Patients with metastatic sarcoma have limited treatment options. Nivolumab and ipilimumab are monoclonal antibodies targeting PD-1 and CTLA-4, respectively. We investigated the activity and safety of nivolumab alone or in combination with ipilimumab in patients with locally advanced, unresectable, or metastatic sarcoma.
Methods
We did a multicentre, open-label, non-comparative, randomised, phase 2 study that enrolled patients aged 18 years or older and had central pathology confirmation of sarcoma with at least one measurable lesion by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1, evidence of metastatic, locally advanced or unresectable disease, an ECOG performance status of 0–1, and received at least one previous line of systemic therapy. Patients were assigned to treatment in an unblinded manner, as this trial was conducted as two independent, non-comparative phase 2 trials. Enrolled patients were assigned (1:1) via a dynamic allocation algorithm to intravenous nivolumab 3 mg/kg every 2 weeks, or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses. Thereafter, all patients received nivolumab monotherapy (3 mg/kg) every 2 weeks for up to 2 years. The primary endpoint was the proportion of patients with locally advanced, unresectable or metastatic soft tissue sarcoma achieving a confirmed objective response. Analysis was per protocol. This study is ongoing although enrolment is closed. It is registered with ClinicalTrials.gov, number NCT02500797.
Findings
Between Aug 13, 2015, and March 17, 2016, 96 patients from 15 sites in the USA underwent central pathology review for eligibility and 85 eligible patients, including planned over-enrolment, were allocated to receive either nivolumab monotherapy (43 patients) or nivolumab plus ipilimumab (42 patients). The primary endpoint analysis was done according to protocol specifications in the first 76 eligible patients (38 patients per group). The number of confirmed responses was two (5% [92% CI 1–16] of 38 patients) in the nivolumab group and six (16% [7–30] of 38 patients) in the nivolumab plus ipilimumab group. The most common grade 3 or worse adverse events were anaemia (four [10%] patients), decreased lymphocyte count (three [7%]), and dehydration, increased lipase, pain, pleural effusion, respiratory failure, secondary benign neoplasm, and urinary tract obstruction (two [5%] patients each) among the 42 patients in the nivolumab group and anaemia (eight [19%] patients), hypotension (four [10%] patients), and pain and urinary tract infection (three [7%] patients each) among the 42 patients in the nivolumab plus ipilimumab group. Serious treatment-related adverse events occurred in eight (19%) of 42 patients receiving monotherapy and 11 (26%) of 42 patients receiving combination therapy, and included anaemia, anorexia, dehydration, decreased platelet count, diarrhoea, fatigue, fever, increased creatinine, increased alanine aminotransferase, increased aspartate aminotransferase, hyponatraemia, pain, pleural effusion, and pruritus. There were no treatment-related deaths.
Interpretation
Nivolumab alone does not warrant further study in an unselected sarcoma population given the limited efficacy. Nivolumab combined with ipilimumab demonstrated promising efficacy in certain sarcoma subtypes, with a manageable safety profile comparable to current available treatment options. The combination therapy met its predefined primary study endpoint; further evaluation of nivolumab plus ipilimumab in a randomised study is warranted.
Funding
Alliance Clinical Trials in Oncology, National Cancer Institute Cancer Therapy Evaluation Program, Bristol-Myers Squibb, Cycle for Survival.
Introduction
Sarcomas are rare, heterogeneous malignant tumours of mesenchymal origin characterised into more than 100 distinct subtypes, accounting for 1% of malignancies in adults.1 For newly diagnosed patients with metastatic sarcoma who are chemotherapy naive, the efficacy of approved treatments, doxorubicin alone or gemcitabine plus docetaxel, is similar,2 with approximately 18% of patients achieving objective responses with these regimens, with progression-free survival of approximately 5 months and overall survival of 16 months. Beyond the front-line setting, the US Food and Drug Administration (FDA) has granted approval for systemic agents, including pazopanib, trabectedin, and eribulin, for selected sarcoma subtypes.3, 4, 5 Each of these agents conferred modest improvements in either progression-free survival or overall survival. Yet the overall proportion of patients achieving objective responses remains less than 10%, with median progression-free survival of 4 months and overall survival of less than 14 months.3, 4, 5 In a recent phase 2 study in patients with advanced soft tissue sarcoma,6 the median overall survival of patients treated with doxorubicin plus olaratumab was superior to the monotherapy (stratified hazard ratio [HR] 0·46, 95% CI 0·30–0·71, p=0·0003), 26·5 months (20·9–31·7) versus 14·7 months (9·2–17·1) in the doxorubicin alone group, which lead to the approval of doxorubicin plus olaratumab treatment in these patients.6 These findings are pending confirmation in a larger, randomised, phase 3 study (NCT02451943), which has now closed to accrual. Despite these recent approvals by the FDA, the need for therapies that are less toxic, and offer durable disease control and improved survival in patients with metastatic sarcoma remains.
