B cells are associated with survival and immunotherapy response in sarcoma.

Soft-tissue sarcomas represent a heterogeneous group of cancer, with more than 50 histological subtypes1,2. The clinical presentation of patients with different subtypes is often atypical, and responses to therapies such as immune checkpoint blockade vary widely3,4. To explain this clinical variability, here we study gene expression profiles in 608 tumours across subtypes of soft-tissue sarcoma. We establish an immune-based classification on the basis of the composition of the tumour microenvironment and identify five distinct phenotypes: immune-low (A and B), immune-high (D and E), and highly vascularized (C) groups. In situ analysis of an independent validation cohort shows that class E was characterized by the presence of tertiary lymphoid structures that contain T cells and follicular dendritic cells and are particularly rich in B cells. B cells are the strongest prognostic factor even in the context of high or low CD8+ T cells and cytotoxic contents. The class-E group demonstrated improved survival and a high response rate to PD1 blockade with pembrolizumab in a phase 2 clinical trial. Together, this work confirms the immune subtypes in patients with soft-tissue sarcoma, and unravels the potential of B-cell-rich tertiary lymphoid structures to guide clinical decision-making and treatments, which could have broader applications in other diseases.

Impact of metronomic trabectedin combined with low-dose cyclophosphamide on sarcoma microenvironment and correlation with clinical outcome: results from the TARMIC study.

Soft tissue sarcomas (STS) are diverse mesenchymal tumors with few therapeutic options in advanced stages. Trabectedin has global approval for treating STS patients resistant to anthracycline-based regimens. Recent pre-clinical data suggest that trabectedin's antitumor activity extends beyond tumor cells to influencing the tumor microenvironment (TME), especially affecting tumor-associated macrophages and their pro-tumoral functions. We present the phase I/II results evaluating a combination of metronomic trabectedin and low-dose cyclophosphamide on the TME in patients with advanced sarcomas. 50 patients participated: 20 in phase I and 30 in phase II. Changes in the TME were assessed in 28 patients using sequential tumor samples at baseline and day two of the cycle. Treatment notably decreased CD68 + CD163 + macrophages in biopsies from tumor lesions compared to pre-treatment samples in 9 of the 28 patients after 4 weeks. Baseline CD8 + T cell presence increased in 11 of these patients. In summary, up to 57% of patients exhibited a positive immunological response marked by reduced M2 macrophages or increased CD8 + T cells post-treatment. This positive shift in the TME correlated with improved clinical benefit and progression-free survival. This study offers the first prospective evidence of trabectedin's immunological effect in advanced STS patients, highlighting a relationship between TME modulation and patient outcomes.This study was registered with ClinicalTrial.gov, number NCT02406781.

Reshaping the tumor microenvironment of cold soft-tissue sarcomas with oncolytic viral therapy: a phase 2 trial of intratumoral JX-594 combined with avelumab and low-dose cyclophosphamide.

Most soft-tissue sarcomas (STS) exhibit an immunosuppressive tumor microenvironment (TME), leading to resistance against immune checkpoint inhibitors (ICIs) and limited therapeutic response. Preclinical data suggest that oncolytic viral therapy can remodel the TME, facilitating T cell accumulation and enhancing the immunogenicity of these tumors.We conducted the METROMAJX, a phase II clinical trial, to investigate the combination of JX-594, an oncolytic vaccinia virus engineered for selective tumor cell replication, with metronomic cyclophosphamide and the PD-L1 inhibitor avelumab in patients with advanced, 'cold' STS, characterized by an absence of tertiary lymphoid structures. The trial employed a two-stage Simon design. JX-594 was administered intratumorally at a dose of 1.109 pfu every 2 weeks for up to 4 intra-tumoral administrations. Cyclophosphamide was given orally at 50 mg twice daily in a week-on, week-off schedule, and avelumab was administered at 10 mg/kg biweekly. The primary endpoint was the 6-month non-progression rate.Fifteen patients were enrolled, with the most frequent toxicities being grade 1 fatigue and fever. Fourteen patients were assessable for efficacy analysis. At 6 months, only one patient remained progression-free, indicating that the trial did not meet the first stage endpoint of Simon's design. Analysis of sequential tissue biopsies and plasma samples revealed an increase in CD8 density and upregulation of immune-related protein biomarkers, including CXCL10.Intra-tumoral administration of JX-594 in combination with cyclophosphamide and avelumab is safe and capable of modulating the TME in cold STS. However, the limited efficacy observed warrants further research to define the therapeutic potential of oncolytic viruses, particularly in relation to specific histological subtypes of STS.

PEC-PRO: A new prognostic score from a series of 87 patients with localized perivascular epithelioid cell neoplasms (PEComas) treated with curative intent.

