Malignant peripheral nerve sheath tumors (MPNST) are soft tissue sarcomas, occurring either in people with Neurofibromatosis Type 1 (NF1) or sporadically, with a tendency for recurrence and distant metastases, and poor survival rates. The only proven curative treatment is complete oncologic resection, and there is currently no FDA-approved drug for the treatment of MPNST. Multiple clinical trials have failed to achieve improvement in survival and novel therapeutic approaches are urgently needed. To address this need, members of the MPNST Committee of the Congressionally Directed Medical Research Programs-supported Neurofibromatosis Clinical Trials Consortium convened to develop a framework to prioritize therapeutic agents with the highest potential for successful clinical development. We review the potential agents that may be prioritized and propose a methodology to evaluate available preclinical and clinical data. Increasing the availability and use of diverse preclinical models and defining the best preclinical endpoints prior to clinical translation can increase the success of clinical trials. Subsequently, utilizing a platform trial design can accelerate the clinical development process and facilitate patient accrual. It is imperative to foster collaborations with pharmaceutical companies and community partners. The integration of preclinical and clinical evaluation in an iterative and informative process can accelerate effective clinical development.

Background Arginine deprivation with pegylated arginine deiminase (ADI-PEG 20, pegargiminase) may enhance chemotherapy efficacy in soft tissue sarcomas (STS). We conducted a phase II trial (NCT03449901) evaluating ADI-PEG20 plus gemcitabine/docetaxel in advanced STS. Methods Seventy-five evaluable patients received ADI-PEG20 with gemcitabine/docetaxel across three dose cohorts. Correlative analyses included immunogenicity, transcriptomics, and metabolomics for a subset of patients. Results Median PFS was 4.03 months and OS was 18.83 months, with a clinical benefit rate of 66.2%. Clinical benefit was preserved across gemcitabine/docetaxel dose cohorts, including the reduced-dose 600/60 mg/m² cohort selected after protocol-directed safety monitoring. Transcriptomics revealed MYC pathway enrichment in treated tumors. Metabolomics confirmed arginine depletion with compensatory glutamine anaplerosis and increased nucleotide turnover. Conclusions ADI-PEG20 plus gemcitabine/docetaxel demonstrates clinical activity in advanced STS. Correlative analyses provide the first clinical validation of arginine deprivation-induced metabolic reprogramming, supporting combination strategies targeting compensatory metabolic pathways.

Supplementary Table 1 includes the metadata on all subjects, including basic demographics and medical history. Supplementary Table 2 provides statistics on chrom 8 gene expression among tumors with H3K27me3 loss. Note: no changes have been made to this file since our last resubmission.

Supplementary figures provide additional details on the genomic landscape of MPNST and interesting cases within the cohort.

The treatment landscape for soft tissue sarcomas (STS) is evolving constantly. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for STS specific to surgical management and systemic therapy recommendations for various subtypes.

The treatment landscape for soft tissue sarcomas (STS) is evolving constantly. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for STS specific to surgical management and systemic therapy recommendations for various subtypes.

