer; however, BRAF–MEK combinations were not included due to limited evidence (30–32). The updated 2025 ATA guidelines now support BRAF-directed therapy as a first-line option for patients unsuitable for lenvatinib or those who progress or develop intolerance to prior kinase inhibitors (33).

Toxicity remains a major limitation of BRAF–MEK inhibition. All four patients in this series (100%) developed grade ≥3 adverse events requiring dose modification or discontinuation. The most common toxicities were pyrexia (100%), myalgia (75%), gastrointestinal intolerance (75%), and hepatotoxicity (50%). Given the high incidence and severity of adverse events, rechallenge with BRAF–MEK inhibitors should be cautiously considered, particularly in frail or elderly patients. In case 1, reintroduction of dabrafenib–trametinib following prior encephalopathy and disease progression on encorafenib–binimetinib led to a transient partial response.

Similar toxicity rates are reported in clinical trials. In the phase II ROAR study, 100% of patients experienced adverse events on the standard dabrafenib (150 mg BID) and trametinib (2 mg daily) regimen, with 58% having grade 3–4 toxicity and half requiring dose interruption or reduction (12). Similar toxicity patterns were reported in melanoma, as shown by Long et al., where treatment with dabrafenib and trametinib for stage III BRAF-mutated melanoma resulted in adverse events in 97% of patients, including 41% with grade 3–4 events that led to dose interruption, dose reduction, and treatment discontinuation in 66%, 38%, and 26% of cases, respectively (34). Although large phase III randomized controlled trials evaluating BRAF and MEK inhibitors in thyroid cancer are lacking, case reports, systematic reviews, and meta-analyses of early-phase and non-randomized studies have demonstrated meaningful clinical activity, manageable safety profiles, and improved outcomes in this historically aggressive and treatment-refractory population (12, 14, 15, 17–19, 35, 36). In other settings, trials in advanced RAI-resistant differentiated thyroid cancer have shown the feasibility of using BRAF and MEK inhibitors as part of a redifferentiation treatment strategy, thereby broadening the therapeutic potential of these drug combinations (25, 37).

In a phase II trial by Marcia S. Brose et al. (7), the efficacy of vemurafenib was evaluated in 51 patients with metastatic or unresectable BRAF V600E–positive, RAI-refractory PTC. Vemurafenib achieved a partial response in 38% of patients who had not received prior VEGFR inhibitor therapy, compared with 27% among those previously treated with a VEGFR inhibitor. The corresponding median PFS was 18.2 months versus 8.9 months, respectively. The lower response rates observed in both cohorts may be attributed to the use of BRAF inhibitor monotherapy without concurrent MEK inhibition, and to the latter cohort being more heavily pretreated and having received multiple prior systemic therapies, including chemotherapy, which is rarely used in current practice. Grade 3–4 adverse events occurred in approximately two-thirds of patients, with no treatment-related deaths reported.

Extrapolating from melanoma experience, alternative BRAF and MEK inhibitor combinations beyond dabrafenib–trametinib may help mitigate toxicity while maintaining efficacy in advanced thyroid cancer. In our series, following severe adverse events with two prior regimens, switching to vemurafenib–cobimetinib in case 4 achieved 14 months of stable disease, underscoring the potential benefit of strategic sequencing of alternative targeted combinations.

Although these combinations share overlapping toxicities, each agent has a distinctive adverse effect profile: vemurafenib–cobimetinib is associated with photosensitivity and ocular toxicity; dabrafenib–trametinib with pyrexia; while encorafenib–binimetinib with relatively lower pyrexia risk. These differences in adverse effects were thoroughly evaluated in three major clinical trials for advanced melanoma and previously published in ESMO Open, as illustrated in Figure 5 (38). Notably, encephalopathy is a rarely reported adverse effect; however, in case 1, it developed during treatment and, following thorough neurological evaluation, was attributed to dabrafenib and trametinib therapy.

