Prices and Trends in FDA-Approved Medications for Sarcomas.

Sarcomas represent a diverse set of both malignant and benign subtypes consisting of often rare and ultra-rare conditions. Over the course of the last decade, there have been numerous FDA approvals for agents treating various sarcoma subtypes. Given this burgeoning landscape of sarcoma treatments, we seek to review current FDA-approved agents with respect to their rates of incidence, approval rates, and financial costs. We gathered clinical trial data by searching FDA approval announcements from 2013 to 2023. We determined the 30 day and one year cost of therapy for patients of FDA-approved sarcoma treatments in the aforementioned timeframe. From 2013 to 2023, 14 medications have been FDA-approved for sarcoma subtypes. The 30-day dosing prices for these medications range from $11,162.86 to $46,926.00. Since 2013, the rates of approval for sarcoma medications have been higher than in prior decades. Nonetheless, there remains the potential for significant financial toxicity for patients living with sarcoma.

PD-1 Inhibition in metastatic high tumour mutational burden (TMB) leiomyosarcoma with clinicopathological correlates.

Leiomyosarcoma (LMS) is a subtype of sarcoma derived from smooth muscle cells. Unfortunately, this malignancy has a high rate of metastatic disease. Palliative systemic therapy has historically relied on cytotoxic agents such as doxorubicin, which have low rates of response. Immunotherapy has not been shown to be effective for most patients with sarcoma, including those with LMS. However, this has not been well described for patients with LMS and high tumour mutational burden (TMB). Herein, we report the case of a woman in her late 50s with metastatic high TMB (>10) leiomyosarcoma treated with pembrolizumab.

Cardiac Safety of Pegylated Liposomal Doxorubicin After Conventional Doxorubicin Exposure in Patients With Sarcoma and Breast Cancer.

BACKGROUND: Lifetime cumulative doses of conventional doxorubicin (>450 mg/m2) are associated with dose-dependent cardiotoxicity. In sarcoma and breast cancer, conventional doxorubicin is often utilized in the adjuvant setting, whereas pegylated liposomal doxorubicin (PLD) is typically reserved for recurrent and metastatic disease. PLD is believed to be associated with reduced cardiotoxicity compared to conventional doxorubicin. Limited data exists evaluating the cardiotoxicity associated with PLD treatment after conventional doxorubicin, especially when doxorubicin lifetime doses approach the established cumulative total lifetime dose of 450-550 mg/m2. This study aims to further qualify the cardiac safety of PLD use in patients who have had prior exposure to conventional doxorubicin. METHODS: This was a single-center, observational, retrospective cohort study conducted in patients ≥18 years with sarcoma or breast cancer who were exposed to conventional doxorubicin from an earlier line of treatment before PLD between January 2010 to May 2022. Patients were evaluated for the presence of cardiac toxicity at any point in their treatment course. Cardiac toxicity was defined as ≥ 10% decrease in left ventricle ejection fraction (LVEF) or a new diagnosis of heart failure within six months after PLD cessation. The time interval between the last conventional doxorubicin exposure and PLD initiation and the time interval between PLD initiation and LVEF monitoring were also analyzed. RESULTS: 494 patients were screened, and 50 met inclusion criteria: eight with sarcoma and 42 with breast cancer. The median lifetime cumulative conventional doxorubicin dose in patients with sarcoma was 450 mg/m2 with a maximum dose of 825 mg/m2 and 240 mg/m2 with a maximum dose of 300 mg/m2 in breast cancer patients. The median lifetime cumulative PLD dose was 105 mg/m2 (range: 35-150 mg/m2) in the sarcoma group and 105 mg/m2 (range: 35-510 mg/m2) in the breast cancer group. A decrease of ≥ 10% in LVEF was not observed in the sarcoma group. Patients with breast cancer had available LVEF data on PLD, and three of these patients experienced ≥ 10% in LVEF drop, with one of these patients diagnosed with heart failure. The average cumulative dose of PLD administered in patients with > 10% decrease in LVEF was 177 mg/m2 and had an average of 3.5 cycles. Five sarcoma patients initiated PLD treatment within two years after conventional doxorubicin exposure, while most breast patients initiated PLD treatment at least 10 years following conventional doxorubicin exposure. The average time from PLD initiation to first and second available LVEF monitoring was one and five months in the sarcoma group and three and eight months in the breast cancer group, respectively. CONCLUSION: PLD administration in patients with prior exposure to conventional doxorubicin appears to be safe, with limited cardiotoxicity in patients with sarcoma and breast cancer. Future research is needed to determine if and how often routine cardiac monitoring is needed for patients on PLD without existing cardiac risk.

