LBA20 - Vandetanib plus fulvestrant versus placebo plus fulvestrant after relapse or progression on an aromatase inhibitor in metastatic ER positive breast cancer (FURVA): A randomised, double-blind, placebo-controlled, phase II trial

Background

Vandetanib is a multi-kinase inhibitor of VEGFR, EGFR and RET. Preclinical data suggests an activated RET pathway can contribute to endocrine resistance. The FURVA trial investigated whether the addition of vandetanib (v) to fulvestrant (f) improved progression-free survival in patients with aromatase inhibitor (AI) resistant advanced breast cancer.

Methods

FURVA is an investigator-led, double-blind, placebo-controlled, randomised phase II trial. AI resistant patients were recruited from 19 UK sites and randomly assigned (1:1) to fulvestrant 500mg (day 1 and 15 of cycle 1 and day 1 only of subsequent 28 day cycles) with either vandetanib 300mg (f+v) or placebo (f+p) daily until disease progression, unacceptable toxicity or withdrawal of consent. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), safety, and the influence of RET signalling pathway component expression (e.g. total RET immunostaining) on vandetanib activity.

Results

Between 20 Apr 2015 and 30 Oct 2017, 165 patients were randomised to f+v (n=80) or f+ p (n=85). In the Intention-to-treat analysis, after 138 events, median PFS was 5.5 months (m) for f+v compared to 5.5m for f+p (Hazard Ratio (HR) 0.88; 95% CI: 0.62 to 1.23; p = 0.22). Median OS was 19.5m for f+v compared to 19.9m for f+p (HR=0.92; 95% CI: 0.60 to 1.42; p = 0.71). Unexpectedly, high total RET protein expression was associated with a significant PFS advantage of 8.87m vs 3.94m in the low RET group (HR 0.493: 95% CI 0.32 to 0.77; p=0.002), which was independent of treatment arm. This was supported by an OS advantage 21.95m vs 18.04m (HR 0.584; 95% CI 0.34 to 1.00; p=0.051). High RET expression did not predict an advantage of vandetanib use. Toxicity data will be presented.

Conclusions

The trial has shown that addition of vandetanib to fulvestrant does not improve PFS significantly. However, in the pre-planned exploratory analysis, high total RET expression was significantly associated with improved PFS, suggesting RET may predict tumour sensitivity to fulvestrant in AI resistant disease. This finding would require further validation.

Clinical trial identification

No editorial assistance was provided by a third party in the writing of the abstract.

Editorial acknowledgement

Legal entity responsible for the study

Velindre University NHS Trust, Cardiff.

Funding

AstraZeneca, Cancer Research UK (CRUK).

Disclosure

T. Hickish: Full/Part-time employment, Medical Director: iQHealth Tech. D. Wheatley: Honoraria (institution), Travel/Accommodation/Expenses: Roche; Honoraria (institution): Lilly; Honoraria (institution): Novartis; Honoraria (institution): Amgen; Honoraria (institution): Daiichi Sankyo. All other authors have declared no conflicts of interest.