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Purpose: To assess the safety and efficacy of local ablation plus PD-1 inhibitor toripalimab in previously treated unresectable hepatocellular carcinoma (HCC). Patients and Methods: In the multicenter, two-stage, and randomized phase 1/2 trial, patients were randomly assigned to receive toripalimab alone (240mg, every 3 weeks), subtotal local ablation followed by toripalimab starting on post-ablation day 3 (Schedule D3) or on post-ablation day 14 (Schedule D14). The first endpoint of stage 1 was to determine which combination schedule could continue and progression-free survival (PFS) as the primary endpoint for stage 1/2. Results: A total of 146 patients were recruited. During stage 1, Schedule D3 achieved numerically higher objective response rate than Schedule D14 for non-ablation lesions (37.5% versus 31.3%), and was chosen for stage 2 evaluation. For the entire cohort of both stages, patients with Schedule D3 had a significantly higher objective response rate than with toripalimab alone (33.8% versus 16.9%, P = 0.027). Moreover, patients with Schedule D3 had improved median PFS (7.1 months versus 3.8 months, P ﹤0.001) and median overall survival (18.4 months versus 13.2 months, P = 0.005), as compared with toripalimab alone. In addition, six (9%) patients with toripalimab, 8 (12%) with Schedule D3, and 4 (25%) with Schedule D14 developed grade 3 or 4 adverse events, and one patient (2%) with Schedule D3 manifested grade 5 treatment-related pneumonitis. Conclusions: In patients with previously treated unresectable HCC, subtotal ablation plus toripalimab improved the clinical efficacy as compared with toripalimab alone with an acceptable safety profile.

Background: Biliary tract cancers, which arise from the intrahepatic or extrahepatic bile ducts and the gallbladder, generally have a poor prognosis and are rising in incidence worldwide. The standard-of-care treatment for advanced biliary tract cancer is chemotherapy with gemcitabine and cisplatin. Because most biliary tract cancers have an immune-suppressed microenvironment, immune checkpoint inhibitor monotherapy is associated with a low objective response rate. We aimed to assess whether adding the immune checkpoint inhibitor pembrolizumab to gemcitabine and cisplatin would improve outcomes compared with gemcitabine and cisplatin alone in patients with advanced biliary tract cancer. Methods: KEYNOTE-966 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 175 medical centres globally. Eligible participants were aged 18 years or older; had previously untreated, unresectable, locally advanced or metastatic biliary tract cancer; had disease measurable per Response Evaluation Criteria in Solid Tumours version 1.1; and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks (maximum 35 cycles), in combination with gemcitabine (1000 mg/m2 intravenously on days 1 and 8 every 3 weeks; no maximum duration) and cisplatin (25 mg/m2 intravenously on days 1 and 8 every 3 weeks; maximum 8 cycles). Randomisation was done using a central interactive voice-response system and stratified by geographical region, disease stage, and site of origin in block sizes of four. The primary endpoint of overall survival was evaluated in the intention-to-treat population. The secondary endpoint of safety was evaluated in the as-treated population. This study is registered at ClinicalTrials.gov, NCT04003636. Findings: Between Oct 4, 2019, and June 8, 2021, 1564 patients were screened for eligibility, 1069 of whom were randomly assigned to pembrolizumab plus gemcitabine and cisplatin (pembrolizumab group; n=533) or placebo plus gemcitabine and cisplatin (placebo group; n=536). Median study follow-up at final analysis was 25·6 months (IQR 21·7–30·4). Median overall survival was 12·7 months (95% CI 11·5–13·6) in the pembrolizumab group versus 10·9 months (9·9–11·6) in the placebo group (hazard ratio 0·83 [95% CI 0·72–0·95]; one-sided p=0·0034 [significance threshold, p=0·0200]). In the as-treated population, the maximum adverse event grade was 3 to 4 in 420 (79%) of 529 participants in the pembrolizumab group and 400 (75%) of 534 in the placebo group; 369 (70%) participants in the pembrolizumab group and 367 (69%) in the placebo group had treatment-related adverse events with a maximum grade of 3 to 4. 31 (6%) participants in the pembrolizumab group and 49 (9%) in the placebo group died due to adverse events, including eight (2%) in the pembrolizumab group and three (1%) in the placebo group who died due to treatment-related adverse events. Interpretation: Based on a statistically significant, clinically meaningful improvement in overall survival compared with gemcitabine and cisplatin without any new safety signals, pembrolizumab plus gemcitabine and cisplatin could be a new treatment option for patients with previously untreated metastatic or unresectable biliary tract cancer. Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