Capacity of ChatGPT to Identify Guideline-Based Treatments for Advanced Solid Tumors.

BACKGROUND:  ChatGPT, created by OpenAI, is a large language model which has become the fastest growing consumer application in history, recognized for its expansive knowledge of varied subjects. The field of oncology is highly specialized and requires nuanced understanding of medications and conditions. Herein, we sought to better qualify the ability of ChatGPT to name applicable treatments for patients with advanced solid cancers. METHODS:  This observational study was conducted utilizing ChatGPT. The capacity of ChatGPT to tabulate appropriate systemic therapies for new diagnoses of advanced solid malignancies was ascertained through standardized prompts. A ratio of those medications listed by ChatGPT to those suggested in the National Comprehensive Cancer Network (NCCN) guidelines was produced and called the valid therapy quotient (VTQ). Additional descriptive analyses of the VTQ and its association with incidence and type of treatment were performed. RESULTS:  Some 51 distinct diagnoses were utilized within this experiment. ChatGPT was able to identify 91 distinct medications in response to prompts related to advanced solid tumors. The overall VTQ is 0.77. In all cases, ChatGPT was able to provide at least one example of systemic therapy suggested by the NCCN. There was a weak association between incidence of each malignancy and the VTQ. CONCLUSION:  The capacity of ChatGPT to identify medications used to treat advanced solid tumors indicates a level of concordance with the NCCN guidelines. As it stands, the role of ChatGPT to assist oncologists and patients in treatment decision making remains unknown. Nonetheless, in future iterations, it may be anticipated that accuracy and consistency in this domain will improve, and further studies will be needed to better quantify its capabilities.

Targeted therapies for the treatment of soft tissue sarcoma.

Soft tissue sarcomas are rare malignant tumors derived from mesenchymal cells that have a high morbidity and mortality related to frequent occurrence of advanced and metastatic disease. Over the past two decades there have been significant advances in the use of targeted therapies for the treatment of soft tissue sarcoma. The ability to study various cellular markers and pathways related to sarcomagenesis has led to the creation and approval of multiple novel therapies. Herein, we describe the current landscape of targeted medications used in the management of advanced or metastatic soft tissue sarcomas, excluding GIST. We distinguish three categories: targeted therapies that have current US Food and Drug Administration (FDA) approval for treatment of soft tissue sarcoma, non-FDA approved targeted therapies, and medications in development for treatment of patients with soft tissue sarcoma.

Emerging targeted and cellular therapies in the treatment of advanced and metastatic synovial sarcoma.

Synovial sarcoma is a soft tissue sarcoma accounting for approximately 1,000 cases per year in the United States. Currently, standard treatment of advanced and metastatic synovial sarcoma is anthracycline-based chemotherapy. While advanced synovial sarcoma is more responsive to chemotherapy compared to other soft tissue sarcomas, survival rates are poor, with a median survival time of less than 18 months. Enhanced understanding of tumor antigen expression and molecular mechanisms behind synovial sarcoma provide potential targets for treatment. Adoptive Cell Transfer using engineered T-cell receptors is in clinical trials for treatment of synovial sarcoma, specifically targeting New York esophageal squamous cell carcinoma-1 (NY-ESO-1), preferentially expressed antigen in melanoma (PRAME), and melanoma antigen-A4 (MAGE-A4). In this review, we explore the opportunities and challenges of these treatments. We also describe artificial adjuvant vector cells (aAVCs) and BRD9 inhibitors, two additional potential targets for treatment of advanced synovial sarcoma. This review demonstrates the progress that has been made in treatment of synovial sarcoma and highlights the future study and qualification needed to implement these technologies as standard of care.

B7-H3 Specific CAR T Cells for the Naturally Occurring, Spontaneous Canine Sarcoma Model.

One obstacle for human solid tumor immunotherapy research is the lack of clinically relevant animal models. In this study, we sought to establish a chimeric antigen receptor (CAR) T-cell treatment model for naturally occurring canine sarcomas as a model for human CAR T-cell therapy. Canine CARs specific for B7-H3 were constructed using a single-chain variable fragment derived from the human B7-H3-specific antibody MGA271, which we confirmed to be cross-reactive with canine B7-H3. After refining activation, transduction, and expansion methods, we confirmed target killing in a tumor spheroid three-dimensional assay. We designed a B7-H3 canine CAR T-cell and achieved consistently high levels of transduction efficacy, expansion, and in vitro tumor killing. Safety of the CAR T cells were confirmed in two purposely bred healthy canine subjects following lymphodepletion by cyclophosphamide and fludarabine. Immune response, clinical parameters, and manifestation were closely monitored after treatments and were shown to resemble that of humans. No severe adverse events were observed. In summary, we demonstrated that similar to human cancers, B7-H3 can serve as a target for canine solid tumors. We successfully generated highly functional canine B7-H3-specific CAR T-cell products using a production protocol that closely models human CAR T-cell production procedure. The treatment regimen that we designed was confirmed to be safe in vivo. Our research provides a promising direction to establish in vitro and in vivo models for immunotherapy for canine and human solid tumor treatment.

