11505 Background: Afamitresgene autoleucel (afami-cel) is a melanoma-associated antigen A4 (MAGEA4)-directed genetically modified autologous T cell immunotherapy consisting of CD4 and CD8 positive T cells transduced with a self-inactivating lentiviral vector (LV) expressing an affinity-enhanced T cell receptor (TCR) specific for the human MAGE-A4. Here we report the pooled results of afami-cel in phase 1 and phase 2 trials in patients (pts) with advanced (unresectable/metastatic) synovial sarcoma (SyS). Methods: Pts who were HLA-A*02 positive with previously treated, advanced SyS positive for MAGE-A4 received afami-cel after lymphodepleting chemotherapy containing fludarabine and cyclophosphamide. The pooled analyses evaluated overall response rate (ORR) per RECIST v1.1 by investigator review, duration of response (DoR), ORR in sub-populations, overall survival (OS), safety and pharmacokinetics. Results: As of May 2025, 153 pts with advanced SyS received afami-cel (1.00 –9.99×10 9 MAGE-A4 TCR positive T cells). The median age was 40 years (range: 13–76 years), 54% of pts were male, and 86% of pts were white. The median MAGE-A4 expression by H-score was 256.0 (range: 60–300). All pts received prior anthracycline and/or ifosfamide therapy and received a median of 2 prior lines of therapy (range: 1–12). ORR by investigator review was 43.8% (95% CI 35.8, 52.0). Responses were observed across all subgroups, including pediatric SyS pts. The median DoR was 7.1 months (95% CI 4.7, 10.6) and ranged from 1 to 58+ months. Median OS was 18.7 months (95% CI: 14.1, 22.5) with 44% of pts censored at the data cut-off. The 12-month or longer and 24-month or longer OS probabilities were 64.4% and 40.5%, respectively. Among the 67 pts who had a RECIST response, the median OS was 37.5 months (95% CI 26.3, 50.5). The most common any-grade non-laboratory TEAEs (≥20% of pts) were cytokine release syndrome (CRS) (73.2%), nausea (64.1%), fatigue (45.8%), pyrexia (33.3%), vomiting (29.4%), constipation (28.1%), diarrhea (27.1%), headache (26.8%), and cough (20.9%). The most common Grade ≥3 laboratory TEAEs (≥20% of pts) were lymphopenia, neutropenia, leukopenia, and anemia. Afami-cel persisted long-term, including >3 years. Conclusions: To the best of our knowledge, this is the largest dataset of T-cell therapy treated pts with advanced SyS. The magnitude of ORR supported by DOR demonstrated with afami-cel treatment is considered clinically meaningful in this rare pt population with a poor prognosis and limited effective therapies. CRS and cytopenias were common and manageable. Pts with advanced SyS treated with afami-cel had encouraging survival, especially those pts with a RECIST response. Clinical trial information: NCT04044768 , NCT03132922

PURPOSE:Euro-EWING99 study was a large, international, prospective study recruiting patients with Ewing sarcoma (EWS) between 1999 and 2015. It assessed three different clinical questions through randomized trials. We report here the characteristics and outcomes of all patients. METHODS:Patients younger than 50 years with EWS were included in the study. They received induction chemotherapy (six courses of vincristine [day 1], ifosfamide [day 1-3], doxorubicin [day 1-3], and etoposide [day 1-3; VIDE], administered every 3 weeks), local therapy (surgery/radiotherapy), and different consolidation treatments according to clinical risk group and trial.The objectives of the study were to describe the entire cohort according to the initial staging group, to describe the survival outcomes (overall survival [OS]; progression-free survival [PFS]; and local control), and to evaluate prognostic factors associated with OS and PFS. RESULTS:Three thousand three hundred ninety-five patients were included in the study, including 2,267 with a localized disease, 614 with pleuropulmonary metastases, and 514 with extrapulmonary metastases. Ninety-eight percent of patients received ≥4 neoadjuvant VIDE courses. The modalities of local treatment and consolidation therapy differed among the three staging groups. With a median follow-up of 7.2 years, PFS of the entire cohort was 60.2% and 55.4% at 3 and 5 years, respectively. OS was 72.6% and 64.6% at 3 and 5 years, respectively. In addition to metastatic status at diagnosis, main prognostic factors included patient age, tumor volume, and histologic response both for PFS and OS, independent of metastatic status. CONCLUSION:To our knowledge, this study is the largest published series of patients with EWS and may serve as a landmark paper for EWS. It confirms the major prognostic value of the complete histologic response after neoadjuvant therapy.