Purpose:We assessed the efficacy and safety of camrelizumab [an anti-programmed death (PD-1) mAb] plus apatinib (a VEGFR-2 tyrosine kinase inhibitor) in patients with advanced hepatocellular carcinoma (HCC).Patients and Methods:This nonrandomized, open-label, multicenter, phase II study enrolled patients with advanced HCC who were treatment-naïve or refractory/intolerant to first-line targeted therapy. Patients received intravenous camrelizumab 200 mg (for bodyweight ≥50 kg) or 3 mg/kg (for bodyweight Results:Seventy patients in the first-line setting and 120 patients in the second-line setting were enrolled. As of January 10, 2020, the ORR was 34.3% [24/70; 95% confidence interval (CI), 23.3–46.6] in the first-line and 22.5% (27/120; 95% CI, 15.4–31.0) in the second-line cohort per IRC. Median progression-free survival in both cohorts was 5.7 months (95% CI, 5.4–7.4) and 5.5 months (95% CI, 3.7–5.6), respectively. The 12-month survival rate was 74.7% (95% CI, 62.5–83.5) and 68.2% (95% CI, 59.0–75.7), respectively. Grade ≥3 treatment-related adverse events (TRAE) were reported in 147 (77.4%) of 190 patients, with the most common being hypertension (34.2%). Serious TRAEs occurred in 55 (28.9%) patients. Two (1.1%) treatment-related deaths occurred.Conclusions:Camrelizumab combined with apatinib showed promising efficacy and manageable safety in patients with advanced HCC in both the first-line and second-line setting. It might represent a novel treatment option for these patients.See related commentary by Pinato et al., p. 908

Supplementary Methods, Supplementary Figure S1-4, Supplementary Table S1-8

Biliary tract cancer (BTC) is a highly malignant tumor with limited treatment options and poor prognosis. Our study aimed to evaluate camrelizumab plus oxaliplatin-based chemotherapy as first-line therapy for advanced BTC. In this multicenter, open-label, phase 2 trial conducted in China (ClinicalTrials.gov, NCT03092895), untreated patients with advanced BTC were given camrelizumab (3 mg/kg iv drip injection, every 2 weeks) plus typical FOLFOX4 (Cam-FOLFOX4 group; infusional 5-fluorouracil, leucovorin and oxaliplatin) or GEMOX (Cam-GEMOX group; infusional gemcitabine and oxaliplatin). The primary endpoint was objective response rate (ORR). Ninety-two patients were enrolled: 29 received Cam-FOLFOX4 and 63 received Cam-GEMOX. The confirmed ORR and disease control rate were 16.3% (95% confidence interval [CI] = 9.4-25.5) and 75.0% (95% CI = 64.9-83.4), respectively. Median duration of response was 8.7 months (95% CI = 5.1-not reached). Median progression-free survival and overall survival were 5.3 months (95% CI = 3.7-5.7) and 12.4 months (95% CI = 8.9-16.1), respectively. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 82.8% of patients receiving Cam-FOLFOX4 and in 68.3% receiving Cam-GEMOX, with no unexpected effects observed. Six (6.5%) patients discontinued treatment due to TRAE. Camrelizumab plus FOLFOX4 or GEMOX as first-line treatment was effective and tolerable for Chinese patients with advanced BTC, warranting phase 3 trials.

The main contents of the Clinical Practice Guidelines on Image-Guided Thermal Ablation (IGTA) of Primary and Metastatic Lung Tumors (2022 Edition) include the following: epidemiology of primary and metastatic lung tumors; the concepts of the IGTA and common technical features; procedures, indications, contraindications, outcomes evaluation, and related complications of IGTA on primary and metastatic lung tumors; and limitations and future development.

