Cabozantinib versus placebo in patients with radioiodine-refractory differentiated thyroid cancer after prior vascular endothelial growth factor receptor-targeted therapy (COSMIC-311): outcomes by BRAF status

Marcia Brose^1*Bhumsuk Keam²Jolanta Krajewska³Ana Hoff⁴Fernanda Vaisman⁵Chia-Chi Lin⁶Erika Hitre⁷Daniel W. Bowles⁸Bruce Robinson⁹Steven I. Sherman¹⁰Nuttapong Ngamphaiboon¹¹Xiang Guo¹²Andrew Simmons¹²Denise Williamson¹³Svetlana Andrianova¹⁴Nicholas Berry¹⁵Jaume Capdevila¹⁶

• ¹Sidney Kimmel Cancer Center, Jefferson Health Northeast, Philadelphia, United States
• ²Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
• ³Department of Nuclear Medicine and Endocrine Oncology, Maria Skłodowska-Curie National Research Institute of Oncology Gliwice Branch, Gliwice, Poland
• ⁴Department of Endocrinology, Instituto do Câncer do Estado de São Paulo, Universidade de São Paulo, São Paulo, Brazil
• ⁵Department of Endocrinology, Instituto Nacional de Câncer, Rio De Janeiro, Brazil
• ⁶Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
• ⁷Department of Medical Oncology, The Multidisciplinary Head and Neck Cancer Center, Országos Onkológiai Intézet, Budapest, Hungary
• ⁸Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, United States
• ⁹Department of Medicine, Royal North Shore Hospital, University of Sydney, Sydney, Australia
• ¹⁰Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center, Houston, United States
• ¹¹Department of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
• ¹²Department of Translational Medicine and Bioinformatics, Exelixis, Inc., Alameda, United States
• ¹³Department of Biostatistics, Exelixis, Inc., Alameda, United States
• ¹⁴Department of Late Phase Clinical Development, Exelixis, Inc., Alameda, United States
• ¹⁵Department of Medical Affairs, Exelixis, Inc., Alameda, United States
• ¹⁶Department of Medical Oncology, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), IOB Quiron-Teknon, Barcelona, Spain

Background: Cabozantinib is approved for previously treated radioiodine-refractory differentiated thyroid cancer (RAIR-DTC) based on improved progression-free survival (PFS) versus placebo in the COSMIC-311 study. The BRAFV600E mutation is common in DTC and is associated with poor prognosis. This planned exploratory analysis of COSMIC-311 reports outcomes by BRAF status. Methods: In this exploratory analysis, outcomes by BRAFwt (wild-type) or BRAFV600E status were evaluated in the COSMIC-311 phase 3 study in patients with RAIR-DTC who had previously received lenvatinib and/or sorafenib. Results: BRAF status was available for 106 of 258 patients enrolled in COSMIC-311; of these, 74 had BRAFwt and 27 had BRAFV600E. Cabozantinib prolonged PFS versus placebo in both the BRAFwt (hazard ratio [HR] 0.23 [95% CI 0.12-0.44]; median PFS, 11.1 versus 1.9 months) and BRAFV600E (HR 0.15 [95% CI 0.04-0.59]; median PFS, 9.2 versus 1.9 months) subgroups. While no responses were observed with placebo in both BRAF subgroups, objective response rates (ORRs) of 11% and 18% were observed with cabozantinib in the BRAFwt and BRAFV600Esubgroups, respectively. Among patients treated with cabozantinib, 68% of the BRAFwt group and 53% of the BRAFV600E group reported grade 3/4 treatment-emergent adverse events; the incidences were 17% and 50% in the corresponding groups treated with placebo. Conclusions: In this subgroup analysis of COSMIC-311, cabozantinib improved PFS and ORR versus placebo irrespective of BRAF mutation status. Thus, cabozantinib is an efficacious treatment option with a manageable safety profile for previously treated patients with RAIR-DTC, including those with BRAFV600E.