Research in context
Evidence before this study
We searched PubMed using the terms, “metastatic sarcoma” and “immunotherapy or immune checkpoint and sarcoma” for articles published up to June 1, 2017, without language restrictions. We excluded review articles and meta-analyses. Programmed death ligand 1 (PD-L1) expression has been investigated in sarcoma samples. Results have varied with the assay used, type of sarcoma, and timing of testing thereby limiting its role as a predictive biomarker of treatment benefit. A comprehensive overview of the sarcoma immune microenvironment was reported for four sarcoma subtypes, including undifferentiated pleomorphic sarcoma, leiomyosarcoma, synovial sarcoma, and liposarcoma. In this analysis, undifferentiated pleomorphic sarcoma and leiomyosarcoma were shown to have high expression of genes related to antigen presentation and T-cell infiltration compared with synovial sarcoma or liposarcoma. These analyses could provide rationale for the exploration of immunotherapeutic approaches, including checkpoint inhibitors, in sarcoma. Thus far, there has been limited success with either T-lymphocyte (CTLA-4) or anti programmed death-1 (PD-1) antibodies, alone in sarcomas such as leiomyosarcoma, synovial sarcoma and most bone sarcomas. However, pembrolizumab led to promising results in undifferentiated pleomorphic sarcoma and liposarcoma.
Added value of this study
To our knowledge, this is the first investigation of combination checkpoint inhibition in patients with sarcoma. Combination treatment with nivolumab plus ipilimumab in patients with advanced, previously treated sarcoma achieved promising objective responses that seemed to be clinically meaningful in undifferentiated pleomorphic sarcoma, leiomyosarcoma, myxofibrosarcoma, and angiosarcoma. Additionally, the current dose and schedule for the combination tested (3 mg/kg nivolumab plus 1 mg/kg ipilimumab) had acceptable toxicity, with 14% of patients having grade 3 or 4 treatment-related adverse events. Our results are similar to those obtained with existing systemic chemotherapeutic agents. The combination cohort met the primary endpoint, thereby forming the basis for a confirmatory phase 3 clinical trial that is being planned in selected sarcoma subtypes in which responses were observed.
Implications of all the available evidence
Monotherapy checkpoint inhibition has promising activity in undifferentiated pleomorphic sarcoma and liposarcoma. Our findings might support future studies of nivolumab plus ipilimumab in patients with these specific subtypes of metastatic sarcoma, as well as those with angiosarcoma, leiomyosarcoma, and myxofibrosarcoma. These findings also highlight the need for the identification of a predictive biomarker that can inform treatment decisions.
Modulating the immune system with monoclonal antibodies that block immune checkpoints has emerged as a promising strategy in cancer care that leads to durable antitumour activity and improved survival in multiple malignancies when compared with other systemic therapies.7, 8, 9, 10, 11, 12, 13 Immune checkpoints molecules such as programmed death ligand 1 (PD-L1) can be overexpressed by tumours or the tumour microenvironment, inhibiting the antitumour activity of effector T cells.14 Some sarcomas express PD-L1, with reported expression of positive PD-L1 cells ranging from 12% to 65%, depending on the sarcoma histology, timing of sample collection, and assay used for PD-L1 detection.15, 16 This variability poses a challenge in the use of PD-L1 expression as a prognostic biomarker. Additionally, clinical data from patients treated with checkpoint inhibitors have suggested that patients can benefit from this therapy irrespective of PD-L1 expression.8, 9, 12, 17 While this finding highlights the need for more effective biomarkers, it should not preclude the exploration of available checkpoint inhibitors in sarcoma.