Summary Background China has a high burden of hepatocellular carcinoma, and hepatitis B virus (HBV) infection is the main causative factor. Patients with hepatocellular carcinoma have a poor prognosis and a substantial unmet clinical need. The phase 2–3 ORIENT-32 study aimed to assess sintilimab (a PD-1 inhibitor) plus IBI305, a bevacizumab biosimilar, versus sorafenib as a first-line treatment for unresectable HBV-associated hepatocellular carcinoma. Methods This randomised, open-label, phase 2–3 study was done at 50 clinical sites in China. Patients aged 18 years or older with histologically or cytologically diagnosed or clinically confirmed unresectable or metastatic hepatocellular carcinoma, no previous systemic treatment, and a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were eligible for inclusion. In the phase 2 part of the study, patients received intravenous sintilimab (200 mg every 3 weeks) plus intravenous IBI305 (15 mg/kg every 3 weeks). In the phase 3 part, patients were randomly assigned (2:1) to receive either sintilimab plus IBI305 (sintilimab–bevacizumab biosimilar group) or sorafenib (400 mg orally twice daily; sorafenib group), until disease progression or unacceptable toxicity. Randomisation was done using permuted block randomisation, with a block size of six, via an interactive web response system, and stratified by macrovascular invasion or extrahepatic metastasis, baseline α-fetoprotein, and ECOG performance status. The primary endpoint of the phase 2 part of the study was safety, assessed in all patients who received at least one dose of study drug. The co-primary endpoints of the phase 3 part of the study were overall survival and independent radiological review committee (IRRC)-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in the intention-to-treat population. The study is registered with ClinicalTrials.gov , NCT03794440 . The study is closed to new participants and follow-up is ongoing for long-term outcomes. Findings Between Feb 11, 2019 and Jan 15, 2020, we enrolled 595 patients: 24 were enrolled directly into the phase 2 safety run-in and 571 were randomly assigned to sintilimab–bevacizumab biosimilar (n=380) or sorafenib (n=191). In the phase 2 part of the trial, 24 patients received at least one dose of the study drug, with an objective response rate of 25·0% (95% CI 9·8–46·7). Based on the preliminary safety and activity data of the phase 2 part, in which grade 3 or worse treatment-related adverse events occurred in seven (29%) of 24 patients, the randomised phase 3 part was started. At data cutoff (Aug 15, 2020), the median follow-up was 10·0 months (IQR 8·5–11·7) in the sintilimab–bevacizumab biosimilar group and 10·0 months (8·4–11·7) in the sorafenib group. Patients in the sintilimab–bevacizumab biosimilar group had a significantly longer IRRC-assessed median progression-free survival (4·6 months [95% CI 4·1–5·7]) than did patients in the sorafenib group (2·8 months [2·7–3·2]; stratified hazard ratio [HR] 0·56, 95% CI 0·46–0·70; p Interpretation Sintilimab plus IBI305 showed a significant overall survival and progression-free survival benefit versus sorafenib in the first-line setting for Chinese patients with unresectable, HBV-associated hepatocellular carcinoma, with an acceptable safety profile. This combination regimen could provide a novel treatment option for such patients. Funding Innovent Biologics. Translation For the Chinese translation of the abstract see Supplementary Materials section.

Summary Background Inhibition of vascular endothelial growth factor receptor (VEGFR) has shown antitumour activity in advanced hepatocellular carcinoma, but few studies of VEGFR inhibitors have been done in populations with a high prevalence of hepatitis B virus infection. The aim of this study was to evaluate the efficacy and safety of apatinib in patients with pretreated advanced hepatocellular carcinoma. Methods AHELP was a randomised, double-blind, placebo-controlled, phase 3 trial done at 31 hospitals in China, in patients (aged ≥18 years) with advanced hepatocellular carcinoma who had previously been refractory or intolerant to at least one line of systemic chemotherapy or targeted therapy. Patients were randomly assigned (2:1) to receive apatinib 750 mg or placebo orally once daily in 28-day treatment cycles. Group allocation was done with a central randomisation system, with a block size of six, and was stratified by Eastern Cooperative Oncology Group performance status, previous sorafenib treatment, and presence of vascular invasion or extrahepatic metastasis. The primary endpoint was overall survival, which was defined as time from randomisation to death from any cause, and was analysed in patients who were randomly assigned and received at least one dose of the study drug. Safety analyses were done in patients who received at least one dose of the study treatment and had post-dose safety assessments. This trial is registered with ClinicalTrials.gov , NCT02329860 . Findings Between April 1, 2014, and May 3, 2017, 400 eligible patients were randomly assigned to receive apatinib (n=267) or placebo (n=133). Seven patients (six in the apatinib group and one in the placebo group) did not receive study treatment and were excluded from efficacy analyses. Overall survival was significantly improved in the apatinib group compared with the placebo group (median 8·7 months [95% CI 7·5‒9·8] vs 6·8 months [5·7‒9·1]; hazard ratio 0·785 [95% CI 0·617‒0·998], p=0·048). 387 patients (257 in the apatinib group and 130 in the placebo group) had a safety assessment after study treatment and were included in safety analyses. The most common treatment-related adverse events of grade 3 or 4 were hypertension (71 [28%] patients in the apatinib group vs three [2%] in the placebo group), hand–foot syndrome (46 [18%] vs none), and decreased platelet count (34 [13%] vs one [1%]). 24 (9%) patients in the apatinib group and 13 (10%) in the placebo group died due to adverse events, but none of these deaths were deemed to be related to treatment by investigators. Interpretation Apatinib significantly improved overall survival in patients with pretreated advanced hepatocellular carcinoma compared with placebo, with a manageable safety profile. Funding Jiangsu Hengrui Medicine.