BACKGROUND: Perivascular epithelioid cell neoplasms (PEComas) encompass a heterogeneous family of mesenchymal tumors. Previously described clinicopathologic features aimed at distinguishing benign from malignant variants but lacked prognostic value. METHODS: This retrospective analysis examined clinicopathologic data from patients who had localized PEComa across French Sarcoma Network centers. The authors analyzed 12 clinicopathologic features in a Cox proportional hazard framework to derive a multivariate prognostic risk model for event-free survival (EFS). They built the PEComa prognostic score (PEC-PRO), in which scores ranged from 0 to 5, based on the coefficients of the multivariate model. Three groups were identified: low risk (score = 0), intermediate risk (score = 1), and high risk (score ≥ 2). RESULTS: Analyzing 87 patients who had a median 46-month follow-up (interquartile range, 20-74 months), the median EFS was 96.5 months (95% confidence interval [CI], 47.1 months to not applicable), with 2-year and 5-year EFS rates of 64.7% and 58%, respectively. The median overall survival was unreached, with 2-year and 5-year overall survival rates of 82.3% and 69.3%, respectively. The simplified Folpe classification did not correlate with EFS. Multivariate analysis identified three factors affecting EFS: positive surgical margins (hazard ratio [HR], 5.17; 95% CI, 1.65-16.24; p = .008), necrosis (HR, 3.94; 95% CI, 1.16-13.43; p = .030), and male sex (HR, 3.13; 95% CI, 1.19-8.27; p = 0.023). Four variables were retained in the prognostic model. Patients with low-risk PEC-PRO scores had a 2-year EFS rate of 93.7% (95% CI, 83.8%-100.0%), those with intermediate-risk PEC-PRO scores had a 2-year EFS rate of 67.4% (95% CI, 53.9%-80.9%), and those with high-risk PEC-PRO scores had a 2-year EFS rate of 2.3% (95% CI, 0.0%-18.3%). CONCLUSIONS: The PEC-PRO score reliably predicts the risk of postoperative recurrence in patients with localized PEComa. It has the potential to improve follow-up strategies but requires validation in a prospective trial.

Pain in desmoid-type fibromatosis: Prevalence, determinants and prognosis value.

The aim of this study is to evaluate the prevalence, determinants and prognostic value of pain at diagnosis in patients with desmoid-type fibromatosis (DF). We selected patients from the ALTITUDES cohort (NCT02867033), managed by surgery, active surveillance or systemic treatments, with pain assessment at diagnosis. Patients were invited to fill QLQ-C30 questionnaire and Hospital Anxiety Depression Scale. Determinants were identified using logistic models. Prognostic value on event-free survival (EFS) was evaluated using the Cox model. Overall, 382 patients were included in the current study (median age: 40.2 years; 117 men). The prevalence of pain was 36%, without significant difference according to first-line treatment (P = .18). In the multivariate analysis, pain was significantly associated with tumor size >50 mm (P = .013) and tumor site (P < .001); pain was more frequent in the neck and shoulder locations (odds ratio: 3.05 [1.27-7.29]). Pain at baseline was significantly associated with poor quality of life (P < .001), depression (P = .02), lower performance status (P = .03) and functional impairment (P = .001); we also observed a nonsignificant association with anxiety (P = .10). In the univariate analysis, baseline pain was associated with poor EFS; the 3-year EFS was 54% in patients with pain compared to 72% in those without pain. After adjustment for sex, age, size and line of treatment, pain was still associated with poor EFS (hazard ratio: 1.82 [1.23-2.68], P = .003). One third of recently diagnosed patients with DF experienced pain, especially those with larger tumors and neck/shoulder locations. Pain was associated with unfavorable EFS after adjustment for the confounders.

Late toxicity comparison of alkylating-based maintenance regimen with cyclophosphamide (VAC) vs ifosfamide (VAI) in Ewing sarcoma survivors treated in the randomized clinical trial Euro-EWING99-R1 in France.

In Euro-EWING99-R1 randomized trial, cyclophosphamide was shown to be noninferior to ifosfamide in the consolidation of standard-risk Ewing sarcoma (SR-EWS) after a common induction with VIDE (vincristine-ifosfamide-doxorubicin-etoposide). We present the results of the late effects analysis of VAC (vincristine-dactinomycin-cyclophoshamide) vs VAI (vincristine-dactinomycin-ifosfamide) conducted in Euro-EWING99-R1 French cohort. Of 267 French randomized patients, 204 were alive and free-of-relapse at 5-years including 172 with available long-term follow-up data concerning cardiac, renal and/or gonadal functions (sex-ratio M/F = 1.3, median age at diagnosis = 14 years): 84 randomized in VAC (median cumulative doses: cyclophosphamide = 9.7 g/m2 , ifosfamide = 59.4 g/m2 ) and 88 in VAI (ifosfamide = 97.1 g/m2 ). With a median follow-up of 10 years (range = 5-17), five late relapses and five second malignancies were recorded. The 10-year event-free survival among 5-year free-of-relapse survivors was similar between VAC and VAI (93% vs 95%, P = .63). We estimated the 10-year cumulative probabilities of cardiac and kidney toxicities at 4.4% (95% confidence interval [95% CI] = 1.1%-7.6%) and 34.8% (95% CI = 26.8%-42.0%), respectively. Cardiac toxicity cumulative probability was similar in both arms, whereas kidney toxicity was higher in VAI (at 10 years, 43.0% vs 25.7%, P = .02), resulting from significant difference in glomerular toxicity (31.1% vs 13.1%, P < .01). At 10 years, gonadal toxicity was observed in 27% and 28% of pubertal men and women, respectively, without significant difference between VAC and VAI. Kidney and gonadal toxicities represent major issues in Euro-EWING99-R1, with significantly higher risk of kidney toxicities with VAI, without significant gonadal toxicity reduction. These results support the need to limit cumulative doses of both alkylating agents and to use mixed regimen as in VIDE-VAC or VDC/IE (vincristine-doxorubicin-cyclophoshamide/ifosfamide-etoposide).

Management and outcomes of adolescent and young adult sarcoma patients: results from the French nationwide database NETSARC.

