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The prognosis for patients with unresectable or metastatic soft tissue sarcomas remains poor. Evidence shows that a combination of antiangiogenic agents and chemotherapy inhibit tumour growth. We aimed to investigate the dual targeting of VEGF and MET pathways with cabozantinib and temozolomide in patients with unresectable or metastatic leiomyosarcoma and other soft tissue sarcomas. This multicentre, single-arm, lead-in phase 2 trial was conducted at five academic Sarcoma Centers of Excellence of the Midwest Sarcoma Trials Partnership in the USA. Eligible patients were aged 18 years or older, had histologically-confirmed unresectable or metastatic uterine and non-uterine leiomyosarcoma (cohort 1) and other soft tissue sarcomas (cohort 2; exploratory), an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, up to five previous chemotherapy regimens, adequate organ and bone marrow function, and measurable disease as per Response Evaluation Criteria in Solid Tumors (version 1.1). Patients received oral cabozantinib 40 mg (as a starting dose) once per day and temozolomide 150 mg/m2 on days 1–5 of a 28-day cycle for cycle one. Starting from cycle two, temozolomide was escalated to 200 mg/m2 on days 1–5 of each cycle, if the absolute neutrophil count was more than 1·5 × 109/L and platelet count was more than 100·0 × 109/L, and treatment continued until disease progression or unacceptable drug-related adverse events. The primary endpoint in cohort 1 was progression-free survival at 12 weeks, assessed in the intention-to-treat population (defined as all enrolled patients). This study is registered with ClinicalTrials.gov, NCT04200443 (completed accrual). Between Jan 17, 2020, and Feb 6, 2023, 96 patients were assessed for eligibility, 24 were ineligible, and 72 were enrolled. The median age at enrolment was 59 years (IQR 52–66) in cohort 1 (n=42) and 63 years (50–69) in cohort 2 (n=30), with a median follow-up of 18·0 months (17·5–20·7). 42 (58%) of 72 patients were female and 30 (42%) were male. In cohort 1, progression-free survival at 12 weeks was reached by 31 (74%) of 42 patients who were still receiving cabozantinib and temozolomide. The Kaplan–Meier estimate of progression-free survival was higher due to censoring and not requiring patients to be receiving treatment at 12 weeks (79·4% [95% CI 68·6–86·8]). 20 (48%) patients in cohort 1 and 23 (77%) in cohort 2 had died due to disease progression at the end of the study. 71 (99%) of 72 patients had grade 1 or higher treatment-related adverse events. The most common grade 3–4 adverse events attributed to either one or both drugs were platelet count decrease (22 [30%]), neutrophil count decrease (13 [18%]), hypertension (seven [10%]), and diarrhoea (six [8%]). There were no treatment-related deaths. Cabozantinib with temozolomide showed a meaningful clinical benefit and could potentially be a viable treatment option for patients with unresectable or metastatic leiomyosarcoma. Treatment was tolerable and did not reveal any new safety signals. Exelixis.

Afamitresgene autoleucel (afami-cel) showed acceptable safety and promising efficacy in a phase 1 trial (NCT03132922). The aim of this study was to further evaluate the efficacy of afami-cel for the treatment of patients with HLA-A*02 and MAGE-A4-expressing advanced synovial sarcoma or myxoid round cell liposarcoma. SPEARHEAD-1 was an open-label, non-randomised, phase 2 trial done across 23 sites in Canada, the USA, and Europe. The trial included three cohorts, of which the main investigational cohort (cohort 1) is reported here. Cohort 1 included patients with HLA-A*02, aged 16–75 years, with metastatic or unresectable synovial sarcoma or myxoid round cell liposarcoma (confirmed by cytogenetics) expressing MAGE-A4, and who had received at least one previous line of anthracycline-containing or ifosfamide-containing chemotherapy. Patients received a single intravenous dose of afami-cel (transduced dose range 1·0 × 109–10·0 × 109 T cells) after lymphodepletion. The primary endpoint was overall response rate in cohort 1, assessed by a masked independent review committee using Response Evaluation Criteria in Solid Tumours (version 1.1) in the modified intention-to-treat population (all patients who received afami-cel). Adverse events, including those of special interest (cytokine release syndrome, prolonged cytopenia, and neurotoxicity), were monitored and are reported for the modified intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT04044768; recruitment is closed and follow-up is ongoing for cohorts 1 and 2, and recruitment is open for cohort 3. Between Dec 17, 2019, and July 27, 2021, 52 patients with cytogenetically confirmed synovial sarcoma (n=44) and myxoid round cell liposarcoma (n=8) were enrolled and received afami-cel in cohort 1. Patients were heavily pre-treated (median three [IQR two to four] previous lines of systemic therapy). Median follow-up time was 32·6 months (IQR 29·4–36·1). Overall response rate was 37% (19 of 52; 95% CI 24–51) overall, 39% (17 of 44; 24–55) for patients with synovial sarcoma, and 25% (two of eight; 3–65) for patients with myxoid round cell liposarcoma. Cytokine release syndrome occurred in 37 (71%) of 52 of patients (one grade 3 event). Cytopenias were the most common grade 3 or worse adverse events (lymphopenia in 50 [96%], neutropenia 44 [85%], leukopenia 42 [81%] of 52 patients). No treatment-related deaths occurred. Afami-cel treatment resulted in durable responses in heavily pre-treated patients with HLA-A*02 and MAGE-A4-expressing synovial sarcoma. This study shows that T-cell receptor therapy can be used to effectively target solid tumours and provides rationale to expand this approach to other solid malignancies. Adaptimmune.