Cannabis is one of the most commonly used psychoactive substances, which could induce moderate-severe cannabis use disorders (CUD). Here, a tissue-specific transcriptome-wide association study (TWAS) of CUD was performed by FUSION and S-PrediXcan, utilizing a genome-wide association study (GWAS) dataset of CUD (including 43,380 cases and 141,385 controls of European ancestry) and gene expression reference data from 17 different brain-related and non-brain related tissues, with totally 26 TWAS-associated genes were identified, including CADM2 (P = 2.13 × 10

Macrophages, which are highly plastic, can be polarized to M1 or M2 subtypes according to the diverse signals in complex microenvironment. Studies have shown the activation of YAP, an oncogenic transcriptional co-activator, increased macrophage recruitment. However, its role in macrophage polarization remains to be elucidated, especially in triple-negative breast cancer (TNBC) progression. Here we found TNBC cells increased YAP expression in macrophages, which depended on OTUD5-mediated deubiquitination and stabilization of YAP, then the high expression of YAP polarized macrophage to the M2-like phenotype. Moreover, the elevation of YAP in M2-like macrophage promotes the pro-metastatic potential of TNBC cells via MCP-1/CCR2 pathway. We also observed high expression of YAP in M2 macrophage was negatively related to survival. Collectively, our finding suggested the therapeutic strategy that targets YAP+ M2 macrophage could be a novel option for TNBC treatment.

Purpose: We assessed the efficacy and safety of camrelizumab [an anti-programmed death (PD-1) mAb] plus apatinib (a VEGFR-2 tyrosine kinase inhibitor) in patients with advanced hepatocellular carcinoma (HCC). Patients and Methods: This nonrandomized, open-label, multicenter, phase II study enrolled patients with advanced HCC who were treatment-naïve or refractory/intolerant to first-line targeted therapy. Patients received intravenous camrelizumab 200 mg (for bodyweight ≥50 kg) or 3 mg/kg (for bodyweight Results: Seventy patients in the first-line setting and 120 patients in the second-line setting were enrolled. As of January 10, 2020, the ORR was 34.3% [24/70; 95% confidence interval (CI), 23.3–46.6] in the first-line and 22.5% (27/120; 95% CI, 15.4–31.0) in the second-line cohort per IRC. Median progression-free survival in both cohorts was 5.7 months (95% CI, 5.4–7.4) and 5.5 months (95% CI, 3.7–5.6), respectively. The 12-month survival rate was 74.7% (95% CI, 62.5–83.5) and 68.2% (95% CI, 59.0–75.7), respectively. Grade ≥3 treatment-related adverse events (TRAE) were reported in 147 (77.4%) of 190 patients, with the most common being hypertension (34.2%). Serious TRAEs occurred in 55 (28.9%) patients. Two (1.1%) treatment-related deaths occurred. Conclusions: Camrelizumab combined with apatinib showed promising efficacy and manageable safety in patients with advanced HCC in both the first-line and second-line setting. It might represent a novel treatment option for these patients. See related commentary by Pinato et al., p. 908

