title: 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.
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= 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 withPIK3CAE542K-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.
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas. vsubbiah@mdanderson.org.
authors.forename: Vivek
authors.initials: V
authors.lastname: Subbiah
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Christian
authors.initials: C
authors.lastname: Meyer
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas.|Thomas Jefferson University Hospital, Philadelphia, Pennsylvania.
authors.forename: Ralph
authors.initials: R
authors.lastname: Zinner
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Funda
authors.initials: F
authors.lastname: Meric-Bernstam
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Marianna L
authors.initials: ML
authors.lastname: Zahurak
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Ashley
authors.initials: A
authors.lastname: O'Connor
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jason
authors.initials: J
authors.lastname: Roszik
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Kenna
authors.initials: K
authors.lastname: Shaw
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Ludwig
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas.|University of California, San Diego, San Diego, California.
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Nilofer A
authors.initials: NA
authors.lastname: Azad
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D018572:Disease-Free Survival; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D007191:Indazoles; D048728:MAP Kinase Kinase Kinase 1 / Q000037:antagonists & inhibitors; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011728:Pyridones / Q000008:administration & dosage* / Q000009:adverse effects; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects; D011744:Pyrimidinones / Q000008:administration & dosage* / Q000009:adverse effects; D012509:Sarcoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D007191:Indazoles; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011743:Pyrimidines; D011744:Pyrimidinones; D013449:Sulfonamides; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C560077:trametinib; C516667:pazopanib; D048728:MAP Kinase Kinase Kinase 1