Search

We present the case of a patient with Myxofibrosarcoma (MFS), a mesenchymal type of soft tissue sarcoma (STS) and the response to combination immunotherapy with anti PD-1 and anti-CTLA-4 therapy, following disease progression after Standard chemotherapy (SACT) and Radiotherapy (RT). We have shown a timeline of treatment and responses, as well as the overall safety profile and the management of immunotherapy related adverse events. This study demonstrates the potential of checkpoint inhibitors as therapeutic agents in the treatment of MFS. [ABSTRACT FROM AUTHOR]

Somatic KIT activating mutations drive most gastrointestinal stromal tumors (GISTs). Disease progression eventually develops with first-line imatinib, commonly due to KIT secondary mutations, and different kinase inhibitors have various levels of treatment efficacy dependent on specific acquired resistance mutations. Ripretinib is a broad-spectrum switch-control KIT/PDGFRA tyrosine kinase inhibitor for patients with advanced GIST who received prior treatment with three or more kinase inhibitors, including imatinib. Exploratory baseline circulating tumor DNA analysis from the second-line INTRIGUE trial determined that patients with advanced GIST previously treated with imatinib harboring primary KIT exon 11 mutations and secondary resistance mutations restricted to KIT exons 17/18 had greater clinical benefit with ripretinib versus sunitinib. We describe the rationale and design of INSIGHT (NCT05734105), an ongoing Phase III open-label study of ripretinib versus sunitinib in patients with advanced GIST previously treated with imatinib exclusively harboring KIT exon 11 + 17/18 mutations detected by circulating tumor DNA. Clinical Trial Registration:NCT05734105 (ClinicalTrials.gov) Plain Language Summary Gastrointestinal stromal tumor (GIST) is rare, but it is the most common mesenchymal tumor (a type of tumor that develops from cells which give rise to soft tissues) of the gastrointestinal tract. The primary treatment for advanced GIST is medication that targets the abnormal mechanisms in cancer cells in order to block tumor growth and spread. Ripretinib is an inhibitor of a protein known as KIT, which is a member of the tyrosine kinase protein family and is involved in the growth of GIST. In a Phase III clinical trial called INTRIGUE, the effects of ripretinib and another receptor tyrosine kinase inhibitor, sunitinib, were compared in patients with advanced GIST previously treated with the drug imatinib. An exploratory analysis from the INTRIGUE trial that characterized baseline circulating tumor DNA in the blood showed a greater clinical benefit with ripretinib versus sunitinib in patients with gene mutations solely occurring in KIT exon 11 + 17 and/or 18 (exon 11 + 17/18). This article describes the rationale and design for a Phase III clinical trial called INSIGHT that will evaluate the benefit of ripretinib compared with sunitinib in patients with advanced GIST whose tumors have mutations in KIT exon 11 and KIT exon 17 and/or 18. Patients will receive ripretinib or sunitinib in 6-week cycles, and investigators will assess survival without cancer progression as the primary outcome, and overall survival, and response of the tumor to these two drugs as secondary outcomes. Tweetable Abstract This article describes the rationale and design for the INSIGHT Phase III trial evaluating patients with second-line advanced GIST who harbor primary KIT exon 11 mutations and secondary resistance mutations restricted to the activation loop (KIT exons 17/18). Executive summary Disease overview & management Gastrointestinal stromal tumor (GIST) is the most common gastrointestinal sarcoma, with approximately 80% of cases driven by activating mutations in KIT. Sunitinib is a multitargeted tyrosine kinase inhibitor (TKI) approved as a second-line therapy for advanced GIST after disease progression on or intolerance to imatinib. Ripretinib is a broad-spectrum switch-control KIT/PDGFRA TKI approved as a fourth-line therapy for advanced GIST. Differential activity of ripretinib & sunitinib against secondary KIT mutations Exploratory baseline circulating tumor DNA (ctDNA) analysis from INTRIGUE determined that patients with KIT exon 11 + 13/14 mutations had improved progression-free survival (PFS) and objective response rate (ORR) with sunitinib versus ripretinib, while those with KIT exon 11 + 17/18 mutations had improved PFS, ORR and overall survival (OS) and a better safety profile with ripretinib versus sunitinib. Design INSIGHT is an international, Phase III, randomized, multicenter, open-label study evaluating the efficacy of ripretinib versus sunitinib in patients with advanced GIST previously treated with imatinib and who have KIT exon 11 mutations and co-occurring mutations exclusively in KIT exons 17/18, as identified by ctDNA. Approximately 54 patients will be randomized 2:1 to receive ripretinib 150 mg once daily (QD; continuous) or sunitinib 50 mg QD (4 weeks on/2 weeks off) in 6-week cycles. Eligible patients must have a histologic diagnosis of advanced GIST and co-occurring KIT exon 11 + 17/18 mutations confirmed by central laboratory ctDNA analysis, as well as radiologic progression on imatinib. The primary outcome measure is PFS based on blinded independent radiologic review (IRR) using modified Response Evaluation Criteria in Solid Tumors version 1.1 (mRECIST v1.1), while key secondary outcome measures are ORR based on blinded IRR using mRECIST v1.1 and OS. Infographic [ABSTRACT FROM AUTHOR]