BACKGROUND:Population-based studies detailing the incidence and survival of patients with primary bone sarcomas (PBS) are limited and often group morphologies and primary sites together. We examined incidence and outcomes for PBS in England and evaluated changes over time, within and across groups. METHODS:All patients diagnosed with PBS in England between 1996 and 2020 were identified from the National Cancer Registration Dataset. Age-specific incidence rates and five-year average age-standardised incidence rates (ASRs) were calculated using the 2013 European Standard Population. Five-year relative survival (RS) was estimated by diagnosis period, histological subtype and patient subgroup. Excess mortality models were used to assess survival trends over time. RESULTS:Between 1996 and 2020, 12,282 patients were diagnosed with PBS (mean 491 annually). Chondrosarcoma (31%) and osteosarcoma (28%) were the most common subtypes. Overall PBS incidence changed little over the study period; however, incidence increased for chondrosarcoma and chordoma and decreased for osteosarcoma. Five-year RS for all PBS improved from 52% in 1998-2002-65% in 2013-2017. Significant survival improvements were observed for chondrosarcoma, chordoma and osteosarcoma. In Ewing sarcoma, survival improved particularly among patients with pelvic tumours. Improvements remained evident after adjustment for measured case mix. Younger age, female sex and extremity primary site were associated with better survival in several subtypes. CONCLUSIONS:This national population-based analysis provides contemporary estimates of PBS incidence and survival in England. Despite the rarity and heterogeneity of these tumours, survival improved for PBS overall and for several clinically important patient subgroups. These findings provide an important benchmark for international comparisons and ongoing evaluation of sarcoma services and outcomes.

The outcome of patients with osteosarcoma after relapse is very poor, with a 5-year overall survival (OS) below 30

INTRODUCTION:Pretreatment prognostic factors in newly diagnosed osteosarcoma are important for clinical management and stratifying patients in clinical trials. Such factors include the presence of metastases, primary tumor size, and site. Factors surrounded by controversy include pathological fracture, histologic subtype, and P-glycoprotein expression. No prognostic tumor biomarker has been established. We performed a systematic review with the aim to compile available evidence for pretreatment prognostic factors and define optimal cut-off values for patient stratification or further validation in the upcoming European FOSTER-CabOS trial. METHODS:Predefined search terms were used to search PubMed, Web-of-science, and Embase for all studies investigating pretreatment prognostic factors in newly diagnosed osteosarcoma patients published 2000-2023. After applying strict inclusion and exclusion criteria, 49 papers were included. RESULTS:We found 14 factors investigated in at least two separate studies or in a single study using one discovery and at least one validation cohort. CONCLUSIONS:We confirmed the prognostic value of patient age, presence of metastasis, tumor size, and site (axial vs. appendicular). Future studies of these factors should focus on specific patient populations and defining optimal cut-off values. Although serum level of alkaline phosphatase and lactate dehydrogenase were associated with outcome, it remains unclear if they are independent of other prognostic factors. The prognostic value remains unclear for sex, pathological fracture, histologic subtype, and P-glycoprotein expression. We could not establish any new prognostic biomarker. However, circulating tumor DNA in plasma and the G1/G2 RNA signature in diagnostic tumor biopsies show promise and will be further validated in the upcoming FOSTER-CabOS trial.

