He, Aiwu Ruth

4122 Background: BTCs are rare and aggressive malignancies. The first-line standard of care regimen for advanced BTC (aBTC) is gemcitabine (GEM), cisplatin, and an immune checkpoint inhibitor. Although FOLFOX is a preferred second-line treatment, it is limited by neuropathy. Nal-IRI contains IRI free base in liposome nanoparticles, which shelter IRI from conversion to its active metabolite (SN-38) and increase intratumoral SN-38 compared with IRI alone. The NAPOLI-1 trial of FU/LV/nal-IRI vs. FU/LV in second-line advanced pancreatic adenocarcinoma showed an overall survival (OS) benefit. The NIFTY trial (South Korea) demonstrated median OS (mOS) benefit of FU/LV/nal-IRI over FU/LV in a second-line aBTC population (8.6 vs. 5.3 months [mo], HR 0.68, 95% CI 0.48-0.95); however, the NALIRICC trial (Germany) did not (6.9 vs. 8.2 mo, HR 1.08, 95% CI 0.68-1.72). We sought to characterize second-line FU/LV/nal-IRI efficacy in US patients (pts) with second-line aBTC. Methods: This was a single-arm, open-label, multicenter phase II study of pts with aBTC previously treated with GEM/platinum chemotherapy. Pts received nal-IRI 70 mg/m 2 IV over 90 minutes, LV 400 mg/m 2 IV over 30 minutes every 14 days, and FU 2400 mg/m 2 IV over 46 hours every 14 days. The primary objective was to determine progression-free survival rate at 4 mo (PFS 4mo ) using RECIST v. 1.1 criteria. Median PFS reported for pts receiving second-line 5-FU doublet chemotherapy was 3 mo with a PFS of 30%. FU/LV/nal-IRI was of interest if it could increase the PFS 4mo to 50% or higher. Using a one-sided α of 0.05 and 80% power, 17 of 39 evaluable pts had to be progression-free at 4 mo to detect a difference in PFS 4mo between 30% and 50%. Results: Forty-eight pts were enrolled: median age 64.5 years; 69% women; 27% gallbladder primary; 54% intra- and 19% extrahepatic. Ten pts came off study due to toxicity without disease progression before 4 mo on study and were replaced to evaluate the PFS 4mo endpoint. Of 38 evaluable pts, 18 pts (PFS 4mo 47%) were alive and progression-free at 4 mo, meeting the primary endpoint. With a median follow-up of 7.1 mo, median time to disease progression or study discontinuation due to toxicity for all pts was 2.3 mo (95% CI 1.8-4.6, PFS 4mo 38%), and for pts evaluable for the primary endpoint, median PFS was 3.5 mo (95% CI 1.8-5.5). Five pts (10%) had PFS beyond 12 mo. mOS for all pts was 7.9 mo (95% CI 5.7-11.7). Of 41 evaluable pts, the response rate was 2% (1 PR), and the disease control rate was 54%. Adverse events (AEs) were consistent with known toxicities from the FU/LV/nal-IRI regimen. Conclusions: FU/LV/nal-IRI is an effective second-line regimen for aBTC in US pts. There was significant early toxicity as 21% of pts came off study due to AEs before 4 mo. Correlative studies, including longitudinal analyses of circulating tumor DNA using banked blood specimens, are planned (NCT04005339). Clinical trial information: NCT04005339 .

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.

TPS358 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 IMbrave 150 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. 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, and a second tumor biopsy at 4 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. Enrollment began in September 2020. Clinical trial information: NCT04541173.