Background: With advances in antiretroviral therapy, aging people with HIV (PWH) are increasingly at risk for non–AIDS-defining cancers (NADCs) and chronic morbidities. This study examines whether PWH with NADCs face a higher risk of new-onset chronic health conditions compared with those without cancer. Patients and Methods: We conducted a retrospective cohort study using data from the CFAR (Centers for AIDS Research) Network of Integrated Clinical Systems (CNICS) for PWH enrolled between 1995 and 2018 from 8 US academic institutions. We included PWH with the 5 most common NADCs: anal cancer, non–small cell lung cancer (NSCLC), prostate cancer, classic Hodgkin lymphoma (HL), and hepatocellular carcinoma (HCC). A 1:2 matching for each NADC subgroup was performed based on age, cohort entry year, and sex (noncancer cohort). Chronic health conditions were graded using the CTCAE, with the primary outcome being the risk of new-onset grade ≥3 morbidities, analyzed using Cox regression. Results: The study included 693 PWH with NADCs and 1,345 matched PWH without cancer. At a median follow-up of 13.7 years for PWH with NADCs and 10.7 years for the noncancer group, the prevalence of grade ≥3 morbidities was significantly higher in the NADC group (24.8% vs 13.8%; P ≤.01). Multivariable Cox regression showed a higher risk of new-onset grade ≥3 conditions in the NADC group (hazard ratio, 2.94; P <.0001), specifically diabetes mellitus (all NADCs), myocardial infarction (NSCLC and HL), and congestive heart failure (prostate cancer). Conclusions: Our study showed an excess risk of new-onset morbidities among PWH with NADCs. These findings have critical implications for the care of survivors of HIV and cancer and underscore the importance of integrated care approaches to address late effects in this vulnerable population.

BACKGROUND AND OBJECTIVES:Delay in treatment may be associated with worse outcomes for soft tissue sarcoma, which often requires multidisciplinary management. Our objective was to evaluate the implementation of a sarcoma multidisciplinary clinic (MDC) on time to treatment initiation (TTI) at our tertiary cancer center. METHODS:Patients with localized or metastatic soft tissue sarcoma were seen at our tertiary referral center from November 2021-January 2024 in MDC or usual care (single specialty clinic). Treatment delay was defined as greater than 50 days from initial assessment to first treatment (surgery, radiation, or systemic therapy), compared using chi-squared tests and multivariable logistic regression. RESULTS:Among 275 patients, 33 were seen in MDC and 242 usual care. Median TTI was 33.0 days (interquartile range (IQR) 18-57). Eighty-two patients (29.8%) had treatment delays, with no difference for MDC (31.1%) versus usual care (15.2%) (p = 0.05) (adjusted odds ratio 0.39, 95% Confidence Interval 0.14-1.06). Patients evaluated in the MDC were more likely to receive multimodal therapy (75.8% vs. 41.7%, p < 0.01) and radiation as their first treatment (54.5% vs. 27.3%, p < 0.01). CONCLUSION:Implementation of a MDC did not significantly reduce treatment delay but was associated with increased likelihood of multimodal therapy. Future work should evaluate TTI in cohorts with greater penetrance of MDC care and assess other oncology and patient-centered endpoints.

Dedifferentiated liposarcoma (DDLPS) has an appealing therapeutic target due to its CDK4 amplification on chromosome 12q. The understanding of geroconversion from quiescent cells to senescent cells defines a patient's response to CDK4 inhibitors. This new observation will inform not only the ongoing phase III clinical trial of abemaciclib, but all future clinical trials in DDLPS. See related article by Gleason et al., p. 703.

Most malignant peripheral nerve sheath tumors (MPNSTs) are clinically aggressive high-grade sarcomas, arising in individuals with neurofibromatosis type 1 (NF1) at a significantly elevated estimated lifetime frequency of 8%-13%. In the setting of NF1, MPNSTs arise from malignant transformation of benign plexiform neurofibroma and borderline atypical neurofibromas. Composed of neoplastic cells from the Schwannian lineage, these cancers recur in approximately 50% of individuals, and most patients die within five years of diagnosis, despite surgical resection, radiation, and chemotherapy. Treatment for metastatic disease is limited to cytotoxic chemotherapy and investigational clinical trials. In this article, we review the pathophysiology of this aggressive cancer and current approaches to surveillance and treatment.

