Nivolumab plus lenvatinib for unresectable anaplastic thyroid cancer: Results of the phase 2 NAVIGATION study.

6021 Background: Anaplastic thyroid cancer (ATC) is one of the most aggressive and lethal malignancies, characterized by limited treatment options and a dismal prognosis. Although lenvatinib has shown some efficacy, its impact remains modest, and no standard systemic therapy has been established for unresectable ATC—particularly for BRAF wild-type (BRAF-negative) disease. Methods: The NAVIGATION study (NCT05696548) is an open-label, multicenter, phase 2 trial evaluating the combination of nivolumab and lenvatinib in patients with unresectable ATC. As primary endpoints, Step 1 assessed dose-limiting toxicities (DLTs), while Step 2 evaluated the objective response rate (ORR) by independent radiological central review (IRCR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), best overall response, disease control rate, clinical benefit rate, safety, and quality of life. Eligible patients had histologically confirmed unresectable ATC, measurable disease per RECIST v1.1, adequate organ function, an ECOG performance status of 0–1, and a life expectancy of over 90 days. Lenvatinib was administered orally at 24 mg once daily, and nivolumab intravenously at 240 mg every two weeks, continued until disease progression or unacceptable toxicity. The Step 2 sample size of 48 patients was determined based on a historical ORR of 23.5% and an expected ORR of 44%, providing 80% power with a two-sided α of 0.05, accounting for a 20% dropout rate. ORR was evaluated in the full analysis set of patients with ATC confirmed by independent pathological central review (IPCR). Results: Between December 2019 and February 2024, 51 patients were enrolled across 10 sites in Japan (Step 1: n=3; Step 2: n=48). No DLTs were observed in Step 1. In Step 2, the median age was 69.5 years (range, 43-89); 46 patients had metastatic disease, 40 had prior history of surgery, and 42 were pathologically confirmed as ATC by IPCR. The ORR by IRCR was 47.6% (95% CI: 33.4-62.3), meeting the primary endpoint. At a median follow-up of 11.6 months, the median duration of response was 12.9 months (95% CI: 6.28 -27.6), median PFS was 5.6 months (95% CI: 5.5-9.1), and median OS was 14.7 months (95% CI: 10.1-29.2). The 1-year OS rate was 56.9%. In Step 2, grade 3 or 4 treatment-related adverse events (TRAEs) occurred in 38/48 patients (79.2%), serious TRAEs in 20 (41.7%), and there was one treatment-related death (2.1%). Conclusions: Nivolumab plus lenvatinib demonstrated a clinically meaningful ORR, meeting the primary endpoint. The combination also achieved favorable PFS and OS with manageable toxicity under appropriate supportive care, suggesting that this regimen may represent a new treatment option for patients with unresectable ATC. Clinical trial information: NCT05696548 .