%0 Journal Article %J Mol Oncol %D 2021 %T A DNA damage repair gene-associated signature predicts responses of patients with advanced soft-tissue sarcoma to treatment with trabectedin. %A Moura, David S %A Peña-Chilet, Maria %A Cordero Varela, Juan Antonio %A Alvarez-Alegret, Ramiro %A Agra-Pujol, Carolina %A Izquierdo, Francisco %A Ramos, Rafael %A Ortega-Medina, Luis %A Martin-Davila, Francisco %A Castilla-Ramirez, Carolina %A Hernandez-Leon, Carmen Nieves %A Romagosa, Cleofe %A Vaz Salgado, Maria Angeles %A Lavernia, Javier %A Bagué, Silvia %A Mayodormo-Aranda, Empar %A Vicioso, Luis %A Hernández Barceló, Jose Emilio %A Rubio-Casadevall, Jordi %A de Juan, Ana %A Fiaño-Valverde, Maria Concepcion %A Hindi, Nadia %A Lopez-Alvarez, Maria %A Lacerenza, Serena %A Dopazo, Joaquin %A Gutierrez, Antonio %A Alvarez, Rosa %A Valverde, Claudia %A Martinez-Trufero, Javier %A Martin-Broto, Javier %X

Predictive biomarkers of trabectedin represent an unmet need in advanced soft-tissue sarcomas (STS). DNA damage repair (DDR) genes, involved in homologous recombination or nucleotide excision repair, had been previously described as biomarkers of trabectedin resistance or sensitivity, respectively. The majority of these studies only focused on specific factors (ERCC1, ERCC5, and BRCA1) and did not evaluate several other DDR-related genes that could have a relevant role for trabectedin efficacy. In this retrospective translational study, 118 genes involved in DDR were evaluated to determine, by transcriptomics, a predictive gene signature of trabectedin efficacy. A six-gene predictive signature of trabectedin efficacy was built in a series of 139 tumor samples from patients with advanced STS. Patients in the high-risk gene signature group showed a significantly worse progression-free survival compared with patients in the low-risk group (2.1 vs 6.0 months, respectively). Differential gene expression analysis defined new potential predictive biomarkers of trabectedin sensitivity (PARP3 and CCNH) or resistance (DNAJB11 and PARP1). Our study identified a new gene signature that significantly predicts patients with higher probability to respond to treatment with trabectedin. Targeting some genes of this signature emerges as a potential strategy to enhance trabectedin efficacy.

%B Mol Oncol %V 15 %P 3691-3705 %8 2021 12 %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/33983674?dopt=Abstract %R 10.1002/1878-0261.12996 %0 Journal Article %J J Immunother Cancer %D 2020 %T Nivolumab and sunitinib combination in advanced soft tissue sarcomas: a multicenter, single-arm, phase Ib/II trial. %A Martin-Broto, Javier %A Hindi, Nadia %A Grignani, Giovanni %A Martinez-Trufero, Javier %A Redondo, Andres %A Valverde, Claudia %A Stacchiotti, Silvia %A Lopez-Pousa, Antonio %A D'Ambrosio, Lorenzo %A Gutierrez, Antonio %A Perez-Vega, Herminia %A Encinas-Tobajas, Victor %A de Alava, Enrique %A Collini, Paola %A Peña-Chilet, Maria %A Dopazo, Joaquin %A Carrasco-Garcia, Irene %A Lopez-Alvarez, Maria %A Moura, David S %A Lopez-Martin, Jose A %K Adult %K Aged %K Antineoplastic Agents, Immunological %K Female %K Humans %K Male %K Middle Aged %K Nivolumab %K Sarcoma %K Sunitinib %K Young Adult %X

BACKGROUND: Sarcomas exhibit low expression of factors related to immune response, which could explain the modest activity of PD-1 inhibitors. A potential strategy to convert a cold into an inflamed microenvironment lies on a combination therapy. As tumor angiogenesis promotes immunosuppression, we designed a phase Ib/II trial to test the double inhibition of angiogenesis (sunitinib) and PD-1/PD-L1 axis (nivolumab).

METHODS: This single-arm, phase Ib/II trial enrolled adult patients with selected subtypes of sarcoma. Phase Ib established two dose levels: level 0 with sunitinib 37.5 mg daily from day 1, plus nivolumab 3 mg/kg intravenously on day 15, and then every 2 weeks; and level -1 with sunitinib 37.5 mg on the first 14 days (induction) and then 25 mg per day plus nivolumab on the same schedule. The primary endpoint was to determine the recommended dose for phase II (phase I) and the 6-month progression-free survival rate, according to Response Evaluation Criteria in Solid Tumors 1.1 (phase II).

RESULTS: From May 2017 to April 2019, 68 patients were enrolled: 16 in phase Ib and 52 in phase II. The recommended dose of sunitinib for phase II was 37.5 mg as induction and then 25 mg in combination with nivolumab. After a median follow-up of 17 months (4-26), the 6-month progression-free survival rate was 48% (95% CI 41% to 55%). The most common grade 3-4 adverse events included transaminitis (17.3%) and neutropenia (11.5%).