BACKGROUND: The initial management of patients with sarcoma is a critical issue. We used the nationwide French National Cancer Institute-funded prospective sarcoma database NETSARC to report the management and oncologic outcomes in adolescents and young adults (AYAs) patients with sarcoma at the national level. PATIENTS AND METHODS: NETSARC database gathers regularly monitored and updated data from patients with sarcoma. NETSARC was queried for patients (15-30 years) with sarcoma diagnosed from 2010 to 2017 for whom tumor resection had been performed. We reported management, locoregional recurrence-free survival (LRFS), progression-free survival (PFS), and overall survival (OS) in AYA treated in French reference sarcoma centers (RSC) and outside RSC (non-RSC) and conducted multivariable survival analyses adjusted for classical prognostic factors. RESULTS: Among 3,227 patients aged 15-30 years with sarcoma diagnosed between 2010 and 2017, the study included 2,227 patients with surgery data available, among whom 1,290 AYAs had been operated in RSC, and 937 AYAs in non-RSC. Significant differences in compliance to guidelines were observed including pre-treatment biopsy (RSC: 85.9%; non-RSC 48.1%), pre-treatment imaging (RSC: 86.8%; non-RSC: 56.5%) and R0 margins (RSC 57.6%; non-RSC: 20.2%) (p < 0.001). 3y-OS rates were 81.1% (95%CI 78.3-83.6) in AYA in RSC and 82.7% (95%CI 79.4-85.5) in AYA in non-RSC, respectively. Whereas no significant differences in OS was observed in AYAs treated in RSC and in non-RSC, LRFS and PFS were improved in AYAs treated in RSC compared to AYAs treated in non-RSC (Hazard Ratios (HR): 0.58 and 0.83, respectively). CONCLUSIONS: This study highlights the importance for AYA patients with sarcoma to be managed in national sarcoma reference centers involving multidisciplinary medical teams with paediatric and adult oncologists.

Rare bone sarcomas: A retrospective analysis of 145 adult patients from the French Sarcoma Group.

The benefit of chemotherapy (CT) in rare bone sarcomas is not documented in prospective studies. Our retrospective study from the French sarcoma network for bone tumors ResOs was performed in adult patients (pts) from 1976 to 2014, with histologically verified diagnosis of leiomyosarcomas (LMS), undifferentiated pleomorphic sarcoma (UPS) or radiation-associated sarcomas of bone. The median follow-up was 4.7 years (95% CI: 3.7-6.5). Clinical features, treatment modalities and outcomes were recorded and analyzed from 145 pts (median age 53 years [range 20-87]). Site of disease was extremities (66%) or axial skeleton (34%), 111 (77%) presented with localized and potentially resectable disease. The most common histological subtypes were UPS (58%) and LMS (33%); 58% were high-grade tumors. Surgery was performed in 127 pts. In the 111 localized pts, 28 pts (25%) underwent upfront surgery or exclusive radiotherapy (RT; >50 Gy) without CT, whereas 83 pts (75%) received either neoadjuvant (n = 26) or adjuvant CT (n = 13) or both (n = 44). Neoadjuvant and adjuvant CT was mostly doxorubicin-based (95%/86%) and cisplatin-based (67%/63%). R0 resection was achieved in 59 pts, and a good histological response in 15 patients (25%). Adjuvant RT was performed in 24 (22%) pts. For the whole cohort (n = 145), the 5-year overall survival (OS) rate was 53% [42; 62]. In univariate analysis, age ≤ 60 was associated with a longer disease-free survival (DFS) (P = .0436). Neoadjuvant and adjuvant CT tended to be associated with better DFS (P = .056) with no significant impact on OS in this retrospective series.

Cabozantinib in patients with advanced Ewing sarcoma or osteosarcoma (CABONE): a multicentre, single-arm, phase 2 trial.

BACKGROUND: Patients with Ewing sarcoma or osteosarcoma have a median overall survival of less than 12 months after diagnosis, and a standard treatment strategy has not yet been established. Pharmacological inhibition of MET signalling and aberrant angiogenesis has shown promising results in several preclinical models of Ewing sarcoma and osteosarcoma. We aimed to investigate the activity of cabozantinib, an inhibitor of MET and VEGFR2, in patients with advanced Ewing sarcoma and osteosarcoma. METHODS: We did a multicentre, single-arm, two-stage, phase 2 trial in patients with advanced Ewing sarcoma or osteosarcoma recruited from ten centres in the French Sarcoma Group. Key eligibility criteria were aged 12 years or older, Eastern Cooperative Oncology Group performance status of 0-1, and documented disease progression (according to Response Evaluation Criteria in Solid Tumors version 1.1) before study entry. The number of previous lines of treatment was not limited. Patients received cabozantinib (adults 60 mg, children [<16 years] 40 mg/m2) orally once daily in 28-day cycles until disease progression, unacceptable toxicity, the investigator's decision to discontinue, or participant withdrawal. The primary endpoint for Ewing sarcoma was best objective response within 6 months of treatment onset; for osteosarcoma, a dual primary endpoint of 6-month objective response and 6-month non-progression was assessed. All enrolled patients who received at least one dose of cabozantinib were included in the safety analysis, and all participants who received at least one complete or two incomplete treatment cycles were included in the efficacy population. This study was registered with ClinicalTrials.gov, number NCT02243605. FINDINGS: Between April 16, 2015, and July 12, 2018, 90 patients (45 with Ewing sarcoma 45 with osteosarcoma) were recruited to the study. Median follow-up was 31·3 months (95% CI 12·4-35·4) for patients with Ewing sarcoma and 31·1 months (24·4-31·7) for patients with osteosarcoma. 39 (87%) patients with Ewing sarcoma and 42 (93%) patients with osteosarcoma were assessable for efficacy after histological and radiological review. In patients with Ewing sarcoma, ten (26%; 95% CI 13-42) of 39 patients had an objective response (all partial responses) by 6 months; in patients with osteosarcoma, five (12%; 4-26) of 42 patients had an objective response (all partial responses) and 14 (33%; 20-50) had 6-month non-progression. The most common grade 3 or 4 adverse events were hypophosphataemia (five [11%] for Ewing sarcoma, three [7%] for osteosarcoma), aspartate aminotransferase increase (two [4%] for Ewing sarcoma, three [7%] for osteosarcoma), palmar-plantar syndrome (three [7%] for Ewing sarcoma, two [4%] for osteosarcoma), pneumothorax (one [2%] for Ewing sarcoma, four [9%] for osteosarcoma), and neutropenia (two [4%] for Ewing sarcoma, four [9%] for osteosarcoma). At least one serious adverse event was reported in 61 (68%) of 90 patients. No patients died from drug-related toxic effects. INTERPRETATION: Cabozantinib has antitumor activity in patients with advanced Ewing sarcoma and osteosarcoma and was generally well tolerated. Cabozantinib could represent a new therapeutic option in this setting, and deserves further investigation. FUNDING: Institut Bergonié; French National Cancer Institute; Association pour la Recherche contre le Cancer.