Abstract Background: Atezolizumab (atezo) and bevacizumab (bev) combination therapy has demonstrated robust clinical activity in patients with unresectable HCC who have not received prior systemic therapy (Lee et al., APPLE 2019; Cheng et al., ESMO Asia 2019). In this exploratory analysis, we aimed to identify tumor-based molecular biomarkers that may be associated with clinical response or resistance to atezo + bev. We also investigated how VEGF blockade with bev could potentiate PD-L1 checkpoint inhibition with atezo in pts with advanced HCC. Methods: Archival tumor tissues or fresh biopsies taken prior to treatment were collected from HCC pts enrolled in the Phase 1b trial GO30140 (NCT02715531). Arm A (n = 104) was a single-arm evaluation of atezo + bev; Arm F (n = 119) was a randomized arm comparing atezo + bev with atezo. Whole-exome sequencing was carried out on these tumor tissues to determine tumor mutation burden (TMB). Gene expression in tumors was profiled by RNAseq analysis. The association between biomarker expression and clinical response (responders [R] vs. non-responders [NR]) or PFS was assessed by t-tests or Cox regression models, respectively. All p-values are descriptive. Results: In Arm A, 90/104 pts were biomarker evaluable. TMB was not associated with response to atezo + bev or PFS. In contrast, analysis of baseline tumor gene expression showed that pre-existing immunity appeared to be associated with clinical response and longer PFS, which included high expression of CD274 (PD-L1) (R vs. NR, p < 2.1 × 10−5; PFS: HR = 0.42 [0.25-0.72]), and T effector signature (GZMB, PRF1, CXCL9) (R vs. NR, p < 0.0004; PFS: HR = 0.46 [0.27-0.78]). Gene expression related to Notch pathway activation (i.e. high expression of HES1) appeared to be associated with lack of response to atezo + bev (p < 0.039) and shorter PFS (HR = 2.1 [1.3-3.6]). In Arm F, 91/119 pts were biomarker evaluable. High expression of VEGF receptor 2 (VEGFR2; HR = 0.36 [0.16-0.81]), Treg (HR = 0.35 [0.15-0.82]), myeloid inflammation (HR = 0.43 [0.19-0.95]), and TREM1/MDSC signatures (HR = 0.43 [0.19-0.94]) was associated with longer PFS in patients treated with atezo + bev than in those treated with atezo alone. Analysis of 12 serial biopsy pairs confirmed reduced levels of VEGFR2 and Treg signatures after atezo + bev treatment. Conclusion: We identified candidate biomarkers for predicting response to atezo + bev in HCC. Furthermore, the findings in Arm F are consistent with previous preclinical studies supporting a multi-faceted role of VEGF/VEGFR signaling in promoting immune suppression in addition to angiogenesis. Overall, the data presented here further support the mechanistic hypotheses on how anti-VEGF may combine with immune checkpoint blockade to increase its clinical benefit. As these results are exploratory, future study is needed to confirm these findings in a larger population. Citation Format: Andrew X. Zhu, Yinghui Guan, Alexander R. Abbas, Hartmut Koeppen, Shan Lu, Chih-Hung Hsu, Kyung-Hun Lee, Michael S. Lee, Aiwu Ruth He, Amit Mahipal, Beiying Ding, Jessica Spahn, Wendy Verret, Baek-Yeol Ryoo, Yulei Wang. Genomic correlates of clinical benefits from atezolizumab combined with bevacizumab vs. atezolizumab alone in patients with advanced hepatocellular carcinoma (HCC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT044.

3531 Background: ctDNA has emerged as a promising biomarker for noninvasive monitoring of treatment response and disease progression in many tumor types. However, the clinical use of ctDNA in patients with HCC has not been established. Here, we evaluated longitudinal and personalized detection of ctDNA for monitoring the treatment response to atezolizumab (atezo) + bevacizumab (bev) in patients with unresectable HCC not previously treated with systemic therapy. Methods: A subset (n = 48) of 104 patients with HCC who enrolled in Arm A of GO30140 (NCT02715531; Phase 1b) and received atezo + bev treatment were included in this study. These patients had 10 CR, 11 PR, 12 SD and 15 PD per IRF-assessed RECIST 1.1. Serial plasma samples were collected at baseline (Cycle [C]1 Day [D]1), during treatment (C2D1, C4D1) and at disease progression. Somatic mutations in individual tumors were identified via whole exome sequencing of archival tumor tissues or fresh biopsies collected before treatment. Personalized ctDNA assays (Signatera 16-plex multiplex PCR next-generation sequencing assay) specific to each patient’s tumor mutational signatures were successfully designed for 47 of 48 patients. Results: At C1D1, a median of 25.7 ng of cell-free DNA was extracted from 2-mL plasma samples. ctDNA was detected in 45 of 47 patients (96%), with a median of 70.6 mean tumor molecules/mL of plasma (MTM/mL) and a median of 1.8% mean variant allele frequency (mean VAF) in plasma. Higher ctDNA levels detected at C1D1 appeared to be associated with increased tumor burden ( P < 0.03). Dynamic changes in ctDNA levels post-treatment were associated with response at C4D1. ctDNA status changed from positive at baseline to negative in 7 of 10 CR (70%), 3 of 11 PR (27%), 1 of 11 SD (9%) and 0 of 11 PD (0%) patients. Longer PFS was observed in patients whose ctDNA became undetectable post-treatment. The median PFS in patients with ctDNA present vs cleared at C4D1 was 6.5 months and not reached, respectively (HR, 12 [1.7-93], log-rank P < 0.00029). Conclusions: Our study showed that Signatera, a personalized and tumor-informed ctDNA assay, could be used as a sensitive method for detecting ctDNA in patients with unresectable HCC. More importantly, our results illustrate the promise of ctDNA as an emerging biomarker that may potentially help to monitor treatment responses and disease progression in patients with HCC.