Background: High-grade soft tissue sarcoma is rare and associated with poor prognosis. This study examines racial and ethnic variation in presentation and outcomes at a Southeastern US cancer center. Methods: Among an institutional cohort of patients seen between January 2016-December 2021, racial and ethnic differences were evaluated using chi-squared tests, Kaplan Meier curves, and Cox proportional hazards models. Results: There were 295 patients (71 % Non-Hispanic White, 24 % Black, 3 % Hispanic White, 2 % Other). Black representation was greater than national cohorts (24 % vs. 12 %). Histological subtype varied by race/ethnicity (p 1/4 0.007). Adjusting for histology and stage, survival was worse for Black vs. White patients (HR 1.71, 95 % CI 1.07-2.76) and those with metastatic disease (5.47, 3.54-8.44). In non-metastatic patients, survival differences for Black vs. White patients were attenuated by receipt of multi-modal treatment (1.53, 0.82-2.88). Conclusion: Observed racial disparities in survival of high-grade sarcoma may be addressed by early, multidisciplinary management.

PURPOSE:Cancer Immunotherapy Trials Network 12 demonstrated safety of pembrolizumab in treating advanced cancer in people with HIV. Here, we report results of the Kaposi sarcoma (KS) cohort. METHODS:In this multicenter phase I trial, we enrolled participants with HIV-associated KS on antiretroviral therapy with CD4+ ≥50 cells/μL and HIV plasma RNA <200 copies/mL. Pembrolizumab 200 mg intravenously was administered once every 3 weeks for up to 35 cycles. The primary end point was safety, and the secondary end point was KS response by modified AIDS Clinical Trials Group Criteria. RESULTS:Thirty-two cisgender men enrolled with baseline median CD4+ T-cell count of 274 cells/µL. All but nine participants had received previous systemic KS therapy. Participants received a median of 11 cycles of pembrolizumab (range, 1-35). Sixty-six percent had grade ≥1 treatment-emergent adverse events, including one death from polyclonal KS herpesvirus-related B-cell lymphoproliferation. Thirty-one percent had ≥one immune-mediated AEs (imAEs) with 25% requiring systemic steroids. In 29 participants with evaluable KS, the overall response rate (ORR) was 62.1% (95% CI, 42.3 to 79.3) and did not differ by CD4+ T-cell count. ORR in the eight participants with evaluable disease without previous KS therapy was 87.5% (95% CI, 47.3 to 99.7). Median duration of response (DOR) was not reached, and the Kaplan-Meier estimate of DOR of ≥12 months was 92.3% (95% CI, 56.6 to 98.8). Median progression-free survival was 28.2 months (95% CI, 4.2 to noncalculable). CONCLUSION:Pembrolizumab yielded a high rate of durable responses in HIV-associated KS. imAEs were successfully managed with standard guidelines.

Abstract Malignant peripheral nerve sheath tumor (MPNST), an aggressive soft-tissue sarcoma, occurs in people with neurofibromatosis type 1 (NF1) and sporadically. Whole-genome and multiregional exome sequencing, transcriptomic, and methylation profiling of 95 tumor samples revealed the order of genomic events in tumor evolution. Following biallelic inactivation of NF1, loss of CDKN2A or TP53 with or without inactivation of polycomb repressive complex 2 (PRC2) leads to extensive somatic copy-number aberrations (SCNA). Distinct pathways of tumor evolution are associated with inactivation of PRC2 genes and H3K27 trimethylation (H3K27me3) status. Tumors with H3K27me3 loss evolve through extensive chromosomal losses followed by whole-genome doubling and chromosome 8 amplification, and show lower levels of immune cell infiltration. Retention of H3K27me3 leads to extensive genomic instability, but an immune cell-rich phenotype. Specific SCNAs detected in both tumor samples and cell-free DNA (cfDNA) act as a surrogate for H3K27me3 loss and immune infiltration, and predict prognosis. Significance: MPNST is the most common cause of death and morbidity for individuals with NF1, a relatively common tumor predisposition syndrome. Our results suggest that somatic copy-number and methylation profiling of tumor or cfDNA could serve as a biomarker for early diagnosis and to stratify patients into prognostic and treatment-related subgroups. This article is highlighted in the In This Issue feature, p. 517