Background: The mammalian target of rapamycin (mTOR) is a serine/threonine kinase related to the lipid kinases of the phosphoinositide 3-kinase (PI3K) family, which has been confirmed to be closely related to the development of a variety of human cancers. Onatasertib (ATG-008) is a 2nd generation mTOR inhibitor which inactivates both mTORC1 and mTORC2. Our previous clinical investigation (NCT01177397) has demonstrated preliminary evidence of antitumor activity of onatasertib across multiple solid and hematologic malignancies, with encouraging signals of activity in subjects with hepatitis B virus (HBV)+ unresectable, refractory HCC. Methods: Asian patients with advanced HBV+ HCC who had experienced progressive disease after at least 1 line of systemic therapy were enrolled in this study. Onatasertib was administered orally once a day (QD) at 3 dose levels (15 mg, 30 mg and 45 mg) or 20 mg twice daily (BID). The primary endpoints were pharmacokinetics (PK), safety and efficacy (NCT03591965). Results: As of July 11, 2022, 73 patients were enrolled and evaluated. The median age was 52.0 years and the median follow up duration was 26.5 months. The mean number of prior lines was 1.8. 63 patients (86.3%) had at least one Grade 3-4 treatment emergent adverse event (TEAE), and 25 (34.2%) had at least one serious adverse event (SAE). Among the 73 subjects, 3 achieved confirmed partial response (PR), all in the 45 mg QD cohort. 18 pts were enrolled in the 45 mg QD cohort, in which 11 (61.1%) pts had received at least 2 prior lines of systemic therapy and 15 (83.3%) pts had been exposed to an anti-PD-1/PD-L1 antibody. The overall response rate (ORR) in the 45 mg QD cohort was 16.7%. The median progression-free survival (mPFS) was 3.0 months (95% CI 1.9, 4.6) in the intention to treat (ITT) population and was 5.3 months (95% CI 1.9, 7.6) in the 45mg QD cohort. Median overall survival time (mOS) was not evaluable in the 45 mg QD cohort and the mOS was 13.4 months (95% CI 7.4, 19.8) in the ITT population. Onatasertib demonstrated linear pharmacokinetics between 15 mg QD and 45 mg QD in this Asian population and there was no significant exposure accumulation after multiple dosing, as previously seen in the US population. Conclusion: Onatasertib (ATG-008) showed encouraging single agent antitumor activity in patients with HBV+ advanced HCC after at least 1 prior systemic therapy, notably in the 45 mg QD dose level, in which most patients had been previously exposed to anti-PD-L1/PD-1 therapy. The results indicates that onatasertib has potential efficacy in HBV+ HCC patients who failed prior CPI treatment. Further study may be warranted, particularly in HBV+ HCC patients who have failed prior anti-VEGFR and anti-PDL1/PD-1 therapy. Citation Format: Shukui Qin, Xiaoyan Lin, Zhiqaing Meng, Zhenggang Ren, Yuxian Bai, Shanzhi Gu, Li Zheng, Qiu Li, Sun-Yong Oh, Yabing Guo, Yoong-Koo Kang, Wei-Yu Kao, Wei Li, Jung-Hwan Yoon, Helong Zhang, Pei-Jer Chen, Tsai-Sheng Yang, Jeong Heo, Zhendong Zheng, Hui Xie, Zhinuan Yu. Result of an open-label phase 2 trial of dual TORC1/TORC2 inhibitor onatasertib (ATG-008) in HBV+ advanced hepatocellular carcinoma (HCC) subjects who have received at least one prior line of systemic therapy (TORCH) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT150.