CD4+ T cell and M2 macrophage infiltration predict dedifferentiated liposarcoma patient outcomes.

BACKGROUND: Dedifferentiated liposarcoma (DDLPS) is one of the most common soft tissue sarcoma subtypes and is devastating in the advanced/metastatic stage. Despite the observation of clinical responses to PD-1 inhibitors, little is known about the immune microenvironment in relation to patient prognosis. METHODS: We performed a retrospective study of 61 patients with DDLPS. We completed deep sequencing of the T-cell receptor (TCR) ß-chain and RNA sequencing for predictive modeling, evaluating both immune markers and tumor escape genes. Hierarchical clustering and recursive partitioning were employed to elucidate relationships of cellular infiltrates within the tumor microenvironment, while an immune score for single markers was created as a predictive tool. RESULTS: Although many DDLPS samples had low TCR clonality, high TCR clonality combined with low T-cell fraction predicted lower 3-year overall survival (p=0.05). Higher levels of CD14+ monocytes (p=0.02) inversely correlated with 3-year recurrence-free survival (RFS), while CD4+ T-cell infiltration (p=0.05) was associated with a higher RFS. Genes associated with longer RFS included PD-1 (p=0.003), ICOS (p=0.006), BTLA (p=0.033), and CTLA4 (p=0.02). In a composite immune score, CD4+ T cells had the strongest positive predictive value, while CD14+ monocytes and M2 macrophages had the strongest negative predictive values. CONCLUSIONS: Immune cell infiltration predicts clinical outcome in DDLPS, with CD4+ cells associated with better outcomes; CD14+ cells and M2 macrophages are associated with worse outcomes. Future checkpoint inhibitor studies in DDLPS should incorporate immunosequencing and gene expression profiling techniques that can generate immune landscape profiles.

An open-label single-arm phase II study of regorafenib for the treatment of angiosarcoma.

PURPOSE: Angiosarcomas represents a diverse group of aggressive high-grade vascular tumours with limited therapeutic options. We sought to determine the safety and efficacy of regorafenib, a small-molecule multikinase inhibitor, in the treatment of metastatic or locally advanced unresectable angiosarcoma. PATIENTS AND METHODS: In this single-arm multicentre, open-label phase II clinical trial, 31 patients were enrolled and received regorafenib 160 mg PO daily for 21 days of a 28-day cycle. The primary endpoint for the study was progression-free survival at 4 months. Secondary endpoints included overall survival, response rate, and safety. Patients (≥18 years) with an Eastern Cooperative Oncology Group (ECOG) score of 0-1, a life expectancy of at least 4 months who had progressed on at least one but no more than 4 prior lines of therapy were eligible. RESULTS: Of the 23 patients evaluable for efficacy, 2 had a complete response (8.7%), and 2 had a partial response (8.7%), for a total overall response rate of 17.4%. Median PFS was 5.5 months, and 12/23 patients (52.2%) had a PFS of greater than 4 months. 10/31 (32.3%) patients evaluable for toxicity had a grade 3 or higher adverse events. CONCLUSIONS: Regorafenib is a safe and active treatment for refractory metastatic and unresectable angiosarcoma. Rates of adverse events were comparable to prior studies of regorafenib for other tumour types. Regorafenib, the single agent, could be considered as therapy for patients with metastatic or unresectable AS.

Glandular metastases from renal cell carcinoma show poor clinical responses to immune checkpoint inhibition but durable responses to angiogenesis inhibitors.

