Siontis, Brittany L.

e24016 Background: Recent studies of patients (pts) with gastrointestinal stromal tumor (GIST) have included an older patient population. The majority of these have focused on treatment, but little is known regarding the optimal duration of surveillance following surgery for localized disease. Methods: We conducted a retrospective study of pts age 70 years (yrs) and above (≥) at diagnosis (dx), who underwent surgery for their localized GIST. Charts were reviewed of GIST diagnosed between 1992 to 2016, to allow at least 5 yrs for surveillance, if performed. Demographics were analyzed and pts were risk stratified using modified NIH criteria. Results: We identified 42 pts with a median age of 74 yrs (70 to 89 yrs) at dx. The majority of pts were male (31, 74%) and non-Hispanic White (37, 88%). Most pts had gastric GIST (25, 60%). The median resected tumor was 47 mm (range 6 to 190). Thirty-nine of 42 pts had margin status documented R0 resection. The median overall survival for all pts was 7.9 yrs (1.1 to 17.7), with median recurrence free survival 5.6 yrs (1.1 to 13.7). Only 4 of 16 (25%) pts died from GIST recurrence, and all were detected under 5 yrs from surgery. Fourteen of 34 pts (41%) who survived over 5 yrs from resection had extended surveillance imaging. Demographics and risk stratification are shown in Table. None of the 16 low risk pts developed recurrence, including 6 (38%) whose surveillance imaging continued beyond 5 yrs. Among 7 intermediate risk pts, only 1 pt (14%) extended surveillance imaging beyond 5 yrs. Two intermediate risk pts (29%) developed recurrence and were symptomatic at dx. One intermediate risk pt died from GIST metastasis within 1 yr from surgery. Seven of 19 (37%) high risk pts had surveillance imaging beyond 5 yrs following surgical resection. Seven high risk pts (37%) developed recurrence within median 5.6 yrs (1.6 to 13.7) from surgery; five of these were detected on imaging. In the high risk pts with recurrence, 5 had received adjuvant imatinib and 2 declined any systemic therapy. Three pts (16%) in the high risk cohort died from GIST. Conclusions: In this cohort of pts age ≥ 70 yrs with resected GIST, the majority of pts were symptomatic at relapse. Older pts who undergo surgery for low risk GIST may not require extended surveillance. Fit, older pts with high risk GIST may benefit from extended surveillance imaging, even if they received adjuvant imatinib.[Table: see text]

Abstract PURPOSE Vertebral compression fracture (VCF) is a potential adverse effect following stereotactic body radiation therapy (SBRT) for spinal metastases. In this analysis, we developed and internally validated a risk stratification model for VCF. METHODS From an initial set of 680 treatments, we excluded those with proton therapy, prior surgical intervention, or missing data. The final dataset had 464 treatments in 313 patients. Delineations of VCF and all radiographic components of the spinal instability neoplastic score (SINS) were determined by a radiologist. Recursive partitioning analysis (RPA) was conducted using separate training (70%), internal validation (15%), and test (15%) sets. The log-rank test was used as the criterion for node splitting. RESULTS With a median follow-up of 21 months, we identified 84 VCF (18%), including 65 (77%) de novo and 19 (23%) progressive fractures. There was a median 9 months (IQR: 3 – 21) to VCF. From an initial set of 15 candidate variables, six were identified using the backwards selection method, feature importance testing, and a correlation heatmap. Four were then selected in the highest-fidelity RPA models: epidural tumor extension, lumbar location, gross tumor volume > 10 cc, and SINS > 6. One point was assigned to each variable, and the resulting multivariate Cox model had a concordance of 0.760. Each one point increase in score was associated with increasing rates of VCF. Low-risk lesions (score: 0-1, n=273) had 2-year freedom from VCF of 92%, compared to 80% for intermediate-risk (score: 2, n=99) and 56% (score: 3-4, n=92) for high-risk lesions (p < 0.0001). Cumulative incidence curves with death as a competing risk showed increased VCF with higher scores via Gray’s test (p < 0.001). CONCLUSIONS Our internally-validated model identifies a subgroup of patients with high risk for VCF who may benefit from prophylactic surgical stabilization or vertebroplasty.

