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.
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.
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.
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.
Alliance Clinical Trials in Oncology, National Cancer Institute Cancer Therapy Evaluation Program, Bristol-Myers Squibb, Cycle for Survival.
Tumors characterized by co‐expression of S100 and CD34, in the absence of SOX10, remain difficult to classify. Triggered by a few index cases with monomorphic cytomorphology and distinctive stromal ...and perivascular hyalinization, immunopositivity for S100 and CD34, and RAF1 and NTRK1 fusions, the authors undertook a systematic review of tumors with similar features. Most of the cases selected were previously diagnosed as low‐grade malignant peripheral nerve sheath tumors, while others were deemed unclassified. The tumors were studied with targeted RNA sequencing and/or FISH. A total of 25 cases (15 adults and 10 children) with kinase fusions were identified, including 8 cases involving RAF1, 2 BRAF, 14 NTRK1, and 1 NTRK2 gene rearrangements. Most tumors showed a monomorphic spindle cell proliferation with stromal and perivascular keloidal collagen, in a patternless architecture, with only occasional scattered pleomorphic or multinucleated cells. Most cases showed low cellularity, a low mitotic count, and absence of necrosis. Although a subset showed overlap with lipofibromatosis‐like neural tumors, the study group showed distinctive hyalinization and overt malignant features, such as highly cellular fascicular growth and primitive appearance. All tumors showed co‐expression of S100 and CD34, ranging from focal to diffuse. SOX10 was negative in all cases. NTRK1 immunohistochemistry showed high levels of expression in all tumors with NTRK1 gene rearrangements. H3K27me3 expression performed in a subset of cases was retained. These findings together with the recurrent gene fusions in RAF1, BRAF, and NTRK1/2 kinases suggest a distinct molecular tumor subtype with consistent S100 and CD34 immunoreactivity.
Sarcomas are malignant soft tissue and bone tumours affecting adults, adolescents and children. They represent a morphologically heterogeneous class of tumours and some entities lack defining ...histopathological features. Therefore, the diagnosis of sarcomas is burdened with a high inter-observer variability and misclassification rate. Here, we demonstrate classification of soft tissue and bone tumours using a machine learning classifier algorithm based on array-generated DNA methylation data. This sarcoma classifier is trained using a dataset of 1077 methylation profiles from comprehensively pre-characterized cases comprising 62 tumour methylation classes constituting a broad range of soft tissue and bone sarcoma subtypes across the entire age spectrum. The performance is validated in a cohort of 428 sarcomatous tumours, of which 322 cases were classified by the sarcoma classifier. Our results demonstrate the potential of the DNA methylation-based sarcoma classification for research and future diagnostic applications.
A major breakthrough in the classification of soft tissue tumors has been the recent identification of NTRK-fusion related neoplasms which are amenable to highly effective targeted therapies. Despite ...these therapeutic opportunities, diagnostic challenges have emerged in recognizing tumors characterized by protein kinase fusions, as they are associated with a wide morphologic spectrum, variable risk of malignancy and a rather nonspecific immunoprofile. As such, NTRK-related fusions may occur in infantile fibrosarcoma, lipofibromatosis-like neural tumors (LPF-NTs), tumors resembling malignant peripheral nerve sheath tumors, etc. Triggered by an index case resembling LPF-NT but harboring RET gene rearrangement, we investigated our files for cases showing RET gene abnormalities to establish their clinicopathologic features. Tumors were tested with a combination of targeted RNA sequencing and fluorescence in situ hybridization methods. Six cases with RET gene rearrangements were identified, all except 1 occurred in children, including 4 infants. Their morphologic spectrum was quite diverse, but closely reproduced the phenotype of NTRK–fusion-positive tumors, including LPF-NTs (n=3), infantile fibrosarcoma-like tumor (n=2) and malignant peripheral nerve sheath tumor-like (n=1). Three cases showed coexpression of S100 and CD34, whereas the remaining 3 had a nonspecific immunoprofile. The tumors ranged morphologically and clinically from benign to highly malignant. None of the LPF-NT cases recurred, whereas 2 patients with malignant histology had a highly aggressive course with distant metastases to lung and other viscera. By targeted RNA sequencing these tumors harbored RET fusions with an identical break in exon 12, which retains the tyrosine kinase domain in the fusion oncoprotein and involving various gene partners (CLIP2, CCDC6, SPECC1L, MYH10, and NCOA4). Our results suggest that RET fusion-positive neoplasms share a similar phenotypic spectrum with the NTRK-positive tumors, displaying either fibroblastic or neural-like differentiation, and spanning a wide spectrum of clinical behavior. These findings open new avenues for targeted therapy with RET inhibitors currently available in clinical trials.
