Differences in the responses to pazopanib and the prognoses of soft tissue sarcomas by their histological eligibility for the PALETTE study

Nakano, Kenji; Motoi, Noriko; Inagaki, Lina; Tomomatsu, Junichi; Gokita, Tabu; Ae, Keisuke; Tanizawa, Taisuke; Shimoji, Takeyoshi; Matsumoto, Seiichi; Takahashi, Shunji

doi:10.1093/jjco/hyv022

Cited by 13 publications

(12 citation statements)

References 20 publications

(12 reference statements)

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“…Thirdly, PALETTE ineligible patients with histology such as embryonal rhabdomyosarcoma, liposarcoma and Ewing’s sarcoma were included on the trial. In addition a recent study by Nakano et al notes that PALLETTE study ineligible patients might have worse prognosis on pazopanib than PALETTE-eligible patients and our study confirms this (24). The resistance mechanisms to VEGF inhibitors such as pazopanib are complex.…”

Section: Discussionsupporting

confidence: 90%

Phase Ib/II Study of the Safety and Efficacy of Combination Therapy with Multikinase VEGF Inhibitor Pazopanib and MEK Inhibitor Trametinib In Advanced Soft Tissue Sarcoma

Subbiah

Meyer

Zinner

et al. 2017

Clinical Cancer Research

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Purpose Pazopanib, a multi-receptor tyrosine kinase inhibitor targeting primarily vascular endothelial growth factor receptors 1-3 (VEGFRs1-3), is approved for advanced soft tissue sarcoma and renal cell cancer. Downstream of VEGFR, trametinib is an FDA-approved MEK inhibitor used for melanoma. We hypothesized that vertical pathway inhibition using a trametinib would synergize with pazopanib in advanced soft tissue sarcoma (STS). Experimental Design In an open-label, multicenter, investigator-initiated NCCN-sponsored trial, patients with metastatic or advanced STS received pazopanib 800 mg and 2 mg of trametinib continuously for 28-day cycles. The primary endpoint was 4-month progression-free survival (PFS). Secondary endpoints were overall survival, response rate and disease control rate. Results Twenty-five patients were enrolled. The median age was 49 years (range 22–77 years) and 52% were male. Median PFS was 2.27 months (95% confidence interval [CI] 1.9–3.9), and the 4-month PFS rate was 21.1% (95% CI 9.7–45.9%), which was not an improvement over the hypothesized null 4-month PFS rate of 28.3% (p = 0.79). Median overall survival was 9.0 months (95% CI 5.7–17.7). A partial response occurred in 2 (8%) of the evaluable patients (95% CI 1.0–26.0%), one with PIK3CA E542K mutant embryonal rhabdomyosarcoma and another with spindle cell sarcoma. The disease control rate was 14/25 (56%; 95% CI 34.9–75.6%). The most common adverse events were diarrhea (84%), nausea (64%), and fatigue (56%). Conclusion The combination of pazopanib and trametinib was tolerable without indication of added activity of the combination in STS. Further study may be warranted in RAS/RAF aberrant sarcomas.

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Section: Discussionsupporting

confidence: 90%

Phase Ib/II Study of the Safety and Efficacy of Combination Therapy with Multikinase VEGF Inhibitor Pazopanib and MEK Inhibitor Trametinib In Advanced Soft Tissue Sarcoma

Subbiah

Meyer

Zinner

et al. 2017

Clinical Cancer Research

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“…For instance, when choosing an anticancer drug for second-line treatment of liposarcoma and leiomyosarcoma, in addition to the clinical evidence, safety issues such as the onset or worsening of cardiac dysfunction caused by doxorubicin should be considered. Furthermore, retrospective studies from Japan have shown the inferior efficacy of pazopanib in the treatment of liposarcoma compared with other subtypes [35, 36]. Ifosfamide can also be an option for second-line and later treatment for metastatic STS, especially in cases of fibrosarcoma and synovial sarcoma.…”

Section: Discussionmentioning

confidence: 99%

Systemic Therapy for Soft Tissue Sarcoma: Proposals for the Optimal Use of Pazopanib, Trabectedin, and Eribulin

