Citations

TPS11587 Background: Recurrent or metastatic dedifferentiated liposarcoma (DDLS) remains a difficult disease to treat. Available agents such as doxorubicin, eribulin, trabectedin, ifosfamide, dacarbazine, or gemcitabine-based regimens are associated with low response rates and only modest improvements in progression free or overall survival. The oncogene CDK4 is ubiquitously amplified in this disease and represents a rational therapeutic target. In single-arm phase 2 studies, treatment with selective CDK4 inhibitors resulted in clinical benefit (12-week progression-free survival (PFS) of 57% with palbociclib and 74% with abemaciclib). We hypothesize that treatment with abemaciclib will improve PFS compared to placebo in patients with recurrent or metastatic DDLS. Methods: This is a phase 3 randomized double-blind study of abemaciclib versus placebo. Eligible patients have recurrent or metastatic dedifferentiated liposarcoma (purely well-differentiated liposarcoma excluded), progression of disease by RECIST 1.1 in the 6 months prior to study entry, any number of prior systemic therapies, and adequate organ function and performance status. Patients are stratified by number of prior lines of therapy (0 vs 1 or more) and randomized 1:1 between abemaciclib 200 mg PO twice a day and matching placebo. Patients are followed with scans every 6 weeks (every 12w after 36w) and those with progression of disease on placebo may cross over to open label abemaciclib. The primary endpoint is PFS. Target enrollment is 108 evaluable patients which provides 80% power with two-sided 10% significance level to detect a hazard ratio of 0.6. Secondary endpoints include response rate, PFS and response rate after crossover, and overall survival. Archival tissue will be collected to explore potential biomarkers. As of Feb 1, 2023, 43 patients have been accrued at 9 participating centers. Clinical trial information: NCT04967521 .

11563 Background: Afami-cel is an autologous, T-cell receptor (TCR) T-cell therapy to treat human leukocyte antigen (HLA) A*02–eligible patients (pts) with advanced solid tumors positive for the cancer testis antigen melanoma-associated antigen A4 (MAGE-A4). The efficacy and safety of afami-cel in pretreated pts with advanced/metastatic synovial sarcoma or myxoid/round cell liposarcoma are being evaluated in the Phase 2, two-cohort, open-label, SPEARHEAD-1 (NCT04044768) trial. Here we report interim overall survival (OS) data in the pts with advanced synovial sarcoma in Cohort 1. Methods: Pts who were HLA-A*02 positive with advanced synovial sarcoma (with evidence of clinical/radiological progression) positive for MAGE-A4 received afami-cel after lymphodepleting chemotherapy containing fludarabine and cyclophosphamide. The primary endpoint was overall response rate per RECIST v1.1 by independent review. Secondary endpoints included OS and progression-free survival (PFS), estimated utilizing the Kaplan-Meier method. Results: As of August 29, 2022, 44 pts with synovial sarcoma received afami-cel (2.68–9.99×109 transduced T-cells) in Cohort 1. The median age was 41 years (range: 19–73 years), 50% of pts were female, 89% of pts were white, 96% of pts were typed as HLA-A*02:01P, and median tumor MAGE-A4 expression H-score was 257 (132–300). Pts were heavily pre-treated with a median of 3 prior lines of therapy (range: 1–12). The median follow-up time at the data cut-off was 20.8 months. Median PFS was 3.8 months (95% CI: 2.8, 5.8) and 4.1 months (95% CI: 2.8, 6.9) by independent and investigator review, respectively. Median OS by independent review was 15.4 months (95% CI: 10.9, not estimable) with 52% of pts censored at the data cut-off. The 12-month OS probability was 60% and 24-month OS probability was 40%. Twenty-one pts received additional therapy during long term follow up (systemic therapy, n = 20; radiation, n = 6; other, n = 4). In the 17 pts who had a RECIST response by independent review, the median OS was not reached, the 12-month OS probability was 90%, and 24-month OS probability was 60%. Conclusions: Pts with advanced synovial sarcoma treated with afami-cel in SPEARHEAD-1 had encouraging survival, especially those pts with a RECIST response. Clinical trial information: NCT04044768 .

