Abstract
Purpose There are no known effective medical treatments for refractory MPNST. Inactivation of the NF1 tumor suppressor in MPNST results in upregulation of mTOR (mammalian target of rapamycin) signaling and angiogenesis, which contributes to disease progression. We conducted a phase II study for patients (pts) with refractory MPNST combining everolimus (10 mg PO once daily) with bevacizumab (10 mg/kg IV every 2 weeks) to determine the clinical benefit rate (CBR) (complete response, partial response (PR), or stable disease (SD) ≥ 4 months). Patients and Methods Patients ≥18 years old with chemotherapy refractory sporadic or NF1 MPNST were eligible. Tumor response was assessed after every 2 cycles (the WHO criteria). A two-stage design targeting a 25% CBR was used: if ≥ 1/15 pts in stage 1 responded, enrollment would be expanded by 10 pts, and if ≥ 4/25 patients had clinical benefit, the combination would be considered active. Results Twenty-five pts, 17 with NF1 and 8 with sporadic MPNST, enrolled. One of 15 pts in stage 1 had clinical benefit. Of 10 additional pts enrolled, 2 had clinical benefit. The median number of completed cycles was 3 (range 1–16). Adverse events were similar to those known for this combination. Conclusion With a CBR of 12% (3/25), the combination of everolimus and bevacizumab did not reach the study's target response rate and is not considered active in refractory MPNST.
Highlights
Malignant peripheral nerve sheath tumors (MPNST) are rare and clinically aggressive soft tissue sarcomas that occur with greater incidence in individuals with neurofibromatosis type 1 (NF1) [1, 2]
Angiogenesis contributes to progression of MPNST, and in this mouse model, development of resistance was associated with revascularization and upregulation of the vascular endothelial growth factor. e combination of sunitinib, a multitargeted kinase inhibitor, which in part, mediates antitumor activity by inhibition of angiogenesis, with sirolimus resulted in prolongation of survival compared to treatment with either agent alone (Cichowski lab, unpublished data)
Everolimus was supplied by Novartis and bevacizumab by Genentech. e study was conducted after approval from the Department of Defense Protocol Review, and institutional review boards from all participating sites and all patients provided written informed consent before participating. e trial was registered with ClinicalTrials.gov (NCT01661283)
Summary
Malignant peripheral nerve sheath tumors (MPNST) are rare and clinically aggressive soft tissue sarcomas that occur with greater incidence in individuals with neurofibromatosis type 1 (NF1) [1, 2]. No phase II trials with targeted therapies have resulted in clinical benefit as demonstrated by tumor shrinkage or improvement in progression-free survival [4]. In an Nf1/p53-mutant MPNST model, the Cichowski group identified that the mammalian target of rapamycin (mTOR) is hyperactive and that the mTOR inhibitor sirolimus substantially delayed tumor growth [5]. E combination of sunitinib, a multitargeted kinase inhibitor, which in part, mediates antitumor activity by inhibition of angiogenesis, with sirolimus resulted in prolongation of survival compared to treatment with either agent alone (Cichowski lab, unpublished data) Angiogenesis contributes to progression of MPNST, and in this mouse model, development of resistance was associated with revascularization and upregulation of the vascular endothelial growth factor. e combination of sunitinib, a multitargeted kinase inhibitor, which in part, mediates antitumor activity by inhibition of angiogenesis, with sirolimus resulted in prolongation of survival compared to treatment with either agent alone (Cichowski lab, unpublished data)
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