Background: Epidemiological data for sarcoma in adolescents and young adults (AYAs) and across age groups are limited. We aim to: 1) update sarcoma incidence, survival, and changes over time in European AYAs; 2) provide an updated comparison of sarcoma survival in AYAs versus children and mature adults. Methods: We calculated crude incidence rates (IR) per 100,000 European population per year from 2006 to 2013. Using the period approach, we calculated 5-year relative survival (RS) for the follow-up period 2010-2014. We estimated changes in incidence and survival for bone sarcoma (BS) and soft tissue sarcoma (STS) subtypes in AYAs in the years 2000-2013. Findings: In European AYAs, the IR was 0.81/100,000 for BS and 1.45/100,000 for STS. Five-year RS was 69% and 65 % for BS and STS, respectively. Compared to children, AYAs had poorer survival for Ewing sarcoma of bone, synovial sarcoma, Ewing sarcoma of soft tissue and rhabdomyosarcoma. Compared to mature adults, AYAs had higher 5-year RS for all BS and for most of the STS subtypes. In AYAs, incidence increased for a few bone and soft tissue subtypes. Survival increased mainly for BS. Interpretation: The reason for the better survival observed in AYAs compared to mature adults is probably multifactorial. The limited improvement of STS survival in AYAs may reflect the relative absence of new drugs for STS during the study period. The increase in RS for BS might relate to general improvements in radiological and surgical approaches and radiotherapy techniques.

11574 Background: Few effective therapies exist for pts with R/R DSRCT and SS, and hence, their prognosis remains poor. Preclinical data suggested the relevance of vascular endothelial growth factor receptor 2 (VEGFR2) inhibition in these diseases. We evaluated the efficacy of ramucirumab (RAM, VEGFR2 receptor antagonist) + chemotherapy vs. chemotherapy alone in pediatric and young adult pts with R/R DSRCT (JV01) or SS (JV02). Methods: JV01 and JV02 were randomized, global, multicenter, Phase 1/2 studies in pts aged ≤29 years with R/R DSRCT or SS and evaluated pts treated with RAM + cyclophosphamide/vinorelbine (CV; JV01) and RAM + gemcitabine/docetaxel (GD; JV02). Pts were randomized 2:1 to the experimental and control groups. The primary endpoint was progression-free survival (PFS) per RECIST v1.1, analyzed via a Bayesian hierarchical model allowing adaptive borrowing on effect size (log hazard ratio [HR]) between JV01 and JV02 and control arm augmentation with historical (real world) data. Interim futility required a probability (Pr) of PFS (HR < 1) > 60%, and intervention success at final analysis was declared at Pr > 99%. Frequentist analysis (1-sided α = 0.1) was performed as a sensitivity analysis. Safety was a secondary endpoint. Results: Baseline characteristics were balanced between the treatment arms in both studies: RAM+CV, n = 20; CV, n = 10; RAM+GD, n = 16; GD, n = 7. JV02 met the futility criterion (Table) and was suspended without completing enrollment. JV01 fully enrolled but did not meet the primary endpoint at the final analysis (PFS HR = 0.7, 98% credible interval = 0.3, 1.7; pr [HR < 1] = 86.4% vs. 99%). However, frequentist analysis in JV01 showed that pts in the RAM+CV arm had a numerical improvement of 5 months in median PFS vs. the CV arm. Overall, no significant safety events were reported in either study. Conclusions: The PFS outcome was not met for either rare disease. The numerical trend in JV01 is noteworthy, especially considering the limited treatment options available for DSRCT. Safety was consistent with the known profiles of the individual treatments and the population. Clinical trial information: NCT04145700 , NCT04145349 . JV01 JV02 RAM+CV (n=20) CV (n=10) HR(80% CrI) b RAM+GD (n=16) GD (n=7) HR (80% CrI) b Median PFS (months), 98% Crl a Median PFS (months), 98% Crl a Primary Bayesian Analysis 5.7(3.2, 10.0) 3.7(1.8, 8.3) 0.7(0.3, 1.7)Pr (HR <1) = 86.4 % 3.7(1.5, 11.5) 6(2.1, 18.0) 1.8(0.8, 3.1)Pr (HR <1) = 20.1% PFS events, n 16 8 9 5 Frequentist Analysis c 6.8(5.5, 10.4) 1.7(1.4, 2.7) 0.5(0.3, 0.8)p = 0.082 2.1(1.9, 6.1) 2.0 (1.4, NR) 0.7(0.3, 1.5)p = 0.544 CI = confidence interval; CrI = credible interval; CV = cyclophosphamide/vinorelbine; GD = gemcitabine/docetaxel; HR = hazard ratio; NR = not reached; PFS = progression-free survival; Pr = probability; RAM = ramucirumab. a Posterior median. b Posterior mean displayed. c 80% CI for JV01 and JV02.