TPS11578 Background: Conventional chondrosarcoma (cCS) accounts for ̃25% of primary bone cancers and is the second most common primary bone tumor after osteosarcoma. Surgical resection is the primary treatment for localized disease. No FDA approved therapy exists for advanced disease and chemotherapy has marginal efficacy with ORR < 12%. IDH1/2 mutation is seen in 50% of cases. Epigenetic dysregulation is central to oncogenesis in both IDH1/2 mutant and wild-type CS. Pre-clinical studies from our group show that combination treatment with HDAC and DNMT inhibitors is significantly more effective at suppressing the growth of CS models in vitro and in vivo compared to either therapy alone. The combination regimen mediates anti-tumor effects on CS by induction of apoptosis, induction of tumor suppressor genes (eg. E-cadherin), the induction of interferon responsive genes (eg. IRF7, OASL, ISG15, DDX58) and reversal of global hypomethylated state. Based on these findings we have designed a phase 2 clinical trial with an HDAC inhibitor (belinostat) and a DNMT inhibitor (guadecitabine) in patients with advanced cCS. Methods: NCI # 10330 is a single-arm, multi-center, Simon 2-stage, phase 2 clinical trial evaluating belinostat and guadecitabine in patients with advanced cCS. Eligible patients will have biopsy proven cCS which is measurable by RECIST v1.1 and amenable to biopsy, ECOG PS ≤ 2, any number of prior treatments (including none). Patients will receive guadecitabine 45 mg/m2 SC followed by belinostat 1000 mg/m2 IV once daily on days 1-5 of a 28-day cycle. A safety lead-in and continuous toxicity monitoring rule will be applied. The primary endpoint will be ORR. Since chemotherapy is associated with an ORR of 8-12% and targeted agents have shown an ORR of 0% in cCS, we will consider an ORR of 8% as inactive while an ORR of 28% will suggest promising activity. A Simon 2-stage design is employed. The design calls for 26 patients. If ≥ 2 responses are observed among 13 patients in stage I, the study will proceed to full accrual. If ≥ 5 responses are seen among 26 patients, the study treatment is considered promising. This design has 85% power with α of 0.054 to test for a response rate of 8% vs 28%. Secondary objectives include safety, tolerability and PFS. All patients will undergo pre-treatment and on-treatment tumor biopsies. Paired tissue will be used for correlative analysis including: 1) whole exome sequencing/RNAseq to evaluate changes in gene expression in response to treatment, 2) multiplex IHC to interrogate the effect of combination therapy on tumor immune microenvironment and 3) a global DNA methylation assay to better understand the changes in epigenetic landscape in response to treatment. This study is open throughout the ETCTN (NCT04340843). Six of the planned 26 patients in the safety lead-in have been enrolled without DLT. Further accrual is on hold pending completion of the safety lead-in. Clinical trial information: 04340843.

11505 Background: AL3818 (Catequentinib, Anlotinib) is a novel, orally administered, small molecule tyrosine kinase inhibitor. The primary objective of this Phase 3 study is to evaluate the efficacy of AL3818 monotherapy in patients (pts) with synovial sarcoma (SS) comparing with dacarbazine in randomization setting. Methods: Patients with a diagnosis of synovial sarcoma requiring second line or further line treatment were eligible for enrollment. The regimen was a 21-day cycle with oral AL3818 administered on 14 days on and 7 days off. This phase 3 trial is randomized in 2:1 ratio of AL3818 comparing to dacarbazine with option of crossover after PD of dacarbazine treatment. Progression free survival (PFS) with Log Rank test is the primary endpoint and this trial for SS is currently completed enrolled in US and Italy. Results: Total 79 pts initiated treatment and are evaluable, 52 received AL3818 as treatment arm (T), and 27 received dacarbazine (D) as control arm (C). Arms T/C median ages were 40.5/42.0 years (range: 18-70+) and 20/16 (38.5%/59.3%) were male. Overall, PFS was 2.89 months (95% CI: 2.73 – 6.87) for AL3818 and 1.64 (95% CI: 1.45 – 2.70) for D. The PFS of study met the primary endpoint with a p-value of 0.0015 and a HR of 0.449 (95% CI: 0.270– 0.744). At the month 4, 6, and 12, the percentages of progression free patients for AL3818 were 48.1%, 42.3% and 26.9%; and for D were 14.85%, 11.1% and 3.7%. For grade 3 treatment-related adverse events, 12(23.1%) of pts experienced for AL3818 and 7(25.9%) of pts experienced for D. The most common AL3818 related grade 3 AEs were diarrhea (5.8%) and hypertension (3.8%). Conclusions: This phase III trial demonstrates improved disease control and superior progression free survival for AL3818 vs dacarbazine in advanced SS. In addition, the study further confirms the acceptable benefit-risk profile of AL3818 from the prior randomized Phase 2b soft tissue sarcoma study (NCT02449343). AL3818 is a meaningful treatment option for pts with advanced SS. Clinical trial information: NCT 03016819 Clinical trial information: NCT03016819.