Limited evidence exists on the activity of checkpoint inhibitors in sarcoma. In a small phase 2 study,18 six patients with synovial sarcoma were treated with ipilimumab 3 mg/kg every 3 weeks without achieving any documented responses. Another phase 2 study19 in 80 patients with bone or soft tissue sarcomas showed that 18% of patients in the soft tissue sarcoma group achieved objective responses, with all these patients having either undifferentiated pleomorphic sarcoma or liposarcoma. Of the 40 patients with bone sarcoma, only two had objective responses, one in a patient with osteosarcoma and the other in a patient with dedifferentiated chondrosarcoma. The low clinical activity of pembrolizumab alone in most sarcoma subtypes suggests that this agent cannot adequately activate suppressed effector T cells in these patients. Undifferentiated pleomorphic sarcoma is an inflamed tumour characterised by high numbers of tumour infiltrating lymphocytes, which could explain the clinical activity of pembrolizumab noted in this subgroup of sarcoma patients.20 Most subtypes of sarcoma do not have infiltration of immune cells, emphasising the need to explore other combinatorial immunotherapy strategies. Combination of agents that enhance antitumour effects through different mechanisms, such as cytotoxic T-lymphocyte (CTLA-4) and programmed death-1 (PD-1), have been shown to be synergistic in preclinical mouse models of melanoma.21 Additionally, clinical data of these agents in multiple malignancies, have shown their efficacy when compared with chemotherapy regimens.7, 10, 22 We did this study to assess the activity of nivolumab alone and nivolumab plus ipilimumab in patients with metastatic sarcoma.
Section snippets
Study design and participants
This multicentre, open-label, non-comparative, randomised, phase 2 trial recruited patients from 15 centres in the USA that were members of the Alliance Clinical Trials in Oncology Group (A091401) and the National Clinical Trials Network (NCTN; appendix p 11).
Eligible patients aged 18 years or older had histologically confirmed bone or soft tissue sarcoma by central pathology review, locally advanced, unresectable, or metastatic sarcoma by Response Evaluation Criteria In Solid Tumors (RECIST)
Results
96 patients underwent central pathology review for eligibility, 81 patients from Aug 13 to Dec 24, 2015, and 15 patients from March 16 to March 17, 2016. 11 of 96 patients were excluded, so 85 patients from 13 Alliance Clinical Trials in Oncology sites and two NCTN groups in the USA proceeded to randomisation (appendix p 11). 43 patients were assigned to nivolumab alone group and 42 patients to nivolumab plus ipilimumab group. One patient withdrew consent to initiate nivolumab monotherapy after
Discussion
In these phase 2 trials of nivolumab with or without ipilimumab, 85 patients were rapidly enrolled in 5 months. Two (5%) of 38 evaluable patients with advanced sarcoma achieved a confirmed objective response when treated with nivolumab monotherapy, while six (16%) of 38 achieved a confirmed objective response with a combination of nivolumab plus ipilimumab. Across both treatment groups, patients were heavily treated, with 52 (61%) of 85 patients having received at least three previous lines of
Efficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy: results of a phase III randomized multicenter clinical trial
The study investigates the anticancer activity of mefenamic acid against osteosarcoma, shedding light on its underlying mechanisms and therapeutic potential. Mefenamic acid exhibited robust inhibitory effects on the proliferation of MG-63, HOS, and H2OS osteosarcoma cells in a dose-dependent manner. Moreover, mefenamic acid induced cellular toxicity in MG63 cells, as evidenced by LDH leakage, reflecting its cytotoxic impact. Furthermore, mefenamic acid effectively suppressed the migration and invasion of MG-63 cells. Mechanistically, mefenamic acid induced apoptosis in MG-63 cells through mitochondrial depolarization, activation of caspase-dependent pathways, and modulation of the Bcl-2/Bax axis. Additionally, mefenamic acid promoted autophagy and inhibited the PI3K/Akt/mTOR pathway, further contributing to its antitumor effects. The molecular docking studies provide compelling evidence that mefenamic acid interacts specifically and strongly with key proteins in the PI3K/AKT/mTOR pathway, suggesting a novel mechanism by which mefenamic acid could exert anti-osteosarcoma effects. In vivo studies using a xenograft mouse model demonstrated significant inhibition of MG-63 tumor growth without adverse effects, supporting the translational potential of mefenamic acid as a safe and effective therapeutic agent against osteosarcoma. Immunohistochemistry staining corroborated the in vivo findings, highlighting mefenamic acid's ability to suppress tumor proliferation and inhibit the PI3K/AKT/mTOR pathway within the tumor microenvironment. Collectively, these results underscore the promising therapeutic implications of mefenamic acid in combating osteosarcoma, warranting further investigation for clinical translation and development.
Well-differentiated liposarcomas (WDLPS) and dedifferentiated liposarcomas (DDLPS) account for 60 % of all liposarcomas, reflecting the heterogeneity of this type of sarcoma. Genetically, both types of liposarcomas are characterized by the amplification of MDM2 and CDK4 genes, which indicates an important molecular event with diagnostic and therapeutic relevance. In both localized WDLPS and DDLPS of the retroperitoneum and the extremities, between 25 % and 30 % of patients have local or distant recurrence, even when perioperatively treated, with clear margins present. The systemic treatment of WDLPS and DDLPS remains a challenge, with anthracyclines as the gold standard for first-line treatment. Several regimens have been tested with modest results regarding their efficacy. Herein we discuss the systemic treatment options for WDLPS and DDLPS and review their reported clinical efficacy results.