11507 Background: Single agent or combination chemotherapy, typically Dox- or gemcitabine-based, are standard 1st- and 2nd-line therapies in patients (pts) with metastatic LMS; however, objective response rates (ORR), progression-free, and overall survival (PFS/OS) remain inadequate. Lurbi (PharmaMar S.A. / Jazz Pharmaceuticals) binds to DNA inhibiting transcription and inducing double strand breaks leading to apoptosis and delaying S/G2 progression. In a prior pilot study, we showed Lurbi+Dox is well-tolerated, with signs of activity, particularly in LMS. We designed this phase 1b to optimize dosing to lead into a randomized (1:1) phase 2 trial of Dox+/-Lurbi in anthracycline-naïve LMS. Herein we provide updated efficacy and tolerability data for this Phase 1b cohort. Methods: Pts > 18 yrs with locally advanced/metastatic, unresectable non-GIST STS (Phase 1b only) w/o prior anthracycline or Lurbi/trabectedin, ECOG PS < 3, RECIST 1.1 measurable, and normal organ function were eligible. The phase 1b followed a 3+3 design. Dosing included fixed Lurbi (3.2 mg/m2 d1) with two Dox dose levels (DL; DL1: 25 mg/m2 d1; DL2 25 mg/m2 d1+8). All pts received GCSF prophylaxis. Tumor assessments were every 2 cycles. DL1 was chosen as RP2D and the phase 2 trial began accrual in Aug 2022 aiming to enroll 50 LMS pts randomized 1:1 (stratified by uterine LMS [uLMS]] v. other LMS) with PFS as primary endpoint. Pts progressing on Dox are allowed to cross to Lurbi monotherapy. Results: 10 patients were enrolled in Phase 1b. Histologies included 5 LMS (4 uLMS) and 1 each of myxofibrosarcoma (myxFS), undifferentiated pleomorphic sarcoma (UPS), dedifferentiated liposarcoma (DDLPS), endometrial stromal sarcoma (ESS), and solitary fibrous tumor (SFT). With a median follow-up of 344 days, 5/10 pts remain on treatment with median PFS of 357 days (95%CI 175-ND). 6 pts demonstrated partial response (PR; 5 confirmed), 3 with stable disease (SD), and 1 with progressive disease (PD, Table). Median time to PR was 81 days (range 46-207). Duration of response was over 132 days in all responders with 3 still on treatment. Treatment-related AEs were typical for Dox/Lurbi, including nausea, fatigue, and reversible LFT elevations/cytopenias. Updated safety and response data will be provided at the time of the meeting. Conclusions: Lurbi+Dox is well-tolerated with efficacy in STS including 6/10 pts achieving PR, 9/10 pts staying on treatment for >120d, and 6/10 pts >200d. The randomized phase 2 study is currently enrolling. Clinical trial information: NCT05099666 . [Table: see text]

