Efficacy of Pazopanib With or Without Gemcitabine in Patients With Anthracycline- and/or Ifosfamide-Refractory Soft Tissue Sarcoma

Abstract

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).

The real‐world clinical outcomes and treatment patterns of patients with unresectable locally advanced or metastatic soft tissue sarcoma treated with anlotinib in the post‐ALTER0203 trial era

“…In addition to combining chemotherapy, anlotinib was also combined with immunotherapy or local treatment in some cases. This may explain the difference in the findings of the PAPAGEMO study 39 and our study. Promisingly, switching maintenance therapy with anlotinib after chemotherapy was also significantly associated with longer median PFS and OS (Tables 4 and 5, Figure 2).…”

“…The PAPAGEMO phase II trial was conducted in patients with anthracycline-and/or ifosfamide-failed STS and showed that pazopanib combined with gemcitabine significantly prolonged the median PFS compared with pazopanib monotherapy, but with similar median OS. 39 Our findings suggested that compared with anlotinib monotherapy, anlotinib in combination with other therapies not only improved the ORR and median PFS, but also prolonged the median OS (Tables 4 and 5, Figure 2). In addition to combining chemotherapy, anlotinib was also combined with immunotherapy or local treatment in some cases.…”

Phase II study of pazopanib with oral topotecan in patients with metastatic and non-resectable soft tissue and bone sarcomas

“…Although the combination of pazopanib and topotecan did not meet predefined endpoints, other recent trials of the combination of gemcitabine with pazopanib have demonstrated efficacy above that of single agent pazopanib alone. 12 In the PAPAGEMO study, patients with anthracycline and/or ifosfamide refractory STS had a PFS of 5.6 months with gemcitabine and pazopanib, as opposed to 2.0 months with single agent pazopanib (HR 0.58, 95% CI 0.36-0.92). Median prior lines of therapy was 2 in the PAPAGEMO trial, with 30% of patients having received more than 2.…”

“…There remained some uncertainties, however, regarding the role of pazopanib in the care of liposarcoma, with recent studies indicating perhaps some efficacy alone, or in combination with cytotoxic treatment. 11,12 Topotecan, when used as treatment for STS demonstrated tolerability, as well as objective response in leiomyosarcoma. 13,14 Combination regimens with topotecan likewise have shown efficacy in populations of patients with relapsed and refractory osteosarcoma.…”

Gemcitabine Plus Anlotinib Is Effective and Safe Compared to Gemcitabine Plus Docetaxel in Advanced Soft Tissue Sarcoma

“…The LMS03 study ( 34 ) assessed the efficacy and safety of G plus pazopanib followed by pazopanib (G 1,000 mg/m 2 on days 1 and 8 and pazopanib 800 mg daily of each for 21 days, for no more than 8 cycles, followed by pazopanib) as the second-line treatment in advanced LMS; although the PFS rate at 9 months (PFR 9m) of 32% with a median PFS of 6.5 months failed to meet the target of 44%, a PFR 9m of 34.6% and a median PFS of 7.1 months in the per-protocol population were promising. The PAPAGEMO study ( 39 ) examined the efficacy of pazopanib plus G (pazopanib 800 mg once daily and G 1,000 mg/m 2 on days 1 and 8 every 3 weeks) and G (G 1,000 mg/m 2 on days 1 and 8 every 3 weeks) in advanced STS patients who failed with anthracycline and/or ifosfamide. The results show that compared with pazopanib alone, G+D significantly increased PFSR at 12 weeks (74% vs. 47%), with prolonged median PFS (5.6 months vs. 2.0 months), respectively.…”