10006 Background: rEECur, the first randomised controlled trial (RCT) in RR-ES, has previously defined high dose ifosfamide (IFOS) as the most effective regimen in this setting compared to gemcitabine-docetaxel, irinotecan-temozolomide and topotecan-cyclophosphamide. Platinum drugs show activity in RR-ES and are frequently given with etoposide in this setting. Methods: Patients aged at least 2 years with RR-ES were randomised to 3-week cycles of either IFOS 15 g/m 2 by continuous intravenous (IV) infusion over 5 days or IV carboplatin 400 mg/m 2 day 1 and etoposide 120 mg/m 2 days 1 to 3 (CE). Primary outcome was event-free survival time (EFS). Secondary outcomes included overall survival time (OS), toxicity and quality of life (QoL). A probability-based Bayesian approach was used. Results: 139 patients recruited between 22/03/21 and 28/05/24, were randomised 1:1 to IFOS (n = 69) or CE (70). Median age was 18 years (range 3-59). Patients had refractory disease (14%), 1 st recurrence (81%), > 1 st recurrence (6%). Sites of progression were primary site only (21%), pleuropulmonary metastases only (24%), and other or combined metastatic disease (55%). More CE patients had baseline GFR < 90 ml/min/1.73m 2 (41% versus 23%). Median follow-up (reverse Kaplan-Meier) was 18 months (mos). Median EFS was 5.1 mos (95% CI 3.1, 6.3) for IFOS and 3.5 mos (95% CI 2.5, 6.1) for CE. Median OS was 14.4 mos (95% CI 11.5, 20.7) for IFOS and 19.0 mos (95% CI 11.2, 24.6) for CE. Given the observed data the posterior probabilities that EFS and OS were better after IFOS than after CE (ie Pr[true hazard ratio > 1 | data]) were 87% and 55% respectively. Grade 3+ adverse events present in > 5% of patients randomised to IFOS (left hand values) compared with CE were febrile neutropenia (30% v 10%), anaemia (9% v 9%) and thrombocytopenia (3% v 7%). Acute kidney injury was present in 2% v 0% and encephalopathy in 5% v 0%. There were no measurable differences in QoL. Conclusions: There was insufficient evidence of efficacy with CE compared to IFOS to continue recruitment to phase III in this first RCT of a platinum-etoposide combination in RR-ES. IFOS remains the most effective regimen in this disease setting. The trial remains open, comparing IFOS with and without the tyrosine kinase inhibitor lenvatinib. Funded by Cancer Research UK (C22436/A28028, CTUQQR-Dec22/100006, A28474). Clinical trial information: ISRCTN36453794 .

Background Afamitresgene autoleucel (afami-cel) is an autologous engineered T-cell therapy targeting tumors expressing MAGE-A4. We analyzed the impact of afami-cel treatment on patients’ performance status (PS) and quality of life (QoL) in SPEARHEAD-1 cohort 1. Materials and methods SPEARHEAD-1 (NCT04044768) was an open-label, nonrandomized, phase II trial in HLA-A∗02-eligible patients aged 16-75 years with metastatic/unresectable synovial sarcoma or myxoid/round cell liposarcoma expressing MAGE-A4 who had received one or more previous chemotherapies. Following lymphodepletion, chemotherapy patients received a single afami-cel T-cell infusion. Eastern Cooperative Oncology Group (ECOG) PS at baseline, weekly at days 8-29, weeks 6, 8, 12, 16, 24, and every 2 months thereafter, and European QoL 5-Dimension 3-Level (EQ-5D-3L) at baseline and weeks 8, 16, and 24 were recorded. Results At days 22 and 29, 78% (40/51 recorded) and 78% (38/49 recorded) of patients, respectively, had improvement/maintenance from baseline PS. From week 6 to month 12, 87%-100% of patients with data had improved/maintained PS. Median baseline EQ-5D-3L visual analog scale (VAS) health score was 61 (n = 45), improving to 70 at week 8 (n = 37). Of 45 patients with baseline data, 76% and 58% had some/extreme problems with pain/discomfort or anxiety/depression, respectively. Median time to next treatment or death was 10.0 months [95% confidence interval (CI) 6.5-18.2 months] in 27 patients with stable/improving VAS and 5.7 months (95% CI 2.5-8.1 months) in 7 patients with worsening VAS. Conclusions Although limited by small sample size and nonresponder dropout, this suggests afami-cel is associated with improvement/maintenance in overall health and QoL.

