The FLAIL-C Phase 2 trial tested whether combining anti-PD-1 immunotherapy with the tyrosine kinase inhibitor anlotinib could improve outcomes for patients with advanced, unresectable chondrosarcoma. Seventy patients participated, including 32 with dedifferentiated chondrosarcoma, 8 with Grade III conventional disease, and 30 with Grade II disease. Patients received either anlotinib alone or the combination therapy, with more aggressive dedifferentiated cases increasingly assigned to the combination arm.
The combination improved progression-free survival compared with anlotinib alone, increasing median progression-free survival from 5.6 to 7.2 months and nearly doubling the 6-month progression-free rate from 31.4% to 60%. Objective responses were higher with the combination, which produced one complete response and seven partial responses versus two partial responses for monotherapy. Patients with dedifferentiated chondrosarcoma saw the greatest benefit, with median progression-free survival rising from 3.8 to 7.0 months and median overall survival from 7.4 to 11.5 months. Among six patients who crossed over to the combination after progressing on anlotinib alone, two achieved partial responses.
Exploratory biomarker analysis showed that responders had higher levels of tumor-infiltrating memory T cells and carried IDH1 or IDH2 mutations. The oncometabolite D-2-HG, produced by these mutations, correlated with suppressive myeloid cells. For conventional chondrosarcoma, anlotinib alone produced a median progression-free survival of 6.0 months and overall survival up to 20.1 months. These findings suggest that adding anti-PD-1 therapy is promising for aggressive dedifferentiated chondrosarcoma, and memory T-cell infiltration and IDH mutations may help identify patients most likely to benefit.