TPS11583 Background: Soft tissue sarcomas (STS) are rare malignancies with poor prognosis in the metastatic setting. Current standard therapy includes anthracycline based chemotherapy. Cabozantinib is a multikinase inhibitor that has demonstrated efficacy in solid tumors such as renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC). A phase II study of cabozantinib in advanced STS is underway. Cabozantinib in combination with immune checkpoint blockade has shown clinical benefit in several tumor types including HCC, RCC, non-small cell lung cancer, and urothelial carcinoma. Since cabozantinib may alter PD-1 expression in regulatory T-cells and promote an immune permissive environment, we hypothesize that combining cabozantinib with immune checkpoint inhibition is a therapeutic strategy that will be more effective than cabozantinib alone. Additionally, the design of the trial will allow assessment of whether pretreatment with cabozantinib will enhance the efficacy of nivolumab and ipilimumab alone. Methods: This is an open label, multicenter, randomized phase II clinical trial of cabozantinib (60mg orally daily as a single agent, 40mg in combination) with or without combination Ipilimumab (ipi, 1mg/kg IV every 3 weeks for 4 doses) and Nivolumab (nivo, 3mg/kg IV every 3 weeks for four doses, then 480mg IV every 4 weeks) in patients (pts) with unresectable or metastatic STS refractory to up to two lines of chemotherapy. 105 pts with non-translocation driven sarcomas will be enrolled at three US sites and randomized 2:1 to the combination group. Pts will be stratified by prior pazopanib use and balanced for histologies. Patients who progress on arm A will cross over to combination therapy (arm B). The primary efficacy endpoint is objective response rate (ORR) by RECIST 1.1. 35 patients in Cohort A (cabozantinib alone) and 70 patients in Cohort B (cabozantinib plus ipi/nivo) will be required to detect an increase of the ORR from 10% in cohort A to 30% in cohort B with 81% power with a one-sided alpha level of 10%. Key eligibility criteria include: at least 18 years of age, ECOG performance status of 0 or 1, ≤2 prior lines of therapy and measurable disease. Exclusion criteria include: translocation-driven sarcoma except alveolar soft part sarcoma (ASPS), prior immunotherapy, and chronic use of corticosteroids or other immunosuppression. Secondary endpoints are safety, overall and progression free survival, disease control rate, and response rate to ipilimumab and nivolumab after cabozantinib pretreatment. Mandatory tumor biopsies pre-treatment and at 6 weeks will be obtained. Peripheral blood will be collected for circulating immune phenotyping. Enrollment will occur at 3 participating institutions and is expected to be completed in 2022. Clinical trial information: NCT04551430.

62 Background: Management of soft tissue sarcomas often requires coordinated multidisciplinary care including radiation, medical, and surgical oncology. Delays in the multidisciplinary evaluation and treatment may lead to poorer outcomes. Coordination of care through a multidisciplinary clinic (MDC) offering access to all three specialties during the same clinic visit may reduce time from initial evaluation to treatment. Methods: Adult patients treated for soft tissue sarcoma at an NCI-designated comprehensive cancer center following the opening of a sarcoma MDC in November 2021 to May 2023 were included. Patients were either seen in the sarcoma MDC or separately by oncologic providers (usual care). The primary outcome was delay in treatment initiation, defined as greater than 21 days from initial consultation to first treatment. Reasons for delay were abstracted. Descriptive statistics and bivariate analyses were performed. Results: Among 147 patients, 20 were (13.6%) seen in MDC and 127 (86.4%) by usual care. Initial treatments were surgery (46.9%), radiation (30.6%), or systemic therapy (22.4%). Median time to treatment was 34 days (IQR 14-57 days), which differed by treatment modality (surgery 34 days, radiation 37 days, systemic 18 days). There were no significant differences in time to treatment for MDC patients (33 days, IQR 25-44) versus usual care (34 days, IQR 13-57) (p=0.93). However, a significantly higher proportion of MDC patients received multiple modalities of treatment (75.0% vs 48.8% usual care, p=0.011), with a longer average time to treatment in the multi- versus single-modality groups (41 vs 22 days, p<0.001). Among patients requiring multimodal therapy, median time to treatment was 33 days for MDC patients versus 44 days for usual care (p=0.07). MDC patients were also much more likely to receive radiation (90.0% MDC vs 45.6% usual care, p=0.001). Delays in care (n=76, 51.7% of cohort) were seen in 66.7% (12/18) of MDC patients versus 58.3% (63/108) of usual care patients. The most common reasons for delay were need for additional imaging (29.7%) or preoperative testing (18.8%). Conclusions: In this single-center study, no improvement in time to treatment was seen following the opening of a sarcoma multidisciplinary clinic, likely explained by higher proportion of MDC patients receiving multiple treatment modalities. Primary reasons for delay could be anticipated prior to initial evaluation and represent an opportunity for more active case review prior to in-person evaluation to reduce delays in sarcoma treatment.