Background: High‐risk soft tissue sarcomas of the extremities and trunk wall (eSTS), as defined by the Sarculator nomogram, are more likely to benefit from (neo)adjuvant anthracycline‐based therapy compared to low/intermediate‐risk patients. The biology underpinning these differential treatment outcomes remain unknown. Methods: We analysed proteomic profiles and clinical outcomes of 123 eSTS patients. A Cox model for overall survival including the Sarculator was fitted to individual data to define four risk groups. A DNA replication protein signature‐Sarcoma Proteomic Module 6 (SPM6) was evaluated for association with clinicopathological factors and risk groups. SPM6 was added as a covariate together with Sarculator in a multivariable Cox model to assess improvement in prognostic risk stratification. Results: DNA replication and cell cycle proteins were upregulated in high‐risk versus very low‐risk patients. Evaluation of the functional effects of CRISPR‐Cas9 gene knockdown of proteins enriched in high‐risk patients using the cancer cell line encyclopaedia database identified candidate drug targets. SPM6 was significantly associated with tumour malignancy grade (p = 1.6e‐06), histology (p = 1.4e‐05) and risk groups (p = 2.6e‐06). Cox model analysis showed that SPM6 substantially contributed to a better calibration of the Sarculator nomogram (Index of Prediction Accuracy = 0.109 for Sarculator alone versus 0.165 for Sarculator + SPM6). Conclusions: Risk stratification of patient with STS is defined by distinct biological pathways across a range of cancer hallmarks. Incorporation of SPM6 protein signature improves prognostic risk stratification of the Sarculator nomogram. This study highlights the utility of integrating protein signatures for the development of next‐generation nomograms. [ABSTRACT FROM AUTHOR]

Background: Epithelioid hemangioendothelioma (EHE) is an ultra-rare, vascular sarcoma with clinical presentation ranging from an indolent to an aggressive form. Over 50% of patients present with metastatic disease, requiring systemic therapy, although no systemic therapies are specifically approved for EHE. Retrospective evidence supports the activity of mTOR inhibitors (e.g. sirolimus), although available only off-label. EHE patients and advocates are therefore working to support approval of effective treatments by collecting data on patient perspectives and experiences. Materials and methods: In February 2023, the EHE Rare Cancer Charity (UK) and The EHE Foundation (US), with other advocates, conducted a survey of perspectives and experiences of EHE patients regarding the use and accessibility of sirolimus. The survey consisted of 20 questions designed for individuals undergoing treatment, those who had been treated, or had never been treated with the drug. Widely promoted within the patient community, the online survey categorized patients into three cohorts for the analysis: liver transplant patients, non-transplant patients who had ever taken sirolimus and sirolimus-naïve non-transplant patients. Results: The survey evaluated data from 129 patient responses from 21 countries, mostly from USA, UK, Australia, and Canada (70%). The liver transplant, sirolimus and non-sirolimus cohorts were 16%, 25% and 59%, respectively. In the sirolimus group 66% reported treatment durations exceeding one year, with 16% exceeding five years, indicating the drug's efficacy. In the non-sirolimus group, the drug was not available for 42% and for 11% sirolimus was available but not selected for treatment because of its off-label status. Overall, 87% of all patients across all cohorts expressed the importance of the drug's availability as hugely or very important. Conclusion: The survey responses highlight the activity of sirolimus for EHE and the importance of securing a label extension for the drug delivering equitable access to this treatment for patients. [ABSTRACT FROM AUTHOR]

