A Phase II Trial of Pazopanib in Patients with Metastatic Alveolar Soft Part Sarcoma.

LESSONS LEARNED: Pazopanib shows a modest efficacy in metastatic alveolar soft part sarcoma.Clinical outcomes were comparable to those in previous studies using antiangiogenic drugs.Further prospective studies evaluating the benefit of pazopanib in alveolar soft part sarcoma with a larger sample are warranted to validate results.
BACKGROUND: Alveolar soft part sarcoma (ASPS) is a rare mesenchymal malignant tumor characterized by an unbalanced translocation, t(X;17)(p11.2;q25), which leads to the fusion of ASPSCR1 to the TFE3 transcription factor. Because this results in the upregulation of angiogenesis-related transcripts, antiangiogenic drugs have been used in ASPS patients.
METHODS: This open-label, single-arm, multicenter, investigator-initiated phase II trial was designed to evaluate efficacy and safety of pazopanib 800 mg once daily in patients with metastatic ASPS. The primary endpoint was investigator-assessed overall response rate (ORR), and secondary endpoints were toxicity, progression-free survival (PFS), and overall survival (OS). 68Ga-RGD (Arg-Gly-Asp) positron emission tomography (PET) scan and gene expression profiling using NanoString platform were performed for biomarker analysis.
RESULTS: Six patients with histologically confirmed metastatic ASPS were enrolled between December 2013 and November 2014. Among six patients, one achieved a partial response (PR) (ORR 16.7%) and five patients showed stable disease (SD). With a median follow-up of 33 months (range 18.7-39.3 months), median PFS was 5.5 months (95% confidence interval [CI] 3.4-7.6 months), and median OS was not reached. There were no severe toxicities except one patient with grade 3 diarrhea.
CONCLUSION: Pazopanib showed modest antitumor activity with manageable toxicities for patients with metastatic ASPS. © AlphaMed Press; the data published online to support this summary is the property of the authors.

Discussion

ASPS is a rare histological subtype of soft‐tissue sarcomas (STS). It shows a poor prognosis in the metastatic setting, and the standard chemotherapy regimens do not improve treatment outcomes. Several antiangiogenic drugs have been studied in metastatic ASPS patients.

We performed an open‐label, single‐arm, phase II study to evaluate the efficacy and safety of pazopanib in patients with metastatic ASPS. We included patients who met the following key eligibility criteria: age ≥18 years; histologically confirmed diagnosis of metastatic or unresectable ASPS confirmed by positive immunostaining for TFE3; treatment‐naïve or received prior chemotherapy except vascular endothelial growth factor (VEGF) inhibitors. Six patients were enrolled into this trial. The median number of cycles administered was 7.5 (range 6–21), with a median follow‐up duration of 33 months (range 18.7–39.3 months). The baseline characteristics are presented in Table 1. One patient (16.7%) achieved PR after two cycles of pazopanib treatment. The remaining five (83.3%) showed SD during the treatment (tumor reduction, mean ± standard deviation, 9.4 ± 13.1%). The median PFS was 5.5 months (95% CI 3.4–7.6 months), and the 6‐month PFS rate was 50%. Among four patients with SD, there was one patient (patient 3) who showed disease stabilization over the long period of time. She was 23 years of age and diagnosed with ASPS with metastases to the lung and bone. As shown in Figure 1, computed tomography (CT) scan during pazopanib treatment showed clinical improvement, and the value of maximal standardized uptake value measured on 68Ga‐RGD PET/CT was also slightly decreased. The period of disease stabilization lasted 22 months. Treatment was discontinued for all six patients due to disease progression, and two patients died of disease progression.

Table 1.

Patients' characteristics and treatment outcomes

Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; PFS, progression‐free survival; PR, partial response; OS, overall survival; SD, stable disease.

Figure 1.

Computed tomography (CT) scan and 68Ga‐RGD positron emission tomography‐CT scan of patient 3. CT scan before treatment (A), after 2 months of pazopanib treatment (B), and at disease progression (C). 68Ga‐RGD PET/CT before treatment (D) and after 14 days of pazopanib treatment (E).

The most common treatment‐related toxicities were diarrhea (100%) and abdominal pain (50%; Adverse events table). There were no severe toxicities except one patient with grade 3 diarrhea.

To our knowledge, clinical outcomes in our study were comparable to those in previous studies in metastatic ASPS using antiangiogenic TKIs. However, our study was closed early because of the low accrual rate that was attributable to the rarity of the subtype (<1% of STS). In addition, a wait‐and‐see policy was adopted in ASPS patients who showed stable or slow‐growing metastases. Further large‐scale, prospective studies evaluating the efficacy of pazopanib in ASPS are warranted.

Trial Information

Sarcomas – Adult

Metastatic/advanced

No designated number of regimens

Phase II

Single arm

Overall response rate

Progression‐free survival

Progression‐free survival at 6 months

Overall survival

Toxicity

Simon's two‐stage minimax design was used to evaluate a null hypothesis of an ORR <15% versus an alternative hypothesis of ≥40% ORR, with a significance level of 0.05 and a power of 0.80. The target accrual was nine patients in the first stage. If ≥2 responders were observed, then an additional 10 patients would be enrolled in the second stage.

Active but results overtaken by other developments

Drug Information

Pazopanib

Votrient

Novartis

Small molecule

VEGF receptor

800 mg per flat dose

p.o.

800 mg once daily administered continuouslyin 4‐week interval per cycle

Patient Characteristics

3

3

Metastatic

Median (range): 29.5 (23–36)

Median (range): 0 (0–2)

0 — 2

1 — 4

2 — 0

3 — 0

Unknown —

Previous surgery: 6

Alveolar soft part sarcoma: 6

Primary Assessment Method

7

6

6

6

RECIST 1.1

n = 0 (0%)

n = 1 (16.7%)

n = 5 (83.3%)

n = 0 (0%)

5.5 months, CI: 3.4–7.6

Median OS was not reached.