Summary Background Diffuse-type tenosynovial giant cell tumour (dt-GCT) of the soft tissue (alternatively known as pigmented villonodular synovitis), an orphan disease with unmet medical need, is ...characterised by an overexpression of colony-stimulating factor 1 (CSF1), and is usually caused by a chromosomal translocation involving CSF1. CSF1 receptor (CSF1R) activation leads to the recruitment of CSF1R-expressing cells of the mononuclear phagocyte lineage that constitute the tumor mass in dt-GCT. Emactuzumab (RG7155) is a novel monoclonal antibody that inhibits CSF1R activation. We have assessed the safety, tolerability and activity of emactuzumab in patients with Dt-GCT of the soft tissue. Methods In this phase 1, first-in-human dose-escalation and dose-expansion study, eligible patients were aged 18 years or older with dt-GCT of the soft tissue with locally advanced disease or resectable tumours requiring extensive surgery, an Eastern Cooperative Oncology Group performance status of 1 or less, measurable disease according to Response Evaluation Criteria In Solid Tumors version 1.1, and adequate end-organ function. Patients with GCT of the bone were not eligible. Patients received intravenous emactuzumab at 900 mg, 1350 mg, or 2000 mg every 2 weeks in the dose-escalation phase and at the optimal biological dose in a dose-expansion phase. The primary objective was to evaluate the safety and tolerability of emactuzumab, and to determine the maximum tolerated dose or optimal biological dose. All treated patients were included in the analyses. Expansion cohorts are currently ongoing. This study is registered with ClinicalTrials.gov , number NCT01494688. Findings Between July 26, 2012, and Oct 21, 2013, 12 patients were enrolled in the dose-escalation phase. No dose-limiting toxicities were noted in the dose-escalation cohort; on the basis of pharmacokinetic, pharmacodynamic, and safety information, we chose a dose of 1000 mg every 2 week for the dose-expansion cohort, into which 17 patients were enrolled. Owing to different cutoff dates for safety and efficacy readouts, the safety population comprised 25 patients. Common adverse events after emactuzumab treatment were facial oedema (16 64% of 25 patients), asthenia (14 56%), and pruritus (14 56%). Five serious adverse events (periorbital oedema, lupus erythematosus occurring twice, erythema, and dermohypodermitis all experienced by one 4% patient each) were reported in five patients. Three of the five serious adverse events—periorbital oedema (one 4%), lupus erythematosus (one 4%), and dermohypodermitis (one 4%)—were assessed as grade 3. Two other grade 3 events were reported: mucositis (one 4%) and fatigue (one 4%). 24 (86%) of 28 patients achieved an objective response; two (7%) patients achieved a complete response. Interpretation Further study of dt-GCT is warranted and different possibilities, such as an international collaboration with cooperative groups to assure appropriate recruitment in this rare disease, are currently being assessed. Funding F Hoffmann-La Roche.
Sclerosing epithelioid fibrosarcoma (SEF) is an aggressive soft tissue sarcoma. In the majority of cases, there is overexpression of MUC4, and most cases show EWSR1-CREB3L1 gene fusions. A subset of ...SEF displays composite histologic features of SEF and low-grade fibromyxoid sarcoma (LGFMS). These “hybrid” tumors are more likely to harbor the FUS-CREB3L2 fusion, which is also seen in most LGFMS. We, here, characterize a series of 8 soft tissue neoplasms with morphologic features highly overlapping with LGFMS and SEF but lacking MUC4 expression and EWSR1/FUS-CREB3L gene fusions. Seven tumors showed fusions of the YAP1 and KMT2A genes, and 1 had a fusion of PRRX1 and KMT2D; all but 1 case displayed reciprocal gene fusions. At gene expression profiling, YAP1 and KMT2A/PRRX1 and KMT2D tumors were distinct from LGFMS/SEF. The patients were 4 female individuals and 4 male individuals aged 11 to 91 years. Tumors with known locations were in the lower extremity (5), trunk (2), and upper extremity (1); 3 originated in acral locations. Tumor size ranged from 2.5 to 13 cm. Proportions of SEF-like and LGFMS-like areas varied considerably among tumors. All tumors that showed infiltrative growth and mitotic figures per 10 HPFs ranged from 0 to 18. Tumor necrosis was present in 1 case. Follow-up was available for 5 patients (11 to 321 mo), 2 of whom developed local recurrences, and 1 died of metastatic disease. The clinical behavior of these soft tissue sarcomas remains to be further delineated in larger series with extended follow-up; however, our limited clinical data indicate that they are potentially aggressive.
