Dataset Information

Early phase trials in soft-tissue sarcomas: clinical benefit of inclusion in early lines of treatment, molecular screening, and histology-driven trials.

ABSTRACT:

Background

The prognosis of patients with advanced soft-tissue sarcomas (STS) remains dismal, and systemic therapeutic options are limited. Early phase trials are becoming increasingly safe and effective. This study aimed to identify the prognostic factors for progression-free survival (PFS).

Patients and methods

This retrospective analysis included all STS patients participating in early phase trials at Gustave Roussy and Léon Bérard between 1 January 2012 and 31 December 2020.

Results

Overall, 199 patients accounted for 214 inclusions in advanced STS. The most frequent histotypes were well-differentiated/dedifferentiated liposarcomas (n = 55), leiomyosarcomas (n = 53), synovial sarcomas (n = 22), undifferentiated pleomorphic sarcomas (n = 15), angiosarcomas (n = 12), and myxoid liposarcomas (n = 10). The median PFS was 2.8 months (95% confidence interval 2.7-4.1 months). The median PFS in the first, second, and later lines was 8.3, 5.4, and 2.6 months, respectively (P = 0.00015). The median PFS was 2.8 months in case of molecular screening, 4.1 months in case of histology-driven screening, and 1.6 months (P = 0.00014) in the absence of either screening modalities. In univariate analysis, histotype (P = 0.026), complex genomics (P = 0.008), number of prior lines (P < 0.001), prior anthracyclines (P < 0.001), number of metastatic sites (P = 0.003), liver metastasis (P < 0.001), lung metastasis (P < 0.001), absence of molecular or histology-driven screening (P < 0.001), first-in-human trials (P < 0.001), dose-escalation cohorts (P = 0.011), and Royal Marsden Hospital (RMH) score >1 (P < 0.001) were significantly associated with shorter PFS. In multivariate analysis, independent prognostic factors for shorter PFS were myxoid liposarcoma (P = 0.031), ≥2 prior lines of treatment (P = 0.033), liver metastasis (P = 0.007), and RMH score >2 (P = 0.006). Factors associated with improved PFS were leiomyosarcomas (P = 0.010), molecular screening (P = 0.025), and histology-driven screening (P = 0.010). The median overall survival rates were 36.3, 12.6, and 9.2 months in the first, second, and later lines, respectively (P = 0.0067). The grade 3-4 toxicity rate was 36%.

Conclusions

Early phase trials provide an active therapeutic option for STS, even in first-line settings. Molecular screening and histology-driven trials further improve the clinical benefit.

SUBMITTER: Nassif EF

PROVIDER: S-EPMC9058915 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Publications

Early phase trials in soft-tissue sarcomas: clinical benefit of inclusion in early lines of treatment, molecular screening, and histology-driven trials.

Nassif E F EF Blay J-Y JY Massard C C Dufresne A A Brahmi M M Cassier P P Ray-Coquard I I Pautier P P Leary A A Sunyach M-P MP Bahleda R R Levy A A Le Pechoux C C Honoré C C Mir O O Le Cesne A A

ESMO open 20220305 2

<h4>Background</h4>The prognosis of patients with advanced soft-tissue sarcomas (STS) remains dismal, and systemic therapeutic options are limited. Early phase trials are becoming increasingly safe and effective. This study aimed to identify the prognostic factors for progression-free survival (PFS).<h4>Patients and methods</h4>This retrospective analysis included all STS patients participating in early phase trials at Gustave Roussy and Léon Bérard between 1 January 2012 and 31 December 2020.<h ...[more]

