Cabozantinib a new SoC for previously treated RAI-refractory DTC?

In individuals with radio-iodine-refractory differentiated thyroid cancer (RAI-refractory DTC) who have progressed during/after prior VEGFR-targeted therapy, the VEGFR2/MET/AXL/RET inhibitor cabozantinib showed a significant progression-free survival (PFS) benefit, according to findings of the phase III COSMIC-311 trial presented at ASCO 2021.

 

“RAI-refractory DTC patients who progress on prior VEGF-receptor-targeted therapies have a poor prognosis and no standard of care (SoC),” said Dr Marcia Brose from the University of Pennsylvania, Philadelphia, Pennsylvania, US, during her virtual presentation. Early-phase trials have demonstrated the clinical activity of cabozantinib in this setting. [Thyroid 2014;24:1508-1514; J Clin Oncol 2017;35:3315-3321; J Clin Oncol 2018;36(suppl 15):6088]

 

The team sought to evaluate the efficacy and safety of cabozantinib in 187 RAI-refractory DTC patients (median age 66 years, 45 percent male) who have progressed during or following treatment with ≤2 prior VEGFR inhibitors*. They were randomized 2:1 to receive cabozantinib 60 mg QD or placebo. Placebo recipients may cross over to open-label cabozantinib upon disease progression per BIRC**. Primary endpoints were objective response rate (ORR; first 100 randomized patients) and PFS (all patients). Median follow-up was 6.2 months. [ASCO 2021, abstract 6001]

 

ORR was greater with cabozantinib vs placebo (15 percent vs 0 percent). However, this did not achieve the prespecified statistical significance for ORR (p=0.028).

 

Disease control rate was also higher with cabozantinib vs placebo (60 percent vs 27 percent), as was post-baseline tumour reduction rate (76 percent vs 29 percent) . “Of interest [was the] low rate of progressive disease as best response in the cabozantinib arm,” noted Brose.

 

In terms of PFS, cabozantinib significantly outdid placebo (median, not reached vs 1.9 months; hazard ratio [HR], 0.22; p<0.0001) during the planned interim analysis and met the study’s other primary endpoint. “The [Kaplan-Meier] curves show an early and wide separation … The median PFS in the placebo arm [suggests] that this study had enrolled a patient population with a poor prognosis,” explained Brose.

 

“The PFS [for] placebo is important because it indicates that, unlike patients prior to initiating first-line therapy that may have indolent growth rates, those following one or two lines of therapy are much more aggressive and need treatment to be initiated quickly,” she continued.

 

The interim PFS is considered the final PFS, as the first planned interim PFS analysis was positive and rejected the null hypothesis, noted Brose. “Meeting one or both primary endpoints would indicate that the study successfully met its primary goal.”

 

The PFS benefit was also observed across prespecified subgroups such as prior lenvatinib use (HRs, 0.26 [yes] and 0.11 [no]) and age (HRs, 0.16 and 0.31 [≤65 and >65 years, respectively).

 

A favourable overall survival trend was also seen in favour of cabozantinib over placebo (HR, 0.54). Despite potential confounding from the placebo-cabozantinib cross over, there was a clear trend for survival benefit favouring cabozantinib, said Brose, also noting an early separation of the Kaplan-Meier curves.

 

Treatment-emergent adverse event (AE) rates (any grade) were higher with cabozantinib vs placebo, the most common being diarrhoea (51 percent vs 3 percent), hand/foot skin reaction (46 percent vs 0 percent), and hypertension (28 percent vs 5 percent).

 

There were also more cabozantinib vs placebo recipients who had grade 3/4 AEs (57 percent vs 26 percent), dose reductions due to AEs (57 percent vs 5 percent), and treatment discontinuations due to AEs (5 percent vs 0 percent). No treatment-related deaths were reported in either study arm.

 

“The safety profile was consistent with the known profile of cabozantinib in solid tumours … AEs were also managed with supportive care, dose holds, and dose modifications,” said Brose.

 

Taken together, despite the higher percentage of bone and liver lesions – which are associated with poor prognosis in RAI-refractory DTC – among cabozantinib recipients, cabozantinib still demonstrated superior efficacy over placebo, she added. “[As such, our findings suggest that] cabozantinib may represent a new SoC [in this patient setting].”