11503 Background: EHE is a rare vascular cancer arising in liver, lung, soft tissue and bone. The natural history of metastatic disease varies considerably from indolent growth over years to rapid growth with fatal outcome in months. Treatment of patients (pts) with metastatic EHE with antiangiogenic therapy induces tumor response in a minority of pts, and median PFS is 6-12 months. TAZ-CAMTA1 translocation results in activation of MAPK pathway and is an oncogenic driver in EHE. We sought to evaluate the effect of MEK inhibition using trametinib in pts with unresectable EHE. Methods: A phase 2 trial of trametinib 2 mg daily was conducted in pts with EHE though the Experimental Therapeutics Clinical Trials Network supported by NCI in collaboration with SARC. Additional support was provided by the EHE Rare Cancer Charity and the EHE Foundation. Pts had to have evidence of objective tumor progression or EHE-related pain requiring narcotics for relief prior to enrollment. Presence of TAZ-CAMTA1 translocation was analyzed by fusion-FISH after enrollment. Primary trial endpoint was objective response rate (ORR) per RECIST1.1 with at least 1 objective response required in the 1st 13 pts to expand enrollment to 27. The trial was amended after stage 1 to continue enrollment to 27 pts with TAZ-CAMTA1 detected by FISH with goal of >4 objective responses in this group. Secondary objectives were PFS and OS rates, safety and change in pt-reported global health and pain scores per PROMIS questionnaires. Results: 43 pts were enrolled between 6/2017 – 9/2020 across 10 sites and 41 started therapy. TAZ-CAMTA1 fusion was detected in 26, not detected in 7, test failed in 5 and was not performed due to insufficient tumor in 5. Median pt age was 54 (range 22-81 yrs) and 11 were >65 yrs; 25 were female; ECOG was 0 in 23, 1 in 16 and 2 in 3 pts. Most pts experienced reduction in tumor size. ORR per RECIST was 7% (3/41); in pts with TAZ-CAMTA1 detected, the ORR was 0% (0/26). Mean pain intensity and interference scores had a statistically significant improvement and global quality of life scores did not statistically change after 4 weeks of therapy. 17 pts remained on treatment > 6 months and 7 > 12 months. 25 pts stopped trametinib due to EHE progression, 6 died during treatment, 6 withdrew from treatment, 3 stopped drug due to adverse event and 1 is on treatment. The most common AEs related to trametinib were rash, fatigue, nausea/vomiting, diarrhea, alopecia and edema; Grade >3 AEs included anemia, dyspnea, hypoxia, hypotension, syncope and dermatitis. Conclusions: To our knowledge, this is the largest prospective clinical study focused on pts with EHE. Although the trial did not meet the ORR goal, stable disease > 6 months was seen in 40% of pts, and EHE-related pain improved on treatment. Trametinib was associated with expected cutaneous and GI adverse effects. Additional pt-reported outcomes and biomarkers of inflammation are undergoing analysis. Clinical trial information: NCT03148275.

e23544 Background: Rare diseases are defined as conditions that affect less than 200,000 people annually in the United States. Around 17000 cases of sarcoma will be diagnosed in 2020. Collaboration among institutions is needed to best understand rare diseases such as sarcoma. One measure of collaboration is publications with multiple institutions as authors. We sought to determine if collaboration in sarcoma has increased since 2011 and compared that to another rare disease, CNS tumors based on multi-institution-authored abstracts presented at ASCO. Methods: All sarcoma and CNS oral abstracts, clinical science symposia, poster presentations, poster discussions, and published-only ASCO Annual Meetings from 2011 to 2019 were reviewed. Collaboration was determined if the abstract authors were from more than one institution. Results: 2,134 abstracts were reviewed. Collaboration for sarcoma ranged from 0.603 to 0.720 and 0.582 to 0.755 for CNS. From 2011-2019 a positive linear trend in collaboration was found in CNS (P < 0.05), but not in sarcoma (P = NS). There was no significant trend in the incidence of collaboration in Sarcoma based on the type of presentation at ASCO. There was no difference in collaboration between bone or soft tissue sarcoma abstracts or median number of institutions collaborating between sarcoma and CNS. There were more international collaborations and absolute number of institutions in sarcoma vs CNS. Conclusions: Sarcoma collaboration has remained constant from 2011-2019 with greater number of institutions and more international collaborations as compared to CNS. CNS collaboration has increased from 2011-2019. Sarcoma collaboration at ASCO is robust and reflects the need for multi-institutional partnership.

