Toskich, Beau

TPS622 Background: In patients with early and intermediate hepatocellular carcinoma (HCC) who are ineligible for resection, thermal ablation, or liver transplant, transarterial radioembolization (TARE) with yttrium-90 glass microspheres has shown superior efficacy compared to transarterial chemoembolization; a subset of patients progress despite effective local therapy. Immunotherapy using the single tremelimumab regular interval durvalumab (STRIDE) regimen has demonstrated superior overall survival to sorafenib in advanced HCC. Recent work showed that TARE upregulates both the innate and adaptive immune systems. The possibility for TARE and STRIDE to have additive or synergistic effects when combined is of current scientific and clinical interest. The primary objective of the Phase II ROWAN Study is to assess the objective response rate and durability of local tumor control with TARE followed by STRIDE vs. TARE alone. Methods: ROWAN is a global, open-label, prospective, multicenter randomized controlled trial comparing treatment with TARE using glass microspheres followed by the STRIDE regimen (a single dose of 300 mg tremelimumab combined with 1500 mg monthly dose of durvalumab for 18 months) to TARE alone in HCC. ROWAN will include 150 patients across approximately 20 study sites in North America and Europe. Key inclusion criteria: HCC, diagnosed by radiographic imaging or histology; ineligible for or declined liver resection, thermal ablation, or transplantation; Child-Pugh A; ECOG 0; life expectancy ≥6 months; treatment naïve; unilobar tumor; measurable by mRECIST; tumor volume ≤25% of whole liver volume; and untreated future liver remnant volume ≥30% of whole liver volume. Key exclusion criteria: extrahepatic metastases; shunt fraction with a lung dose of >30 Gy; macrovascular invasion; infiltrative disease not evaluable by mRECIST; history of any organ allograph; autoimmune or inflammatory disorder; current use of immunosuppressive medication; history of malignancy other than HCC within past 3 years; and active infection. Patients will be randomized in a 1:1 ratio to two study arms (TARE followed by STRIDE or TARE alone) using two stratification factors (TARE treatment goal [ablative vs. non-ablative] and alpha fetoprotein level [>400 vs. ≤400 ng/mL]). Tumor and blood samples will be collected for correlative studies. Co-primary efficacy endpoints are objective response rate and duration of response (localized mRECIST). The primary safety endpoint is the number of adverse events (AEs) and serious AEs. Interim statistical analyses will be conducted after 25 patients have been randomized to each arm and completed the second imaging assessment 6 months post-randomization; final analysis will be after the last evaluable patient has completed the 18 months follow-up visit post-randomization or discontinued treatment. Clinical trial information: 05063565 .

TPS629 Background: The anti–PD-L1 antibody ATEZO prevents PD-L1 from interacting with PD-1 and B7.1, thus reinvigorating antitumor T cell activity. Anti-VEGF BEV can increase dendritic cell maturation, enhance T cell infiltration, and reduce myeloid-derived suppressor cells and regulatory T-cells in tumors. This combination has been FDA approved for first-line treatment of advanced HCC based on the IMbrave150 study. On the other hand, locoregional radiotherapy (e.g., Y90 TARE) enhances the diversity of the intratumoral T cell receptor repertoire. It is the standard of care for pts with intermediate-stage HCC (iHCC). Based on preclinical and clinical data, we hypothesize that the combination of Y90 TARE, BEV, and ATEZO induces synergistic tumor-killing. Methods: This is an open-label, multicenter, randomized phase II study of Y90 TARE and BEV plus ATEZO compared with Y90 TARE alone in pts with unresectable IHCC (NCT04541173). The primary study objective is to assess and compare the progression-free survival (PFS) (per mRECIST 1.1) of pts in each arm. The main secondary objective is to determine the safety and tolerability (CTCAE v5) of TARE combined with ATEZO and BEV in pts with HCC. Exploratory objectives are to assess the role of the immunoscore and PD-L1 expression levels in the prediction of improved clinical outcome in pts receiving Y-90 TARE and BEV plus ATEZO; the composition of tumor-infiltrating immune cell subtypes in predicting response to a chosen therapy; how Y90 therapy affects the proportion of antigen-presenting cells in the tumor; and symptoms experienced by pts receiving TARE and BEV plus ATEZO treatment, using patient-reported outcomes. Eligible pts have either HCC that is not amenable to surgical resection, confirmed by pathology review, or at least BCLC stage B HCC outside of downstaging criteria. Other standard eligibility criteria apply. Pts must have a pretreatment liver biopsy taken and then be randomized 1:1 to TARE (Arm A) or TARE followed by ATEZO and BEV (Arm B). Pts will have TARE mapping during week (wk) 1 and TARE treatment during wk 2. In Arm B, pts will start BEV plus ATEZO 4 wks (±1 wk) after TARE treatment. Pts will have abdominal MRI or CT scans every 12 weeks, CT scans of the chest every 24 wks. Disease progression will be captured by both RECIST 1.1 and mRECIST. We plan to assess the safety of TARE with BEV and ATEZO in the first 10 pts randomized to Arm B for two cycles. If there are no Grade ≥ 3 unexpected toxicities possibly, probably or definitely related to combined TARE plus BEV plus ATEZO, the study will continue to accrue 128 pts in total. Pts will continue study treatment (Arm B) for a total of 24 months from initiation of TARE or until intolerable toxicity or disease progression occur, whichever is earlier. Clinical trial information: NCT04541173 .