Pazopanib or methotrexate-vinblastine combination chemotherapy in adult patients with progressive desmoid tumours (DESMOPAZ): a non-comparative, randomised, open-label, multicentre, phase 2 study.

BACKGROUND: Desmoid tumours are locally aggressive tumours associated with substantial morbidity. No systemic treatments are approved for this disease, with methotrexate-vinblastine the only chemotherapy regimen assessed in a clinical trial setting to date. VEGF overexpression is a common feature in aggressive desmoid tumours. Pazopanib is an oral antiangiogenic agent targeting VEGF receptors 1, 2, and 3, platelet-derived growth factor receptor-like protein (PDGFR) α and ß, and c-KIT tyrosine kinases. We aimed to assess antitumour activity and safety of targeted therapy or combination chemotherapy in progressive desmoid tumours. METHODS: DESMOPAZ was a non-comparative, randomised, open-label, phase 2 trial conducted at 12 centres from the French Sarcoma Group. We enrolled adults (≥18 years) with progressive desmoid tumours, normal organ function and centrally documented progressive disease according to Response Evaluation Criteria in Solid Tumors version 1.1 based on two imaging assessments obtained within less than a 6-month interval. Participants were randomly assigned (2:1) to oral pazopanib 800 mg per day for up to 1 year or to an intravenous regimen combining vinblastine (5 mg/m2 per dose) and methotrexate (30 mg/m2 per dose), administered weekly for 6 months and then every other week for 6 months. Randomisation was stratified according to inclusion centre and tumour location. The primary endpoint was the proportion of patients who had not progressed at 6 months in the first 43 patients who had received one complete or two incomplete cycles of pazopanib. This endpoint was also assessed as a prespecified exploratory endpoint in all patients who had received one complete or two incomplete cycles of methotrexate-vinblastane. Safety analyses were done for all patients who received at least one dose of allocated treatment. This trial was registered with ClinicalTrials.gov, number NCT01876082. FINDINGS: From Dec 4, 2012, to Aug 18, 2017, 72 patients were enrolled and randomly assigned (n=48 in the pazopanib group; n=24 in the methotrexate-vinblastine group). Median follow-up was 23·4 months (IQR 17·1-25·5). 46 patients in the pazopanib group and 20 patients in the methotrexate-vinblastine group were assessable for activity. In the first 43 patients assessable for the primary endpoint in the pazopanib group, the proportion of patients who had not progressed at 6 months was 83·7% (95% CI 69·3-93·2). The proportion of patients treated with methotrexate-vinblastine who had not progressed at 6 months was 45·0% (95% CI 23·1-68·5). The most common grade 3 or 4 adverse events in the pazopanib group were hypertension (n=10, 21%) and diarrhoea (n=7, 15%) and in the methotrexate-vinblastine group were neutropenia (n=10, 45%) and liver transaminitis (n=4, 18%). 11 patients (23%) had at least one serious adverse event related to study treatment in the pazopanib group, as did and six patients (27%) in the methotrexate-vinblastine group. INTERPRETATION: Pazopanib has clinical activity in patients with progressive desmoid tumours and could be a valid treatment option in this rare and disabling disease. FUNDING: GlaxoSmithKline and Novartis.

Sarcomas in patients over 90: Natural history and treatment-A nationwide study over 6 years.

Soft tissue sarcomas (STS) are rare tumors accounting for less than 1% of human cancers. While the highest incidence of sarcomas is observed in elderly, this population is often excluded or poorly represented in clinical trials. The present study reports on clinicopathological presentation, and outcome of sarcoma patients over 90 recorded in the Netsarc.org French national database. NETSARC (netsarc.org) is a network of 26 reference sarcoma centers with specialized multidisciplinary tumor board (MDTB), funded by the French National Cancer Institute to improve the outcome of sarcoma patients. Since 2010, presentation to an MDTB, second pathological review, and collection of sarcoma patient characteristics and follow-up are collected in a database Information of patients registered from January 1, 2010, to December 31, 2016, in NETSARC were collected, analyzed and compared to the younger population. Patients with sarcomas aged >90 have almost exclusively sarcomas with complex genomics (92.0% vs. 66.3%), are less frequently metastatic (5.3% vs. 14·7%) at diagnosis, have more often superficial tumors (39.8% vs. 14.7%), as well as limbs and head and neck sites (75.2% vs. 38.7%) (all p < 0.001). Optimal diagnostic procedures and surgery were less frequently performed in patients over 90 (p < 0.001). These patients were less frequently operated in NETSARC centers, as compared to those of younger age groups including aged 80-90. However, local relapse-free survival, metastatic relapse-free survival and relapse-free survival were not significantly different from those of younger patients, in the whole cohort, as well as in the subgroup of operated patients. As expected overall survival was worse in patients over 90 (p < 0.001). Patients over 90 who were not operated had worse overall survival than younger patients (9.9 vs. 27.3 months, p < 0.001). Patients with STS diagnosed after 90 have distinct clinicopathological features, but comparable relapse-free survival, unless clinical practice guidelines recommendations are not applied. Standard management should be proposed to these patients if oncogeriatric status allows.

