The STELLAR trial: a phase II/III randomized trial of high-dose, intermittent sunitinib in patients with recurrent glioblastoma

Jorien B E Janssen ^1,#, Cyrillo G Brahm ^2,#, Chantal M L Driessen ³, Janine Nuver ⁴, Mariette Labots ⁵, Mathilde C M Kouwenhoven ⁶, Esther Sanchez Aliaga ⁷, Roelien H Enting ⁸, Jan Cees de Groot ⁹, Annemiek M E Walenkamp ¹⁰, Myra E van Linde ¹¹, Henk M W Verheul ^12,13,✉

Brain Commun. 2024 Jul 30;6(4):fcae241. doi: 10.1093/braincomms/fcae241

Abstract Previously, the tyrosine kinase inhibitor sunitinib failed to show clinical benefit in patients with recurrent glioblastoma. Low intratumoural sunitinib accumulation in glioblastoma patients was reported as a possible explanation for the lack of therapeutic benefit. We designed a randomized phase II/III trial to evaluate whether a high-dose intermittent sunitinib schedule, aimed to increase intratumoural drug concentrations, would result in improved clinical benefit compared to standard treatment with lomustine. Patients with recurrent glioblastoma were randomized 1:1 to high-dose intermittent sunitinib 300 mg once weekly (Q1W, part 1) or 700 mg once every two weeks (Q2W, part 2) or lomustine. The primary end-point was progression-free survival. Based on the pre-planned interim analysis, the trial was terminated for futility after including 26 and 29 patients in parts 1 and 2. Median progression-free survival of sunitinib 300 mg Q1W was 1.5 months (95% CI 1.4–1.7) compared to 1.5 months (95% CI 1.4–1.6) in the lomustine arm (P = 0.59). Median progression-free survival of sunitinib 700 mg Q2W was 1.4 months (95% CI 1.2–1.6) versus 1.6 months (95% CI 1.3–1.8) for lomustine (P = 0.70). Adverse events (≥grade 3) were observed in 25%, 21% and 31% of patients treated with sunitinib 300 mg Q1W, sunitinib 700 mg Q2W and lomustine, respectively (P = 0.92). To conclude, high-dose intermittent sunitinib treatment failed to improve the outcome of patients with recurrent glioblastoma when compared to standard lomustine therapy. Since lomustine remains a poor standard treatment strategy for glioblastoma, innovative treatment strategies are urgently needed.

Keywords: glioblastoma, tyrosine kinase inhibitors, sunitinib, high-dose, lomustine

Abstract

-연구 배경-

• 기존 수니티닙 치료는 재발성 교모세포종에서 임상적 유익성 입증 실패

• 혈액뇌장벽으로 인한 종양 내 약물 농도 부족이 원인일 가능성

• 고용량 간헐 투여로 종양 내 약물 농도를 높여 치료 효과를 개선하고자 함

-연구 설계-

• 연구 유형: 다기관, 공개, 무작위배정 제2/3상 임상시험

• 대상: 재발성 교모세포종 환자

• 시험군: 수니티닙 300mg 주 1회 또는 700mg 2주마다 1회

• 대조군: 로무스틴

• 1차 평가변수: 무진행생존기간(PFS)

-주요 결과-

평가변수	수니티닙	로무스틴	P값
중앙 PFS, 300mg 주 1회	1.5개월	1.5개월	0.59
중앙 PFS, 700mg 2주마다	1.4개월	1.6개월	0.70
3등급 이상 이상반응	25% / 21%	31%	0.92

* 수니티닙 300mg 주 1회 투여군 25%, 700mg 2주마다 투여군 21%입니다.

-결론-

• 고용량 간헐적 수니티닙 투여에도 무진행생존기간 개선 실패

• 사전 계획된 중간분석에서 유효성 부족으로 임상시험 조기 종료

• 재발성 교모세포종의 치료 성적을 개선할 새로운 치료 전략 필요

Figure 2. Progression-free survival and overall survival. Progression-free survival (A) and overall survival (B) in part 1. Part 1: lomustine n = 14, high-dose intermittent sunitinib n = 12. Progression-free survival (C) and overall survival (D) in part 2. Part 2: lomustine n = 15, high-dose intermittent sunitinib n = 14. PFS, progression-free survival; HR, hazard ratio; OS, overall survival.