Tinoco, Gabriel

11504 Background: Surgery & radiation therapy (RT) yield high local control rates for soft tissue sarcoma (STS) of the extremity and limb girdle. However, patients (pts) with high-grade stage III STS are at significant risk for developing metastasis. Median survival for pts with metastatic STS is < 2 years. SARC028 (NCT02301039) evaluated the efficacy of pembrolizumab (pembro) for metastatic STS, showing 20% and 8.7% response rates in undifferentiated pleomorphic sarcoma (UPS) and pleomorphic/dedifferentiated liposarcoma (LPS), respectively. We hypothesized that neoadjuvant pembro with concurrent RT followed by surgery and adjuvant pembro for stage III UPS, including myxofibrosarcoma, or LPS would stimulate an anti-tumor immune response to eliminate micrometastatic disease & improve disease-free survival (DFS). SU2C-SARC032 (NCT03092323) is a multi-institutional, international, randomized phase 2 trial evaluating the safety and efficacy of adding pembro to standard of care (SOC) RT & surgery for pts with stage III UPS or LPS. Methods: Pts aged > 12 yo with stage III (FNCLCC grade 2 or 3) UPS or LPS of the extremity and limb girdle were enrolled. Pts were randomized (1:1, stratified by grade) to neoadjuvant RT (50 Gy/25 fx) then surgery (SOC arm) or neoadjuvant pembro and RT then surgery & adjuvant pembro (EXP arm). Pembro was given 200 mg IV Q3 wk for 3 doses (before, during & after RT) & up to 14 adjuvant cycles. The primary endpoint was 2-yr DFS. Secondary endpoints included local recurrence-free survival (LRFS), distant disease-free survival (DDFS), & overall survival (OS). Target enrollment of 126 evaluable patients (max 144 total) provided 80% power (1-sided α = 0.05) to distinguish between a null hypothesis of 50% 2-yr DFS rate & alternative hypothesis of 75% 2-yr DFS rate by log-rank test, with initial analysis at 45 DFS events. Cox models were stratified by grade; primary analysis was a one-sided stratified log-rank test. Results: Between July 2017-November 2023, 143 patients were enrolled, predominantly with UPS (85%) & grade 3 (64%) histology. Median follow-up for alive patients is 24.1 mo. DFS in the EXP arm is significantly higher than the SOC arm (p = 0.023; HR 0.57, 90% CI: 0.35, 0.91). Estimated 2-yr DFS is 53% (90% CI: 43, 66%) for SOC vs 70% (90% CI: 61, 81%) for EXP arm. Currently, there is no statistically significant difference in LRFS (HR 0.55, 95% CI: 0.21, 1.42), DDFS (HR 0.57, 95% CI: 0.32, 1.01), or OS (HR 0.39, 95% CI: 0.14, 1.12). Pts with grade 3 sarcomas had improved DFS with pembro (HR 0.47, 95% CI: 0.25, 0.89), but no difference in DFS was observed in grade 2 tumors (HR 1.21, 95% CI: 0.35, 4.18). The proportion of patients with grade 3+ adverse events was significantly higher in EXP (52%) vs SOC arm (26%) (p = 0.002). Conclusions: Theaddition of neoadjuvant & adjuvant pembro to RT and surgery significantly improves DFS for pts with stage III UPS and LPS of the extremity and limb girdle. Clinical trial information: NCT03092323 .

Abstract Purpose: Epithelioid hemangioendothelioma (EHE) is a rare vascular cancer with pathogenic TAZ–CAMTA1 (calmodulinbinding transcription activator 1) operating as an oncogenic driver through activation of the MAPK pathway. Trametinib is an inhibitor of MEK, a critical kinase in the MAPK pathway. We sought to evaluate the effect of trametinib in patients with EHE. Patients and Methods: A phase 2 trial of trametinib was conducted in patients with locally advanced or metastatic EHE. Eligibility requirements included evidence of tumor progression or presence of EHE-related pain requiring opiates for management before enrollment. The primary endpoint was objective response rate (ORR) as per RECIST1.1 in cases with TAZ– CAMTA1 confirmed by fusion-FISH. Secondary objectives were to estimate ORR for all patients, median progression-free survival (PFS), 2-year overall survival (OS) rate, patient safety, and change in patient-reported global health and pain scores per PROMIS questionnaires. Results: 44 patients enrolled and 42 started trametinib. TAZ– CAMTA1 was detected in 27 tumor samples. TheORRwas 3.7%[95% confidence interval (CI), 0.094–19.0], median PFS was 10.4 months (95%CI, 7.1–NA), and 2-year OS rate was 33.3%(95%CI, 19.1–58.2) in the target population. Median pain intensity and interference scores improved significantly after 4 weeks of trametinib in patients using opiates. Common adverse events related to trametinib were rash, fatigue, nausea/vomiting, diarrhea/constipation, alopecia, and edema; one grade 5 ARDS/pneumonitis was related to trametinib. Conclusions: Trametinib was associated with reduction in EHE-related pain and median PFS of more than 6 months, providing palliative benefit in patients with advanced EHE, but the trial did not meet the ORR goal. See related commentary by Van Tine and Haarberg, p. 4552

Background and purpose: A bolus is required when treating scalp lesions with photon radiation therapy. Traditional bolus materials face several issues, including air gaps and setup difficulty due to irregular, convex scalp geometry. A 3D-milled bolus is custom-formed to match individual patient anatomy, allowing improved dose coverage and homogeneity. Here, we describe the creation process of a 3D-milled bolus and report the outcomes for patients with scalp malignancies treated with Volumetric Modulated Arc Therapy (VMAT) utilizing a 3D-milled bolus. Materials and methods: Twenty-two patients treated from 2016 to 2022 using a 3D-milled bolus and VMAT were included. Histologies included squamous cell carcinoma (n = 14, 64%) and angiosarcoma (n = 8, 36%). A total of 7 (32%) patients were treated in the intact and 15 (68%) in the postoperative setting. The median prescription dose was 66.0 Gy (range: 60.0–69.96). Results: The target included the entire scalp for 8 (36%) patients; in the remaining 14 (64%), the median ratio of planning target volume to scalp volume was 35% (range: 25–90%). The median dose homogeneity index was 1.07 (range: 1.03–1.15). Six (27%) patients experienced acute grade 3 dermatitis and one (5%) patient experienced late grade 3 skin ulceration. With a median follow-up of 21.4 months (range: 4.0–75.4), the 18-month rates of locoregional control and overall survival were 75% and 79%, respectively. Conclusions: To our knowledge, this is the first study to report the clinical outcomes for patients with scalp malignancies treated with the combination of VMAT and a 3D-milled bolus. This technique resulted in favorable clinical outcomes and an acceptable toxicity profile in comparison with historic controls and warrants further investigation in a larger prospective study.

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.