Patients with anthracycline-treated sarcomas had a 3-fold improvement in PFS with antiangiogenic agent pazopanib versus placebo.
Winette T. A. van der Graaf, MD, PhD
Data from a randomized clinical trial showed that patients with anthracycline-treated sarcomas had a 3-fold improvement in progression-free survival (PFS) with antiangiogenic agent pazopanib versus placebo.
Pazopanib treatment was associated with a median PFS of 4.6 months versus 1.5 months in the placebo group. The difference translated into a 69% reduction in the hazard for progression, as reported at last month’s ASCO meeting in Chicago.
“We may now conclude that, after decades of chemotherapy, we finally have a new drug for our patients with soft-tissue sarcomas,” said Winette T. A. van der Graaf, MD, PhD, a medical oncologist at Radboud University Nijmegen Medical Center in the Netherlands. “I think pazopanib can be added to the palette of potentially active drugs. It is also important that this benefit is not restricted to rare sarcomas but has been shown to be effective in more common types of sarcomas.”
The findings came from the international multicenter phase III PALETTE trial involving patients with soft-tissue sarcomas, including leiomyosarcoma, synovial sarcoma, and fibrohistiocytic and fibroblastic sarcomas. Much of the basis for the trial came from a phase II study of pazopanib, which showed a 12-week progression-free rate of 40% to 50% in patients with advanced soft-tissue sarcomas (J Clin Oncol. 2009;27:3127-3132).
After decades of chemotherapy, we finally have a new drug for our patients with softtissue sarcomas.”
—Winette T. A. van der Graaf, MD, PhD
PALETTE investigators at 72 centers in 13 countries enrolled patients treated with as many as 4 prior chemotherapy regimens, and all patients had prior anthracycline exposure but no prior treatment with antiangiogenesis agents. Patients were randomized 2:1 to pazopanib 800 mg/day or placebo and followed until progression, unacceptable toxicity, withdrawal of consent, or death. The primary endpoint was PFS, and secondary endpoints were overall survival, overall response rate, quality of life, and safety.
The final analysis included 369 randomized patients. The trial ended November 2010 with a median follow-up of 15 months.
Leiomyosarcoma accounted for more than 40% of the tumors, and about 70% of the patients had high-grade tumors at diagnosis. Aside from the required anthracycline exposure, the patients’ treatment history most often included ifosfamide (>70%), gemcitabine (35%), and docetaxel (30%). A majority of patients had received more than 2 lines of chemotherapy for advanced disease.
Analysis of the primary endpoint demonstrates a significant advantage in favor of pazopanib (P <.0001). The benefit was consistent across the 3 major histologic strata (leiomyosarcoma, synovial, and other), associated with hazard ratios of 0.19 to 0.36, all of which achieved statistical significance (P = .0002 to P <.0001).
The interim analysis of overall survival showed no significant difference between treatment groups, as the pazopanib arm had a median overall survival of 11.9 months compared with 10.4 months in the placebo group (P = .1782). van der Graaf said the final analysis of overall survival will occur before the end of the year.
n = 239
n = 123
Adapted from van der Graaf et al. J Clin Oncol. 2011;29(suppl; abstr LBA10002).
Best overall response in the pazopanib arm included partial responses in 6% of patients and stable disease in 67%, resulting in a clinical benefit rate of 73%. In contrast, no patient in the placebo arm had an objective response, and 38% had stable disease (Table).
The median treatment duration was 16.4 months in the pazopanib arm and 8.1 months in the placebo group. Half of patients in the pazopanib group required treatment interruptions, and 37% had dose reductions. Nonetheless, the dose intensity was 96.3%.
Adverse events most commonly associated with pazopanib treatment included fatigue (65%), diarrhea (58%), nausea (54%), weight loss (48%), hypertension (41%), and anorexia (40%). Grade 3/4 adverse events were infrequent.
Some patients in the pazopanib arm had liver enzyme abnormalities, which were expected. The most common grade 3/4 liver events involved gamma-GT (12%). The abnormalities were reversible in all cases.
“With adequate monitoring and timely interventions, adverse events are manageable,” said van der Graaf.
van der Graaf WT, Blay J, Chawla SP, et al. PALLETTE: a randomized, double-blind, phase III trial of pazopanib versus placebo in patients with soft-tissue sarcoma whose disease has progressed during or following prior chemotherapy—An EORTC STBSG Global Network Study (EORTC 62072). J Clin Oncol. 2011;29(suppl; abstr LBA10002).