Sarcomas are a heterogeneous group of malignancies with limited therapeutic options, particularly in the metastatic setting. Adoptive cellular therapies (ACTs), including tumor-infiltrating lymphocyte (TIL) therapy, chimeric antigen receptor (CAR) T-cell therapy, and T-cell receptor (TCR) gene-modified T-cell therapy, offer promising novel approaches for these refractory tumors. TIL-based therapy has demonstrated early efficacy in melanoma and myeloma, with ongoing trials exploring its role in sarcoma. CAR T-cell strategies targeting HER2, GD2, and B7-H3 antigens are in development, though challenges such as tumor microenvironment-mediated resistance and antigen escape remain significant. Engineered TCRs, particularly those targeting MAGE-A4 and NY-ESO-1, have shown promising clinical results in synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCLS), leading to the recent FDA approval of afamitresgene autoleucel (afami-cel) and letetresgene autoleucel (lete-cel). Despite encouraging preliminary data, ACT implementation faces barriers including limited antigen specificity, off-tumor toxicity, immune evasion, and manufacturing scalability. Future research will focus on optimizing lymphodepleting regimens, mitigating toxicity, enhancing in vivo persistence, and combining ACT with other therapeutic agents. As clinical trials expand, ACT holds the potential to revolutionize sarcoma treatment by offering durable, targeted therapies for previously refractory disease.

Background. The management for unplanned excision (UE) of soft tissue sarcomas (STS) has not been established. In this study, we compare outcomes of UE versus planned excision (PE) and determine an optimal treatment for UE in STS. Methods. From 2000 to 2014 a review was performed on all patients treated with localized STS. Clinical outcomes including local recurrence-free survival (LRFS), progression-free survival (PFS), and overall survival (OS) were evaluated using the Kaplan-Meier estimate. Univariate (UVA) and multivariate (MVA) analyses were performed to determine prognostic variables. For MVA, Cox proportional hazards model was used. Results. 245 patients were included in the analysis. 14% underwent UE. Median follow-up was 2.8 years. The LR rate was 8.6%. The LR rate in UE was 35% versus 4.2% in PE patients (p<0.0001). 2-year PFS in UE versus PE patients was 4.2 years and 9.3 years, respectively (p=0.08). Preoperative radiation (RT) (p=0.01) and use of any RT for UE (p=0.003) led to improved PFS. On MVA, preoperative RT (p=0.04) and performance status (p=0.01) led to improved PFS. Conclusions. UEs led to decreased LC and PFS versus PE in patients with STS. The use of preoperative RT followed by reexcision improved LC and PFS in patients who had UE of their STS.