CONCLUSIONS: Sunitinib plus nivolumab is an active scheme with manageable toxicity in the treatment of selected patients with advanced soft tissue sarcoma, with almost half of patients free of progression at 6 months. NCT03277924.

%B J Immunother Cancer %V 8 %8 2020 11 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33203665?dopt=Abstract %R 10.1136/jitc-2020-001561 %0 Journal Article %J Lancet Oncol %D 2019 %T Pazopanib for treatment of advanced malignant and dedifferentiated solitary fibrous tumour: a multicentre, single-arm, phase 2 trial. %A Martin-Broto, Javier %A Stacchiotti, Silvia %A Lopez-Pousa, Antonio %A Redondo, Andres %A Bernabeu, Daniel %A de Alava, Enrique %A Casali, Paolo G %A Italiano, Antoine %A Gutierrez, Antonio %A Moura, David S %A Peña-Chilet, Maria %A Diaz-Martin, Juan %A Biscuola, Michele %A Taron, Miguel %A Collini, Paola %A Ranchere-Vince, Dominique %A Garcia Del Muro, Xavier %A Grignani, Giovanni %A Dumont, Sarah %A Martinez-Trufero, Javier %A Palmerini, Emanuela %A Hindi, Nadia %A Sebio, Ana %A Dopazo, Joaquin %A Dei Tos, Angelo Paolo %A LeCesne, Axel %A Blay, Jean-Yves %A Cruz, Josefina %K Adult %K Aged %K Angiogenesis Inhibitors %K Antineoplastic Agents %K Female %K Humans %K Indazoles %K Male %K Middle Aged %K Multivariate Analysis %K Pyrimidines %K Response Evaluation Criteria in Solid Tumors %K Soft Tissue Neoplasms %K Solitary Fibrous Tumors %K Sulfonamides %K Survival Analysis %X

BACKGROUND: A solitary fibrous tumour is a rare soft-tissue tumour with three clinicopathological variants: typical, malignant, and dedifferentiated. Preclinical experiments and retrospective studies have shown different sensitivities of solitary fibrous tumour to chemotherapy and antiangiogenics. We therefore designed a trial to assess the activity of pazopanib in a cohort of patients with malignant or dedifferentiated solitary fibrous tumour. The clinical and translational results are presented here.

METHODS: In this single-arm, phase 2 trial, adult patients (aged ≥ 18 years) with histologically confirmed metastatic or unresectable malignant or dedifferentiated solitary fibrous tumour at any location, who had progressed (by RECIST and Choi criteria) in the previous 6 months and had an ECOG performance status of 0-2, were enrolled at 16 third-level hospitals with expertise in sarcoma care in Spain, Italy, and France. Patients received pazopanib 800 mg once daily, taken orally without food, at least 1 h before or 2 h after a meal, until progression or intolerance. The primary endpoint of the study was overall response measured by Choi criteria in the subset of the intention-to-treat population (patients who received at least 1 month of treatment with at least one radiological assessment). All patients who received at least one dose of the study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02066285, and with the European Clinical Trials Database, EudraCT number 2013-005456-15.

FINDINGS: From June 26, 2014, to Nov 24, 2016, of 40 patients assessed, 36 were enrolled (34 with malignant solitary fibrous tumour and two with dedifferentiated solitary fibrous tumour). Median follow-up was 27 months (IQR 16-31). Based on central radiology review, 18 (51%) of 35 evaluable patients had partial responses, nine (26%) had stable disease, and eight (23%) had progressive disease according to Choi criteria. Further enrolment of patients with dedifferentiated solitary fibrous tumour was stopped after detection of early and fast progressions in a planned interim analysis. 51% (95% CI 34-69) of 35 patients achieved an overall response according to Choi criteria. Ten (29%) of 35 patients died. There were no deaths related to adverse events and the most frequent grade 3 or higher adverse events were hypertension (11 [31%] of 36 patients), neutropenia (four [11%]), increased concentrations of alanine aminotransferase (four [11%]), and increased concentrations of bilirubin (three [8%]).

INTERPRETATION: To our knowledge, this is the first trial of pazopanib for treatment of malignant solitary fibrous tumour showing activity in this patient group. The manageable toxicity profile and the activity shown by pazopanib suggests that this drug could be an option for systemic treatment of advanced malignant solitary fibrous tumour, and provides a benchmark for future trials.

FUNDING: Spanish Group for Research on Sarcomas (GEIS), Italian Sarcoma Group (ISG), French Sarcoma Group (FSG), GlaxoSmithKline, and Novartis.

%B Lancet Oncol %V 20 %P 134-144 %8 2019 01 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/30578023?dopt=Abstract %R 10.1016/S1470-2045(18)30676-4