Efficacy of Pazopanib With or Without Gemcitabine in Patients With Anthracycline- and/or Ifosfamide-Refractory Soft Tissue Sarcoma Final Results of the PAPAGEMO Phase 2 Randomized Clinical Trial

Question What is the tolerability and efficacy of pazopanib and gemcitabine compared with pazopanib alone in pretreated soft tissue sarcoma? Findings In this randomized clinical trial with 86 eligible patients, the combination of gemcitabine and pazopanib showed a significantly higher progression-free survival rate at 12 weeks (primary end point) compared with pazopanib alone. Meaning The combined regimen of gemcitabine and pazopanib seems to have clinical activity and should be further evaluated. Importance Pazopanib and gemcitabine have shown good tolerability, albeit modest single-agent activity in pretreated soft tissue sarcoma. A combined regimen to improve outcomes is required. Objective To determine the efficacy of gemcitabine and pazopanib compared with pazopanib alone. Design, Setting, and Participants This multicenter, randomized phase 2 clinical trial was conducted in Germany from September 2011 to July 2014 and included patients with an Eastern Cooperative Oncology Group performance status score of 0 to 2, adequate organ function, measurable lesion, and progression after at least 1 prior treatment with anthracyclines and/or ifosfamide. Data analysis was performed during 2019 and 2020. Interventions Patients were randomized to pazopanib with gemcitabine (A) or without gemcitabine (B). Main Outcomes and Measures The primary end point was progression-free survival rate (PFSR) at 12 weeks; secondary end points included toxicity, quality of life, overall survival, and response rates. Results A total of 90 patients were randomized, and 86 eligible patients (43 women [50%]) were evaluable, with a median age of 57 (range, 22-84) years and Eastern Cooperative Oncology Group performance status score of 0/1 in 77 participants (90%). The predominant histological subtypes were leiomyosarcoma (22 [26%]) and liposarcoma (16 [19%]). After a median follow-up of 12.4 (range, 1-48) months, the primary end point was met, with a PFSR at 12 weeks of 74% (A) vs 47% (B) (hazard ratio [HR], 1.60; 90% CI, 1.15-2.23; P = .01). In the combination arm, PFSR was significantly longer, with a median of 5.6 vs 2.0 months (HR, 0.58; 95% CI, 0.36-0.92; P = .02) compared with single-agent pazopanib, whereas overall survival was similar, with 13.1 vs 11.2 months (HR, 0.98; 95% CI, 0.60-1.58; P = .83). The objective response rate was overall low, with 11% (A) vs 5% (B) (P = .10). The toxicity of the combination of pazopanib and gemcitabine was increased, but it was manageable and mainly hematological. Conclusions and Relevance This phase 2 randomized clinical trial of patients with soft tissue sarcoma found that the addition of gemcitabine to pazopanib was tolerable, and PFSR at 12 weeks was significantly higher compared with pazopanib alone. These results suggest clinical activity of the combination, but they should be confirmed in a phase 3 trial in a more homogeneous population (eg, leiomyosarcoma). This randomized clinical trial examines the efficacy of gemcitabine and pazopanib compared with pazopanib alone for German patients with soft tissue sarcoma.

Automated summary

In this study, the combination of gemcitabine and pazopanib showed a significantly higher progression-free survival rate in soft tissue sarcoma patients compared to pazopanib alone, indicating clinical activity and good tolerability. However, further confirmation in a more representative population is needed to improve outcomes.