Nilotinib in locally advanced pigmented villonodular synovitis: a multicentre, open-label, single-arm, phase 2 trial.

BACKGROUND: Pigmented villonodular synovitis (alternatively known as diffuse-type giant cell tumour) is a rare, locally aggressive tumour driven by a specific translocation resulting in the overexpression of colony-stimulating factor 1 (CSF1). CSF1 receptor (CSF1R) inhibitors (ie, tyrosine kinase inhibitors and antibodies) induce a response in patients with pigmented villonodular synovitis. We investigated the safety and efficacy of a CSF1R tyrosine kinase inhibitor, nilotinib, in patients with locally advanced non-resectable pigmented villonodular synovitis. METHODS: In this phase 2, open-label, single-arm study, we enrolled patients from 11 cancer centres of hospitals in four countries (France, Netherlands, Italy, and Australia). Eligible patients were aged at least 18 years with a WHO performance status of 2 or less, and histologically confirmed progressive or relapsing pigmented villonodular synovitis that was inoperable, or resectable only with mutilating surgery. Patients received oral nilotinib (400 mg twice per day) until disease progression, unacceptable toxicity, or completion of 1 year of treatment. The primary endpoint was the proportion of patients who were progression free at 12 weeks, which was centrally assessed according to Response Evaluation Criteria in Solid Tumors version 1.1. Analyses were by modified intention to treat (ie, all patients with no major protocol violations who were treated with nilotinib for at least 3 weeks were included). All participants who received at least one dose of study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT01261429, and the results presented here are the final analysis of the trial. FINDINGS: Between Dec 15, 2010, and Sept 28, 2012, we enrolled 56 patients with pigmented villonodular synovitis and treated them with nilotinib. Five (9%) patients discontinued study treatment before week 12; therefore, 51 patients were evaluable for the primary endpoint at 12 weeks. The estimated proportion of patients who were progression free at 12 weeks was 92·6% (95% credible interval 84·3-97·9). 54 (96%) of 56 patients had a treatment-related adverse event. Six (11%) of 56 patients had at least one grade 3 treatment-related adverse event (headache, dizziness, and hepatic disorders [n=1], pruritus and toxidermia [n=1], diarrhoea [n=1], increased γ-glutamyl transferase concentration [n=1], anorexia [n=1], and increased headache [n=1]). No grade 4 or 5 adverse events were reported. One patient had a treatment-related serious adverse event (toxidermia) and two patients had serious adverse events not considered to be related to the study drug (borderline ovarian tumour [n=1] and pilonidal cyst excision [n=1]). INTERPRETATION: More than 90% of patients with locally advanced unresectable progressive pigmented villonodular synovitis achieved disease control with 12 weeks of nilotinib treatment. These results indicate that CSF1R tyrosine kinase inhibitors have anti-tumour activity with manageable toxicity in patients with inoperable progressive pigmented villonodular synovitis. Randomised trials investigating the efficacy of nilotinib for patients with unresectable pigmented villonodular synovitis are warranted. FUNDING: Novartis, Institut National du Cancer, EuroSARC, French National Cancer Institute, General Directorate of Care Supply, Lyon Research Innovation for Cancer, L'Agence nationale de la recherche, Laboratory of Excellence, Fondation ARC pour la recherche sur le cancer, Ligue contre le Cancer (comité de l'Ain), Info Sarcomes, and Association DAM'S.

Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: a first-in-human, open-label, phase 1 study.

BACKGROUND: Activating enhancer of zeste homolog 2 (EZH2) mutations or aberrations of the switch/sucrose non-fermentable (SWI/SNF) complex (eg, mutations or deletions of the subunits INI1 or SMARCA4) can lead to aberrant histone methylation, oncogenic transformation, and a proliferative dependency on EZH2 activity. In this first-in-human study, we aimed to investigate the safety, clinical activity, pharmacokinetics, and pharmacodynamics of tazemetostat, a first-in-class selective inhibitor of EZH2. METHODS: We did an open-label, multicentre, dose-escalation, phase 1 study using a 3 + 3 design with planned cohort expansion at the two highest doses below the maximally tolerated dose. The study was done at two centres in France: Institut Gustave Roussy (Villejuif, Val de Marne) and Institut Bergonié (Bordeaux, Gironde). Eligible patients had relapsed or refractory B-cell non-Hodgkin lymphoma or an advanced solid tumour and were older than 18 years, with Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate end-organ function. Tazemetostat was administered orally from 100 mg twice daily to 1600 mg twice daily in 28-day cycles. The primary endpoint was to establish the maximum tolerated dose or recommended phase 2 dose of tazemetostat, as determined by dose-limiting toxicities, laboratory values, and other safety or pharmacokinetic measures in cycle one according to local investigator assessment. Safety was assessed in patients who received at least one dose of tazemetostat; antitumour activity was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01897571. The phase 1 part of the study is complete, and phase 2 is ongoing. FINDINGS: Between June 13, 2013, and Sept 21, 2016, 64 patients (21 with B-cell non-Hodgkin lymphoma, and 43 with advanced solid tumours) received doses of tazemetostat. The most common treatment-related adverse events, regardless of attribution, were asthenia (21 [33%] of 64 treatment-related events), anaemia (nine [14%]), anorexia (four [6%]), muscle spasms (nine [14%]), nausea (13 [20%]), and vomiting (six [9%]), usually grade 1 or 2 in severity. A single dose-limiting toxicity of grade 4 thrombocytopenia was identified at the highest dose of 1600 mg twice daily. No treatment-related deaths occurred; seven (11%) patients had non-treatment-related deaths (one at 200 mg twice daily, four at 400 mg twice daily, and two at 1600 mg twice daily). The recommended phase 2 dose was determined to be 800 mg twice daily. Durable objective responses, including complete responses, were observed in eight (38%) of 21 patients with B-cell non-Hodgkin lymphoma and two (5%) of 43 patients with solid tumours. INTERPRETATION: Tazemetostat showed a favourable safety profile and antitumour activity in patients with refractory B-cell non-Hodgkin lymphoma and advanced solid tumours, including epithelioid sarcoma. Further clinical investigation of tazemetostat monotherapy is ongoing in phase 2 studies in adults and a phase 1 study for children, which are currently enrolling patients who have B-cell non-Hodgkin lymphoma and INI1-negative or SMARCA4-negative tumours. FUNDING: Epizyme and Eisai.

