Cediranib for metastatic alveolar soft part sarcoma

Abstract

Purpose: Alveolar soft part sarcoma (ASPS) is a rare, highly vascular tumor, for which no effective standard systemic treatment exists for patients with unresectable disease. Cediranib is a potent, oral small-molecule inhibitor of all three vascular endothelial growth factor receptors (VEGFRs).

Patients and methods: We conducted a phase II trial of once-daily cediranib (30 mg) given in 28-day cycles for patients with metastatic, unresectable ASPS to determine the objective response rate (ORR). We also compared gene expression profiles in pre- and post-treatment tumor biopsies and evaluated the effect of cediranib on tumor proliferation and angiogenesis using positron emission tomography and dynamic contrast-enhanced magnetic resonance imaging.

Results: Of 46 patients enrolled, 43 were evaluable for response at the time of analysis. The ORR was 35%, with 15 of 43 patients achieving a partial response. Twenty-six patients (60%) had stable disease as the best response, with a disease control rate (partial response + stable disease) at 24 weeks of 84%. Microarray analysis with validation by quantitative real-time polymerase chain reaction on paired tumor biopsies from eight patients demonstrated downregulation of genes related to vasculogenesis.

Conclusion: In this largest prospective trial to date of systemic therapy for metastatic ASPS, we observed that cediranib has substantial single-agent activity, producing an ORR of 35% and a disease control rate of 84% at 24 weeks. On the basis of these results, an open-label, multicenter, randomized phase II registration trial is currently being conducted for patients with metastatic ASPS comparing cediranib with another VEGFR inhibitor, sunitinib.

Trial registration: ClinicalTrials.gov NCT00942877.

Fig 1.

Tumor response in 43 evaluable patients. (A) Maximal change in tumor size from baseline assessed according to RECIST (version 1.0), which uses 30% shrinkage in the sum of the longest diameters of target lesions as the threshold for partial response (PR; dashed line). The patient number for each patient entered onto the trial is shown below each bar. (*) Prior ARQ 197 treatment. (†) Prior sorafenib treatment. (‡) Prior sunitinib treatment. (§) Prior bevacizumab treatment. One patient died before follow-up assessment. (B) Duration on study for each evaluable patient through the data analysis date of June 30, 2012. (**) Patients who underwent paired tumor biopsies (see Fig 3).

Fig 2.

Computed tomography (CT) scans. (A) CT scans from a 29-year-old woman (patient 24) with metastatic alveolar soft part sarcoma (ASPS) before and after treatment with cediranib; the patient had undergone previous resection and had experienced progression after treatment with ifosfamide plus doxorubicin, gemcitabine with docetaxel, and the MET inhibitor ARQ 197. Significant shrinkage of breast lesions was observed, and the patient received a total of 18 cycles. (B) CT scans from a 25-year-old man (patient 34) with newly diagnosed metastatic ASPS who presented with shortness of breath, was oxygen dependent, and had signs of early hemodynamic compromise from a tumor compressing the heart. Within the first two cycles of cediranib, the patient no longer required oxygen. After eight cycles of therapy, the patient had good exercise tolerance, and significant tumor shrinkage was observed. Patient continues on study, status post 19 cycles. (C) CT scans from a 25-year-old woman (patient 31) who originally presented with a mass in her left calf, underwent resection of primary ASPS followed by radiation, but had disease recurrence in the form of an unresectable subcarinal mass. After six cycles of cediranib, this patient achieved a partial response, underwent resection, and currently has no evidence of disease 16 months later and is off study. Patients did not receive any therapy after resection.

Fig 3.

Microarray expression analysis of tumor biopsies. (A) Hierarchical clustering of expression changes in biopsies from patients 23, 24, 25, 32, 34, 38, 41, and 44 for the top 100 differentially expressed genes based on adjusted P values before and after treatment with cediranib. Each row represents an Affymetrix probe set (Affymetrix, Santa Clara, CA); red indicates high expression, and green indicates low expression. (B) A representative Ingenuity Pathway Analysis map generated for the differentially expressed probe sets. Red nodes indicate genes that were upregulated by microarray, and green nodes indicate those that were downregulated; the more intense the color, the greater the log₂ fold change in expression. (C and D) The log₂ fold changes in expression from (C) microarray and (D) quantitative real-time polymerase chain reaction (qRT-PCR) analyses for cediranib-induced changes in individual patient samples. For each gene, results from patients 23, 24, 25, 32, 34, 38, 41, and 44 are listed sequentially from top to bottom; patient 23 did not have sufficient sample volume for qRT-PCR analysis.