10008 Background: Regorafenib monotherapy has shown interesting but limited activity against relapsed Ewing sarcoma. We present the first results of the phase Ib study to identify the maximum tolerated dose (MTD) of regorafenib in combination with standard multimodal treatment in patients with newly diagnosed multi-metastatic Ewing sarcoma (NCT05830084). Methods: International multi-center phase Ib study of the combination of regorafenib with interval-compressed chemotherapy (VDC/IE) in patients aged 2-50 years with newly diagnosed metastatic (excluding lung/pleura only) Ewing sarcoma. VDC/IE chemotherapy was administered at the standard doses. Regorafenib was given orally for 21 days of a 28-day cycle (from day 5) at a starting dose level of 66 mg/m 2 /day (capped at 120 mg, DL0, 80% of the pediatric recommended phase 2 dose (RP2D)) and escalated to 82 mg/m 2 /day (100% RPD2, capped at 160 mg, DL1) or de-escalated to 50 mg/m 2 /day (60% RPD2, DL-1). The study implemented the Bayesian Optimal Interval (BOIN) design (Yuan et al, Clin Cancer Res 2016). Primary tumour local treatment was surgery and/or radiotherapy. Adjuvant therapy consisted of VC/IE cycles or high dose chemotherapy consolidation with Busulfan/Melphalan (BuMel) and autologous stem cell rescue (ASCR). Regorafenib was given concomitant to adjuvant VC/IE cycles and primary tumor radiotherapy to the extremities but permanently discontinued in those receiving BuMel/ASCR or primary tumour radiotherapy to sites other than extremities. Results: Thirteen patients (DL0: n=2, DL1: n= 11) with a median age of 15.2 years (range, 8.1-23.5), were enrolled between June 2023 and December 2024 in 7 centres and 3 countries. All were evaluable for toxicity. One dose-limiting toxicity (DLT) occurred in one patient at DL1 (pressure ulcer grade 2, requiring regorafenib dose interruption and reduction in a 17-year old patient). After the DLT period, one patient had regorafenib dose interruption/reduction. One patient presented with a grade 3 veno-occlusive disease after Bu-Mel/ASCR. Detailed toxicity data after the DLT period and pharmacokinetic data will be presented. At data cut-off of 21/01/2025, two patients had experienced disease progression before primary tumour local treatment, eight patients had finished all treatment cycles (three received Bu-Mel/ASCR consolidation) and three patients were on therapy. Conclusions: Regorafenib combined with VDC/IE chemotherapy is well tolerated with a MTD of 82 mg/m 2 /day (capped 160 mg). The efficacy of the addition of regorafenib to standard multimodal treatment in newly diagnosed patients with metastatic Ewing sarcoma will be tested in the Inter-Ewing-1 trial developed by the Euro Ewing Consortium (planned initiation in Q3 2025). Recruitment to the Rego-Inter-Ewing-1 continues at DL1 (maximum 24 patients), until Inter-Ewing-1 initiates. Clinical trial information: NCT05830084 .