While half of the metastatic clear cell renal cell carcinomas (ccRCCs) involve the lungs, metastatic lesions have been described in various other organs, including glandular tissues such as the pancreas. Recent evidence suggests that ccRCC lesions affecting the pancreas are poorly responsive to immune checkpoint inhibition (ICI) but show superior responses to tyrosine kinase inhibitors (TKIs) targeting the vascular endothelial growth factor (VEGF) signalling pathway. However, this has yet to be explored in ccRCC spreading to other glandular tissues. Here we present two cases of ccRCC with glandular metastases, the first to the pancreas and the second to the parotid gland. In both patients, ICI-based immunotherapy offered minimal clinical benefit, but both had durable responses to angiogenesis inhibitors. Given the anatomic similarity between the pancreas and parotid glands, ccRCC with involvement of the parotid gland may also benefit from VEGF-targeting TKIs as opposed to ICIs.

Phase II study of pazopanib with oral topotecan in patients with metastatic and non-resectable soft tissue and bone sarcomas.

BACKGROUND: Pazopanib is active in refractory soft-tissue sarcoma (STS) and significantly prolongs PFS. Prior studies of combinations of metronomic topotecan with pazopanib have indicated preclinical evidence of response in patients with sarcoma. METHODS: This prospective, single arm, phase II study evaluated the efficacy of the combination of pazopanib with topotecan in patients with metastatic or unresectable non-adipocytic STS. Furthermore, it incorporated exploratory arms for osteosarcoma and liposarcoma. The primary endpoint was progression-free rate at 12 weeks in the non-adipocytic STS cohort. RESULTS: 57.5% of patients in the non-adipocytic STS cohort were progression free at 12 weeks, which did not meet the primary endpoint of the study (66%). The exploratory osteosarcoma cohort exceeded previously established phase II trial comparator data benchmark of 12% with a PFR at 12 weeks of 69.55%. Treatment with the combination of pazopanib and topotecan was accompanied by a grade 3 or 4 toxicities in most patients. CONCLUSIONS: In this prospective trial in refractory metastatic or unresectable STS and osteosarcoma, the combination of pazopanib with topotecan did not meet its primary endpoint of progression-free rate at 12 weeks. The combination of pazopanib with topotecan was associated with a high degree of toxicity.

Metastatic Myxofibrosarcoma with Durable Response to Temozolomide Followed by Atezolizumab: A Case Report.

Myxofibrosarcoma (MFS) is a well-recognized histotype of soft tissue sarcomas that generally presents with localized disease. Herein, we describe the case of a patient with metastatic MFS who experienced durable response to sixth-line therapy with temozolomide. Upon further progression, his tumor was notable for a high tumor mutational burden, and he was subsequently treated with seventh-line immunotherapy, atezolizumab, achieving a second durable response. This case highlights the role of immunotherapy after administration of alkylating agents. Review of the literature indicates that recurrent tumors treated with alkylating agents often experience hypermutation as a means of developing resistance and that checkpoint inhibitors are subsequently effective in these tumors. KEY POINTS: To the authors' knowledge, this is the first report of a patient with myxofibrosarcoma with high tumor mutational burden after administration of temozolomide monotherapy. Hypermutation may be a resistance mechanism for patients with soft tissue sarcoma who develop resistance to alkylating agents. Checkpoint inhibition may be effective therapy in patients with soft tissue sarcoma with high tumor mutational burden as a consequence of alternate systemic therapy resistance.

Sorting Through the Maze of Treatment Options for Metastatic Castration-Sensitive Prostate Cancer.

Since 1944, when Huggins and Hodges demonstrated the effectiveness of bilateral orchiectomy for metastatic prostate cancer (PCa), androgen deprivation therapy (ADT) has been the first-line treatment for men with advanced PCa. The proportion of PCa cases that are metastatic at diagnosis ranges globally, from 5%-20% in countries with widespread screening practices to upward of 30%-60% where screening is minimal. In the United States alone, there will be an estimated 191,000 new cases of PCa diagnosed in the year 2020, of which approximately 20% will be metastatic.1 Ongoing controversy around prostate-specific antigen (PSA) screening practices, increased access to novel imaging modalities, and a globally aging population will drive increased rates of metastatic castration-sensitive prostate cancer (mCSPC).2,3 At the same time, advances in upfront hormonal or chemohormonal therapy have driven a dramatic shift in treatment paradigms. In this article, we review recent advances in treatment choices for men with newly diagnosed mCSPC and the impact of upfront treatment on subsequent disease biology. Options include treatment with chemohormonal therapy, androgen receptor (AR)-directed therapy in addition to ADT, or, less commonly, ADT alone. Treatment choice must include consideration of clinical and disease characteristics, as well as patient preferences and limitations of geography and financial concerns.

Characterization of clinical grade CD19 chimeric antigen receptor T cells produced using automated CliniMACS Prodigy system.

