Phase Ib/II study of safety & efficacy of combination therapy with multikinase VEGF inhibitor Pazopanib and MEK inhibitor Trametinib in advanced soft tissue sarcoma

Purpose: Pazopanib, a multi-receptor tyrosine kinase inhibitor targeting primarily vascular endothelial growth factor receptors 1-3 (VEGFRs1-3), is approved for advanced soft tissue sarcoma and renal cell cancer. Downstream of VEGFR, trametinib is an FDA-approved MEK inhibitor used for melanoma. We hypothesized that vertical pathway inhibition using a trametinib would synergize with pazopanib in advanced soft tissue sarcoma (STS). <p>Experimental Design: In an open-label, multicenter, investigator-initiated 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.</p> <p>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%), and fatigue (56%).</p> <p>Conclusion: 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.

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