Adverse Events

Assessment, Analysis, and Discussion

Study terminated before completion

Did not fully accrue

Active but results overtaken by other developments

Alveolar soft part sarcoma (ASPS) is a very rare and distinct histologic soft‐tissue sarcoma (STS), mainly arising in adolescents and young adults [1]. Despite its relatively slow progression, ASPS exhibits a very high propensity for metastases to other organs, typically the lung and the brain [2]. Conventional cytotoxic chemotherapy has not proved effective for the treatment of ASPS. Instead, surgical therapy is still the mainstay of treatment and ensures chance for long‐term survival [3], [4]. Microarray gene expression analysis and in vitro preclinical studies reported the markedly elevated expression of several genes involved in angiogenesis, including vascular endothelial growth factor (VEGF), ANGPTL2, HIF‐1α, MDK, c‐MET, and TIMP‐2, in ASPS tumors [5], [6]. The lack of therapeutic alternatives in metastatic ASPS, its highly vascular property, and the abnormal expression of genes related to angiogenesis prompted us to test the possible therapeutic activity of antiangiogenic drugs.

Pazopanib, a small molecule tyrosine kinase inhibitor, exhibits selective activity against VEGF receptors [7]. In a recent phase III study in metastatic STS (PALETTE), the median progression‐free survival (PFS) in patients receiving pazopanib was improved to 4.6 months compared with 1.6 months in patients receiving placebo [8]. However, the number of ASPS patients included in this trial was too small to evaluate its efficacy in this tumor type. Therefore, we designed this phase II study to assess the clinical efficacy and safety of pazopanib in patients with metastatic ASPS.

In the present study, we observed modest clinical benefit with pazopanib—with one (16.7%) and five patients (83%) with metastatic ASPS having partial response and stable disease (SD), respectively. The tumors of patients with SD remained stable for at least 4 months. Among four patients with SD, there was one patient who experienced disease stabilization for 22 months. The efficacy achieved in our study was comparable to that reported in previous phase II and III studies with pazopanib in patients with metastatic ASPS [8], [9]. Other drugs targeting the angiogenic pathways have also been investigated in ASPS. These include sunitinib, cediranib, dasatinib, and bevacizumab. The clinical benefit of sunitinib has been encouraging, based on a series of retrospective studies with median PFS ranging from 17 to 41 months, and the median OS ranging from 19 to 56 months [10], [11], [12]. Cediranib has also demonstrated encouraging efficacy in a phase II trial with an objective response rate of 35% and a disease control rate of 84% at 24 weeks [13]. Also, >10% of the ASPS patients treated with dasatinib showed disease stabilization for >1 year [14]. Finally, Azizi et al. reported that bevacizumab, a monoclonal antibody blocking VEGF‐α, induced tumor regression in a patient with metastatic ASPS [15]. To date, sunitinib seems to provide the most promising results for the treatment of metastatic ASPS compared with other antiangiogenic drugs (Table 2). However, it needs to be further validated by a prospective study on a larger scale before being recommended as the standard treatment for metastatic ASPS.

Table 2.

Comparison of published studies of tyrosine kinase inhibitors for advanced ASPS

Abbreviations: —, no data; ASPS, alveolar soft part sarcoma; OS, overall survival; PFS, progression‐free survival.

It is of note that stabilization of the disease was the most frequent response observed between 53% and 83% for patients treated with TKIs, including those receiving pazopanib in our study [10], [11], [13]. This is not surprising in that antiangiogenic TKIs target the angiogenesis signaling pathways on the endothelial cells rather than tumor itself. In this aspect, one could speculate that TKIs might have some limited benefit in their clinical efficacy due to their indirect mode of action. However, Stacchiotti et al. demonstrated the direct antitumor effect of sunitinib in short‐term ASPS cultures [11]. Pazopanib also has antitumor activity in tumor xenografts derived from non‐ASPS tumor cells [16]. Therefore, it is likely that the spectrum for activity of these multitargeted TKIs might be so broad as to inhibit both angiogenesis and tumor cell growth. Although the action mechanism of pazopanib is mediated via VEGF pathway, the underlying biological processes need to be addressed. In an effort to identify these key mediators, we analyzed the transcriptome of ASPS following the treatment with pazopanib. We analyzed the pretreatment and postprogression paired samples from three patients using the NanoString gene expression array. Using a p value <.05, we selected the top 41 differentially expressed genes (DEGs) between pretreatment and postprogression samples. DEGs with the greatest differential expression were the components of signaling pathways such as mitogen‐activated protein kinase, phosphoinositide 3‐kinase, and wingless‐type MMTV integration site family (Fig. 2). We also identified 10 up‐ or down‐regulated DEGs related to angiogenesis. Our result indicates that pazopanib might modulate multiple signaling pathways in a simultaneous manner.

Figure 2.

Heatmap illustrating the differential expression of 41 genes.

In conclusion, this study demonstrates that pazopanib has modest efficacy with tolerable toxicity in metastatic ASPS. However, our study had several limitations due to the rarity of the disease inherent to ASPS. First, this was a small population size of six patients due to an early closure. Second, our result on the efficacy of pazopanib should be interpreted with caution given that the spontaneous stabilization could occur in ASPS due to its indolent biology. Therefore, a larger, future study will be necessary to accrue a significant number of patients to validate the clinical benefit of pazopanib in patients with metastatic ASPS.

Adverse events observed in any patient during any cycle.

Abbreviation: NC/NA, no change from baseline/no adverse event.