The new World Health Organization (WHO) classification of soft tissue tumours was published in early 2013, almost 11 years after the previous edition. While the number of newly recognized entities ...included for the first time is fewer than that in 2002, there have instead been substantial steps forward in molecular genetic and cytogenetic characterization of this family of tumours, leading to more reproducible diagnosis, a more meaningful classification scheme and providing new insights regarding pathogenesis, which previously has been obscure in most of these lesions. This brief overview summarizes changes in the classification in each of the broad categories of soft tissue tumour (adipocytic, fibroblastic, etc.) and also provides a short summary of newer genetic data which have been incorporated in the WHO classification.
The fourth edition of the World Health Organization (WHO) Classification of Tumours of Soft Tissue and Bone was published in February 2013, and serves to provide an updated classification scheme and ...reproducible diagnostic criteria for pathologists. Given the relative rarity of soft tissue tumours and the rapid rate of immunohistochemical and genetic/molecular developments (not infrequently facilitating recognition of new tumour entities), this updated text edited by a consensus group is important for both practising pathologists and oncologists. The 2013 WHO classification includes several changes in soft tissue tumour classification, including several new entities (e.g., pseudomyogenic haemangioendothe-lioma, haemosiderotic fibrolipomatous tumour, and acral fibromyxoma), three newly included sections for gastrointestinal stromal tumours, nerve sheath tumours, and undifferentiated/unclassified soft tissue tumours, respectively, various ‘reclassified’ tumours, and a plethora of new genetic and molecular data for established tumour types that facilitate better definition and are useful as diagnostic tools. This article briefly outlines these updates based on the 2013 WHO classification of soft tissue tumours.
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, and had at least one lesion accessible for biopsy. All patients were treated with 200 mg intravenous pembrolizumab every 3 weeks. The primary endpoint was investigator-assessed objective response. Patients who received at least one dose of pembrolizumab were included in the safety analysis and patients who progressed or reached at least one scan assessment were included in the activity analysis. Accrual is ongoing in some disease cohorts. This trial is registered with ClinicalTrials.gov, number NCT02301039.
Between March 13, 2015, and Feb 18, 2016, we enrolled 86 patients, 84 of whom received pembrolizumab (42 in each disease cohort) and 80 of whom were evaluable for response (40 in each disease cohort). Median follow-up was 17·8 months (IQR 12·3–19·3). Seven (18%) of 40 patients with soft-tissue sarcoma had an objective response, including four (40%) of ten patients with undifferentiated pleomorphic sarcoma, two (20%) of ten patients with liposarcoma, and one (10%) of ten patients with synovial sarcoma. No patients with leiomyosarcoma (n=10) had an objective response. Two (5%) of 40 patients with bone sarcoma had an objective response, including one (5%) of 22 patients with osteosarcoma and one (20%) of five patients with chondrosarcoma. None of the 13 patients with Ewing's sarcoma had an objective response. The most frequent grade 3 or worse adverse events were anaemia (six 14%), decreased lymphocyte count (five 12%), prolonged activated partial thromboplastin time (four 10%), and decreased platelet count (three 7%) in the bone sarcoma group, and anaemia, decreased lymphocyte count, and prolonged activated partial thromboplastin time in the soft-tissue sarcoma group (three 7% each). Nine (11%) patients (five 12% in the bone sarcoma group and four 10% in the soft-tissue sarcoma group) had treatment-emergent serious adverse events (SAEs), five of whom had immune-related SAEs, including two with adrenal insufficiency, two with pneumonitis, and one with nephritis.
The primary endpoint of overall response was not met for either cohort. However, pembrolizumab showed encouraging activity in patients with undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma. Enrolment to expanded cohorts of those subtypes is ongoing to confirm and characterise the activity of pembrolizumab.
Merck, SARC, Sarcoma Foundation of America, QuadW Foundation, Pittsburgh Cure Sarcoma, and Ewan McGregor.
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