Long-term outcome of dasatinib first-line treatment in gastrointestinal stromal tumor: A multicenter, 2-stage phase 2 trial (Swiss Group for Clinical Cancer Research 56/07).

BACKGROUND: Tyrosine kinase inhibitors (TKIs) have improved the outcome of patients with gastrointestinal stromal tumors (GISTs), but most patients eventually develop resistance and progress. Dasatinib is a potent inhibitor of BCR-ABL, KIT, and SRC family kinases as well as imatinib-resistant cells. In GISTs, response evaluation is routinely done using computed tomography (CT) and 18 F-fluorodeoxyglucose positron emission tomography coupled to CT (FDG-PET/CT) for early response assessment and outcome prediction. METHODS: This was a 2-stage, phase 2 trial investigating dasatinib 2 × 70 mg per day in patients with histologically proven, TKI-naïve, FDG-PET/CT-positive GIST. The primary endpoint was FDG-PET/CT response. RESULTS: Of 52 planned patients, 47 were enrolled from January 2008 to November 2011, when the trial was terminated because of slow accrual. In total, 42 patients were eligible. The median patient age was 61 years, 24 patients were men, and 18 were women. Performance status was 0 in 29 patients and 1 in 13 patients. The median follow-up was 67.2 months. Patients went off trial for elective surgery (n = 8), after 26 cycles as per protocol (n = 5), for disease progression (n = 14), for toxicity (n = 7), and for other reasons (n = 5); and 3 patients died (2 had discontinued drug and 1 was still receiving drug). Toxicity was grade 4 in 5% and grade 3 in 48% of patients and was most often gastrointestinal or pulmonary. Dose was interrupted or reduced in 25% of cycles. The FDG-PET/CT response rate (complete plus partial responses) at 4 weeks was 74% (95% confidence interval, 56%-85%; 14 patients had a complete response, 17 had a partial response, 6 had stable disease, 3 had progressive disease, and 2 were not evaluable). The median progression-free survival was 13.6 months, and the median overall survival was not reached. CONCLUSIONS: Dasatinib produced high metabolic response rates in TKI-naive patients with FDG-PET/CT-positive GIST. Cancer 2018;124:1449-54. © 2018 American Cancer Society.

Presentation and outcome of frequent and rare sarcoma histologic subtypes: A study of 10,262 patients with localized visceral/soft tissue sarcoma managed in reference centers.

BACKGROUND: The objective of this study was to describe characteristics at diagnosis and outcomes of adults with soft tissue sarcoma. METHODS: The authors conducted a retrospective multicenter study of 12,262 patients who were treated between January 1980 and 31 December 2013 in French Sarcoma Group centers and enrolled in the "Conticabase." Diagnoses were systematically reviewed by expert pathologists, and entities were classified according to the 2013 World Health Organization classification. Diagnostic characteristics, treatments, and outcomes are described for the entire cohort, for the subgroup of patients with translocation-related sarcomas, and for 9 different histologic subtypes. RESULTS: The results stressed the magnitude of heterogeneity among adult sarcomas. For example, compared with other sarcomas, translocation-related sarcomas (2143 tumors; 20.8%) were associated with a younger age at presentation (40.6 vs 60.0 years; P < .0001), a low rate of predisposing conditions (0.01% vs 22.3%; P < .0001), a higher rate of lymph node involvement (4.7% vs 1.3%; P < .0001), and a higher rate of synchronous metastasis (11.9% vs 6.7%; P < .001); and complete (R0) resection (41.6% vs 31.9%; P < .0001), receipt of (neo)adjuvant radiation therapy (62.6% vs 42.2%; P < .0001), and receipt of (neo)adjuvant chemotherapy (36.6% vs 22.3%; P < .0001) were significantly more frequent. Overall, translocation-related sarcomas were associated with a lower rate of local relapse (18.1% vs 26.0%; P < .0001) but a higher rate of metastatic relapse (42.0% vs 30.7%; P < .0001). CONCLUSIONS: Collaborative efforts are urgently needed to better assess the natural history and management options for every histologic subtype of sarcoma. Cancer 2018;124:1179-87. © 2017 American Cancer Society.

Doxorubicin plus evofosfamide versus doxorubicin alone in locally advanced, unresectable or metastatic soft-tissue sarcoma (TH CR-406/SARC021): an international, multicentre, open-label, randomised phase 3 trial.