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy is highly effective for treating acute lymphoblastic leukemia and non-Hodgkin's lymphoma with high rate complete responses. However, the broad clinical application of CAR T-cell therapy has been challenging, largely due to the lack of widespread ability to produce and high cost of CAR T-cell products using traditional methods of production. Automated cell processing in a closed system has emerged as a potential method to increase the feasibility of producing CAR T cells locally at academic centers due to its minimal reliance on experienced labor, thereby making the process less expensive and more consistent than traditional methods of production. METHOD: In this study, we describe the successful production of clinical grade CD19 CAR T cells using the Miltenyi CliniMACS Prodigy Automated Cell Processor at University of Colorado Anschutz Medical Campus in a rapid manner with a high frequent CD19 CAR expression. RESULTS: The final CAR T-cell product is highly active, low in immune suppression, and absent in exhaustion. Full panel cytokine assays also showed elevated production of Th1 cytokines upon IL-2 stimulation when specifically killing CD19+ target cells. CONCLUSION: These results demonstrate the feasibility of producing CAR T cells locally in a university hospital setting using automated cell processor for future clinical applications.

Azelaic Acid: Evidence-based Update on Mechanism of Action and Clinical Application.

Azelaic acid is a complex molecule with many diverse activities. The latter include anti-infective and anti-inflammatory action. The agent also inhibits follicular keratinization and epidermal melanogenesis. Due to the wide variety of biological activities, azelaic acid has been utilized as a management tool in a broad spectrum of disease states and cutaneous disorders. This paper reviews the clinical utility of azelaic acid, noting the quality of the evidence supporting each potential use.

Depletion of M2-like tumor-associated macrophages delays cutaneous T-cell lymphoma development in vivo.

Macrophages have key roles in tumor development and invasion in several human cancers, but little is known about their pathogenic role in cutaneous T-cell lymphoma (CTCL). Herein, we used PCR arrays to profile the expression of inflammatory cytokines in 12 patients with mycosis fungoides (MF), the most common variant of CTCL. Compared with normal controls, MF skin displayed increased mRNA levels of macrophage-related cytokines. Moreover, we detected CD163, a reliable marker of tumor-associated macrophages, in the tumor microenvironment of MF biopsies. To demonstrate that macrophages had a role in CTCL tumorigenesis, we xenografted human CTCL tumor cells in immunocompromised mice and compared tumor development using clodronate-containing liposomes to deplete macrophages in mice. Mice treated with clodronate-containing liposomes show markedly less tumor growth compared with mice treated with phosphate-buffered saline-containing liposomes (P<0.001). We also noted a strong correlation between macrophage depletion and decreased expression of vascular marker, CD31, and lymphatic marker, podoplanin, suggesting a role for macrophages in angiogenesis. In vitro, clodronate-containing liposomes killed activated murine M2 macrophages, but not Hut78 cells, demonstrating selective ability to induce apoptosis in macrophages. Our data indicate that macrophages have a critical role in the progression of Hut78 cell tumor formation in skin, thus providing a new therapeutic strategy for CTCL.

Correlation of Titleist Performance Institute (TPI) level 1 movement screens and golf swing faults.

Although some research in the past has examined how physical limitations in strength or flexibility affect a golfer's performance, the performance outcome most measured was driving distance. Currently, there are no data that have examined the relationship between selected strength and flexibility variables and golf swing faults. The purpose of this study was to examine the relationship between Titleist Performance Institute (TPI) level 1 movement screen variables and 14 common golf swing faults. Thirty-six male and female golfers (mean age, 25.4 ± 9.9 years; height, 175.9 ± 16.2 cm; mass, 76.2 ± 14.6 kg; handicap, 14.2 ± 10.4) participated. Twelve physical tests of strength, flexibility, and balance were assessed using the TPI level 1 golf fitness screening tool. Golfers then hit 4 golf shots (with a 5-iron) while being videoed, and those were then analyzed for 14 different golf swing faults (using V1Pro software). Three significant associations between a physical limitation and a particular golf swing fault were found: toe touch and early hip extension (p = 0.015), bridge on right side with both early hip extension (p = 0.050), and loss of posture (p = 0.028). In addition, an odds ratio showed that when a golfer could not overhead deep squat or single leg balance on left side, they were 2-3 times more likely to exhibit a early hip extension, loss of posture, or slide during the golf swing, as compared with those who could perform a correct overhead deep squat. Based on our findings, it is important for the golf fitness professional to particularly address a golfer's core strength, balance, and hamstring flexibility to help avoid common golf swing faults, which affect a golfer's ball striking ability and ultimately their performance.