PALETTE

Background

PALETTE — Phase III double-blind, randomised, placebo-controlled trial. N=369 patients with metastatic or unresectable STS who had progressed on or after standard chemotherapy (typically ≥2 prior lines including anthracycline and ifosfamide). Enrolled at 78 centres in 13 countries 2008–2011. Adipocytic STS (WD-LPS, DDLPS) and GIST were excluded from eligibility. Pazopanib is an oral multi-targeted VEGFR/PDGFR/c-KIT tyrosine kinase inhibitor with prior activity in STS. Registration NCT00753688.

Interventions and follow up

Arm A: Pazopanib 800 mg PO QD until progression
Arm B: Placebo PO QD
Primary endpoint: Progression-free survival (intention-to-treat)
mFollow up: Median 15.3 month

Results

mPFS: 4.6 months (pazopanib) vs 1.6 months (placebo); HR 0.31 (95% CI 0.24–0.40), P<.0001
mOS: 12.5 vs 10.7 months; HR 0.86 (95% CI 0.67–1.11), P=.25 — not significant
ORR: 6% (pazopanib) vs 0% (placebo)
Disease control rate: 67% vs 38%

Adverse events

Main adverse events: Grade ≥3 fatigue: 13%, hypertension: 7%, diarrhea: 5%, dyspnea: 3%. Hepatotoxicity (AST/ALT elevation): 7% grade ≥3. Treatment discontinuation due to AEs: 14%. Dose reduction: 39%.

Conclusions

Pazopanib significantly improved PFS (HR 0.31, P<.0001) compared with placebo in pre-treated advanced STS, with a 3-month absolute PFS gain, but did not significantly improve OS. This established pazopanib as a standard option for second-line or later advanced STS following failure of standard chemotherapy, and represented the first positive phase III trial for a targeted agent in non-GIST STS.

Key Limitations

PFS but not OS was improved — the discrepancy may reflect post-progression therapies or population heterogeneity. Exclusion of adipocytic STS and GIST limits applicability to these common subtypes. ORR of only 6% confirms that disease stabilisation is the primary mechanism of benefit. The control arm's mPFS of 1.6 months underscores the aggressive biology of this pre-treated population. Post-protocol crossover or therapy may have confounded OS. Pazopanib was subsequently withdrawn from the EU for STS in 2020 following EPAR review, though remains used in many countries.

Clinical Context

PALETTE established pazopanib (800 mg/day) as an approved option for pre-treated advanced STS (excluding adipocytic STS and GIST) in the US and EU. NCCN lists pazopanib as a category 1 preferred regimen for second-line STS. Trabectedin (for LMS) and eribulin (for LPS, based on EORTC-SAR Study) are approved alternatives. In the GIST setting, regorafenib (GRID) and ripretinib (INTRIGUE) are preferred. Biomarker predictors of pazopanib response in STS remain unknown. PALETTE remains a landmark trial for STS drug development methodology.
Arm A (pazopanib, n=246): Pazopanib 800 mg orally once daily continuously until PD or unacceptable toxicity
Arm B (placebo, n=123): Placebo orally once daily continuously until PD

References