Background: SHR-A1811 is an ADC comprised of a humanized anti-HER2 monoclonal antibody (trastuzumab), a cleavable linker, and a DNA topoisomerase I inhibitor payload. Here we assessed SHR-A1811 in HER2-expressing/mutated unresectable, advanced, or metastatic solid tumors. Methods: Pts were eligible if they had HER2 positive breast cancer (BC), HER2 positive gastric/GEJ carcinoma, HER2 low-expressing BC, HER2-expressing/mutated NSCLC, or other HER2-expressing/mutated solid tumors, and were refractory or intolerant to standard therapy. SHR-A1811 at doses of 1.0-8.0 mg/kg was given Q3W (IV). The primary endpoints were DLT, safety, and the RP2D. Results: From Sep 7, 2020 to Sep 28, 2022, 250 pts who had undergone a median of 3 prior treatment lines in the metastatic setting received at least one dose of SHR-A1811 in dose escalation, PK expansion, and indication expansion part. As of data cutoff on Sep 28, 2022, 1 pt experienced DLT. Treatment-related adverse events (TRAEs) were reported in 243 (97.2%) pts. Grade ≥3 TRAEs, serious TRAEs, and treatment-related deaths were reported in 131 (52.4%), 31 (12.4%), and 3 (1.2%) pts, respectively. Interstitial lung disease (AESI) was reported in 8 (3.2%) pts. Exposures of SHR-A1811, total antibody, and the payload were generally proportional to dose from 3.2 to 8.0 mg/kg. ORR was 61.6% (154/250, 95% CI 55.3-67.7) in all pts. Objective responses were observed in pts with HER2 positive BC (88/108, ORR 81.5%, 95% CI 72.9-88.3), HER2-low BC (43/77, ORR 55.8%, 95% CI 44.1-67.2), urothelial carcinoma (7/11), colorectal cancer (3/10), gastric/GEJ carcinoma (5/9), biliary tract cancer (5/8), NSCLC (1/3), endometrial cancer (1/2), and H&N cancer (1/1). Subgroup analyses of ORR are shown in Table 1. The 6-month PFS rate was 73.9% in all pts. Conclusions: SHR-A1811 was well-tolerated and showed promising antitumor activity in heavily pretreated advanced solid tumors. Table 1. Subgroup analyses of ORR No. of prior treatment lines in metastatic setting in all pts (N=250) HER2 positive BC (N=108) HER2-low BC (N=77) Other tumor types (N=65) ≤3 81.8% (45/55) 58.7% (27/46) 36.7% (18/49) >3 81.1% (43/53) 51.6% (16/31) 31.3% (5/16) Prior anti-HER2 therapies in pts with BC (N=185)* HER2 positive BC (N=108) HER2-low BC (N=77) All BC (N=185) Any 82.2% (88/107, 73.7-89.0) 68.8% (11/16, 41.3-89.0) 80.5% (99/123, 72.4-87.1) Trastuzumab 81.9% (86/105, 73.2-88.7) 75.0% (9/12, 42.8-94.5) 81.2% (95/117, 72.9-87.8) Pertuzumab 83.0% (39/47, 69.2-92.4) 100% (5/5, 47.8-100) 84.6% (44/52, 71.9-93.1) Pyrotinib 86.9% (53/61, 75.8-94.1) 71.4% (5/7, 29.0-96.3) 85.3% (58/68, 74.6-92.7) Lapatinib 80.0% (28/35, 63.1-91.6) 100% (1/1, 2.5-100) 80.6% (29/36, 64.0-91.8) T-DM1 82.4% (14/17, 56.6-96.2) 100% (3/3, 29.2-100) 85.0% (17/20, 62.1-96.8) Other HER2-ADC (except T-DM1)** 60.0% (9/15, 32.3-83.7) 50.0% (2/4, 6.8-93.2) 57.9% (11/19, 33.5-79.8) ORR in pts with tumor types other than BC (N=65) HER2 IHC3+ or IHC2+/ISH+ (N=36) HER2 IHC2+/ISH- or IHC1+ or unknown (N=29) All other tumor types (N=65) % (n/N) 38.9% (14/36) 31.0% (9/29) 35.4% (23/65) ORR was shown as % (n/N, 95% CI) or % (n/N). *ORR is calculated using the number of subjects previously treated with anti-HER2 cancer therapy in advanced/metastatic setting as denominator; 2-sided 95% CIs are estimated using Clopper-Pearson method. **Includes RC48-ADC, A166, DP303c, MRG002, ARX788, TAA013, DX126-262, PF-06804103, and BAT8001. Citation Format: Herui Yao, Min Yan, Zhongsheng Tong, Xinhong Wu, Min-Hee Ryu, Jee Hyun Kim, John Park, Yahua Zhong, Weiqing Han, Caigang Liu, Mark Voskoboynik, Qun Qin, Jian Zhang, Minal Barve, Ana Acuna-Villaorduna, Vinod Ganju, Seock-Ah Im, Changsheng Ye, Yongmei Yin, Amitesh C. Roy, Li-Yuan Bai, Yung-Chang Lin, Chia-Jui Yen, Hui Li, Ki Young Chung, Shanzhi Gu, Jun Qian, Yuee Teng, Yiding Chen, Yu Shen, Kaijing Zhao, Shangyi Rong, Xiaoyu Zhu, Erwei Song. Safety, tolerability, pharmacokinetics, and antitumor activity of SHR-A1811 in HER2-expressing/mutated advanced solid tumors: A global phase 1, multi-center, first-in-human study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT175.

