Beyond the Driver Mutation: Immunotherapies in Gastrointestinal Stromal Tumors.

Gastrointestinal stromal tumors (GISTs) are a subtype of soft tissue sarcoma (STS), and have become a concept of oncogenic addiction and targeted therapies.The large majority of these tumors develop after a mutation in KIT or platelet derived growth factor receptor α (PDGFRα), resulting in uncontrolled proliferation. GISTs are highly sensitive to imatinib. GISTs are immune infiltrated tumors with a predominance of tumor-associated macrophages (TAMs) and T-cells, including many CD8+ T-cells, whose numbers are prognostic. The genomic expression profile is that of an inhibited Th1 response and the presence of tertiary lymphoid structures and B cell signatures, which are known as predictive to response to ICI. However, the microtumoral environment has immunosuppressive attributes, with immunosuppressive M2 macrophages, overexpression of indoleamine 2,3-dioxygenase (IDO) or PD-L1, and loss of major histocompatibility complex type 1. In addition to inhibiting the KIT oncogene, imatinib appears to act by promoting cytotoxic T-cell activity, interacting with natural killer cells, and inhibiting the expression of PD-L1. Paradoxically, imatinib also appears to induce M2 polarization of macrophages. There have been few immunotherapy trials with anti-CTLA-4 or anti-PD-L1drugs and available clinical data are not very promising. Based on this comprehensive analysis of TME, we believe three immunotherapeutic strategies must be underlined in GIST. First, patients included in clinical trials must be better selected, based on the identified driver mutation (such as PDGFRα D842V mutation), the presence of tertiary lymphoid structures (TLS) or PD-L1 expression. Moreover, innovative immunotherapeutic agents also provide great interest in GIST, and there is a strong rationale for exploring IDO targeting after disease progression during imatinib therapy. Finally and most importantly, there is a strong rationale to combine of c-kit inhibition with immune checkpoint inhibitors.

The Activity of Chemotherapy in Inflammatory Myofibroblastic Tumors: A Multicenter, European Retrospective Case Series Analysis.

BACKGROUND: This study aimed to review the activity of cytotoxic chemotherapy in patients with inflammatory myofibroblastic tumors (IMTs) treated at nine European sarcoma reference centers. MATERIALS AND METHODS: Patients of any age, with histologically proven IMT, treated with anthracycline-based methotrexate plus/minus vinorelbine/vinblastine (MTX-V) or other chemotherapeutic regimens between 1996 and 2018 were retrospectively reviewed. Diagnosis was confirmed at the local level by an expert pathologist. Response was retrospectively assessed by local investigators by RECIST v1.1. Progression-free survival (PFS), relapse-free survival (RFS), and overall survival (OS) were computed by Kaplan-Meier method. RESULTS: Thirty-eight patients were included. Twenty-five patients (8 localized, 17 advanced disease) received an anthracycline-based regimen; 21 were evaluable for response. Overall response rate (ORR) was 10/21 (47.6%). At a 70.8-month median follow-up (FU), median RFS and median OS were not reached (NR) in patients with localized disease; median PFS and median OS were 6.3 (interquartile range [IQR]: 1.9-13.4) and 21.2 (IQR: 7.7-40.7) months in patients with advanced disease. Thirteen patients received MTX-V (4 localized, 9 advanced disease), all evaluable for response. ORR was 7/13 (53.8%). At a 56.6-month median FU, median RFS and median OS were 42.5 (IQR: 12.9-61.2) months and NR (no death events) in patients with localized disease, and NR (IQR: 24.9 to NR) and 83.4 months (IQR: 83.4 to NR) in patients with advanced disease. In the "other-regimens group," responses were seen in 3/4 patients treated with oral cyclophosphamide and 1/2 with docetaxel/gemcitabine. CONCLUSION: Anthracycline-based and MTX-V regimens are very effective in IMT, with a similar ORR in both groups. MTX-V achieved a prolonged disease control. Responses were also seen with oral cyclophosphamide and docetaxel/gemcitabine, but few patients were treated with these schedules. IMPLICATIONS FOR PRACTICE: Inflammatory myofibroblastic tumor (IMT) is an ultrarare sarcoma with known sensitivity to anaplastic lymphoma kinase (ALK) inhibitors in ALK-fused cases, although ALK inhibitors are not licensed in the disease. The current knowledge on the activity of cytotoxic chemotherapy is limited. This multi-institutional retrospective study on pediatric and adult patients with IMT shows that cytotoxic chemotherapy, and in particular anthracycline-based and methotrexate plus/minus vinorelbine/vinblastine regimens, represents a treatment option and can be considered in IMT patients irrespectively from ALK status. This study provides a benchmark for future studies on new medical therapies.

Outcomes of Elderly Patients with Advanced Soft Tissue Sarcoma Treated with First-Line Chemotherapy: A Pooled Analysis of 12 EORTC Soft Tissue and Bone Sarcoma Group Trials.