TPS4177 Background: The anti–PD-L1 antibody atezolizumab (ATEZO) prevents PD-L1 from interacting with PD-1 and B7.1, thus reinvigorating antitumor T cell activity. Anti-VEGF bevacizumab (BEV) increases dendritic cell maturation, enhances T cell infiltration, and reduces myeloid-derived suppressor cells and regulatory T cells in tumors. ATEZO + BEV is FDA approved for first-line treatment of advanced HCC based on the IMbrave 150 study. Locoregional radiotherapy (e.g., Y90 TARE) enhances the diversity of the intratumoral T cell receptor repertoire and increases tumor antigen release. We hypothesize that the Y90 TARE + BEV + ATEZO combination induces synergistic tumor killing and prolongs progression-free survival in patients (pts) receiving Y90 TARE (HR = 0.6 when compared to Y-90 TARE alone). Methods: Eligible pts have HCC that cannot be surgically resected (confirmed by pathology review), is at least BCLC stage B, and is outside Milan criteria. Other requirements include ECOG PS of 0-1 at screening, measurable disease by RECIST 1.1, no prior systemic therapy, and FLR estimated at ≥ 40% post local therapy. Pts must have a pretreatment liver biopsy taken and then be randomized 1:1 to TARE (Arm A) or TARE + ATEZO + BEV (Arm B). Pts will have TARE mapping followed by TARE treatment. In Arm B, pts will begin TARE treatment followed by BEV + ATEZO (4 wks [± 1 wk] later). Pts will have abdominal MRI or CT scans every 12 weeks and CT scans of the chest every 24 wks. The primary study objective is to assess and compare pts' progression-free survival (per mRECIST 1.1) in each study arm. The main secondary objective is to determine the safety and tolerability (CTCAE v5) of pts in Arm B. Exploratory objectives are to define the use of cellular and circulating biomarkers in the prediction of improved clinical outcomes of pts in Arm B. Symptoms experienced by pts in both arms using patient-reported outcomes will be assessed. Disease progression will be captured by both RECIST 1.1 and mRECIST. We plan to assess the safety of Y90 TARE + BEV + ATEZO in the first 10 pts randomized to Arm B for two cycles, and if there are no grade ≥ 3 unexpected toxicities possibly, probably, or definitely related to combined TARE + BEV + ATEZO, continue to accrue 128 pts in total (current enrollment n- = 5). Pts will continue study treatment (Arm B) for a total of 24 months from initiation of TARE or until intolerable toxicity or disease progression occur, whichever is earlier. Enrollment began in September 2020. Clinical trial information: NCT04541173.

e16124 Background: Immune checkpoint inhibitors (ICI) have emerged as a standard treatment option for advanced hepatocellular carcinoma (HCC). Unfortunately, many patients with advanced HCC develop progressive disease on ICI therapy. Furthermore, clinical predictors of response to ICI therapy in HCC are poorly understood. B-catenin mutations are among the most frequent genetic abnormalities in HCC and may provide a mechanism for immune evasion and poor response to ICI (Ruiz de Galarreta, Marina et al. “β-Catenin Activation Promotes Immune Escape and Resistance to Anti-PD-1 Therapy in Hepatocellular Carcinoma.” Cancer discovery 9,8 (2019): 1124-1141. doi:10.1158/2159-8290.CD-19-0074). Methods: We conducted a retrospective cohort study of patients with advanced HCC who were treated with ICI therapy. All patients had ctDNA tumor profiling and were assessed for B-catenin mutation status. Disease status was determined by RECISTv1.1. Median progression-free survival (PFS), 3-month PFS, 6-month PFS, and the disease control rate (DCR) on ICI therapy were compared between B-catenin mutation (BCM) and B-catenin wild-type (BCWT) groups. Results: 15 stage III/IV HCC patients were included in the study. 9 patients harbored BCMs and 6 patients were BCWT. The median PFS in patients with BCM HCC was 4.0 months versus 4.9 months in patients with BCWT HCC. At 3 months, PFS was 56% for BCM HCC compared to 67% for BCWT HCC. Furthermore, the 6-month PFS was 11% for BCM HCC and 50% for BCWT HCC. For best response, 33% of patients with BCM HCC achieved stable disease compared to 67% of patients with BCWT HCC. No patients in our cohort achieved partial or complete response. The DCR for BCM HCC was 33% and the DCR for BCWT HCC was 67%. Conclusions: In patients with advanced HCC, B-catenin mutation status may serve as a potential biomarker of response to ICI therapy. Our data suggests that patients who do not harbor these mutations, have a more durable response to ICI therapy. Further studies are needed to validate these findings.

Background To review long-term outcomes and saphenous vein (SV) occlusion rate after endovenous ablation (EVA) for symptomatic varicose veins. Methods A review of our EVA database (1998–2018) with at least 3-years of clinical and sonographic follow-up. The primary end point was SV closure rate. Results 542 limbs were evaluated. 358 limbs had radiofrequency and 323 limbs had laser ablations; 542 great saphenous veins (GSV), 106 small saphenous veins (SSV) and 33 anterior accessory saphenous veins (AASV) were treated. Follow-up was 5.6 ± 2.3 years; 508 (74.6%) veins were occluded, 53 (7.8%) partially occluded and 120 (17.6%) were patent. On multivariable Cox regression analysis, male sex (HR 1.6, 95% CI [0.46–018], p = 0.012) and use anticoagulation (HR 2.0, 95% CI [0.69–0.34], p = 0.044) were predictors of long-term failure. On Kaplan-Meier curve, we had an 86.3% occlusion rate. Conclusion Our experience revealed a 5-year closure rate of 86.3%. Ablations have satisfactory occlusion rate.