Pazopanib Plus Neoadjuvant Chemoradiotherapy Boosts Advanced STS Response Rate

Author: By Lynda Williams, Senior medwireNews Reporter

medwireNews: Phase II study findings suggest that use of the multitargeted tyrosine kinase inhibitor pazopanib may improve the rate of pathological response for adults and children undergoing neoadjuvant chemoradiotherapy for advanced soft tissue sarcoma (STS).

The ARST1321 investigators describe their trial as “the first collaborative prospective study by paediatric and adult cancer consortia in soft tissue sarcoma to evaluate a novel therapeutic approach in patients across the entire age spectrum.”

Patients with a new diagnosis of trunk or extremity chemotherapy-sensitive STS larger than 5 cm in diameter, with an intermediate or high grade, were randomly assigned to receive ifosfamide and doxorubicin plus 45 Gy radiation alone or alongside oral pazopanib before resection at week 13.

Adults (≥18 years) were given pazopanib 600 mg/day while younger participants were given pazopanib 350 mg/m² once daily, and treatment was withheld immediately before and after resection, the researchers explain.

At the planned second interim analysis, 58% of the 24 patients given pazopanib had achieved a 90% or greater pathological response at week 13, after a median follow-up of 0.8 years, compared with 22% of the 18 controls after a median 1.0 year of follow-up. Progressive disease before surgery at week 13 occurred in 4% of the pazopanib and 22% of the controls.

The 83.8% confidence interval for the difference in pathological response ranged from 16.5% to 55.8% and excluded 0, and enrolment into the study was therefore halted, report Aaron Weiss, from Maine Medical Center in Portland, USA, and co-authors in The Lancet Oncology.

“The notable difference in pathological response rates between the two treatment groups reported here supports that addition of pazopanib to chemoradiotherapy induces tumour response to a much greater degree than chemoradiotherapy alone”, they write.

While suggesting that pazopanib and chemoradiotherapy might offer “a highly active and feasible combination” for advanced STS, the team emphasizes that “[i]t will be important to determine whether greater pathological response rate will translate into improved patient local control and survival.”

A partial or better radiographical response at week 13 before surgery occurred in a comparable 52% of 27 assessed pazopanib-treated patients and 58% of 24 controls, with progressive disease reported for 4% and 8%, respectively.

Safety analysis of 37 pazopanib-treated patients indicated the most common grade 3–4 adverse events were leukopenia (43%), neutropenia (41%) and febrile neutropenia (41%), while 9% of 35 controls each developed grade 3–4 neutropenia and febrile neutropenia. Adverse events were comparable in the adult and paediatric patient groups but 14% of pazopanib-treated patients discontinued therapy for drug-related toxicity versus none of the controls, the researchers add.

“We anticipate that the findings of this study might change the approach to advanced, unresected soft tissue sarcomas in children and adults and encourage additional joint paediatric and adult studies in soft tissue sarcoma and other diseases that extend across age boundaries in the future”, the team concludes.

Reference

Weiss AR, Chen Y-L, Scharschmidt TJ, et al. Pathological response in children and adults with large unresected intermediate-grade or high-grade soft tissue sarcoma receiving preoperative chemoradiotherapy with or without pazopanib (ARST1321): a multicentre, randomised, open-label phase 2 trial. Lancet Oncol; Advance online publication 20 July 2020. https://doi.org/10.1016/S1470-2045(20)30325-9