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.

Authors

Vivek Subbiah, University of Texas MD Anderson Cancer CenterFollow
Christian Meyer, Johns Hopkins University
Ralph G. Zinner, The University of Thomas Jefferson University; University of Texas MD Anderson Cancer CenterFollow
Funda Meric-Bernstam, University of Texas MD Anderson Cancer Center
Marianna L. Zahurak, Johns Hopkins UniversityFollow
Ashley O'Connor, University of Texas MD Anderson Cancer Center; Johns Hopkins University
Jason Roszik, University of Texas MD Anderson Cancer Center
Kenna Shaw, University of Texas MD Anderson Cancer Center
Joseph A. Ludwig, University of Texas MD Anderson Cancer Center
Razelle Kurzrock, University of Texas MD Anderson Cancer Center; University of California, San Diego
Nilofe A. Azad, Johns Hopkins University

Document Type

Article

Publication Date

8-1-2017

Comments

This article has been peer reviewed. It is the authors' final version prior to publication in Clinical Cancer Research, Volume 23, Issue 15, August 2017, Pages 4027-4034.

The published version is available at https://doi.org/10.1158/1078-0432.CCR-17-0272. Copyright © AACR

Abstract

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 ¼ 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%). 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. ©2017 AACR.

Recommended Citation

Subbiah, Vivek; Meyer, Christian; Zinner, Ralph G.; Meric-Bernstam, Funda; Zahurak, Marianna L.; O'Connor, Ashley; Roszik, Jason; Shaw, Kenna; Ludwig, Joseph A.; Kurzrock, Razelle; and Azad, Nilofe A., "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." (2017). Department of Medical Oncology Faculty Papers. Paper 87.
https://jdc.jefferson.edu/medoncfp/87

PubMed ID

28377484

Language

English