Nivolumab and Ipilimumab Show Promise in Aggressive Thyroid Carcinoma Subtypes
核心洞察
A phase II study evaluated nivolumab plus ipilimumab in aggressive thyroid cancers, including radioiodine-refractory differentiated, medullary, and anaplastic subtypes.
The combination showed limited efficacy in radioiodine-refractory differentiated thyroid cancer (DTC), failing to meet the primary endpoint, but some responses were seen in oncocytic and poorly differentiated DTC.
Anaplastic thyroid carcinoma (搜索) (ATC) patients demonstrated a 30% objective response rate, suggesting potential benefit in this aggressive subtype, warranting further investigation.
A phase II study has explored the efficacy of nivolumab combined with ipilimumab in patients with aggressive thyroid carcinoma (搜索). The research, published in JAMA Oncology, assessed the dual immune checkpoint inhibition strategy across various thyroid cancer subtypes, revealing potential benefits in specific groups. The study was conducted at a single institution, Dana-Farber Cancer Institute.
Study Design and Patient Population
The trial enrolled 49 evaluable patients between October 2017 and May 2019. The cohort included 32 patients with radioiodine-refractory differentiated thyroid carcinoma (搜索) (DTC), 7 in an exploratory cohort with medullary thyroid carcinoma (搜索) (MTC), and 10 in an exploratory cohort with anaplastic thyroid carcinoma (搜索) (ATC). Patients received nivolumab at 3 mg/kg every 2 weeks and ipilimumab at 1 mg/kg every 6 weeks until disease progression, intolerable adverse events, or a maximum of 2 years. The primary outcome was objective response rate in the radioiodine-refractory DTC group.
Efficacy Results
In the radioiodine-refractory DTC group, objective responses (all partial) were observed in 3 of 32 patients (9.4%, 95% CI = 2.8%–28.5%), not meeting the predefined efficacy criterion. However, notable responses were seen in specific DTC subtypes, with 2 of 6 patients (33%) with oncocytic carcinoma (搜索) and 1 of 5 (20%) with poorly differentiated DTC exhibiting objective responses. The clinical benefit rate in the radioiodine-refractory DTC group was 62.5%, including 83.3% among those with oncocytic carcinoma and 40% among those with poorly differentiated DTC.
In the exploratory ATC group, 3 of 10 patients (30.0%, 95% CI = 6.7%–65.2%) achieved objective responses (all partial), with a clinical benefit rate of 50%. No objective responses were observed in the MTC group, which had a clinical benefit rate of 28.6%.
Biomarker Analysis
Whole-exome sequencing data from 19 patients with radioiodine-refractory DTC and 9 with ATC revealed that the presence of NRAS (搜索) variants—but not BRAF (搜索) V600E variants—was associated with significantly poorer progression-free survival (HR = 4.8, 95% CI = 1.6–14.3) and overall survival (HR = 7.9, 95% CI = 1.8–35.7). Notably, no patients with NRAS variants experienced an objective response.
Safety Profile
Treatment-related grade 3 and 4 adverse events occurred in 28.5% and 8.2% of patients, respectively. The most common grade 3 event was increased lipase (12%), and the most common grade 4 event was also increased lipase (6%). No treatment-related deaths were reported.
Clinical Implications
The study's investigators concluded that while the trial did not meet its primary endpoint in the radioiodine-refractory DTC population, the observed activity in ATC warrants further evaluation. The identification of NRAS (搜索) variants as a potential predictive biomarker could also help refine patient selection for future trials. According to Dr. Kartik Sehgal, the corresponding author, the signal observed in ATC may merit further evaluation.