Palliative neck radiation therapy (RT) in combination with lenvatinib/pembrolizumab (L/P) in BRAF wild-type anaplastic thyroid cancer (BRAF-WT ATC).

6117 Background: BRAF-WT ATC carries a poor prognosis due to limited effective therapies and rapid, often fatal locoregional (LR) progression. Although L/P has shown some efficacy, response rates remain modest (36-52%). Prior studies have shown that complete surgical resection of the primary tumor significantly improves overall survival (OS). Methods: We retrospectively reviewed patients with BRAF-WT ATC treated with palliative neck RT (PNRT, ≤45 Gy) administered five days before to 21 days after first-line L/P, between January 2016 and August 2025. Primary objective was to evaluate the efficacy and safety of PNRT combined with L/P. Primary endpoints were progression-free survival (PFS), locoregional PFS (LPFS), and OS, defined from RT start, and estimated using Kaplan-Meier method. Secondary endpoints were overall response rate (ORR) and neck response per RECIST v1.1, changes in surgical morbidity assessed by the Thyroid Neck Morbidity and Complexity (TNMC) score, and proportion of patients proceeding to surgery. Results: Twenty-six patients met inclusion criteria. Median age was 66 years (range, 36-82) and 14 were male (54%). 23/26 (88%) had stage IVC disease. 21/26 (81%) received ‘Quadshot’ regimen (14Gy in 4 fractions), two 20 Gy in 5 fractions and three 30 Gy in 10 fractions. Median time from RT to L/P start was 2 days (range, –4 to 21). Median follow-up was 18.5 months (95% CI, 11.7-25.4). After PNRT and L/P, ORR was 72%, and 72% achieved a complete or partial response in the neck. Median OS and PFS were 10.0 (95% CI, 3.4-16.7) and 7.6 (95% CI, 4.4-10.8) months respectively. Median LPFS was not reached. Median TNMC score (0-4 scale, 4=unresectable) decreased from 4 (range, 2-4) at baseline to 3 (range, 0-4) at time of best response with a mean reduction of 1 point (range, 0-3). Ten patients (38%) proceeded to R0/R1 neck surgery after a median of 5.4 months (range, 1.6-9.5) from RT, with absence of residual ATC in the surgical specimens in 70% (7/10). OS and PFS were significantly longer in patients who underwent surgery compared with those who did not, with median OS 22.8 vs 6.1 months (p=0.002) and median PFS 12.7 vs 3.9 months (p=0.034). Seventeen patients (68%) had disease recurrence/progression: 1 LR, 10 distant, and 6 both LR and distant. All but one (6/7) LR recurrences were in patients who did not undergo surgery. PNRT combined with L/P was well tolerated, with most adverse events grade ≤ 2. One patient had a fistula 3 months after RT requiring emergency tracheostomy. Conclusions: Palliative neck RT combined with L/P for BRAF-WT ATC appears safe and may improve surgical resectability in patients with initially unresectable disease or high baseline surgical morbidity. Patients who proceeded to neck surgery had high pathologic complete response rate (70%) and significantly prolonged OS and PFS with low rate of locoregional relapse.