BACKGROUND: Evofosfamide is a hypoxia-activated prodrug of bromo-isophosphoramide mustard. We aimed to assess the benefit of adding evofosfamide to doxorubicin as first-line therapy for advanced soft-tissue sarcomas. METHODS: We did this international, open-label, randomised, phase 3, multicentre trial (TH CR-406/SARC021) at 81 academic or community investigational sites in 13 countries. Eligible patients were aged 15 years or older with a diagnosis of an advanced unresectable or metastatic soft-tissue sarcoma, of intermediate or high grade, for which no standard curative therapy was available, an Eastern Cooperative Oncology Group performance status of 0-1, and measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned (1:1) to receive doxorubicin alone (75 mg/m2 via bolus injection administered over 5-20 min or continuous intravenous infusion for 6-96 h on day 1 of every 21-day cycle for up to six cycles) or doxorubicin (given via the same dose procedure) plus evofosfamide (300 mg/m2 intravenously for 30-60 min on days 1 and 8 of every 21-day cycle for up to six cycles). After six cycles of treatment, patients in the single-drug doxorubicin group were followed up expectantly whereas patients with stable or responsive disease in the combination group were allowed to continue with evofosfamide monotherapy until documented disease progression. A web-based central randomisation with block sizes of two and four was stratified by extent of disease, doxorubicin administration method, and previous systemic therapy. Patients and investigators were not masked to treatment assignment. The primary endpoint was overall survival, analysed in the intention-to-treat population. Safety analyses were done in all patients who received any amount of study drug. This study was registered with ClinicalTrials.gov, number NCT01440088. FINDINGS: Between Sept 26, 2011, and Jan 22, 2014, 640 patients were enrolled and randomly assigned to a treatment group (317 to doxorubicin plus evofosfamide and 323 to doxorubicin alone), all of whom were included in the intention-to-treat analysis. The overall survival endpoint was not reached (hazard ratio 1·06, 95% CI 0·88-1·29; p=0·527), with a median overall survival of 18·4 months (95% CI 15·6-22·1) with doxorubicin plus evofosfamide versus 19·0 months (16·2-22·4) with doxorubicin alone. The most common grade 3 or worse adverse events in both groups were haematological, including anaemia (150 [48%] of 313 patients in the doxorubicin plus evofosfamide group vs 65 [21%] of 308 in the doxorubicin group), neutropenia (47 [15%] vs 92 [30%]), febrile neutropenia (57 [18%] vs 34 [11%]), leucopenia (22 [7%] vs 17 [6%]), decreased neutrophil count (31 [10%] vs 41 [13%]), and decreased white blood cell count (39 [13%] vs 33 [11%]). Grade 3-4 thrombocytopenia was more common in the combination group (45 [14%]) than in the doxorubicin alone group (four [1%]), as was grade 3-4 stomatitis (26 [8%] vs seven [2%]). Serious adverse events were reported in 145 (46%) of 313 patients in the combination group and 99 (32%) of 308 in the doxorubicin alone group. Five (2%) patients died from treatment-related causes in the combination group (sepsis [n=2], septic shock [n=1], congestive cardiac failure [n=1], and unknown cause [n=1]) versus one (<1%) patient in the doxorubicin alone group (lactic acidosis [n=1]). INTERPRETATION: The addition of evofosfamide to doxorubicin as first-line therapy did not improve overall survival compared with single-drug doxorubicin in patients with locally advanced, unresectable, or metastatic soft-tissue sarcomas and so this combination cannot be recommended in this setting. FUNDING: Threshold Pharmaceuticals.

Expression and role of TYRO3 and AXL as potential therapeutical targets in leiomyosarcoma.

BACKGROUND: Leiomyosarcoma (LMS) are 15% of adult sarcomas and remain seldom curable in metastatic phase. The TAM receptors and their ligands are overexpressed or activated in multiple malignancies, including LMS. METHODS: The TAM receptor and ligand expression was evaluated in LMS cell lines and 358 sarcoma samples by either gene expression or immunohistochemistry. TYRO3 and AXL were knocked down. Crizotinib and foretinib were investigated in vitro. RESULTS: High expression of TYRO3 and AXL was detected in LMS cell lines. TYRO3 or AXL gene knockdown reduced cell proliferation/colony formation. Crizotinib and foretinib decreased TYRO3 and AXL phosphorylation, apoptosis, G2/arrest and reduced colony formation. Immunohistochemistry performed in 107 sarcomas showed higher expression of TYRO3 and GAS6 in LMS vs other sarcomas and nuclear TYRO3 only in LMS. Microarray gene expression performed in 251 sarcomas revealed significantly higher expression of TYRO3 and GAS6 in LMS than other sarcomas. Leiomyosarcoma patients with high expression of GAS6 or PROS1 present a significantly worse PFS. CONCLUSIONS: Leiomyosarcoma patients, especially those whom develop metastasis, express higher levels of TYRO3 and GAS6. Crizotinib and foretinib showed effective antitumour activity in LMS through TYRO3 and AXL deactivation indicating that clinical trials using TYRO3 and AXL inhibitors are warranted in advanced LMS.

Patterns of care and outcomes of patients with METAstatic soft tissue SARComa in a real-life setting: the METASARC observational study.