Percutaneous biopsies allow for precise diagnosis in soft tissue sarcomas and have a low rate of complications. However, it is unknown whether biopsies performed in a community setting lead to higher rates of wound complications at the time of resection. The goal of this study was to determine whether percutaneous biopsies performed at a sarcoma center have lower rates of wound complications compared with those performed in the community setting. A total of 125 patients with soft tissue sarcomas were treated with neoadjuvant radiation followed by limb-sparing resection. Of these, 92 underwent percutaneous biopsy. Patient, demographic, and treatment variables and postoperative wound complications were reviewed. Predictors of wound complications were evaluated with Fisher’s exact test for univariate analysis and with logistic regression for multivariate analysis. The wound complication rate was 27% for open or percutaneous biopsies. When only percutaneous biopsies were assessed, the wound complication rate was 25%. The wound complication rate for percutaneous biopsies was 18% when the biopsy was performed at the authors’ sarcoma center and 46% when the biopsy was performed in the community setting (Percutaneous biopsies allow for precise diagnosis in soft tissue sarcomas and have a low rate of complications. However, it is unknown whether biopsies performed in a community setting lead to higher rates of wound complications at the time of resection. The goal of this study was to determine whether percutaneous biopsies performed at a sarcoma center have lower rates of wound complications compared with those performed in the community setting. A total of 125 patients with soft tissue sarcomas were treated with neoadjuvant radiation followed by limb-sparing resection. Of these, 92 underwent percutaneous biopsy. Patient, demographic, and treatment variables and postoperative wound complications were reviewed. Predictors of wound complications were evaluated with Fisher’s exact test for univariate analysis and with logistic regression for multivariate analysis. The wound complication rate was 27% for open or percutaneous biopsies. When only percutaneous biopsies were assessed, the wound complication rate was 25%. The wound complication rate for percutaneous biopsies was 18% when the biopsy was performed at the authors’ sarcoma center and 46% when the biopsy was performed in the community setting ( P =.01). The Common Terminology Criteria for Adverse Events grade 4 wound complication rate was 73% in patients who underwent percutaneous biopsy at a community hospital vs 14% in those who underwent percutaneous biopsy at the authors’ sarcoma center ( P =.005). Multivariate analysis showed that lower-extremity soft tissue sarcomas ( P =.03) and biopsies performed in the community setting ( P =.01) had an increased rate of postoperative wound complications. Percutaneous biopsies performed at community hospitals had an increased incidence of grade 4 postoperative wound toxicity compared with biopsies done at tertiary centers. These wound results confirmed previous recommendations that biopsy of soft tissue sarcomas should be performed at an experienced sarcoma center. [ Orthopedics. 2015; 38(9):e753–e759.]

PurposeAlthough users of aromatase inhibitors have higher total fracture risk in some randomized trials, little is known about their risk outside of clinical trials or in older higher-risk cohorts.MethodsIn a population-based retrospective cohort study, we identified all older US Medicare D prescription drug insurance plan-enrolled women who had initial breast cancer surgery in 2006–2008 and began hormonal therapy (an aromatase inhibitor (AI) or tamoxifen) within the subsequent year. Total nonvertebral and hip fractures through 2012 were identified using a validated algorithm. The association of fracture outcomes with hormonal therapy type was assessed using competing risk regression models that accounted for differences in measured baseline covariates. Treatment assignment bias was reduced using inverse probability of treatment weighting computed from propensity scores.ResultsAmong 23,378 women taking hormonal therapy (23.2% aged 80 or over), there were 3000 total and 436 hip fractures. Although AI users were younger and had lower comorbidity, after propensity score weighting, these and other covariates were balanced. Total nonvertebral risk was higher for users of AIs compared with tamoxifen, HR 1.11 (1.02–1.21), but the small increase in risk for hip fracture was not statistically significant, HR 1.04 (0.84–1.30).ConclusionsAlthough total nonvertebral fracture risk was higher among AI users, differences in hip fractures were not significant in a large population-based cohort of older women.Implications for Cancer SurvivorsUse of aromatase inhibitors by older women is associated with high risk for nonvertebral fracture that is increased compared with use of tamoxifen. Fracture risk should be assessed among patients taking these medications.

Purpose The high expense of newer, more effective adjuvant endocrine therapy agents (aromatase inhibitors [AIs]) for postmenopausal breast cancer contributes to socioeconomic disparities in breast cancer outcomes. This study compares endocrine therapy costs for breast cancer patients during the first five years of Medicare Part D implementation, and when generic alternatives became available. Methods The out of pocket patient costs for AIs and tamoxifen under Medicare Part D drug plans were determined for 2006–2011 from the CMS Website for the 50 US states and District of Columbia. Results Between 2006 and 2010, the mean annual patient drug cost under Medicare Part D in the median state rose 19% for tamoxifen, 113% for anastrozole, 89% for exemestane, and 129% for letrozole, resulting in median annual out of pocket costs in 2010 of $701, $3050, $2804, and $3664 respectively. However, the 2011 availability of generic AI preparations led to median annual costs in 2011 of $804, $872, $1837, and $2217 respectively. Not included in the reported patient costs, the mean monthly drug premiums in the median state increased 58% in 2011 compared to 2007. Conclusions The more effective AI agents became considerably more expensive during the first several years of the Medicare Part D program. Cost decreased with the introduction of generic agents, an intervention that was independent of the Part D program. It is unlikely that the Part D program ameliorated existing socioeconomic disparities in survival among breast cancer patients, but the availability of generic agents may do so.

