Abstract
IntroductionMultikinase inhibitor (MKI) treatments have shown efficacy in progressive radioiodine refractory thyroid cancers (RAIR-TC), but most patients experienced substantial adverse effects. This randomised multicentric study investigated intermittent versus continuous pazopanib administration. Patients and methodsThe PAZOTHYR study included RAIR-TC patients with progressive disease in the last 12 months, who may have received one prior MKI. RAIR-TC patients received pazopanib for 6 months, and patients with stable disease or tumour response were randomly assigned (1:1) to receive continuous (CP) or intermittent (IP) pazopanib until progression. The primary end-point was time to treatment failure (TTF) defined as the time from randomisation to permanent discontinuation of pazopanib, due to any cause. One hundred randomised patients were needed to demonstrate an increase from 50% (CP) to 70% (IP) (hazard ratio (HR) 0.515, 80% power) in the rate of patients still under treatment 6 months (6m-SuT) post-randomisation. Secondary end-points included the overall response rate (ORR), progression-free survival (PFS) under pazopanib and safety. ResultsRAIR-TC patients (168) enrolled from June 18, 2013 to January 16, 2018, received 6-month pazopanib treatment and showed 35.6% (95% CI 28.2–43.6) best response rate and 89.4% (83.5–93.7) disease control rate. One hundred patients were randomised (IP:50; CP:50). With a median follow-up of 31.3 months, median TTF was not statistically different between arms (IP:14.7, 95% confidence interval (CI) 9.3–17.4; CP:11.9, 95% CI 7.5–15.6) months (HR 0.79, 0.49–1.27). 6m-SuT rates were similar (IP:80% 66.0–88.7%; CP:78% 63.8–87.2%). Median PFS under pazopanib were not statistically different (IP:5.7 4.8–7.8; CP: 9.2 7.3–11.1) months (HR 1.36, 0.88–2.12). Pazopanib-related adverse events grade 3–4 occurred in 36 (IP: 19, 38%; CP: 17, 34%) randomised patients. Seven pazopanib-related deaths occurred. ConclusionsIntermittent administration of pazopanib did not demonstrate significant superiority in efficacy or tolerance compared with continuous treatment. An intermittent administration scheme cannot be recommended outside clinical trials.This study was registered with ClinicalTrial.gov, number NCT01813136.
Highlights
Multikinase inhibitor (MKI) treatments have shown efficacy in progressive radioiodine refractory thyroid cancers (RAIR-TC), but most patients experienced substantial adverse effects
As adverse events (AEs) leading to dose interruptions, dose reduction and treatment discontinuation are frequently reported with MKIs [13,14,17e19], we investigated intermittent administration of pazopanib to overcome early treatment permanent discontinuation, globally extend the time to treatment failure (TTF) and improve the clinical outcome in patients with RAIR-TC
We described the response to pazopanib treatment before randomisation, including the objective response rate defined as the proportion of patients with CR or PR as the best response calculated from the date of inclusion to the date of randomisation and the disease control rate defined as the proportion of patients with CR, PR or stable disease (SD) as the best overall response from the date of inclusion to the date of randomisation
Summary
Multikinase inhibitor (MKI) treatments have shown efficacy in progressive radioiodine refractory thyroid cancers (RAIR-TC), but most patients experienced substantial adverse effects. This randomised multicentric study investigated intermittent versus continuous pazopanib administration. Patients and methods: The PAZOTHYR study included RAIR-TC patients with progressive disease in the last 12 months, who may have received one prior MKI. RAIR-TC patients received pazopanib for 6 months, and patients with stable disease or tumour response were randomly assigned (1:1) to receive continuous (CP) or intermittent (IP) pazopanib until progression. Results: RAIR-TC patients (168) enrolled from June 18, 2013 to January 16, 2018, received 6month pazopanib treatment and showed 35.6% (95% CI 28.2e43.6) best response rate and 89.4% (83.5e93.7) disease control rate. The first two studies investigating sorafenib and lenvatinib led to FDA and EMA approval for treatment of progressive RAIR-TC [13,14], and apatinib is currently subject to approval by the Chinese authorities in the same indication [15]
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