Dual Immune Checkpoint Inhibition in Patients With Aggressive Thyroid Carcinoma: A Phase 2 Nonrandomized Clinical...

Area of Science:

• Oncology
• Immunotherapy
• Thyroid Cancer Research

Background:

• Aggressive thyroid carcinomas, including radioiodine-refractory differentiated thyroid carcinoma (RAIR DTC), medullary thyroid carcinoma (MTC), and anaplastic thyroid carcinoma (ATC), have poor prognoses and limited treatment options.
• Immune profiles vary across thyroid cancer subtypes, suggesting potential susceptibility to immune checkpoint inhibitors.

Purpose of the Study:

• To evaluate the efficacy and safety of combined nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) in patients with aggressive thyroid carcinoma.
• To assess response rates, progression-free survival, overall survival, and identify potential biomarkers.

Main Methods:

• Phase 2 nonrandomized clinical trial involving patients with RAIR DTC, with exploratory cohorts for MTC and ATC.
• Patients received intravenous nivolumab (3 mg/kg every 2 weeks) and ipilimumab (1 mg/kg every 6 weeks) until disease progression or intolerable toxicity.
• Objective response rate (ORR) per RECIST v1.1 was the primary endpoint for RAIR DTC.

Main Results:

• The study did not meet its primary endpoint in the RAIR DTC cohort, with an ORR of 9.4%. However, clinical benefit rates were higher in specific subtypes like oncocytic (83.3%) and poorly differentiated (40%) DTC.
• The exploratory anaplastic thyroid carcinoma (ATC) cohort showed an ORR of 30.0% and a clinical benefit rate of 50.0%. No responses were observed in the MTC cohort.
• The safety profile was consistent with previous studies of dual immune checkpoint inhibition. NRAS mutations were associated with worse outcomes, while BRAF V600E was not.

Conclusions:

• Dual immune checkpoint inhibition demonstrated limited clinical activity in RAIR DTC and does not support further investigation in non-biomarker-selected DTC.
• The observed activity in ATC suggests this approach may merit further evaluation in this aggressive thyroid cancer subtype.
• Biomarker analysis indicated NRAS mutations may predict poorer outcomes in aggressive thyroid cancer treated with immunotherapy.