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Purpose: Pazopanib, a multireceptor tyrosine kinase inhibitor targeting primarily VEGFRs1-3, is approved for advanced soft tissue sarcoma (STS) and renal cell cancer. Downstream of VEGFR, trametinib is an FDA-approved MEK inhibitor used for melanoma. We hypothesized that vertical pathway inhibition using trametinib would synergize with pazopanib in advanced STS. Experimental Design: In an open-label, multicenter, investigator-initiated National Comprehensive Cancer Network (NCCN)-sponsored trial, patients with metastatic or advanced STS received pazopanib 800 mg and 2 mg of trametinib continuously for 28-day cycles. The primary endpoint was 4-month progression-free survival (PFS). Secondary endpoints were overall survival, response rate, and disease control rate. Results: Twenty-five patients were enrolled. The median age was 49 years (range, 22-77 years) and 52% were male. Median PFS was 2.27 months [95% confidence interval (CI), 1.9-3.9], and the 4-month PFS rate was 21.1% (95% CI, 9.7-45.9), which was not an improvement over the hypothesized null 4-month PFS rate of 28.3% ( P = 0.79). Median overall survival was 9.0 months (95% CI, 5.7-17.7). A partial response occurred in 2 (8%) of the evaluable patients (95% CI, 1.0-26.0), one with PIK3CA E542K-mutant embryonal rhabdomyosarcoma and another with spindle cell sarcoma. The disease control rate was 14/25 (56%; 95% CI, 34.9-75.6). The most common adverse events were diarrhea (84%), nausea (64%), fatigue (56%), and hypertension (52%). Conclusions: The combination of pazopanib and trametinib was tolerable without indication of added activity of the combination in STS. Further study may be warranted in RAS/RAF aberrant sarcomas. Clin Cancer Res; 23(15); 4027-34. ©2017 AACR .

clinical cancer research

Phase Ib/II Study of the Safety and Efficacy of Combination Therapy with Multikinase VEGF Inhibitor Pazopanib and MEK Inhibitor Trametinib In Advanced Soft Tissue Sarcoma