Purpose: Epithelioid hemangioendothelioma (EHE), an ultra-rare sarcoma, poses therapeutic challenges because of limited efficacy of conventional chemotherapy in advanced cases, necessitating exploration of new treatment avenues and identification of novel aggressive biomarkers. This study aimed at (i) utilizing a patient-derived xenograft model of EHE and its associated cell line to assess the efficacy of sirolimus and (ii) analyzing two distinct patient cohorts to pinpoint circulating biomarkers of EHE aggressiveness., Experimental Design: A patient-derived xenograft model and corresponding cell line were established from a patient with advanced EHE, demonstrating consistency with the original tumor in terms of histomorphology, WWTR1::CAMTA1 fusion presence, and genomic and transcriptomic profiles. Two independent patient series were employed to investigate the association between growth/differentiation factor 15 (GDF-15) serum levels and EHE aggressiveness., Results: ELISA analyses on EHE cell culture medium and blood from EHE-carrying mice revealed the release of GDF-15 by EHE cells. Sirolimus exhibited markedly higher antitumor activity compared with doxorubicin, concurrently reducing GDF-15 expression/release both in vivo and in vitro. This reduction was attributed to the drug-induced inhibition of phosphorylation/activation of 4E-BP1 and subsequent downregulation of the GDF-15 transcription factors ATF4 and ATF5. Blood sample analyses from two independent patient series showed a significant correlation between GDF-15 and EHE aggressiveness., Conclusions: This study identifies GDF-15 as a novel biomarker of EHE aggressiveness and underscores the superior efficacy of sirolimus compared with doxorubicin in our experimental models. The observed inhibition of GDF-15 release by sirolimus suggests its potential as a biomarker for monitoring the drug's activity in patients., (©2024 The Authors; Published by the American Association for Cancer Research.)

The optimal medical treatment of chemotherapy-ineligible patients affected by advanced soft-tissue sarcomas is unclear. In this population, tyrosine kinase inhibitors represent an appealing alternative treatment strategy. First-line use of the tyrosine kinase inhibitor anlotinib in chemotherapy-ineligible patients with soft-tissue sarcoma showed promising activity across multiple histologies. See related article by Li et al., p. 4310., (©2024 American Association for Cancer Research.)

Background: Adolescents and young adult (AYA) patients with soft tissue tumours including sarcomas are an underserved group with disparities in treatment outcomes., Methods: To define the molecular features between AYA and older adult (OA) patients, we analysed the proteomic profiles of a large cohort of soft tissue tumours across 10 histological subtypes (AYA n = 66, OA n = 243), and also analysed publicly available functional genomic data from soft tissue tumour cell lines (AYA n = 5, OA n = 8)., Results: Biological hallmarks analysis demonstrates that OA tumours are significantly enriched in MYC targets compared to AYA tumours. By comparing the patient-level proteomic data with functional genomic profiles from sarcoma cell lines, we show that the mRNA splicing pathway is an intrinsic vulnerability in cell lines from OA patients and that components of the spliceosome complex are independent prognostic factors for metastasis free survival in AYA patients., Conclusions: Our study highlights the importance of performing age-specific molecular profiling studies to identify risk stratification tools and targeted agents tailored for the clinical management of AYA patients., (© 2024. The Author(s).)

Purpose: The efficacy of the selective KIT/PDGFRA inhibitor avapritinib (300 mg once daily) was explored in patients with non-PDGFRA-mutant gastrointestinal stromal tumors (GISTs) from the phase I NAVIGATOR and phase I/II CS3007-001 trials., Patients and Methods: Adults with unresectable/metastatic, KIT-only-mutant GISTs and progression following ≥1 tyrosine kinase inhibitors (TKIs) were included in this post hoc analysis. Baseline mutational status was identified in tumor and plasma. Primary endpoints were objective response rate (ORR) and progression-free survival (PFS) by blinded independent radiology review per modified RECIST v1.1 in patients harboring KIT activation-loop mutations (KIT exons 17 or 18) without ATP binding-pocket mutations (KIT exons 13 or 14; ALposABPneg), and other KIT mutations (OTHERS)., Results: Sixty KIT ALposABPneg and 100 KIT OTHERS predominantly heavily pretreated patients (61.3% with ≥3 prior TKIs) were included. ORR was significantly higher in KIT ALposABPneg than KIT OTHERS patients (unadjusted: 26.7% vs. 12.0%; P = 0.0852; adjusted: 31.4% vs. 12.1%; P = 0.0047). Median PFS (mPFS) was significantly longer in KIT ALposABPneg patients compared with KIT OTHERS patients (unadjusted: 9.1 vs. 3.5 months; P = 0.0002; adjusted: 9.1 vs. 3.4 months; P < 0.0001), and longer in second- versus later-line settings (19.3 vs. 5.6-10.6 months). Benefit with avapritinib was observed in patients with KIT exon 9 mutations in the ≥4 line settings (mPFS: 5.6 and 3.7 months for 4 line and >4 line, respectively)., Conclusions: Avapritinib showed greater antitumor activity in patients with GISTs harboring KIT ALposABPneg mutations versus KIT OTHERS, and may be considered in the former subpopulation. Patients with KIT exon 9 mutations may also benefit in ≥4 line settings., (©2023 American Association for Cancer Research.)