11503 Background: Collectively, sarcomas have demonstrated less benefit from immunotherapy than many other cancers. Pts with AS have limited options, particularly after taxane chemotherapy. Although AS is a vascular malignancy, anti-VEGF therapies have minimal monotherapy clinical activity. Some cutaneous AS have a high UV damage signature, but other AS often do not. Cabozantinib (C) is a multikinase inhibitor that may alter PD-1 expression in regulatory T cells, promoting an immune permissive environment when combined with nivolumab (N), a fully human anti PD-1 MAB. We hypothesize that the combination of C+N will be an effective therapy in AS, across AS subtypes. Methods: This open-label multi-arm study enrolled pts with locally advanced/metastatic AS. Arm 3, reported here, enrolled pts who had received a taxane for AS (including adjuvant) prior to study enrollment. Pts were not restricted on number of prior lines, but prior anti-VEGF and immunotherapies were not allowed. Eligible pts received C (40 mg po daily) with N (480 mg IV every 4 wks). Treatment was permitted beyond progressive disease (PD) in the 1st 12 wks (4 wk confirmatory scan), but PD response was censored at 12 wks. The Simon 2-stage design (null and alternative overall response rate (ORR) were 10% and 35%, respectively) required ≥1 confirmed response in 9 pts in the 1st stage, and >4 of 18 pts (91.4% power, alpha 0.095) for the primary endpoint. Secondary endpoints were adverse events (AEs), progression free, overall survival (PFS, OS), and pt-reported outcomes (PRO). Results: 21 eligible pts [median age 66 yrs (32-92), 10 female] received ≥1 dose of C+N. Primary disease sites: 12 cutaneous (scalp/face), 1 liver, 2 breast, 6 other. All pts received prior taxanes (11/21 = 52% as adjuvant therapy) and 5/21 (24%) had also received prior anthracycline (all relapsed AS). Primary endpoint: 13 of the first 18 evaluable patients (72%) experienced objective response (OR, 95%CI: 47%-90%). After a median follow-up of 11.2 mo, 13 of 21 pts achieved OR (11 partial response, 2 complete), for ORR 62% (95%CI: 38-82%). Responses were seen in pts with primary cutaneous disease 7/12 (58%) and noncutaneous disease 6/9 (67%). Median PFS was 9.6 mo (5.3-NR), and OS 20.5 mo (14.4-NR). Off treatment reasons include: progressive disease (14), comorbid condition unrelated to AS or study (1); 6 pts remain on study. Grade (G) 3 hypertension was the only possibly treatment related AE (TRAE) occurring in ³10%. No G 4/5 TRAE were reported. Conclusions: C + N demonstrated significant antitumor activity in taxane-pretreated AS and was well tolerated without new safety concerns. Activity of the combination was seen across AS subtypes. PRO and exploratory analyses are ongoing. Support: U10CA180821, U10CA180882, U24 CA196171; U10CA180820; https://acknowledgments.alliancefound.org . U10CA180868; U10CA180888. NCT04339738. Clinical trial information: NCT04339738 .

8013 Background: Ide-cel is an FDA-approved treatment for RRMM patients (pts). However, there is limited data on how BT for disease control during its manufacturing process affects clinical outcomes. Methods: Eleven US academic centers contributed data to this analysis without involvement from the manufacturer. By 5/1/2022, 235 pts had undergone leukapheresis, with 214 infused with a median follow up of 9 months (mos). BT was given between leukapheresis and CAR-T infusion. Results: In this analysis, 79% of pts (n = 170) received BT, which included alkylator-based in 35.5%, steroid and/or IMiD/Ab combos (IMiD combos) in 14%, PI combinations (PI combos) in 12%, and selinexor in 10%. BT recipients had higher ECOG PS 2-4, R-ISS 2-3, ferritin, and CRP before lymphodepleting (LD) chemo, however, no difference among BT subgroups. No difference in prior lines of therapy or penta-refractory between BT and No BT (NBT) groups or BT subgroups. Median cycle of the BT was 1 (1-7), with overall response rate (ORR) of 12%, with no difference among BT subgroups. Incidence and severity of CRS and ICANs were comparable in BT and NBT. However, pts who received BT had a longer median hospital stay compared to NBT, particularly in the alkylator/selinexor subgroups. There were no significant difference in cytopenias at day 90 post CAR-T between the BT and NBT or BT subgroups. For the 73% (n = 157) evaluable for day 90 response, there was no difference in the complete or ORR between the BT and NBT groups (41% vs. 52%; p = .2 and 84% vs. 87.5%, p = .8, respectively). Median PFS was worse at 8.1 mos in BT vs 11.5 mos in NBT (p = .03). Among BT subgroups, PFS was the longest with IMiD combos with median PFS not reached (NR), comparable to NBT, and was significantly longer than all other BT subgroups (p = 0.01). The median OS was 13.8 mos with BT and NR in NBT (p = .002). In BT subgroup analysis, alkylators had a shorter OS, although, this was not significant (p = .06). There was no significant difference in PFS and OS in relationship to response to BT (p = .6 and p = .9, respectively). Conclusions: Pts without BT had longer PFS and OS post ide-cel, likely reflective of less aggressive disease. Those who received BT with steroid/IMiD and Ab combos had similar PFS as NBT. However, BT choice is complicated by disease severity and should be evaluated per patient circumstances. [Table: see text]

