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West Oncology 2024: Updates in Sarcoma with Dr David Portnoy

Updated: Mar 7

Presentation by Dr David Portnoy, MD, FACP, West Cancer CenterRare

At the 2024 West Oncology Conference in Memphis, Tennessee, Dr David Portnoy from West Cancer Center presented updates in treatment for sarcomas.


Sarcomas: A Brief Overview


Dr Portnoy began with a brief overview of sarcomas, which are classified as cancers that arise from the bone or soft tissues such as cartilage, fat, muscle, blood vessels, fibrous tissue and other types of connective tissue.  The sarcomas are comparatively rare among cancers. The yearly incidence of soft tissue sarcomas is approximately 13,000 new cases and 5,000 deaths, and for those arising in bone about 3,900 new cases and just over 2,100 deaths.  Sarcomas are also challenging cancers to study because there are over 100 different types, which vary in their biologic characteristics, and earlier studies, especially with soft tissue sarcomas, tended to ‘lump’ all sarcomas together. The differences among sarcoma types and the limited number of patients also make it difficult to accrue significant numbers of patients in clinical trials.  With recent advances in genetic subtyping of tumors, however, Dr Portnoy noted it is now possible to better distinguish among sarcomas on the basis of molecular characteristics, to determine which treatments might be most appropriate for a given subtype.  Indeed, even with more generalized cancer treatments such as chemotherapy, some sarcomas will respond better than others.  For example, Dr Portnoy noted Ewing’s sarcoma is much more sensitive to chemo than conventional chondrosarcoma, which is essentially refractory to chemotherapy.  There are also differences in sarcoma responses among the available types of chemotherapy.  Like other cancers, however, efforts have been focused on reducing the use of chemotherapy, and instead targeting the underlying biology of the sarcoma, by identifying specific driver mutations, or molecular alterations that lead to uncontrolled growth of the sarcoma, and which can be targeted with specific drug compounds.


Tyrosine Kinase Inhibitors and Targeted Therapies


Illustrating the growing impact of targeted therapy, Dr Portnoy related a case of a patient at his institution having a rare form of sarcoma called inflammatory myofibroblastic sarcoma, approximately 50% of which have a rearrangement in the anaplastic lymphoma kinase (ALK) gene.  The patient received treatment with an ALK specific targeted therapy (alectinib) and had significant improvement after 4 months of therapy, with subsequent radiographic and symptomatic improvement in disease, and to date continues to do well.  Alectinib and other tyrosine kinase inhibitor (TKI) type drugs used in sarcoma offer significant advantages over chemotherapy, in that they can be taken orally and generally have fewer side effects, compared to chemotherapy agents.  


In epitheliod sarcomas (ES), an aggressive subtype of sarcoma that is minimally responsive to chemotherapy, Dr Portnoy noted the use of tazemetostat, an inhibitor of EZH2, which is involved in DNA methylation.  Approximately 90% of ES tumors have loss of expression of the INI1 gene, which in turn leads to uncontrolled activation of EZH2.  An overall response rate (ORR) of ~25% and a median progression free survival (PFS) of 9.7 months is seen for ES patients treated with tazemetostat in the first line setting, which, based on historical data, compares very favorably to patients with this sarcoma subtype treated with chemotherapy.  Accordingly, this treatment is now FDA approved for the treatment of patients with ES.


Alectinib and tazemetostat, as described above, are thus two examples of TKI-type approved agents, which show activity in sarcoma, but which have also been used in other tumor types.  With regard to agents developed more specifically for sarcoma, Dr Portnoy described the use of pexidartinib in tenosynovial giant cell tumor (TSGCT), a locally aggressive type of sarcoma that can occur in joints and tendon sheaths.  A portion of the cells in TSGCT have a molecular alteration that results in overexpression of colony stimulating factor 1 (CSF-1) which results in local accumulation of inflammatory cells that result in debilitating symptoms.  Pexidartinib is a specific inhibitor of CSF-1 and an ORR of 60% was seen when used in patients with TSGCT.


In the setting of the more commonly occurring liposarcomas, including well differentiated (WDLPS) and dedifferentiated (DDLPS) liposarcomas, Dr Portnoy also noted the use of brigimadlin, an orally administered inhibitor of the MDM2-p53 pathway.  Nearly all WDLPS and DDLPS have a molecular alteration resulting in MDM2 amplification, which inhibits the activity of p53, a tumor suppressor gene.  When used in these sarcoma subtypes, brigimadlin in a phase 1 study resulted in a disease control rate (DCR) of 100% for WDLPS and 75% for DDLPS.


Dr Portnoy noted that, unlike other solid tumors, immunotherapy, which allows patient’s immune system to more efficiently recognize and target tumor cells, has been less useful overall as a treatment in sarcoma, with some exceptions.  Alveolar Soft Part Sarcomas (ASPS) constitute <1% of all sarcomas and can occur in patients of all ages, especially young adults, and are especially difficult to treat as they are refractory to chemotherapy.  While some TKIs (e.g., sunitinib, axitinib) have shown activity in this subtype, Dr Portnoy noted that atezolizumab immunotherapy has shown a response rate (RR) pf 37% in ASPS, with a duration of response of over 2 years (24.7 months) and a PFS of 20.8 months.  He noted that combination immunotherapy and TKI treatment is a therapy of choice at his institution for this difficult to treat sarcoma subtype.  Another TKI/immunotherapy combination which Dr Portnoy highlighted was the use of the TKI cabozantinib and nivolumab immunotherapy in patients with angiosarcoma tumors that had progressed after taxane chemotherapy.  In this small study of 22 patients, a response rate of 59% was observed, with a median PFS of 9.6 months, and although the results need to be replicated in a larger study, Dr Portnoy considered the combination as promising for this sarcoma subtype.


