Literature Review on the Effectiveness of Pazopanib (Votrient)
Results of a Prospective Phase 2 Study of Pazopanib in Patients With Surgically Unresectable or Metastatic Chondrosarcoma
Warren Chow, MD1; Paul Frankel, PhD2; Chris Ruel, PhD2; Dejka M. Araujo, MD3; Mohammed Milhem, MBBS4; Scott Okuno, MD5; Lee Hartner, MD6; Samir Undevia, MD7; and Arthur Staddon, MD6
BACKGROUND: This single-arm, multicenter, phase 2 study evaluated the safety and antitumor activity of pazopanib in patients with unresectable or metastatic conventional chondrosarcoma.
METHODS: Eligible patients had conventional chondrosarcoma of any grade with measurable tumors that were unresectable or metastatic. Patients with mesenchymal, dedifferentiated, and extraskeletal myxoid chondrosarcoma subtypes and patients who received prior tyrosine kinase inhibitor therapy were excluded. Pazopanib at 800 mg once daily was administered for 28-day cycles. Tumor responses were evaluated by local radiology assessments every 2 cycles. The primary endpoint was the disease control rate (DCR) at week 16 (4 cycles). RESULTS: Forty-seven patients were enrolled. The DCR at 16 weeks was 43% (95% confidence interval [CI], 28%-58%), which was superior to the null hypothesis rate of 30%, but the 2-sided P value (exact test) was .09 (1-sided P = .045). One patient had a partial response. The median overall survival was 17.6 months (95% CI, 11.3-35.0 months), and the median progression-free survival was 7.9 months (95% CI, 3.7-12.6 months). Grade 3 or higher adverse events were infrequent; hypertension (26%) and elevated alanine aminotransferase (9%) were most common. CONCLUSIONS: This study provides evidence of positive drug activity for pazopanib in conventional chondrosarcoma. Cancer 2020;126:105-111. © 2019 American Cancer Society.
KEYWORDS: bone cancer, chemotherapy, chondrosarcoma, pazopanib, phase 2.
Chondrosarcoma is the collective term for a number of heterogeneous, generally slow-growing, primary malignant tumors of bone that are characterized by the formation of hyaline cartilaginous neoplastic tissue. These tumors primarily affect adults and are the second most common primary bone cancer after osteogenic sarcoma.1 There are approximately 3 new cases of chondrosarcoma per 100,000 person-years.2 More than 90% of chondrosarcomas are the conventional subtype, and approximately 90% of these are low- to intermediate-grade (grade 1-2), behave indolently, and rarely metastasize. 3 Only 5% to 10% of conventional chondrosarcomas are grade 3 and have high metastatic potential.4 Conventional chondrosarcomas form principally in the pelvic bone, femur, proximal humerus, and scapula.5
Conventional chondrosarcoma tumors are generally considered to be resistant to conventional chemotherapy and radiotherapy; thus, surgery with adequate margins is the treatment of choice.6 Outcomes are generally good for patients treated surgically with wide margins, but survival can be negatively affected by factors such as a high histologic grade, local recurrence, and the presence of metastases. The cumulative survival of patients with nonmetastatic conventional chondrosarcoma is approximately 70% and 63% at 10 and 15 years, respectively, with the survival rates at 10 years for patients with grade 1, 2, and 3 tumors approximately 89%, 53%, and 38%, respectively.7 The combination of local recurrence and the presence of metastases is associated with a very poor prognosis with a 5-year survival rate of only 5%.7 Unfortunately, there is a high risk of local recurrence when there are inadequate surgical margins or if the tumor is large. It has been estimated that adequate margins may not be achieved in 25% to 55% of patients, and this may happen for many reasons such as the tumor location.5,7
Advances in the understanding of the biology, genetics, and epigenetics of bone sarcomas have led to novel therapeutic approaches to conventional chondrosarcomas.4,5,8 A report of a positive correlation between vascular endothelial growth factor (VEGF) and VEGF-A expression and chondrosarcoma tumor grade suggests that antiangiogenic therapy may be useful in this form of bone sarcoma.9 Indeed, VEGF inhibitors prevented growth and induced apoptosis of chondrosarcoma cells10-12 and prevented them from inducing endothelial cell proliferation.13 Further encouraging clinical data come from a phase 1 study in which 1 patient with chondrosarcoma who received treatment with a VEGF antisense oligonucleotide experienced a decline of VEGF plasma levels and a prolonged stable disease status.14
Pazopanib is an oral, multitargeted tyrosine kinase inhibitor with antiangiogenic activity due to the inhibition of receptors for VEGF, platelet-derived growth factor, and KIT, among others.15,16 Many clinical studies have shown that pazopanib has antitumor activity in soft-tissue sarcoma types.17-20 In the phase 1 trial of pazopanib, there were 2 patients with conventional chondrosarcoma, and they experienced stable disease for 7.6 and 19.8 months, respectively.21 Because of the very poor prognosis of patients with recurrent or metastatic conventional chondrosarcoma, a treatment that prolongs progression-free survival (PFS) would be a significant option for this patient group. Thus, the current study was designed to prospectively evaluate the efficacy and safety of single-agent pazopanib in patients with metastatic or surgically unresectable conventional chondrosarcoma who may or may not have received any prior chemotherapy treatment.
