Nivolumab and sunitinib combination in advanced soft tissue sarcomas: a multicenter, single-arm, phase Ib/II trial (original) (raw)
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Frontiers in Immunology, 2021
BackgroundHigh-grade sarcomas are a heterogeneous group of aggressive tumors arising in bone and soft tissues. After relapse, treatment options are limited. The multi-targeted receptor tyrosine kinase inhibitors (TKIs) sunitinib and inhibitor of PD-1 (anti-PD-1) nivolumab have shown antitumor activity in selected subtypes. In this study, we examine the role of TKIs and PD-1 based therapy in in vitro cocultures of sarcoma.MethodsThe human osteosarcoma (SaOS-2) and synovial sarcoma (SYO-1) cell lines were treated with sunitinib. After cell death and proliferation assessment, expression of PD-L1 was analyzed by flow cytometry. Sunitinib-treated sarcoma cells were cocultured with dendritic cells (DCs), and the phenotype of mature DCs was determined by flow cytometry. Mature DCs were cultured with autologous T cells. PD-1 expression on T cells, their proliferation, T regulatory cell (Tregs) induction and IFN-γ production, before and after nivolumab exposure, were analyzed.ResultsAlong wi...
Cancers
Background: This Phase 1/2 study is based on the hypothesis that immune checkpoint inhibitors are more effective when given earlier in the course of the disease for advanced soft tissue sarcoma. Methods: Phase I endpoints—maximum tolerated dose in previously treated patients; Phase II endpoints—best response, progression free survival and overall survival and incidence of adverse events in previously untreated patients; Phase I treatments—escalating doses of trabectedin (1.0, 1.2, 1.5 mg/m2) as continuous intravenous infusion over 24 h every 3 weeks, 1 mg/kg of ipilimumab given intravenously every 12 weeks, and 3 mg/kg of nivolumab given intravenously every 2 weeks; Phase II treatments—maximum tolerated dose of trabectedin and defined doses of ipilimumab and nivolumab. Results: Phase I (n = 9)—the maximum tolerated dose of trabectedin was 1.2 mg/m2; Phase II (n = 79)—6 complete responses, 14 partial responses, 49 stable disease, 25.3% best response rate, 87.3% disease control rate; ...
Randomized Phase II Trial of Sunitinib or Cediranib in Alveolar Soft Part Sarcoma
Clinical Cancer Research
Purpose: Alveolar soft part sarcoma (ASPS) is a rare, highly vascular tumor with few treatment options. We designed a phase II randomized trial to determine the activity and tolerability of single-agent cediranib or sunitinib in patients with advanced metastatic ASPS. Patients and Methods: Patients 16 years of age and older were randomized to receive cediranib (30 mg) or sunitinib (37.5 mg) in 28-day cycles. Patients could cross over to the other treatment arm at disease progression. The primary endpoint was to measure the objective response rate (ORR) for each agent. Median progression-free survival (mPFS) for the two arms was also determined. Results: Twenty-nine of 34 enrolled patients were evaluable for response. One patient on each of the initial two treatment arms had a partial response (ORR: 6.7% and 7.1% for cediranib and sunitinib, respectively). Twenty-four patients had a best response of stable disease (86.7% and 78.6% for cediranib and sunitinib, respectively). There wer...
Current Status and Future Directions of Immunotherapies in Soft Tissue Sarcomas
Biomedicines, 2022
Immunotherapy in soft tissue sarcoma (STS) has experienced a surge of interest in the past decade, contributing to an expanding number of therapeutic options for this extremely heterogenous group of rare malignancies. Immune checkpoint inhibitors (CPIs) targeting the PD-1 and CTLA-4 axes have demonstrated promising responses in a select number of STS subtypes, including rarer subtypes, such as alveolar soft part sarcoma, SWI/SNF-deficient sarcomas, clear cell sarcoma, and angiosarcoma. Multiple pan-subtype sarcoma trials have facilitated the study of possible predictive biomarkers of the CPI response. It has also become apparent that certain therapies, when combined with CPIs, can enhance response rates, although the specific mechanisms of this possible synergy remain unconfirmed in STS. In addition to CPIs, several other immune targeting agents, including anti-tumour-associated macrophage and antigen-directed therapies, are now under assessment in STS with promising efficacy in som...
Clinical Cancer Research, 2020
Purpose: We recently reported a 17.5% objective RECIST 1.1 response rate in a phase II study of pembrolizumab in patients with advanced sarcoma (SARC028). The majority of responses occurred in undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcoma (DDLPS). We sought to determine whether we can identify immune features that correlate with clinical outcomes from tumor tissues obtained pre- and on-treatment. Patients and Methods: Pretreatment (n = 78) and 8-week on-treatment (n = 68) tumor biopsies were stained for PD-L1 and multiplex immunofluorescence panels. The density of positive cells was quantified to determine associations with anti–PD-1 response. Results: Patients that responded to pembrolizumab were more likely to have higher densities of activated T cells (CD8+ CD3+ PD-1+) and increased percentage of tumor-associated macrophages (TAM) expressing PD-L1 pre-treatment compared with non-responders. Pre-treatment tumors from responders also exhibited higher d...