BACKGROUND: Almost half of patients diagnosed with soft tissue sarcoma (STS) are older than 65 years; however, the outcomes of elderly patients with metastatic disease are not well described. PATIENTS AND METHODS: An elderly cohort of patients aged ≥65 years was extracted from the European Organization for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group database of patients treated with first-line chemotherapy for advanced STS within 12 EORTC clinical trials. Endpoints were overall survival (OS), progression-free survival (PFS), and response rate (RR). RESULTS: Of 2,810 participants in EORTC trials, there were 348 elderly patients (12.4%, median 68 years; interquartile range [IQR], 67-70; maximum 84 years) and 2,462 patients aged <65 years (median 49 years; IQR, 39-57). Most elderly patients had a performance status of 0 (n = 134; 39%) or 1 (n = 177; 51%). Leiomyosarcoma (n = 130; 37%) was the most common histological subtype. Lung metastases were present in 181 patients (52%) and liver metastases in 63 patients (18%). Overall, 126 patients (36%) received doxorubicin, 114 patients (33%) doxorubicin + ifosfamide, 43 patients (12%) epirubicin, 39 patients (11%) trabectedin, and 26 patients (7%) ifosfamide. Overall RR was 14.9% (n = 52), median PFS was 3.5 months (95% confidence interval [CI], 2.7-4.3), and median OS was 10.8 months (95% CI, 9.43-11.83). In patients aged <65 years, overall RR was 20.3% (n = 501), median OS was 12.3 months (95% CI, 11.9-12.9), and median PFS was 4.3 months (95% CI, 3.9-4.6). CONCLUSION: Elderly patients with metastatic STS treated with first-line chemotherapy were largely underrepresented in these EORTC STS trials. Their outcomes were only slightly worse than those of younger patients. Novel trials with broader eligibility criteria are needed for elderly patients. These trials should incorporate geriatric assessments and measurements of age-adjusted health-related quality of life. IMPLICATIONS FOR PRACTICE: This analysis demonstrates that elderly patients with advanced soft tissue sarcoma are underrepresented in clinical trials of first-line chemotherapy by the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. Furthermore, the elderly participants were generally of excellent performance status, which is not representative of an unselected elderly population. These data provide rationale for development of novel trials for elderly patients that are not only for "elite" patients but include comprehensive geriatric assessments for risk stratification. Because chemotherapy for advanced soft tissue sarcomas is largely given with palliative intent, incorporation of health-related quality of life measures with traditional endpoints will provide a more holistic approach to future clinical trials.

Clinical and Molecular Spectrum of Liposarcoma.

Liposarcomas are rare malignant tumors of adipocytic differentiation. The classification of liposarcomas into four principal subtypes reflects the distinct clinical behavior, treatment sensitivity, and underlying biology encompassed by these diseases. Increasingly, clinical management decisions and the development of investigational therapeutics are informed by an improved understanding of subtype-specific molecular pathology. Well-differentiated liposarcoma is the most common subtype and is associated with indolent behavior, local recurrence, and insensitivity to radiotherapy and chemotherapy. Dedifferentiated liposarcoma represents focal progression of well-differentiated disease into a more aggressive, metastasizing, and fatal malignancy. Both of these subtypes are characterized by recurrent amplifications within chromosome 12, resulting in the overexpression of disease-driving genes that have been the focus of therapeutic targeting. Myxoid liposarcoma is characterized by a pathognomonic chromosomal translocation that results in an oncogenic fusion protein, whereas pleomorphic liposarcoma is a karyotypically complex and especially poor-prognosis subtype that accounts for less than 10% of liposarcoma diagnoses. A range of novel pharmaceutical agents that aim to target liposarcoma-specific biology are under active investigation and offer hope of adding to the limited available treatment options for recurrent or inoperable disease.

Efficacy and safety of eribulin mesylate in advanced soft tissue sarcomas.

Despite recent advances in the field, treatment options for metastatic soft tissue sarcoma patients are limited. Eribulin, an antimitotic derived from the natural marine sponge product halichondrin B, is currently approved for the treatment of metastatic breast cancer. Following the promising activity of eribulin in sarcoma in a Phase II trial, the drug was recently compared to dacarbazine in pretreated advanced leiomyosarcoma (LMS) and liposarcoma (LPS) patients in a Phase III trial. Eribulin was associated with a significant 2-month improvement in median overall survival compared to dacarbazine (13.5 vs. 11.5 months, heart rate: 0.768) despite no documented significant difference in progression-free survival. In a subgroup analysis, the survival advantage associated with eribulin was evident in the LPS subgroup but not in the LMS subgroup. Following these encouraging results, the Food and Drug Administration has approved eribulin for the treatment of advanced LPS for patients who received prior anthracycline chemotherapy. In this short review, we will evaluate the evidence for eribulin in soft tissue sarcoma, highlight its mechanisms of action, and summarize the results of the major preclinical and clinical studies with a particular focus on the results of the Phase III trial.