Adjuvant bevacizumab as treatment for melanoma patients at high risk of recurrence: Final results for the AVAST-M trial.

9501 Background: Bevacizumab (Bev) is a recombinant humanised monoclonal antibody to vascular endothelial growth factor (VEGF) shown to improve survival in several advanced solid tumours. As VEGF is a relevant target in melanoma, AVAST-M aimed to evaluate the role of Bev in melanoma patients at high risk of recurrence. Methods: AVAST-M (ISRCTN81261306) is a randomised phase III trial evaluating single agent Bev (7.5mg/kg IV 3 weekly for 1 year) as adjuvant therapy after resection of AJCC stage IIB, IIC and III cutaneous melanoma compared to standard observation (Obs). 1320 patients were needed to detect 8% differences in 5 year overall survival (OS) rate from 40% to 48%; 85% power, 5% alpha level. Primary endpoint was OS; secondary endpoints included disease free interval (DFI), distant-metastasis free interval (DMFI). BRAF and NRASmutation status were obtained in 682 patients in a translational sub-study. Results: From July 2007 to March 2012, 1343 patients were recruited (671 to Bev; 672 to Obs). 56% were male, median age was 56 years (range 18-88 years), 14% were stage IIIA and 59% were stage IIIB/C. With 6 years median follow-up, 505 (38%) patients had died (251 [37%] on Bev; 254 [38%] on Obs); 699 (52%) patients had recurred (335 [50%] on Bev, 369 [55%] on Obs). OS at 5 years was 64% on Bev versus 63% on Obs (Hazard ratio [HR] 0.99; 95% confidence interval [CI] 0.84-1.18, p=0.96). At 5 years, 51% were disease free on Bev versus 45% on Obs (HR 0.85; 95% CI 0.74-0.99, p=0.04) and 59% were distant metastasis free on Bev versus 54% on Obs (HR 0.91; 95% CI 0.77-1.07, p=0.24). A BRAF V600 mutation was found in 44% of tumours assessed; 20% were NRAS mutant. BRAF mutant patients treated with Bev tended to have better DFI (HR=0.79 95% CI 0.58-1.08, p=0.14) and OS (HR=0.79; 95% CI 0.55-1.13, p=0.20); this was not evident for BRAF WT. NRAS mutant patients tended to have worse DFI (HR=1.39; 95% CI 1.03-1.88; p=0.03) and OS (HR=1.18; 95% CI 0.85-1.62, p=0.20) than NRASWT patients. Conclusions: This large, multi-centre trial of melanoma patients at high risk of recurrence has shown that adjuvant Bev improves DFI, but this does not translate into an overall survival benefit. Funding:Cancer Research UK; drug supplied by Roche Products Ltd. Clinical trial information: ISRCTN81261306.