11513 Background: Extraskeletal myxoid chondrosarcoma (EMC) is an ultra-rare sarcoma, with low sensitivity to classic chemotherapy. A previous clinical trial led by our groups showed the activity of antiangiogenics (specifically pazopanib) in patients (pts) with advanced ECM. As IMMUNOSARC I master-trial exploring sunitinib (S) plus nivolumab (N) in sarcoma detected signal of activity in ECM pts, a specific cohort of ECM was designed as a phase II trial within IMMUNOSARC II (NCT03277924). Methods: Adult pts with advanced, progressing, measurable and centrally confirmed EMC were enrolled and treated with S 37.5 mg/d in the first 14 days (d), followed by S 25 mg/d, along with N 240 mg every 2 weeks up to progression or intolerance. Imaging reassessments were done every 8 weeks. The primary endpoint was 6-month(m)-PFS rate, and the statistical assumptions were obtaining a 6m-PFSR in at least 15 pts out of 22 pts, with H 0 = 50% and H 1 = 80%, (α 0.05; β 0.10) to consider the combination as promising. Results: Twenty-four pts were accrued from May 2020 to July 2024 in 9 centres from Spain, Italy and UK. Pts had a median age of 58y (42-83), with a predominance of male (M = 19/F = 5). Thirteen (54%) pts were treatment naïve and 22 (92%) pts had metastatic disease at baseline. Grade 3-4 Adverse Events (AE) occurring in > 5% of pts were: hypertension (29.2%), ALT and AST increase (16.7 and 12.5% respectively), bilirubin increase (12.5%), Lymphocytopenia (12.5%). No G4 hematologic AEs were found, with the exception of 1 pt with G4 leukopenia. With a median FU of 18 mos (8-29), among the 23 evaluable pts, 6m-PFSR was 77% with 16/23 pts free of progression at 6 mos, and a median PFS of 13.2 mos (95%CI 5.7-20.7). Median OS has not been reached and 12m-OS was 90% ( 95%CI 77-100). Two (9%) pts achieved a RECIST 1.1 partial response while 18 (82%) and 2 pts (9%) showed a stable disease and progresion as the best response respectively. Pts (6/23) previously treated with antiangiogenic had a trend to a shorter mPFS (7mos vs 13 mos, p = 0.11) and a significantly shorter OS (28 mos vs NR, p = 0.038). Conclusions: The combination of sunitinib and nivolumab has shown to be active in advanced extraskeletal myxoid chondrosarcoma. Our data suggest that using this combo in upfront lines provides a greater benefit. Clinical trial information: NCT03277924 .

Vascular soft-tissue sarcomas (VSTSs), while rare, are a diverse group of sarcomas that carry a poor prognosis and have limited management options. The most common subtype is angiosarcoma, but this group also includes lymphangiosarcomas, malignant haemangioendotheliomas and malignant glomus tumours. Kaposi sarcoma was not included in this dataset. Epidemiological data on incidence and survival rates are scarce. National data on VSTS and cutaneous subtypes were extracted from the ‘Get Data Out’ National Disease Registration Service programme for England, 2013–20. Confidence intervals (CIs) were measured by using the exact Poisson method. Crude incidence rates (CIRs) are reported per 100 000 person-years (PY). Incidence rate ratios (IRRs) were calculated to assess the impact of the pandemic on incidence rates between 2020 and 2019 and are reported with Poisson CIs and a χ2-statistic. From 2013 to 2020, 1587 new cases of VSTS were diagnosed, with a mean of 198 cases per year and a CIR of 0.33 PY (95% CI 0.29–0.39) in 2013, which increased to 0.37 PY (95% CI 0.32–0.43) in 2020. Of these, 174 were reported as having a cutaneous origin (not including subcutaneous), with a mean of 22 per year and a CIR of 0.04 PY (95% CI 0.03–0.07) in 2013, which increased to 0.06 PY (95% CI 0.04–0.08) in 2020. The IRR for VSTS for 2020 vs. 2019 was −2.4% (95% CI 0.80–1.19; P = 0.80). The IRR for cutaneous vascular sarcoma was not significant due to small counts. The 5-year net survival reported for 2014–2016 for VSTS was 35.7% (95% CI 31.3–40.1) and was not reported for cutaneous vascular sarcomas due to small counts. Limitations of these data include the lack of more detailed data on subtype and site of VSTS, patient demographics and stage. The 2.4% reduction in incidence rates between 2020 and 2019 is nonsignificant and a smaller reduction than that seen for many other cancers during the pandemic on the background of healthcare service disruption, which may reflect the aggressive nature of VSTS. The 5-year net survival rate is similar to that of stage IV melanoma and worse than for most other skin cancers. Analysis of these data is key in highlighting this rare group of cancers, to better understand the effectiveness of current treatments and identify the direction of further research.