This was a single-arm, prospective, multicenter study of the safety and efficacy of pazopanib in patients with unresectable or metastatic conventional chondrosarcoma. Notably, 81% of the patients had metastatic disease at the time of study entry, and this demonstrated the advanced nature of the majority of the patients. Furthermore, in agreement with the reported chemotherapy resistance of
this disease, only 32% of the patients had received prior systemic chemotherapy. In the study patients, treatment with pazopanib resulted in a DCR of 43% after 16 weeks of treatment. The median PFS was 7.9 months, and the median OS was 17.6 months. One patient experienced a partial response that lasted 72 weeks. These findings suggest that pazopanib has positive drug activity in chondrosarcoma, and they compare favorably against a benchmark 3-month PFS rate of 40% or more as being efficacious for second-line therapy in advanced soft-tissue sarcomas.23
Previous studies of chemotherapy in unresectableconventional chondrosarcoma have evaluated a varietyof therapeutic agents, with no clear standard of careestablished for this stage of the disease. In a large seriesof 171 patients with advanced, unresectable conventionalchondrosarcoma from the Rizzoli Institute and LeidenUniversity Medical Center, OS was observed to be 48%at 1 year and only 2% at 5 years.24 The use of eitherdoxorubicin-based or noncytotoxic chemotherapy (imatinib combined with sirolimus) in this cohort significantly prolonged the median OS to 20 months in contrast to 15 months for those who received no treatment. In a small, retrospective cohort of 10 patients, the median PFS was 13.2 months, and 70% of the patients had disease control 6 months after the initiation of a treatment combinationof sirolimus and cyclophosphamide; in patients for whomtreatment failed, the median survival was 8.2 months.25 Imatinib mesylate did not have meaningful activity ina cohort of 26 patients with advanced chondrosarcomaand positive platelet-derived growth factor expression.26
However, preliminary data for other kinase inhibitors provide promising evidence of drug activity. In a heterogeneous group of patients with sarcoma treated with dasatinib in a phase 2 trial, the median 6-month PFS for subjects with conventional chondrosarcoma was 47% and 3 patients (of 33) had disease stabilization for more than 2 years.27 There is a case report of a partial response after 6 months of pazopanib treatment after anthracycline failure in a patient with metastatic, grade 2 to 3 conventional chondrosarcoma.28 Finally, results from a small cohort of patients treated with either pazopanib
(n = 8) or ramucirumab (n = 2) showed that 7 patients had prolonged disease stabilization for at least 6 months, and 2 patients with prior treatment failures maintained their stable disease for at least 2 years. The group of pazopanib-treated patients included conventional chondrosarcoma (n = 7) and clear cell sarcoma (n = 1), and the median PFS was 22.6 months.29 One patient maintained stable disease on pazopanib treatment for more than 2.5 years. Overall, the results of our study and those in the aforementioned literature support the idea that pazopanib may have activity in conventional chondrosarcoma, in which traditional systemic chemotherapy has been ineffective. It is unclear whether pazopanib could be further beneficial if used in a combination regimen; however, there are currently no appropriate agents to combine with pazopanib.
The AE profile seen in this study of patients with advanced chondrosarcoma reflects what has been seen in previous studies of pazopanib in patients with othertumor types. Treatment-related AEs were typically grade2 or lower, and most grade 3 or higher toxicities were manageable. A cerebellar hemorrhage leading to death was observed in a patient who entered the study with recurrent chondrosarcoma at the base of the skull and prior neurosurgical interventions for intratumoral bleeding; upon a detailed review of the patient’s history of similar events, it was felt that this event was unlikely to be related to, but could have been exacerbated by, treatmentwith pazopanib.
Although our study did not include a control group, a comparison of our results against other reported survival data for patients with advanced conventional chondrosarcoma suggest that pazopanib has positive drug activity in this tumor type and can have a beneficial impact on survival.7,24 Another limitation of this multicenter study is that local pathology and radiology reviews were used with an investigator determination of the tumor status.
Although centralized reviews are generally preferablethis was a small study conducted at specialized sarcoma treatment centers with experienced investigators, sarcoma pathologists, and radiology staff who are believed to provide reliable and consistent assessments. Furthermore, the study conclusions of positive drug activity are corroborated by clinically meaningful survival results that exceed the thresholds established by expert consensus to be representative of positive drug activity in the absence of a control group. Strengths of our study include the prospective design and the relatively large sample size for this rare tumor type. In summary, patients with primary, advanced conventional chondrosarcoma experienced a DCR of 43% after 16 weeks of pazopanib treatment, and 1 patient had
a partial response for a duration of 72 weeks. Importantly, the median OS was 17.6 months, which represents a meaningful outcome for patients and is evidence of positive drug activity for pazopanib in a traditionally chemotherapy-resistant disease.
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