Cabozantinib Improves PFS in Patients with RAI-Refractory DTC

A phase 3 trial found cabozantinib offered improvement in progression-free survival (PFS) for patients with radioiodine (RAI) refractory differentiated thyroid cancer (DTC) who progressed after previous VEGFR-targeted therapy (J Clin Oncol 39, 2021).

In previous phase 1/2 studies, cabozantinib, an inhibitor of VEGFR2, MET, AXL, and RET, demonstrated clinical activity in patients with RAI-refractory DTC (Cabanillas 2017; Brose 2018). 

With this in mind, Marcia S. Brose, MD, PhD, Abramson Cancer Center, University of Pennsylvania, Philadelphia, and her team conducted this double-blind, phase 3 trial to evaluate the efficacy and safety of cabozantinib compared to a placebo in patients with RAI-refractory DTC who progressed during/after prior VEGFR-targeted therapy. 

To be eligible, patients with RAI-refractory DTC must have received prior lenvatinib or sorafenib treatment and progressed during or following treatment with ≤ two prior VEGFR inhibitors. Patients were randomized 2:1 to received cabozantinib (60mg once daily) or a placebo. Those in the placebo group could cross over to cabozantinib upon disease progression per blinded independent radiology committee (BIRC).

The primary endpoints included objective response rate (ORR) in the first 100 randomized patients and PFS in all randomized patients; both PFS and ORR were assessed by BIRC per RECIST v1.1.

There were 125 patients randomized to cabozantinib, 62 to placebo; 63% received prior lenvatinib treatment. The median follow-up was 6.2 months, and the trial met the primary endpoint of PFS, with cabozantinib demonstrating significant improvement over the placebo (HR 0.22, 96% CI 0.13–0.36; P < 0.0001) at the interim analysis.

The median PFS was 1.9 months for placebo but was not reached for cabozantinib. While ORR was 15% for cabozantinib vs. 0% for placebo (P = 0.0281), it did not meet the prespecified criteria for statistical significance (p < 0.01). 

Treatment-related adverse events (AEs) of any grade were higher in the cabozantinib vs. placebo arm. The most common were diarrhea (51% vs 3%), hand-foot skin reaction (46% vs 0%), hypertension (28% vs 5%), fatigue (27% vs 8%), and nausea (24% vs 2%). Furthermore, 57% of patients in the cabozantinib arm experienced grade 3/4 AEs, compared to 26% of those who received placebo. No treatment-related deaths occurred in either arm.

“[Cabozantinib] showed a clinically and statistically significant improvement in PFS over P in pts with RAI-refractory DTC after prior VEGFR-targeted therapy with no unexpected toxicities. [Cabozantinib] may represent a new standard of care in pts with previously treated DTC,” concluded Dr Brose et al.—Alexandra Graziano