Kawai¹,

Yonemori²,

Takahashi

et al. 2017

Adv Ther

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Soft tissue sarcoma (STS) is a rare tumor with more than 50 histologic subtypes. Although treatment outcomes for patients with STS have improved greatly over the past few decades owing to the adoption of a multidisciplinary approach, patients with advanced disease have a poor prognosis. The development of anticancer drugs has been directed toward improving overall survival (OS). Doxorubicin monotherapy is currently the only standard option for the first-line treatment of STS. However, there is no standard therapy for second-line and later treatment at present. Since 2012, three anticancer drugs—pazopanib, trabectedin, and eribulin—have been approved in Japan for the second-line or later treatment of patients with advanced STS of any histologic subtype. However, the chemosensitivity of STS to each of these drugs varies by histologic subtype and their safety profiles differ; thus, histologic subtype and patient characteristics must be considered when determining optimal treatment. In this article, we review data from clinical studies related to the efficacy of all three drugs, including their effect on OS, and propose optimal treatment strategies for advanced STS by histologic subtype. In addition, with regard to the safety profiles, we highlight the key issues to be considered when selecting patients for treatment with pazopanib, trabectedin, or eribulin and ensuring their appropriate use, based on our combined clinical experience as specialists in the treatment of patients with STS. The proposed treatment strategies as well as treatment precautions based on clinical experience would benefit patients by maximizing the therapeutic effects and enhancing the proper use of these drugs. Funding: Eisai Co., Ltd.

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“…Moreover, an interruption or reduction of pazopanib was required in 10 patients because of thrombocytopenia. Nakano et al reported that 28% of Japanese patients with STS (13 of 47 patients) developed grade 1 or 2 thrombocytopenia, although there were no patients who required an interruption or reduction of pazopanib treatment . Physicians should be alert to the occurrence of pneumothorax and thrombocytopenia as well as other well known adverse events.…”

Section: Discussionmentioning

confidence: 99%

The clinical outcome of pazopanib treatment in Japanese patients with relapsed soft tissue sarcoma: A Japanese Musculoskeletal Oncology Group (JMOG) study

Nakamura

Matsumine

Kawai

et al. 2016

Cancer

107

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BACKGROUNDBecause the efficacy and safety of pazopanib in Japanese patients with soft tissue sarcoma (STS) had not been evaluated previously in a large‐scale cohort, the authors investigated the efficacy and safety of pazopanib in 156 Japanese patients with relapsed STS. This was a retrospective study based on the collection of real‐life, postmarketing surveillance data.METHODSPatients received pazopanib with the objective of treating local recurrence (n = 20), metastasis (n = 104), and both (n = 32). The patient median age was 53.8 years. The primary objective of this study was to clarify the efficacy of pazopanib for patients with STS.RESULTSThe median treatment duration was 28.7 weeks, and the average dose intensity of pazopanib was 609 mg. Adverse events occurred in 127 patients (81.4%). In addition to the main common toxicities, such as hypertension and liver disorder, pneumothorax (n = 11) and thrombocytopenia (n = 16) also were observed. The median progression‐free survival for all patients was 15.4 weeks. The median progression‐free survival for patients with leiomyosarcoma, synovial sarcoma, undifferentiated pleomorphic sarcoma, and liposarcoma was 18.6 weeks, 16.4 weeks, 15.3 weeks, and 8 weeks, respectively. The median survival for all patients was 11.2 months. The median survival for patients with leiomyosarcoma, synovial sarcoma, undifferentiated pleomorphic sarcoma, and liposarcoma was 20.1 months, 10.6 months, 9.5 months, and 7.3 months, respectively.CONCLUSIONSThere were apparent differences in the efficacy of pazopanib treatment among histologic types of STS. Pazopanib treatment is a new treatment option; however, adverse events like pneumothorax and thrombocytopenia, which did not occur frequently in the PALETTE study (pazopanib for metastatic soft‐tissue sarcoma), should be taken into consideration. Cancer 2016;122:1408‐16. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

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Differences in the responses to pazopanib and the prognoses of soft tissue sarcomas by their histological eligibility for the PALETTE study

Cited by 13 publications

References 20 publications

Phase Ib/II Study of the Safety and Efficacy of Combination Therapy with Multikinase VEGF Inhibitor Pazopanib and MEK Inhibitor Trametinib In Advanced Soft Tissue Sarcoma

Phase Ib/II Study of the Safety and Efficacy of Combination Therapy with Multikinase VEGF Inhibitor Pazopanib and MEK Inhibitor Trametinib In Advanced Soft Tissue Sarcoma

Systemic Therapy for Soft Tissue Sarcoma: Proposals for the Optimal Use of Pazopanib, Trabectedin, and Eribulin

The clinical outcome of pazopanib treatment in Japanese patients with relapsed soft tissue sarcoma: A Japanese Musculoskeletal Oncology Group (JMOG) study

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