Perioperative Therapy


Dr Portnoy noted a current controversy in sarcoma, which is whether to use perioperative chemotherapy in combination with surgery and radiation for high risk sarcoma patients.  He noted that, owing to the rarity of sarcoma, differences in study design and methodology, and contradictory results which have been observed across trials, it has not been definitively established that such treatment is beneficial across the range of sarcoma types.  He described one trial attempting to tailor perioperative chemotherapy according to sarcoma subtype which yielded negative results, favoring the preferred, but fairly toxic regimen for soft tissue sarcomas, typically anthracyclines in combination with ifosfamide.  Dr Portnoy also described an app called the ‘Sarculator’ which is used to stratify patients for treatment according to age, size of tumor, tumor grade, and histologic subtype.  The app is used to predict 5 and 10 year overall survival (OS), as well as rate of distant metastasis.  Using the Sarculator, patients could be stratified by 10 year OS (>60% or <60%), and multiple studies have now shown that the benefit of the anthracycline/ifosfamide regimen was greatest in those with a 40% or higher risk of death over 10 years.  Dr Portnoy noted that currently this is the method of choice at their institution to determine which high risk sarcoma patients to treat with chemotherapy.


Desmoid Tumors


Dr Portnoy also reviewed the treatment of desmoid tumors, a unique subtype of sarcomas which are locally aggressive tumors that can affect organs and adjacent structures causing pain and functional impairment, but which are unable to metastasize.  While surgery is an option for these tumors, Dr Portnoy noted that recurrence rates are high (up to 77%); other options include radiotherapy, ablative techniques, and high intensity ultrasound.  While TKIs such as sorafenib have been used to treat desmoid tumors, clinical trial results have shown a limited benefit over placebo, and further suggest that after an initial period of growth, many patients will experience prolonged stabilization of their disease. As such, for many desmoid tumors, Dr Portnoy noted that simple observation is a first line approach. Recently, however, he noted there have been attempts to more specifically address the underlying biology of desmoid tumors, and the molecular alterations responsible for their uncontrolled growth, using targeted therapies. Specifically, mutations in genes of the Wnt-adenomatous polyposis coli-beta-catenin pathway, such as CTNNB1, are commonly seen in desmoid tumors, and a class of drugs known as gamma-secretase inhibitors can inhibit a key growth protein in this pathway called Notch1.  One such drug, nirogacestat, has been recently shown to significantly improve PFS over placebo in a randomized trial (hazard ratio for disease progression or death = 0.29; P<0.001).  There was also significant improvement in pain, quality of life measures and symptoms with nirogacestat.  While there are specific adverse events associated with the therapy including a reversible ovarian dysfunction in women of childbearing age, the treatment holds promise to better target the unique biology and symptomatology of desmoid tumors.


Gastrointestinal Stromal Tumors (GIST)


In the final portion of his presentation, Dr Portnoy reviewed treatment of gastrointestinal stromal tumor (GIST), the most common sarcoma subtype.  GIST can arise in any portion of the GI tract but over half (55%) occur in the stomach.  A majority of GISTs have mutations in the KIT gene, and about 10% have PDGFRA mutations.  Owing to these molecular alterations, TKIs have been used in patients with metastatic GIST since 2002, and most successfully using imatinib (median PFS 20.4 months, ORR 51%).  More recently, the TKI ripretinib, designed to have activity against a variety of KIT and PDGFRA mutations, has been compared with sunitinib as a second line treatment in the INTRIGUE phase III clinical study.  The study results showed no significant difference in PFS, although there were fewer adverse events with ripretinib, and better patient reported tolerability.  Additional analysis from INTRIGUE showed that sunitinib was active against specific KIT mutations, whereas ripretinib was active against other types, and Dr Portnoy noted that molecular profiling of GIST using circulating tumor DNA (ctDNA) monitoring in patients with progression may be one means of selecting the most appropriate TKI to use.  Based upon these findings, the 2 drugs will again be compared in the INSIGHT trial with selective use of ripretinib or sunitinib based on molecular profile.

Updates in Sarcoma with Dr Portnoy: Quick Summary

  • Sarcomas are challenging tumors to study because they are comparatively rare among cancers, with many different subtypes having unique features.

    • Survival of patients with sarcoma has been improving with greater recognition and testing for molecular alterations (driver mutations) that result in uncontrolled growth.

    • Targeted therapies including the tyrosine kinase inhibitors (TKIs) offer an advantage over chemotherapy with many having an oral route of administration and lower toxicity.


  • For patients with high risk sarcomas, perioperative chemotherapy using anthracyclines (doxorubicin) and isofosfamide remains the standard of care.

    • Clinical tools (e.g., Sarculator app) can help to identify patients most likely to benefit from perioperative chemotherapy, specifically, those with a 40% or higher risk of death over 10 years.


  • Observation can be a first line treatment for many patients with debilitating desmoid tumors, with many patients experiencing an initial growth period followed by stabilization of disease.

    • More recently, treatments are emerging (e.g., nirogacestat) which are designed to specifically inhibit the unique biology of desmoid tumors.


  • For patients with the more commonly occurring sarcomas such as GIST, targeted therapy with TKIs (imatinib, and more recently ripretinib) remains a cornerstone of treatment. 

    • Monitoring for specific mutations using circulating tumor DNA (ctDNA) in patients with metastatic GIST upon progression may be one means to guide treatment with one TKI versus another.

Speaker Disclosure Information:  Dr Portnoy listed no disclosures for this presentation.


You can see Dr Portnoy's full presentation from the 2024 West Oncology Conference here:


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