OBJECTIVE:Globally, head & neck sarcoma care pathways remain unclear. In 2018, the London Sarcoma Service (LSS) set up a dedicated head and neck sarcoma (HNS) multidisciplinary team (MDT) with a clear objective to provide formal access to super-specialist expertise in diagnosis, treatment planning and management of HNS. The aim of the study is to provide first results of a dedicated HNS MDT. METHODS:All patients discussed between 2018 and 2022, in HNS MDT, with a new histologically confirmed HNS diagnosis were included in the study. Demographics, anatomic site, morphology, MDT recommendation, treatment details and outcomes were obtained from electronic patient records. RESULTS:A total of 337 patients were discussed in the HNS MDT of which 178 patients were included in the study, with a median age of 53 years(range 2-94); 67 % were soft tissue sarcomas(STS) and 33 % were bone sarcomas(BS), of which 43 % and 71 % were high grade, respectively. 55 % BS and 39 % STS underwent surgery. 9 % of BS and 7 % of STS received adjuvant Proton Beam therapy. With a median follow-up of 2.16 years, recurrence was observed in 12 %, distant metastasis in 6 % of patients and overall survival was 72 %. CONCLUSION:The HNS MDT provides expertise on diagnosis and multi-modality management of HNS. STS are more likely to be misdiagnosed. Atypical imaging characteristics should trigger a specialist referral. Adequate surgery at first presentation remains the mainstay of treatment and the strongest prognosticator of overall survival. Formation of an expert working group specific to HNS must work towards streamlining sarcoma care.

Background 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. Methods 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 10 x 10 9 -100 x 10 9 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. Findings 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 pretreated (median three [IQR two to four] previous lines of systemic therapy). Median follow-up time was 326 months (IQR 29 center dot 4-36 center dot 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. Interpretation 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. Funding Adaptimmune. Copyright (c) 2024 Elsevier Ltd. All rights reserved.

Osteosarcoma and Ewing sarcoma are bone tumors mostly diagnosed in children, adolescents, and young adults. Despite multimodal therapy, morbidity is high and survival rates remain low, especially in the metastatic disease setting. Trials investigating targeted therapies and immunotherapies have not been groundbreaking. Better understanding of biological subgroups, the role of the tumor immune microenvironment, factors that promote metastasis, and clinical biomarkers of prognosis and drug response are required to make progress. A prerequisite to achieve desired success is a thorough, systematic, and clinically linked biological analysis of patient samples, but disease rarity and tissue processing challenges such as logistics and infrastructure have contributed to a lack of relevant samples for clinical care and research. There is a need for a Europe-wide framework to be implemented for the adequate and minimal sampling, processing, storage, and analysis of patient samples. Two international panels of scientists, clinicians, and patient and parent advocates have formed the Fight Osteosarcoma Through European Research consortium and the Euro Ewing Consortium. The consortia shared their expertise and institutional practices to formulate new guidelines. We report new reference standards for adequate and minimally required sampling (time points, diagnostic samples, and liquid biopsy tubes), handling, and biobanking to enable advanced biological studies in bone sarcoma. We describe standards for analysis and annotation to drive collaboration and data harmonization with practical, legal, and ethical considerations. This position paper provides comprehensive guidelines that should become the new standards of care that will accelerate scientific progress, promote collaboration, and improve outcomes.

