Bevacizumab and everolimus in the treatment of patients with metastatic melanoma

Abstract

BACKGROUND: In this phase 2 study, the activity and tolerability of the combination of bevacizumab, an inhibitor of angiogenesis, and everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), was evaluated in the treatment of patients with metastatic melanoma. METHODS: Patients with metastatic melanoma who had received up to 2 previous systemic regimens (chemotherapy and/or immunotherapy) were eligible. Previous treatment with angiogenesis or mTOR inhibitors was not allowed. All patients received bevacizumab at a dose of 15 mg/kg intravenously every 21 days and everolimus at a dose of 10 mg orally daily. Patients were re‐evaluated every 6 weeks; those with an objective response or stable disease (according to Response Evaluation Criteria in Solid Tumors [RECIST]) continued therapy until tumor progression or unacceptable toxicity occurred. RESULTS: Fifty‐seven patients with metastatic melanoma received a median of 4 treatment cycles (range, 1‐14+ cycles). Seven patients (12%) achieved major responses, whereas 33 patients (58%) were found to have stable disease at the time of first evaluation. The median progression‐free and overall survivals were 4 months and 8.6 months, respectively. Approximately 43% of patients were alive after 12 months of follow‐up. The treatment regimen was well tolerated by the majority of patients. CONCLUSIONS: The combination of bevacizumab and everolimus was found to have moderate activity and was well tolerated in the treatment of patients with metastatic melanoma. Further exploration of agents with these mechanisms of action is indicated, perhaps in combination with inhibitors of the mitogen‐activated protein kinase (MAPK) pathway. Cancer 2010. © 2010 American Cancer Society.

Phase I study of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumors

“…The MTD for everolimus in this combination was 5mg daily, lower than the FDA approved monotherapy dose of 10mg daily. It is also lower than other bevacizumab-everolimus combinations, suggesting that the addition of chemotherapy results in overlapping toxicity (Altomare et al , 2011; Bullock et al , 2011; Hainsworth et al , 2010a; Hainsworth et al , 2010b). Treatment-related toxicity was consistent with the known toxicity profiles of each of these agents when used separately.…”

“…It is also approved in combination with interferon α for the treatment of renal cell cancer (Escudier et al , 2007) and as a single agent for progressive glioblastoma (Vredenburgh et al , 2007). Multiple studies have reported that the combination of bevacizumab and everolimus is safe (Altomare et al , 2011; Bullock et al , 2011; Hainsworth et al , 2010a; Hainsworth et al , 2010b; Strickler et al , 2012; Vlahovic et al , 2012). Clinically significant toxicities include: fatigue, mucositis, hypertension, vomiting, diarrhea, proteinuria, fistula/abscess/perforation, and hemorrhage.…”

Nine-year change in statistical design, profile, and success rates of Phase II oncology trials

“…The PFS or OS probability within the specified interval was infrequently reported when results were presented and median survival was reported instead. One interesting example of dichotomizing PFS was the trial in Hainsworth et al (2010) where the PFS rate at 6 weeks was used for futility stopping in Simon’s design, and the PFS rate at 12 weeks was used for the final analysis.…”

Molecular targets in melanoma: time for ‘ethnic personalization’

“…The patients were not molecularly profiled before enrollment. A Phase II study that incorporated an angiogenesis inhibitor bevacizumab with the mTOR inhibitor everolimus reported that 12% of melanoma patients achieved a major response [40]. Currently, a Phase II trial of the mTOR inhibitor temsirolimus combined with the MEK inhibitor AZD 6244 in treatment-naive patients with BRAF -mutant stage IV melanoma is ongoing.…”