BackgroundDespite advances in therapy, sarcomas remain a significant unmet need.1 2 Median OS among patients with treatment-refractory soft tissue sarcomas (STS) treated with either trabectedin, pazopanib, or eribulin has been reported to range from 12.5 to 13.6 months.3 4 AXL, a cell-surface receptor tyrosine kinase, is highly expressed in several STS subtypes and has been shown to drive increased metastasis, resistance to chemotherapy, and poor outcomes.5 Mecbotamab vedotin (Mec-V, BA3011, Conditionally Active Biologic CAB-AXL-ADC) is designed to reduce off-tumor toxicity and improve pharmacokinetics by conditionally binding to AXL under low-pH conditions (pH<6.7) of the tumor microenvironment.6 7 MethodsA phase 2 open-label study evaluated Mec-V among adult and adolescent patients with AXL-expressing locally advanced, unresectable, or metastatic STS with measurable disease by RECIST v1.1. Patients received either Mec-V monotherapy 1.8 mg/kg every 2 weeks (Q2W) or Mec-V + nivo combination therapy.ResultsPhase 1 and 2 included 44 patients with STS, of whom 33 received Q2W and 11 received Q2W Mec-V + nivo. This report focuses upon the long term follow up among patients with leiomyosarcoma (LMS, n=27), liposarcoma (LPS, n=9), or undifferentiated pleomorphic sarcoma (UPS, n=8). Patients had a median of 2 prior lines of treatment. Most TEAEs were low grade and reversible; related grade 3/4 TEAE of special interest were neutropenia (21%), hepatic transaminase elevations (16%), and hyperglycemia (3%). No grade 5 TEAE were observed and 9% of related TEAE led to treatment discontinuation. 5% and 52% experienced partial response or disease control respectively. As of March 24, 2025, the OS with Mec-V in LMS, LPS, and UPS was 21.5 months (table 1). Landmark OS at 1 year was 73%. Median OS in Mec-V monotherapy vs. Mec-V + nivo combination therapy was 18.4 vs 22.9 months, respectively (table 1), across STS subtypes with 45% of events recorded.ConclusionsPatients with heavily pretreated leiomyosarcoma, liposarcoma, and undifferentiated mean pleomorphic sarcoma had a median OS of 21.5 months after treatment with Mec-V, a conditionally binding, AXL-targeting ADC. The manageable safety profile remained consistent with previous reports. Further evaluation of Mec-V, potentially in novel combinations, is justified.Trial RegistrationNCT03425279ReferencesZhang G, Liu Z, Xu H, Yang Q, et al. miR-124-3p inhibits cell growth and enhances chemosensitivity of osteosarcoma cells by targeting STAT3. Oncol Lett. 2018;15:2726–2734.Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975–2017. National Cancer Institute. Bethesda, MD. https://seer.cancer.gov/csr/1975_2017/. Based on November 2019 SEER data submission, posted April 2020.Italiano A, Delva F, Mathoulin-Pélissier S, et al. Frequency, characteristics, and management of gastrointestinal stromal tumors in daily practice. Cancer. 2011;117:1049-1054.Isakoff MS, Bielack SS, Meltzer P, Gorlick R, et al. Osteosarcoma: current treatment and a collaborative pathway to success. J Clin Oncol. 2015;33:3029-3035.Gay CM, Balaji AK, Byers LA, et al. Giving AXL the axe: targeting AXL in human malignancy. Br J Cancer. 2017;116:415-423.Chang HW, et al. Proc Natl Acad Sci USA. 2021;118(9):e2020606118.Dy GK, Yau E, Rotow J, et al. Exploratory analysis of overall survival among non-small cell lung cancer (NSCLC) patients with mutated KRAS in a phase 2 trial of mecbotamab vedotin (CAB-AXL-ADC). Presented at: European Lung Cancer Congress; 2025 Mar 26–29; Paris, France. Poster 98P.Ethics ApprovalThe study was performed in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with ICH/GCP.Abstract 523 Table 1Best overall response

[This corrects the article DOI: 10.1186/s40064-015-0827-8.].