PURPOSE OF REVIEW:There is an unmet need to improve outcomes for patients for Ewing sarcoma, a rare, aggressive sarcoma with a peak incidence in adolescents and young adults (AYA). Current therapy at diagnosis involves multiagent chemotherapy and local therapy, but despite intensification of treatment, those with metastases at diagnosis and recurrent disease have poor outcomes. RECENT FINDINGS:Improved understanding of Ewing sarcoma biology has identified novel targets with promising activity in Ewing sarcoma patients, including tyrosine kinase inhibitors that are now undergoing evaluation as combination and maintenance therapy. Other emerging therapies include those that target the EWSR1::FLI1 fusion oncoprotein, and act on DNA damage, cell cycle and apoptotic pathways. Immunotherapeutic approaches, particularly CAR-T-cell therapy directed at GD2, also hold promise. Recent collaborative clinical trials that have defined an international standard of care for patients with newly diagnosed Ewing sarcoma and novel platform studies with adaptive designs offer unique opportunities to investigate these therapies inclusive of all ages. SUMMARY:Close international collaboration between clinicians and biologists will allow us to prioritize promising emerging therapies and develop biomarkers to facilitate their incorporation into standard of care and more rapidly translate into benefit for Ewing sarcoma patients.

11517 Background: EGFR and Her2 overexpression in chordoma is well known, and chordoma cell-lines and mouse models were proven to be sensitive to EGFR inhibitor afatinib. This phase 2, single arm, European multi-center trial was designed to evaluate the efficacy of afatinib as first- or later-line tyrosine kinase inhibitor (TKI) treatment in advanced chordoma. Here we report efficacy and safety data. Methods: Eligible patients (pts) had locally advanced or metastatic, pathologically proven, EGFR expressing chordoma, not amenable for local therapies, with confirmed measurable and progressive lesions according to RECIST1.1. Pts were treated with afatinib 40mg/day in a 4 week cycle until disease progression (PD), unacceptable toxicity or withdrawal. Radiological tumor response assessment was performed every 3 cycles. The primary endpoint was response defined as progression free survival (PFS) rate ≥12 months (mos) for first-line cohort 1 and ≥ 9 mos for further-line treatment cohort 2, and change from baseline in EORTC QLQ- C30 and Brief pain inventory (BPI) questionnaires. Pts were enrolled using a Simon’s two-stage design, enrolling 13 patients in stage one, ≥3 patients with a PFS ≥ 12 or 9 mos were needed to enter stage two, where 43 pts total were to be enrolled, and ≥13 free from progression at 9 or 12 mos were required to meet the primary endpoint for success. Results: From Jun 2018 to Oct 2022, 47 pts were included. Four were ineligible for efficacy analysis (1 withdrawal, 3 stopped due to toxicity before first radiological evaluation). 34 entered cohort 1, 13 cohort 2. 31 (66.0%) were men, median age was 53 (range 28-85) years. 16 (34.0%) pts received prior systemic therapy (3 chemotherapy, 13 TKI, 2 immunotherapy, 2 other). The PFS rate at 12 mos was 40.0% in cohort 1 (12/30 pts), and 38.5% in cohort 2 (5/13 pts). Overall median PFS was 8.6 mos (95% CI 5.6-13.6); 9.1 mos (95% CI 5.8-16.6) in cohort 1 and 7.1 mos (95% CI 2.8-16.5) in cohort 2. Two pts remained on treatment at time of analysis. Best objective response by RECIST 1.1 was partial response in 4 pts (9.3%), stable disease in 33 (76.7%), PD in 5 pts (11.6%) and 1 (2.3%) unknown due to clinical progression. Median follow-up time was 23.7 mos (interquartile range 11.0-21.2). 16/47 pts (30.4%) experienced grade ≥3 adverse events (AEs). No grade 5 AEs related to afatinib were reported. Most common grade 3-4 afatinib-related AEs were skin toxicity (10.6% of pts), diarrhea (10.6%), mucositis (6.4%), hypertension (4.3%). Dose reduction was needed in 20/47 (42.6%) pts, and at least one dose interruption was needed in 31/47 (66.0%) pts. Conclusions: With a PFS rate at 12 mos of 40.0% in the first-line cohort and 38.5% at 9 mos in the further-line cohort, this phase 2 study met the PFS endpoint. QoLQ data will be provided at the conference . Partial response by RECIST was seen in 4/43 pts. Toxicity and dose reductions were relevant but manageable in most pts. Clinical trial information: NCT03083678 .