Sarcomas are a heterogeneous group of bone and soft tissue tumors. Survival outcomes for advanced (unresectable or metastatic) disease remain poor, so therapeutic improvements are needed. Radiotherapy plays an integral role in the neoadjuvant and adjuvant treatment of localized disease as well as in the treatment of metastatic disease. Combining radiotherapy with immunotherapy to potentiate immunotherapy has been used in a variety of cancers other than sarcoma, and there is opportunity to further investigate combining immunotherapy with radiotherapy to try to improve outcomes in sarcoma. In this review, we describe the diversity of the tumor immune microenvironments for sarcomas and describe the immunomodulatory effects of radiotherapy. We discuss studies on the timing of radiotherapy relative to immunotherapy and studies on the radiotherapy dose and fractionation regimen to be used in combination with immunotherapy. We describe the impact of radiotherapy on the tumor immune microenvironment. We review completed and ongoing clinical trials combining radiotherapy with immunotherapy for sarcoma and propose future directions for studies combining immunotherapy with radiotherapy in the treatment of sarcoma.
Extremity and truncal soft tissue sarcomas are a heterogeneous group of rare cancers that arise from mesenchymal tissues. Hence, the adoption of tailored risk assessment and prognostication tools plays a crucial role in optimizing the decision-making for which of the many possible treatment strategies to select. Management of these tumors requires a multidisciplinary strategy, which has seen significant development in recent decades. Surgery has emerged as the primary treatment approach, with the main goal of achieving microscopic negative tumor margins. To reduce the likelihood of local recurrence, loco-regional treatments such as radiation therapy and isolated limb perfusion are often added to the treatment regimen in combination with surgery. This approach also enables surgeons to perform limb-sparing surgery, particularly in cases where a positive tumor margin is expected. Chemotherapy may also provide a further benefit in decreasing the probability of local recurrence or reducing distant metastasis in selected patients. Selecting the optimal treatment strategy for these rare tumors is best accomplished by an experienced multi-disciplinary team.
Due to their rarity and complexity, sarcomas represent a substantial therapeutic challenge. However, the incredible diversity within and across sarcoma subtypes presents an opportunity for personalized care to maximize efficacy and limit toxicity. A deeper understanding of the molecular alterations that drive sarcoma development and treatment response has paved the way for molecular biomarkers to shape sarcoma treatment. Genetic, transcriptomic, and protein biomarkers have become critical tools for diagnosis, prognostication, and treatment selection in patients with sarcomas. In the future, emerging biomarkers like circulating tumor DNA analysis offer the potential to improve early detection, monitoring response to treatment, and identifying mechanisms of resistance to personalize sarcoma treatment. Here, we review the current state of molecular biomarkers for sarcomas and highlight opportunities and challenges for the implementation of new technologies in the future.
Osteosarcoma is usually resistant to immunotherapy and, thus primarily relies on surgical resection and high-dosage chemotherapy. Unfortunately, less invasive or toxic therapies such as photothermal therapy (PTT) and chemodynamic therapy (CDT) generally failed to show satisfactory outcomes. Adequate multimodal therapies with proper safety profiles may provide better solutions for osteosarcoma. Herein, a simple nanocomposite that synergistically combines CDT, PTT, and chemotherapy for osteosarcoma treatment was fabricated. In this composite, small 2D NiFe-LDH flakes were processed into 3D hollow nanospheres via template methods to encapsulate 5-Fluorouracil (5-FU) with high loading capacity. The nanospheres were then adsorbed onto larger 2D Ti3C2 MXene monolayers and finally shielded by bovine serum albumin (BSA) to form 5-FU@NiFe-LDH/Ti3C2/BSA nanoplatforms (5NiTiB). Both in vitro and in vivo data demonstrated that the 5-FU induced chemotherapy, NiFe-LDH driven chemodynamic effects, and MXene-based photothermal killing collectively exhibited a synergistic “all-in-one” anti-tumor effect. 5NiTiB improved tumor suppression rate from <5% by 5-FU alone to ∼80.1%. This nanotherapeutic platform achieved higher therapeutic efficacy with a lower agent dose, thereby minimizing side effects. Moreover, the composite is simple to produce, enabling the fine-tuning of dosages to suit different requirements. Thus, the platform is versatile and efficient, with potential for further development.