TPS3161 Background: VV1 is an oncolytic vesicular stomatitis virus engineered to express human IFNβ to enhance cellular anti-tumor immune responses and tumor selectivity, and the human sodium iodide symporter (NIS) for virus tracking by SPECT imaging. Cancer cells are often hyporesponsive to IFNβ, enabling the efficient spread of VV1 and resulting in increased oncolysis. Differently from other oncolytic viruses, VV1 is suitable for both intra-tumoral (IT) and/or intra-venous (IV) administration. Despite considerable anti-tumor activity with checkpoint inhibitors (CPI) among some malignancies, long term survival and overall cures remain elusive. Prior Ph 1 studies have shown significant anti-tumor activity among several malignancies when VV1 was administered either as monotherapy or in combination with a CPI, despite progression on prior CPI monotherapy. Furthermore, pre- and post-treatment biopsy evaluations after VV1 treatment have demonstrated T cell infiltration and inflammation in both IT injected and non-injected lesions. Among IV treated patients (pts), IFNβ was detectable in the serum correlating with viral replication, making it an effective biomarker. C is a high-affinity potent human IgG4 anti-PD-1 monoclonal antibody. Though approved for use in cutaneous squamous cell carcinoma, C has shown anti-tumor activity, similar to other CPI, in several other indications. Therefore, VV1 and C could be an attractive combination for the immunotherapy for several solid tumors. This study represents the first clinical evaluation of VV1 in combination with C in pts with advanced solid tumors. Methods: The Ph 2 Simon 2 stage five-arm study of IV administration VV1 in combination with IV C will enroll pts with advanced NSCLC, HCC, melanoma & endometrial cancer. Enrolled pts with NSCLC & melanoma will be recent CPI-progressors, whereas enrolled HCC & endometrial cancer will be CPI-naïve. The study’s objectives include assessment of preliminary anti-tumor activity, safety, & immuno-regulatory activity of the combination. Pts will receive IV VV1 once on D1 and IV C once every 3 weeks until confirmed disease progression or intolerable toxicity. Pts enrolled in one melanoma cohort will also receive IT VV1 administered to palpable lesions. Response will be assessed every 9 weeks per RECIST v1.1. The null hypothesis of each cohort’s ORR will be tested versus a one-sided alternative yielding a Type I error rate of 5% and power of 80%. Cohorts will be expanded based on signal of activity. Clinical trial information: NCT .

Abstract Hepatocellular carcinoma (HCC) has emerged as a major cause of cancer deaths globally. The landscape of systemic therapy has recently changed, with six additional systemic agents either approved or awaiting approval for advanced stage HCC. While these agents have the potential to improve outcomes, a survival increase of 2–5 months remains poor and falls short of what has been achieved in many other solid tumor types. The roles of genomics, underlying cirrhosis, and optimal use of treatment strategies that include radiation, liver transplantation, and surgery remain unanswered. Here, we discuss new treatment opportunities, controversies, and future directions in managing HCC.