11561 Background: Angiosarcoma has a particularly poor prognosis with 5-year overall survival rates of approximately 30-40%. Treatment of locally advanced and metastatic angiosarcoma is inadequate. Data strongly suggest concurrent, potent inhibition of VEGFR and Tie2 represents an attractive therapeutic strategy in angiosarcoma. Regorafenib displays potent VEGFR and Tie2 receptor inhibition and also possesses activity against additional potential targets in angiosarcoma including PDGFRs, RAF, KIT and FGFR, amongst others. Methods: A multicenter phase II study of regorafenib in patients with locally advanced or metastatic angiosarcoma was conducted through the Midwest Sarcoma Trials Partnership. Adequate performance status, organ function, measurable disease (RECIST 1.1) and 1-4 prior therapies were required. Regorafenib 160 mg PO daily was given in 28-day cycles (21 days on, 7 days off) until disease progression (PD) or unacceptable toxicity. The primary endpoint was progression-free survival (PFS), assessed at 16 weeks. Secondary endpoints include overall response rate (ORR), clinical benefit rate (CBR), OS, and safety and tolerability. A Simon 2-stage design was used. Results: After final enrollment of the second stage, a total of 31 pts were enrolled at 6 sites, 23 are evaluable for response. Median age was 65 (range 30-91); 50% were female, 67.7% had metastatic disease. PFS at 4 months is 52.2% with a median PFS and OS of 3.55 and 11.4 months. 1 confirmed CR and 2 PR, 12 SD and 8 PD were observed. ORR and CBR are 14.29 and 65.2%, respectively. No uncommon grade 3-4 adverse events were observed. 6 pts were non-evaluable due to refusal of further therapy and 2 patients progressed prior to first evaluation. Conclusions: Regorafenib was well tolerated in this study of pretreated patients with angiosarcomas and met its primary endpoint with a median PFS > 45% at 4 months. Treatment was feasible and did not reveal any previously unreported toxicities. Efficacy outcomes were complicated by early withdrawals of patients. RECIST responses were encouraging and regorafenib has a clinically meaningful 4-month PFS. Clinical trial information: NCT02048722 .

Aims Limited data exist on atypical lipomatous tumour (ALT)/well‐differentiated liposarcoma (WDL) and de‐differentiated liposarcoma (DDLPS) in children and young adults. Methods and results Cases of ALT/WDL/DDLPS arising in patients aged ≤ 40 years were collected from multiple institutional and consultation archives. A total of 116 cases of ALT/WDL (75) and DDLPS (41) were identified, representing fewer than 5% of these tumours seen at our institutions during this time‐period. The patients (59 male/57 female) ranged in age from 8 to 40 years. Sites included deep central (abdomen/retroperitoneum/pelvis/groin) ( n = 60), extremity ( n = 42), trunk ( n = 5), head/neck ( n = 8) and mediastinum ( n = 1). De‐differentiated patterns included: high‐grade pleomorphic sarcoma, myxofibrosarcoma‐like, heterologous rhabdomyoblastic differentiation, low‐grade spindle cell sarcoma and homologous lipoblastic differentiation. Forty‐one patients experienced a local recurrence and 11 patients with DDLPS developed metastasis. ALT arising in the extremities had lower recurrence rates than deep central WDL (5‐year recurrence‐free survival 88.9% versus 59.0%; P = 0.002), while patients with deep central DDLPS experienced significantly more adverse events compared to WDL at this site (5‐year event‐free survival 11.9% versus 59.0%) ( P < 0.0001). Seven (of eight) head/neck tumours had follow‐up available; five recurred, and one patient (DDLPS) with recurrence also experienced a metastasis. The single mediastinal tumour (DDLPS) recurred and metastasised. Conclusion ALT/WDL and DDLPS occurring in patients aged ≤ 40 years is rare, but exhibits similar morphological features to its counterparts in older adults, including potential for heterologous and homologous de‐differentiation in the latter. Although case numbers are limited, tumours arising in the head and neck exhibit high rates of adverse events, suggesting that classification as WDL rather than ALT is more appropriate.