578 Background: Immune checkpoint inhibitors (CPIs) targeting PD-1/PD-L1 have become established treatments for advanced hepatocellular carcinoma (aHCC) but yield low objective response rates (ORRs) in treated patients (pts). Dual inhibition of LAG-3 and PD-1 pathways has demonstrated synergy in activating T-cells and improving immune response. Tebotelimab, also known as MGD013, is a bispecific tetravalent DART molecule that can bind both PD-1 and LAG-3. We initiated an open-label, single-arm, phase 1/2 dose escalation and expansion study to assess the safety and efficacy of tebotelimab in pts with aHCC. Methods: Eligible pts with aHCC who received ≥1 prior systemic treatment with or without prior CPI exposure were enrolled. The dose escalation phase evaluated doses at 120, 240, 400, and 600 mg. Tebotelimab was administered intravenously once every two weeks (Q2W) on days 1 and 15 of each 28-day cycle. The dose expansion phase consisted of one CPI-experienced cohort and one CPI-naïve cohort, both treated at recommended phase 2 dose (RP2D). Primary endpoints were safety for the escalation phase, and safety and ORR per RECIST v1.1 for the expansion phase. Investigator-assessed efficacy results are reported. Results: At data cut-off as of 27 April 2022, 13 pts received tebotelimab in the escalation phase. No dose-limiting toxicity was observed and RP2D was determined as 600 mg Q2W. In the expansion phase, 69 pts (CPI-experienced 33, CPI-naïve 36) were enrolled (median age, 57.0 years; male, 87.0%; ECOG 1, 58.0%; BCLC Stage C, 89.9%; and HBV etiology, 84.1%). Thirteen (18.8%) pts had Grade ≥3 treatment-related adverse events (TRAEs), most commonly hepatic function abnormal (n=3), amylase increased (n=2), and aspartate aminotransferase increased (n=2). Serious TRAEs occurred in nine (13.0%) pts, immune-related adverse events in 30 (43.5%), TRAEs leading to treatment discontinuation in five (7.2%), and treatment-related death in one (1.4%). Of the 30 evaluable pts in the CPI-experienced cohort, one achieved confirmed partial response (PR) and 14 achieved stable disease (SD), with a 3.3% ORR and a 50.0% disease control rate (DCR); of the 30 evaluable pts in the CPI-naïve cohort, four achieved confirmed PR and 10 achieved SD, with a 13.3% ORR and a 46.7% DCR. Median progression-free survival was 2.4 and 3.1 months for CPI-experienced and CPI-naïve cohorts, respectively, with median overall survival not reached in both. Conclusions: Tebotelimab demonstrated a manageable safety profile in pts with aHCC. Antitumor activity, mainly as disease stabilization, was observed in both the CPI-naïve setting and the CPI-experienced setting. No additional clinical trials are planned at this time. Clinical trial information: NCT04212221 .

Objective To investigate the prognostic value of baseline magnetic resonance imaging (MRI) texture analysis of hepatocellular carcinoma (HCC) treated with transcatheter arterial chemoembolization (TACE) and microwave ablation (MWA). Methods MRI was performed on 102 patients with HCC before receiving TACE combined with MWA in this retrospective study. The best 10 texture features were screened as a feature group for each MRI sequence by MaZda software using mutual information coefficient (MI), nonlinear discriminant analysis (NDA) and other methods. The optimal feature group with the lowest misdiagnosis rate was achieved on one MRI sequence between two groups dichotomized by 3-year survival, which was used to optimize the significant texture features with the optimal cutoff values. The Cox proportional hazards model was generated for the significant texture features and clinical variables to determine the independent predictors of overall survival (OS). The predictive performance of the model was further evaluated by the area under the ROC curve (AUC). Kaplan–Meier and log-rank tests were performed for disease-free survival (DFS) and Local recurrence-free survival (LRFS). Results The optimal feature group with the lowest misdiagnosis rate of 8.82% was obtained on T2WI using MI combined with NDA feature analysis. For Cox proportional hazards regression models, the independent prognostic factors associated with OS were albumin (P = 0.047), BCLC stage (P = 0.001), Correlat(1,− 1)T2 (P = 0.01) and SumEntrp(3,0)T2 (P = 0.015), and the prediction efficiency of multivariate model is AUC = 0.876, 95%CI = 0.803–0.949. Kaplan–Meier analyses further demonstrated that BCLC (P (1,− 1)T2 (P = 0.023) and SumEntrp(3,0)T2 (P P = 0.007) related to LRFS. Conclusions MR imaging texture features may be used to predict the prognosis of HCC treated with TACE combined with MWA.

The Notch1 (Notch1 receptor) and yes-associated protein 1 (YAP1) signaling can regulate breast cancer metastasis. This study aimed at investigating whether and how these two signal pathways crosstalk to promote breast cancer lung metastasis. Here, we show that YAP1 expression was positively correlated with Notch1 in breast cancer according to bioinformatics and experimental validation. Mechanistically, YAP1 with TEA domain transcription factors (TEADs) enhanced Jagged1(JAG1)-Notch1 signaling. Meanwhile, Notch1 promoted YAP1 stability in breast cancer cells by inhibiting the β-TrCP-mediated degradation, thereby, forming a YAP1- JAG1/Notch1 positive feedback loop in breast cancer. Furthermore, YAP1 enhanced the mammosphere formation and stemness of MDA-MB-231 cells by attenuating the inhibition of the BMP4-SMAD1/5 signaling. In vivo, the YAP1- JAG1/Notch1 positive feedback loop promoted the lung colonization of MDA-MB-231 cells. Our data for the first time indicate that the YAP1-Notch1 positive feedback loop promotes lung metastasis of breast cancer by modulating self-renewal and inhibiting the BMP4-SMAD1/5 signaling.