e14531 Background: Afami-cel is an autologous, T-cell receptor T-cell therapy engineered to target melanoma-associated antigen A4 (MAGE-A4) in human leukocyte antigen (HLA) A*02–eligible patients (pts) with advanced solid tumors. SPEARHEAD-1 (NCT04044768) is a Phase 2, two cohort, open-label trial to evaluate the efficacy and safety of afami-cel in pretreated pts with advanced/metastatic synovial sarcoma or myxoid/round cell liposarcoma. Here we report data on cytokine release syndrome (CRS) in the pts with advanced synovial sarcoma treated with afami-cel across Cohort 1 and Cohort 2. Methods: Eligible pts had advanced synovial sarcoma and were HLA-A*02 positive with MAGE-A4–positive tumors. Pts received afami-cel after lymphodepleting chemotherapy containing fludarabine and cyclophosphamide. Tocilizumab administration was permitted for Grade 1 CRS if symptoms persisted for ≥ 24 hours or if the pt had co-morbidities, and for Grade ≥2 CRS. Results: As of August 29, 2022, 72 pts with synovial sarcoma received afami-cel (n = 44 Cohort 1; n = 28 Cohort 2). Afami-cel dose range was 1.92–10.00×109 transduced T-cells. The median age was 39.5 years (range: 16–73 years), 47.2% of pts were female, 88.3% of pts were white, and tumor MAGE-A4 expression H-score was 244.5 (range: 66–300). CRS occurred in 72.2% of the pts with synovial sarcoma receiving afami-cel, including Grade 1 in 50% (36/72), Grade 2 in 20.8% (15/72), and Grade 3 in 1.4% (1/72) of pts as per American Society for Transplantation and Cellular Therapy grading. The median time to onset was 2.5 days (range: 1–5 days), and the median time to resolution was 3 days (range: 1 to 14 days). Twenty-seven of 72 (37.5%) pts received at least one dose of tocilizumab. Consistent with expectations, higher serum IL-6 levels were associated with CRS events and the indicated use of tocilizumab for management. RECIST v1.1 responses were observed in pts with and without CRS. Correlation of clinical factors and CRS with response will be presented. Conclusions: CRS was common after afami-cel administration but was mostly low grade. Administration of tocilizumab in SPEARHEAD-1 was effective in the management of CRS. Clinical trial information: NCT04044768 .

We present clinical and imaging predictors of ocular injuries that required medical management versus surgical intervention in cases of orbital fractures. From 2014 to 2020, a retrospective review of patients with orbital fractures who received ophthalmologic consultation and computed scan (CT) analysis at a level I trauma center was performed. Inclusion criteria were patients with confirmed orbital fracture on CT and ophthalmology consultation. Patient demographics, associated injuries, comorbidities, management, and outcomes were collected. Two hundred and one patients and 224 eyes (11.4% bilateral orbital fractures) were included. Overall, 21.9% of orbital fractures presented with a significant concomitant ocular injury. Associated facial fractures were present in 68.8% of eyes. Management included surgical treatment in 33.5% of eyes and ophthalmology-directed medical treatment in 17.4%. On multivariate analysis, clinical predictors of surgical intervention were retinal hemorrhage (OR=4.7 (1.0–21.0), P=0.0437), motor vehicle accident injury (OR=2.7 (1.4–5.1), P=0.0030) and diplopia (OR=2.8 (1.5–5.3), P=0.0011). Imaging predictors of surgical intervention were herniation of orbital contents (OR=2.1 (1.1–4.0), P=0.0281) and multiple wall fractures (OR=1.9 (1.01–3.6), P=0.0450). Predictors of medical management were corneal abrasion (OR=7.7 (1.9–31.4), P=0.0041), periorbital laceration (OR=5.7 (2.1–15.6), P=0.0006), and traumatic iritis (OR=4.7 (1.1–20.3), P=0.0444). We demonstrated a 22% incidence of concomitant ocular trauma in orbital fracture patients at our level I trauma center. Predictors of the surgical intervention included multiple wall fractures, herniation of orbital contents, retinal hemorrhage, diplopia, and motor vehicle accident injury. These findings emphasize the importance of a multidisciplinary team in managing ocular and facial trauma.