PMID: 35255445

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Project description:Anti-PD-(L)1 therapies yield a disappointing response rate of 15% across soft-tissue sarcomas, even if some subtypes benefit more than others. The proportions of TAMs and TILs in their tumor microenvironment are variable, and this heterogeneity correlates to histotype. Tumors with a richer CD8+ T cell, M1 macrophage, and CD20+ cells infiltrate have a better prognosis than those infiltrated by M0/M2 macrophages and a high immune checkpoint protein expression. PD-L1 and CD8+ infiltrate seem correlated to response to immune checkpoint inhibitors (ICI), but tertiary lymphoid structures have the best predictive value and have been validated prospectively. Trials for combination therapies are ongoing and focus on the association of ICI with chemotherapy, achieving encouraging results especially with pembrolizumab and doxorubicin at an early stage, or ICI with antiangiogenics. A synergy with oncolytic viruses is seen and intratumoral talimogene laherpavec yields an impressive 35% ORR when associated to pembrolizumab. Adoptive cellular therapies are also of great interest in tumors with a high expression of cancer-testis antigens (CTA), such as synovial sarcomas or myxoid round cell liposarcomas with an ORR ranging from 20 to 50%. It seems crucial to adapt the design of clinical trials to histology. Leiomyosarcomas are characterized by complex genomics but are poorly infiltrated by immune cells and do not benefit from ICI. They should be tested with PIK3CA/AKT inhibition, IDO blockade, or treatments aiming at increasing antigenicity (radiotherapy, PARP inhibitors). DDLPS are more infiltrated and have higher PD-L1 expression, but responses to ICI remain variable across clinical studies. Combinations with MDM2 antagonists or CDK4/6 inhibitors may improve responses for DDLPS. UPS harbor the highest copy number alterations (CNA) and mutation rates, with a rich immune infiltrate containing TLS. They have a promising 15-40% ORR to ICI. Trials for ICB should focus on immune-high UPS. Association of ICI with FGFR inhibitors warrants further exploration in the immune-low group of UPS. Finally translocation-related sarcomas are heterogeneous, and although synovial sarcomas a poorly infiltrated and have a poor response rate to ICI, ASPS largely benefit from ICB monotherapy or its association with antiangiogenics agents. Targeting specific neoantigens through vaccine or adoptive cellular therapies is probably the most promising approach in synovial sarcomas.

Project description:Rationale: To establish a spatially exact co-registration procedure between in vivo multiparametric magnetic resonance imaging (mpMRI) and (immuno)histopathology of soft tissue sarcomas (STS) to identify imaging parameters that reflect radiation therapy response of STS. Methods: The mpMRI-Protocol included diffusion-weighted (DWI), intravoxel-incoherent motion (IVIM), and dynamic contrast-enhancing (DCE) imaging. The resection specimen was embedded in 6.5% agarose after initial fixation in formalin. To ensure identical alignment of histopathological sectioning and in vivo imaging, an ex vivo MRI scan of the specimen was rigidly co-registered with the in vivo mpMRI. The deviating angulation of the specimen to the in vivo location of the tumor was determined. The agarose block was trimmed accordingly. A second ex vivo MRI in a dedicated localizer with a 4 mm grid was performed, which was matched to a custom-built sectioning machine. Microtomy sections were stained with hematoxylin and eosin. Immunohistochemical staining was performed with anti-ALDH1A1 antibodies as a radioresistance and anti-MIB1 antibodies as a proliferation marker. Fusion of the digitized microtomy sections with the in vivo mpMRI was accomplished through nonrigid co-registration to the in vivo mpMRI. Co-registration accuracy was qualitatively assessed by visual assessment and quantitatively evaluated by computing target registration errors (TRE). Results: The study sample comprised nine tumor sections from three STS patients. Visual assessment after nonrigid co-registration showed a strong morphological correlation of the histopathological specimens with ex vivo MRI and in vivo mpMRI after neoadjuvant radiation therapy. Quantitative assessment of the co-registration procedure using TRE analysis of different pairs of pathology and MRI sections revealed highly accurate structural alignment, with a total median TRE of 2.25 mm (histology - ex vivo MRI), 2.22 mm (histology - in vivo mpMRI), and 2.02 mm (ex vivo MRI - in vivo mpMRI). There was no significant difference between TREs of the different pairs of sections or caudal, middle, and cranial tumor parts, respectively. Conclusion: Our initial results show a promising approach to obtaining accurate co-registration between histopathology and in vivo MRI for STS. In a larger cohort of patients, the method established here will enable the prospective identification and validation of in vivo imaging biomarkers for radiation therapy response prediction and monitoring in STS patients via precise molecular and cellular correlation.

Dataset Information

Early phase trials in soft-tissue sarcomas: clinical benefit of inclusion in early lines of treatment, molecular screening, and histology-driven trials.

Background

Patients and methods

Results

Conclusions

Publications

Early phase trials in soft-tissue sarcomas: clinical benefit of inclusion in early lines of treatment, molecular screening, and histology-driven trials.

Similar Datasets

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