Author: By Lynda Williams, Senior medwireNews Reporter
medwireNews: Cabozantinib significantly improves progression-free survival (PFS) compared with placebo for patients with differentiated thyroid cancer (DTC) refractory to radioiodine therapy (RAI) and vascular endothelial growth factor receptor (VEGFR)-targeted multikinase inhibitors, suggest the COSMIC-311 trial findings.
The phase III study was presented at the 2021 ASCO Annual Meeting by Marcia Brose, from the University of Pennsylvania in Philadelphia, USA, who explained that RAI-refractory DTC patients who progress on multikinase inhibitors have a “poor prognosis and no standard of care”.
Following positive preliminary findings with the multikinase inhibitor cabozantinib in this patient population, the COSMIC-311 trial investigators recruited patients with locally advanced or metastatic RAI-refractory or ineligible DTC who had experienced radiographic progression after up to two VEGFR multikinase inhibitors, including at least one of lenvatinib or sorafenib.
The co-primary endpoint of a significant PFS benefit with cabozantinib 60 mg/day versus placebo was met at the planned interim analysis, with the curves showing “early and wide separation”, the presenter reported. Enrolment was consequently halted for the trial, she said.
The median PFS was unreached for the 125 cabozantinib-treated patients versus 1.9 months for the 62 placebo-treated controls, giving a significant hazard ratio (HR) of 0.22.
Marcia Brose highlighted the short duration of PFS in the control arm, which she said demonstrates the “poor prognosis” of patients who have aggressive disease after one or two lines of multikinase inhibitors and “need treatment to be initiated quickly.”
And PFS significantly favoured cabozantinib use in all the prespecified subgroups of patient age, prior use of sorafenib and lenvatinib, and number of prior VEGFR-targeted kinase inhibitors, the presenter said.
The objective response rate was 15% with cabozantinib versus 0% with placebo but the p value of 0.028 was above the prespecified threshold of 0.010 required to meet this co-primary endpoint, she reported.
All responses in the cabozantinib arm were partial and the median duration of response was unreached. Stable disease lasting at least 16 weeks was achieved by 45% of cabozantinib-treated patients and 27% of controls, giving disease control rates of 60% and 27%, respectively.
Marcia Brose explained that overall survival analysis was confounded by the permission for crossover from placebo to cabozantinib on disease progression. Nevertheless, after a median follow-up of 6.2 months, there was separation of the curves and “a clear trend for survival benefit” with cabozantinib, with a HR of 0.54, she said.
At the time of data cutoff, cabozantinib-treated patients had received treatment for a median 4.4 months versus 2.3 months for controls, with 89 patients continuing with blinded cabozantinib and 28 with placebo.
“Adverse events were consistent with the known safety profile of cabozantinib and were managed with supportive care, dose holds and dose modifications”, she said.
The most common any-grade treatment-emergent adverse events were diarrhoea, hand–foot skin reactions, hypertension and fatigue. Grade 3 adverse events occurred in 51% of cabozantinib-treated patients versus 23% of controls, grade 4 events in 6% and 3%, respectively, and there were no grade 5 treatment-related deaths.
“These results support cabozantinib as a potential new treatment option for previously treated RAI-refractory DTC”, Marcia Brose concluded.
Discussing the COSMIC-311 trial findings at the meeting session, Nicole Chau, from the University of British Columbia in Vancouver, Canada, described the PFS result as “noteworthy” and the disease control rate as “clinically meaningful for this heavily-pretreated population”.
The discussant noted that the US FDA has now granted breakthrough designation for second-line cabozantinib in RAI-refractory DTC and that some patients may also be suitable for genotype-directed therapy with TRK or RET inhibitors.
Nicole Chau concluded that the optimal sequence of these different therapies is “unclear”. She added that the development of validated biomarkers of treatment response and resistance to VEGFR inhibitors will “be increasingly important as we move beyond the targeted era of single-agent VEGFR multikinase inhibitors and evaluate combinations of VEGFR inhibitors with checkpoint inhibitors or dual checkpoint inhibitors.”
Brose MS, Robinson B, Sherman SI, et al. Cabozantinib versus placebo in patients with radioiodine-refractory differentiated thyroid cancer who have progressed after prior VEGFR-targeted therapy: Results from the phase 3 COSMIC-311 trial. J Clin Oncol 2021;39(suppl 15; abstr 6001). DOI: 10.1200/JCO.2021.39.15_suppl.6001
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