Pazopanib for patients with advanced soft tissue sarcomas in a real‐life setting

Non-gastrointestinal stromal tumors (GIST) soft-tissue sarcomas (STSs) comprise a rare and heterogeneous group of more than 50 different subentities that display great differences between each other in terms of molecular background, natural behavior, and sensitivity to antitumor agents. For patients who present with advanced disease and are not amendable to curative treatment options like resection, the prognosis is dismal. Until recently, the number of different systemic agents used against STS was quite limited. The most commonly used agent in the first-line setting, regardless of the exact subtype, is doxorubicin. Because ifosfamide exhibits antitumor activity to a similar extent as doxorubicin monotherapy, it was hoped that the combination of these 2 agents would improve outcome. However, a recently published study from the European Organization for Research and Treatment demonstrated that this combination indeed induces higher response rates and prolongs progression-free survival (PFS) but also indicated that its enhanced activity was not translated into better overall survival (OS). Because doxorubicin has a much more favorable toxicity profile than ifosfamide and can be administered on an outpatient basis, doxorubicin monotherapy remains the standard for many patients. In addition to doxorubicin and ifosfamide, there are several other agents with antitumor activity in STS that frequently are active against specific STS subtypes only. Examples include dacarbazine, gemcitabine, and the combination of gemcitabine and docetaxel, which particularly exerts antitumor activity in leiomyosarcomas, as well as taxanes, which have antitumor activity against angiosarcomas. However, despite the availability of these and other agents, the prognosis for patients with advanced STS is very poor, with a median OS of 12 months, a figure that has remained unchanged in the last decades, obviously stressing the high need for novel treatment strategies. Pazopanib is a tyrosine kinase inhibitor that targets several factors, including vascular endothelial growth factor receptor 1 (VEGFR-1), VEGFR-2, VEGFR-3, and platelet-derived growth factor receptor a. Because it is believed that these factors are involved in the tumor biology of several STS subtypes, pazopanib was explored for its activity in a phase 2 study of patients with advanced STS who had failed on previous doxorubicin-based or ifosfamide-based treatment. Given the known heterogeneity of STS and, consequently, the potential differences in sensitivity to pazopanib, 4 different STS cohorts were assessed. Pazopanib met the primary endpoint for activity, justifying further study, in 3 of the 4 cohorts (leiomyosarcomas, synovial sarcomas, and other eligible STS subtypes), but not in the cohort of patients with liposarcomas. Pazopanib was subsequently assessed in a placebo-controlled, phase 3 study in patients with advanced, nonadipocytic STS who had failed on previous standard chemotherapy (the pazopanib for metastatic soft-tissue sarcoma [PALETTE] study). Pazopanib improved the median PFS from 1.6 months in the placebo arm to 4.6 months in the pazopanib arm (hazard ratio, 0.31; 95% confidence interval. 0.24-20.40), which was similar to the median PFS achieved by doxorubicin in the first-line setting. No OS benefit was observed, an endpoint for which the study was not powered to detect a clinically relevant difference. It is noteworthy that the gain in PFS achieved by pazopanib was not at the cost of deterioration in qualityof-life tests compared with placebo. On the basis of that study, pazopanib was approved. In this issue of Cancer, Nakamura et al present the results from a Japanese postmarketing surveillance (PMS) program on pazopanib in patients with advanced STS. Such reports are of great importance, although it is quite challenging to adequately compare patient outcomes with those from prospective registration studies. For example, no criteria regarding who can receive treatment frequently are not precisely defined in PMS projects, toxicity is less stringently evaluated and managed compared with prospective registration studies, and how and when to perform tumor evaluations are often not strictly defined, rendering outcome parameters like response rates and PFS difficult to put into perspective.