LBA11504 Background: Cabozantinib (C) has been combined successfully with either PD-1 or CTLA-4 inhibition in cancer clinical trials. The combination of nivolumab (N) and ipilimumab (I) previously was evaluated in soft tissue sarcoma (STS) and demonstrated activity as well as an acceptable safety profile. Given these data, we hypothesize that C in combination with both I and N is a therapeutic strategy that will be more effective than C alone in metastatic STS that lack translocations. Additionally, we hypothesized that C priming would enhance the efficacy of combination I and N at the time of crossover. Methods: This is a 2:1 randomized phase 2 clinical trial evaluating the overall response rate (RR) of C 40mg orally daily in combination with I (1mg/kg IV) / N (3mg/kg) for 4 doses Q3W and then maintenance N 480mg Q4W compared to C 60mg oral alone, with crossover. Secondary endpoints include progression free survival (PFS), disease control rate (DCR), RR in crossover, quality of life by FACT-G7, RR by iRECIST and safety. Correlative and biomarker analysis are preplanned. Key patient selection includes ECOG 0-1, 1-2 lines of prior therapy, and sarcomas that lack of translocations. The trial was balanced for leiomyosarcoma (LMS), liposarcoma and UPS. Results: 69 patients were randomized to C+I/N and 36 patients were randomized to C alone. 19 patients crossed over to C+I/N at progression. 54/105 patients had LMS. RR of C+I/N was 11% (5 PR and 2 CR), while the RR of C was 6% (2 PR and 0 CR) (p = NS). C+I/N responding histologies included LMS, angiosarcoma, epithelioid sarcoma, and myxofibrosarcoma. C responding histologies included 2 PRs in LMS. There were also 2 LMS PRs in crossover to C+I/N. The median PFS for C+I/N was 5.4 months and for C was 3.8 months (p = 0.016). The DCR for C+I/N was 80% (41 SD, 5 PR, 2 CR), and 42% for C (11 SD, 2 PR) (p = 0.0004). The most common grade 3-4 adverse events affecting > 10% of patients included hypothyroidism, diarrhea, mucositis, oral dysesthesia, nausea, vomiting, elevated AST and ALT, anorexia, dysgeusia, headache, pruritis, maculopapular rash, and hypertension for C+I/N and hypothyroidism, diarrhea, oral dysesthesia, fatigue, palmar-plantar erythrodysesthesia, and hypertension for C. Conclusions: The combination of C+I/N was superior to C for the treatment of non-translocation STS for DCR and PFS. Most frequent responding histology was LMS. Correlative work is ongoing. Clinical trial information: NCT04551430 .

While metastatic osteosarcoma is rare in humans, it is the most common bone tumor found in any breed of dog. Given the genetic similarities between canine and human osteosarcomas, canine clinical trials allow for rapid testing and drug repurposing at a speed that cannot be achieved using patients with osteosarcoma. See related article by Regan et al., p. 662.