BACKGROUND: Well-designed observational studies of individuals with rare tumors are needed to improve patient care, clinical investigations, and the education of healthcare professionals. METHODS: The patterns of care, outcomes, and prognostic factors of a cohort of 2225 patients with metastatic soft tissue sarcomas who were diagnosed between 1990 and 2013 and documented in the prospectively maintained database of the French Sarcoma Group were analyzed. RESULTS: The median number of systemic treatments was 3 (range, 1-6); 27% of the patients did not receive any systemic treatment and 1054 (49%) patients underwent locoregional treatment of the metastasis. Half of the patients who underwent chemotherapy (n = 810) received an off-label drug. Leiomyosarcoma was associated with a significantly better outcome than the other histological subtypes. With the exception of leiomyosarcomas, the benefit of a greater than third-line regimen was very limited, with a median time to next treatment (TNT) and overall survival (OS) ranging between 2.3 and 3.7 months and 5.4 and 8.5 months, respectively. The TNT was highly correlated with OS. Female sex, leiomyosarcoma histology, locoregional treatment of metastases, inclusion in a clinical trial, and treatment with first-line polychemotherapy were significantly associated with improved OS in the multivariate analysis. CONCLUSIONS: The combination of doxorubicin with a second drug, such as ifosfamide, represents a valid option, particularly when tumor shrinkage is expected to provide clinical benefits. After failure of the second-line therapy, best supportive care should be considered, particularly in patients with non-leiomyosarcoma histology who are not eligible to participate in a clinical trial. Locoregional treatment of metastasis should always be included in the therapeutic strategy when feasible. TNT may represent a useful surrogate endpoint for OS in clinical studies.

Clinical activity of eribulin in advanced desmoplastic small round-cell tumor.

Desmoplastic small round-cell tumor is a rare but highly aggressive tumor occurring mainly in adolescents and young adults. Prolonged progression-free survival has been documented in patients who have undergone aggressive multimodality therapy - that is, multiagent intensive chemotherapy, debulking surgery, and radiation therapy. Eribulin is a microtubule-dynamics inhibitor, and it has recently been shown to be active in liposarcomas. In preclinical models, eribulin activities have also been shown to occur in Ewing's sarcoma cell lines, rhabdomyosarcomas and osteosarcomas. In this study, we report three cases of male patients suffering from desmoplastic small round-cell tumor and the clinical response to eribulin in two of them.

Pazopanib plus best supportive care versus best supportive care alone in advanced gastrointestinal stromal tumours resistant to imatinib and sunitinib (PAZOGIST): a randomised, multicentre, open-label phase 2 trial.

BACKGROUND: Gastrointestinal stromal tumours (GIST) are the most common mesenchymal neoplasms of the gastrointestinal tract. Imatinib followed by sunitinib and regorafenib is the standard sequence of treatment for advanced disease. Pazopanib is effective in soft tissue sarcomas but has never been assessed in advanced GIST in a randomised trial. We aimed to assess the efficacy and safety of pazopanib in patients with previously treated advanced GIST. METHODS: In this randomised, open-label phase 2 study, we enrolled adults (aged ≥18 years) with advanced GIST resistant to imatinib and sunitinib from 12 comprehensive cancer centres or university hospitals in France and randomly assigned them 1:1 using an interactive web-based centralised platform to 800 mg oral pazopanib once daily in 4-week cycles plus best supportive care or best supportive care alone. Randomisation was stratified by the number of previous treatment regimens (2 vs ≥3); no-one was masked to treatment group allocation. Upon disease progression, patients in the best supportive care group were allowed to switch to pazopanib as compassionate treatment. The primary endpoint was investigator-assessed progression-free survival, analysed by intention-to-treat. All randomised participants who received at least one dose of pazopanib were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01323400. FINDINGS: Between April 12, 2011, and Dec 9, 2013, 81 patients were enrolled and randomly assigned to pazopanib plus best supportive care (n=40) or best supportive care alone (n=41). The median follow-up was 26·4 months (IQR 22·0-37·8) in the pazopanib plus best supportive care group and 28·9 months (22·0-35·2) in the best supportive care group. 4-month investigator-assessed progression-free survival was 45·2% (95% CI 29·1-60·0) in the pazopanib plus best supportive care group versus 17·6% (7·8-30·8) in the best supportive care group (hazard ratio [HR] 0·59, 95% CI 0·37-0·96; p=0·029). Median progression-free survival was 3·4 months (95% CI 2·4-5·6) with pazopanib plus best supportive care and 2·3 months (2·1-3·3) with best supportive care alone (HR 0·59 [0·37-0·96], p=0·03). 36 (88%) of the patients originally assigned to the best supportive care group switched to pazopanib following investigator-assessed disease progression; these patients had a median progression-free survival from pazopanib initiation of 3·5 months (95% CI 2·2-5·2). 55 (72%) of the 76 pazopanib-treated patients had pazopanib-related grade 3 or worse adverse events, the most common of which was hypertension (15 [38%] in the pazopanib plus best supportive care group and 13 [36%] in the best supportive care group). 20 (26%) patients had pazopanib-related serious adverse events (14 [35%] in the pazopanib plus best supportive care group and six [17%] in the best supportive care group), including pulmonary embolism in eight (9%) patients (five [13%] in the pazopanib plus best supportive care group and three [7%] in the best supportive care group). Three pazopanib-related deaths occurred (two pulmonary embolisms [one in each group] and one hepatic cytolysis [in the best supportive care group]). Three adverse event-related but not pazopanib-related deaths occurred in the best supportive care group after switch to pazopanib; these deaths were from hyperammonaemic encephalopathy, pneumopathy, and respiratory failure. INTERPRETATION: Pazopanib plus best supportive care improves progression-free survival compared with best supportive care alone in patients with advanced GIST resistant to imatinib and sunitinib, with a toxicity profile similar to that reported for other sarcomas. This trial provides reference outcome data for future studies of targeted inhibitors in the third-line setting for these patients. FUNDING: GlaxoSmithKline, French National Cancer Institute, EuroSARC (FP7-278742), Centre Léon Bérard.