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Bevacizumab alone or in combination with TRC105 for patients with refractory metastatic renal cell cancer.

ABSTRACT: BACKGROUND:Targeting the vascular endothelial growth factor (VEGF) pathway has improved outcomes in metastatic renal cell carcinoma (RCC); however, resistance inevitably occurs. CD105 (endoglin) is an angiogenic pathway that is strongly upregulated after VEGF inhibition, potentially contributing to resistance. The authors tested whether TRC105, a monoclonal antibody against endoglin, impacted disease control in patients with previously treated RCC who were receiving bevacizumab. METHODS:Eligible patients with metastatic RCC who had previously received 1 to 4 prior lines of therapy, including VEGF-targeted agents, were randomized 1:1 to receive bevacizumab 10?mg/kg intravenously every 2 weeks (arm A) or the same plus TRC105 10?mg/kg intravenously every 2 weeks (arm B). The primary endpoint was progression-free survival (PFS) at 12 and 24 weeks. Correlative studies included serum transforming growth factor ? (TGF?) and CD105 levels as well as tissue immunostaining for TGF? receptors. RESULTS:Fifty-nine patients were enrolled (28 on arm A and 31 on arm B), and 1 patient on each arm had a confirmed partial response. The median PFS for bevacizumab alone was 4.6 months compared with 2.8 for bevacizumab plus TRC105 (P?=?.09). Grade???3 toxicities occurred in 16 patients (57%) who received bevacizumab compared with 19 (61%) who received bevacizumab plus TRC105 (P?=?.9). Baseline serum TGF? levels below the median (<10.6?ng/mL) were associated with longer median PFS (5.6 vs 2.1 months; P?=?.014). CONCLUSIONS:TRC105 failed to improve PFS when added to bevacizumab. TGF? warrants further study as a biomarker in RCC. Cancer 2017;123:4566-4573. © 2017 American Cancer Society.

SUBMITTER: Dorff TB

PROVIDER: S-EPMC5726867 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Bevacizumab alone or in combination with TRC105 for patients with refractory metastatic renal cell cancer.

Dorff Tanya B TB Longmate Jeff A JA Pal Sumanta K SK Stadler Walter M WM Fishman Mayer N MN Vaishampayan Ulka N UN Rao Amol A Pinksi Jacek K JK Hu James S JS Quinn David I DI Lara Primo N PN

Cancer 20170822 23

<h4>Background</h4>Targeting the vascular endothelial growth factor (VEGF) pathway has improved outcomes in metastatic renal cell carcinoma (RCC); however, resistance inevitably occurs. CD105 (endoglin) is an angiogenic pathway that is strongly upregulated after VEGF inhibition, potentially contributing to resistance. The authors tested whether TRC105, a monoclonal antibody against endoglin, impacted disease control in patients with previously treated RCC who were receiving bevacizumab.<h4>Metho ...[more]

PMID: 28832978

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Project description:BackgroundGlioblastoma (GBM), the most lethal primary brain tumor, has limited treatment options upon recurrence after chemoradiation and bevacizumab. TRC105 (carotuximab), a chimeric anti-endoglin (CD105) antibody, inhibits angiogenesis and potentiates activity of VEGF inhibitor bevacizumab in preclinical models. This study sought to assess safety, pharmacokinetics, and efficacy of TRC105 for bevacizumab-refractory GBM.MethodsWe conducted a pre-registered (NCT01564914), multicenter, open-label phase II clinical trial (ENDOT). We administered 10 mg/kg TRC105 monotherapy (first cohort) in adults with GBM and radiographic progression following radiation, temozolomide and bevacizumab therapy. Primary outcome was median time-to-progression (TTP), amended after first cohort's enrollment to median overall survival (mOS). Secondary outcomes were objective response rate, safety and tolerability, and progression-free survival (PFS).Results6 patients were enrolled in TRC105 monotherapy cohort. Median TTP and PFS of 5 evaluable patients receiving monotherapy was 1.4 months, in whom plasma VEGF-A levels were elevated post-therapy. Lack of response led to protocol amendment, and second cohort's addition of bevacizumab+TRC105 with primary endpoint of mOS. 16 patients were enrolled in bevacizumab+TRC105 cohort. mOS of 15 evaluable patients was 5.7 (95%CI: 4.2-9.8) months. All 22 patients had measurable disease at baseline. Median PFS of 14 evaluable patients receiving bevacizumab+TRC105 was 1.8 months (95%CI 1.2-2.1). Serum TRC105 was measurable above target concentration of 25 ug/mL in all evaluable patients. Study medications were well-tolerated in both cohorts. Combined administration did not potentiate known toxicities of either medication, with cerebral hemorrhage not observed.ConclusionsSingle-agent TRC105 lacks activity in bevacizumab-refractory GBM, possibly secondary to upregulated VEGF-A expression. Meaningful mOS in bevacizumab+TRC105 cohort warrants further trials to investigate efficacy of combination therapy.

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Bevacizumab alone or in combination with TRC105 for patients with refractory metastatic renal cell cancer.

Publications

Bevacizumab alone or in combination with TRC105 for patients with refractory metastatic renal cell cancer.

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