Journal of Clinical Oncology, 2018
Immune checkpoint inhibitors revive pre-existing immune responses that are suppressed in cancer. To restore innate tumour surveillance that is lost in cancer patients, a tumoricidal agent may have synergistic activity with certain immune checkpoint inhibitors. Herein, we report on our clinical experience using two FDA-approved drugs, trabectedin, a marine derived natural alkaloid with pro-apoptosis and immune modulator properties, in combination with nivolumab, a PD-1 immune checkpoint inhibitor, in advanced Soft Tissue Sarcoma (STS). Twenty-eight heavily pre-treated STS patients received trabectedin (1.5 mg/m 2 Continuous Intravenous Infusion, CIV, for 24 hours) every 3 weeks, and nivolumab (3 mg/kg IV over 30 minutes) every 2 weeks. Retrospective analysis of safety/toxicity was conducted using the NIH/NCI CTCAE v.4.03. Tumour responses were assessed by RECIST v1.1 and irRECIST. Histologic subtypes in 28 patients include undifferentiated pleomorphic sarcoma (UPS; n=7), myofibroblastic sarcoma (n=1), leiomyosarcoma (n=6), synovial sarcoma (n=4), liposarcoma (n=6), chondrosarcoma (n=2), and Ewing sarcoma (n=2). All patients had metastatic disease and a median of 4 lines of prior chemotherapy. Safety analysis (n=28): Grade 3 treatment emergent adverse events include anaemia (n=2), fatigue (n=1), decreased platelet count (n=1), decreased granulocyte count (n=1) and increased creatine kinase (n=1). Efficacy analysis (n=22): Twenty-two patients were followed for at least 6 months and their results are reported here. There were 4 partial responses (UPS=1, myxoid liposarcoma=1, chondrosarcoma=1, leiomyosarcoma=1), 12 stable disease and 6 progressive disease, with best overall response rate of 18.2%, median progression free survival (PFS) of >45.4 weeks (range: 10->95 weeks), median Overall Survival (OS) of >66.5 weeks (10->95 weeks), 6 month PFS rate of 68.2%, and 6 month OS rate of 95.4%. Taken together, the data suggest that paired administration of trabectedin and nivolumab is safe, and that this chemo-/immunotherapy approach has synergistic activity that can lead to improved clinical outcomes.
Journal of Clinical Oncology, 2009
Purpose Given the importance of angiogenesis in soft tissue sarcoma (STS), pazopanib, an oral angiogenesis inhibitor that targets vascular endothelial growth factor receptor and platelet-derived growth factor receptor, was explored in patients with advanced STS. Patients and Methods Patients with intermediate- or high-grade advanced STS who were ineligible for chemotherapy or who had received no more than two prior cytotoxic agents for advanced disease, who had documented progression, who had adequate performance status, and who had good organ function were eligible. Pazopanib 800 mg was given daily. The primary end point was progression-free rate at 12 weeks (PFR12 weeks). Secondary end points were response, safety, and overall survival. Four different strata were studied: adipocytic STS, leiomyosarcomas, synovial sarcomas, and other STS types. A Simon two-stage design was applied (P1 = 40%; P0 = 20%; α = β = .1) for each stratum. Results One hundred forty-two patients were enrolle...
The Lancet. Oncology, 2017
Patients with advanced sarcomas have a poor prognosis and few treatment options that improve overall survival. Chemotherapy and targeted therapies offer short-lived disease control. We assessed pembrolizumab, an anti-PD-1 antibody, for safety and activity in patients with advanced soft-tissue sarcoma or bone sarcoma. In this two-cohort, single-arm, open-label, phase 2 study, we enrolled patients with soft-tissue sarcoma or bone sarcoma from 12 academic centres in the USA that were members of the Sarcoma Alliance for Research through Collaboration (SARC). Patients with soft-tissue sarcoma had to be aged 18 years or older to enrol; patients with bone sarcoma could enrol if they were aged 12 years or older. Patients had histological evidence of metastatic or surgically unresectable locally advanced sarcoma, had received up to three previous lines of systemic anticancer therapy, had at least one measurable lesion according to the Response Evaluation Criteria In Solid Tumors version 1.1,...
European Journal of Cancer, 2021
Background: Soft-tissue sarcomas (STSs) are rare malignancies, accounting for approximately 1% of adult cancer. Metastatic disease carries a poor prognosis, and various efforts have been made to improve the prognosis of advanced STS, to date with little success. Immune checkpoint inhibitors (ICPIs) have substantially improved prognosis for many cancer types. Their role in the treatment of STS, however, remains unravelled. Objective: The objective of the study is to assess the activity of ICPIs in the treatment of STS. Methods: We performed a systematic review using MEDLINE, Embase and Cochrane Central Register of Controlled Trials. Furthermore, abstracts from European Society of Medical Oncology (ESMO), American Society of Clinical Oncology (ASCO) and Connective Tissue Society Oncology (CTOS) congress were searched from 2017 until 2020. Prospective clinical trials investigating ICPIs, either monotherapy or combination therapy, in STS were available for inclusion. The outcomes of interest were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and major toxicity. Cutoff for clinical activity was defined as an ORR of !0.15. Subgroup analysis was carried out as per treatment category, disease setting and histologic subtype, using a random effects model. Results: We identified 27 studies, including a total of 1012 patients (range 6e85) with more than 25 histologic subtypes. The pooled ORR was 0.14 (95% confidence interval [CI] 0.09