Despite initial responses to targeted therapies, all cases eventually showed disease progression, indicating the development of treatment resistance. Resistance due to escape phenomenon is well-documented in BRAF-mutated cancers, develops faster in thyroid cancer relatively to BRAF positive melanomas, and underscores the need for sequential treatment strategies and ongoing research into resistance mechanisms (24, 32). Reported mechanisms include reactivation of the MAPK pathway through NRAS, KRAS, or CRAF mutations, enhanced receptor tyrosine kinase signaling (HER2, HER3, MET), and secondary alterations in MEK or BRAF splice variants (39, 40). Tumor heterogeneity and clonal evolution further limit response durability (41). These findings emphasize the need for re-biopsy and molecular re-profiling at progression to inform second-line strategies or trial enrollment.

Two patients (50%) in our series harbored concomitant TERT promoter mutations. Although BRAF and TERT co-mutations are well recognized for their association with radioiodine resistance and more aggressive disease (42), the limited sample size in our cohort precludes definitive conclusions regarding their role in treatment resistance. Further studies are warranted to elucidate their potential contribution to resistance to BRAF and MEK inhibitors.

In the updated phase II ROAR trial, the objective response rate (ORR) was 56% with a median progression-free survival (PFS) of 6.7 months (12). The Japanese BELIEVE trial demonstrated a lower ORR of 33.3% and median PFS of 5.7 months in a cohort comprising 10 PTC patients and 5 with undifferentiated thyroid cancer, without distinction between poorly differentiated carcinoma (PDC) and ATC (20). In our series, progression-free survival for dabrafenib trametinib averaged 5.75 months (based on two evaluated patients), 5.75 for encorafenib–binimetinib (based on four evaluated patients), and 14 for vemurafenib–cobimetinib (based on one evaluated patient).

Superior outcomes were reported by the Korean group of Jeon et al. (2024), with a total ORR of 73.1% and differential PFS outcomes of 23.3 months for PTC and 4.5 months for undifferentiated histologies (21). Notably, this improved efficacy may be attributed to the study design, wherein out of the 27 patients two-thirds of patients received dabrafenib plus trametinib as first-line therapy, without prior exposure to cytotoxic chemotherapy or multiple kinase inhibitors. An additional small phase 2 trial including 22 patients, of whom 17 had differentiated thyroid cancer and 9 ATC, found that encorafenib and binimetinib achieved an ORR of 47.1% in the differentiated subgroup and 54.5% overall (95% CI 32.2–75.6), with partial responses in 12 patients and stable disease in 10 (22). Grade 3 adverse events occurred in 27.3%, with no grade 4 or 5 events, highlighting a modest safety profile (22).

Case 1 illustrates the therapeutic potential of BRAF-directed therapy in ATC, historically associated with dismal prognosis (4, 43). The use of BRAF-targeted therapy in this case aligns with recent advancements in ATC treatment, offering a potential avenue for improved outcomes in this historically difficult-to-treat malignancy (26, 27, 29, 44). Treatment with BRAF+MEK inhibitors as well as the initiation of chemoradiation therapy not only saved the patient from undergoing total laryngectomy but also made the tumor operable with the opportunity of achieving clear surgical margins. Unfortunately, the tumor recurred and the patient refused further treatment even though the last pathology confirmed a combined positivity score of 80.

In case 3, BRAF–MEK inhibition demonstrated intracranial activity in brain metastases, consistent with literature reporting adequate central nervous system penetration over multiple kinase inhibitores (45). Although lenvatinib is considered as the first-line treatment for RAI-refractory PTC (33), the use of BRAF and MEK inhibitors is often preferred in the immediate postoperative period following major surgery because of the risk of impaired wound healing (46). This consideration was the primary rationale for selecting BRAF and MEK inhibitor regimen in case 4, after the patient had undergone tracheal resection.

These cases underscore the necessity of a multimodal, individualized approach to advanced thyroid cancer. The integration of surgery, radiation, radioiodine, and targeted systemic therapy optimizes disease control, while molecular profiling has become indispensable in guiding precision treatment. BRAF and MEK inhibition represents a major therapeutic advancement; however, toxicity management, treatment sequencing, and the emergence of resistance remain significant challenges. This case series highlights both the progress achieved and the unmet needs in managing advanced thyroid malignancies. Continued clinical investigation and translational research are essential to refine patient selection, enhance tolerability, and improve long-term outcomes in this complex disease spectrum.