Final results of the multicenter, open-label, randomized phase II trial PAZOTHYR evaluating continuous versus intermittent administration of pazopanib in radio-iodine-refractory thyroid cancers (NCT01813136).

Abstract

6540 Background: Multikinase inhibitors (MKI) targeting angiogenesis, including pazopanib (P), have shown efficacy in progressive radioiodine refractory thyroid cancers (RAIR-TC) but are accompanied by adverse effects, leading to dose adjustments/interruptions. We aimed to investigate the efficacy and tolerance of a discontinuous scheme of pazopanib administration in this situation. Methods: This randomized phase II study enrolled RAIR-TC patients (pts) in first or second-line of MKI with documented disease progression within 12 months (m). After a 6-m pazopanib continuous induction phase, pts with stable disease (SD) or tumor response were randomly assigned in a 1:1 ratio to receive continuous pazopanib (CP) or intermittent pazopanib (IP) until progression and restart. They were stratified by best tumor response [stable disease vs. objective response] and prior MKI treatment [yes vs. no]). Primary endpoint was time to treatment failure (TTF) defined as time between randomization and permanent discontinuation of pazopanib (either for disease progression or intolerance); secondary endpoints included overall response rate (ORR), progression-free survival (PFS) and safety. Results: 168 pts (66.5 years median age; 51.8% female) were included and 100 pts randomized (CP: 50, IP: 50). The median number of metastatic sites was 2.0 (1-7) and 50 pts (29.8%) were pretreated with MKI. With a median follow-up of 31.3 m, we did not show any statistically significant difference in the TTF, 80% (66.0-88.7%)] of the pts being under P at 6 m after randomization in the IP arm versus 78% (63.8-87.2%) in the CP arm. Median TTF was 14.7 m 95% CI [9.3; 17.4] and 11.9 m 95% CI [7.5; 15.6] respectively (HR 0.79 [0.49-1.27]). The best response with P was 35.6% (95% CI [28.2; 43.6]) and the disease control rate was 89.4% 95% CI [83.5; 93.7]. Median time to progression under P was not statistically different between 2 arms (5.7m 95% CI [4.8;7.8] in the IP arm vs. 9.2m 95% CI [7.3;11.1] in the CP arm (HR 1.36 [0.88; 2.12]). 36/100 pts (36%) experienced pazopanib-related grade 3/4 AEs (CP:17; IP: 19) mainly represented by gastrointestinal disorders, hypertension, cardiac disorders and asthenia. Five pazopanib-related deaths were reported (CP:1;IP: 4). Conclusions: The intermittent administration of pazopanib study did not significantly demonstrate superiority in efficacy or tolerance over continuous treatment. Continuous administration of MKI remains the standard in RAIR-TC. Clinical trial information: NCT01813136 .