The Expert Consensus reviews current literatures and provides clinical practice guidelines for thermal ablation of pulmonary subsolid nodules or ground-glass nodule (GGN). The main contents include the following: (1) clinical evaluation of GGN; (2) procedures, indications, contraindications, outcomes evaluation, and related complications of thermal ablation for GGN; and (3) future development directions.

The aim of multi-agent reinforcement learning systems is to provide interacting agents with the ability to collaboratively learn and adapt to the behavior of other agents. Typically, an agent receives its private observations providing a partial view of the true state of the environment. However, in realistic settings, the harsh environment might cause one or more agents to show arbitrarily faulty or malicious behavior, which may suffice to allow the current coordination mechanisms fail. In this paper, we study a practical scenario of multi-agent reinforcement learning systems considering the security issues in the presence of agents with arbitrarily faulty or malicious behavior. The previous state-of-the-art work that coped with extremely noisy environments was designed on the basis that the noise intensity in the environment was known in advance. However, when the noise intensity changes, the existing method has to adjust the configuration of the model to learn in new environments, which limits the practical applications. To overcome these difficulties, we present an Attention-based Fault-Tolerant (FT-Attn) model, which can select not only correct, but also relevant information for each agent at every time step in noisy environments. The multihead attention mechanism enables the agents to learn effective communication policies through experience concurrent with the action policies. Empirical results showed that FT-Attn beats previous state-of-the-art methods in some extremely noisy environments in both cooperative and competitive scenarios, much closer to the upper-bound performance. Furthermore, FT-Attn maintains a more general fault tolerance ability and does not rely on the prior knowledge about the noise intensity of the environment.

PURPOSE Donafenib, a novel multikinase inhibitor and a deuterated sorafenib derivative, has shown efficacy in phase Ia and Ib hepatocellular carcinoma (HCC) studies. This study compared the efficacy and safety of donafenib versus sorafenib as first-line therapy for advanced HCC. PATIENTS AND METHODS This open-label, randomized, parallel-controlled, multicenter phase II-III trial enrolled patients with unresectable or metastatic HCC, a Child-Pugh score ≤ 7, and no prior systemic therapy from 37 sites across China. Patients were randomly assigned (1:1) to receive oral donafenib (0.2 g) or sorafenib (0.4 g) twice daily until intolerable toxicity or disease progression. The primary end point was overall survival (OS), tested for noninferiority and superiority. Efficacy was primarily assessed in the full analysis set (FAS), and safety was assessed in all treated patients. RESULTS Between March 21, 2016, and April 16, 2018, 668 patients (intention-to-treat) were randomly assigned to donafenib and sorafenib treatment arms; the FAS included 328 and 331 patients, respectively. Median OS was significantly longer with donafenib than sorafenib treatment (FAS; 12.1 v 10.3 months; hazard ratio, 0.831; 95% CI, 0.699 to 0.988; P = .0245); donafenib also exhibited superior OS outcomes versus sorafenib in the intention-to-treat population. The median progression-free survival was 3.7 v 3.6 months ( P = .0570). The objective response rate was 4.6% v 2.7% ( P = .2448), and the disease control rate was 30.8% v 28.7% (FAS; P = .5532). Drug-related grade ≥ 3 adverse events occurred in significantly fewer patients receiving donafenib than sorafenib (125 [38%] v 165 [50%]; P = .0018). CONCLUSION Donafenib showed superiority over sorafenib in improving OS and has favorable safety and tolerability in Chinese patients with advanced HCC, showing promise as a potential first-line monotherapy for these patients.

The recurrence and metastasis of breast cancer limit the effectiveness of clinical treatments, making them important issues for clinicians to address. Tumor‑associated macrophages (TAMs) contribute to regulating the immune system. C‑C motif chemokine ligand 5 (CCL5) is an inflammatory chemokine that promotes chemotaxis on cells involved in the immune/inflammatory response. Breast cancer cells that secrete CCL5 act on THP‑1 cells, influencing the invasion and metastasis of tumors. However, knowledge remains limited regarding the mechanism underlying the effects of CCL5 on breast cancer cells and TAMs, as well as the mechanisms promoting the migration and invasion of breast cancer. The present study demonstrated that the positive expression of CCL5 was associated with lymph node status and tumor‑node‑metastasis stage. Treatment with ≥20 ng/ml CCL5 significantly promoted the migration and invasion of MCF‑7 and MDA‑MB‑231 cells. CCL5‑small interfering RNA intervention significantly decreased the migration and invasion of the two cell types. In vitro, THP‑1 cells were successfully induced to become TAMs, which were then recruited via the chemotactic effects of CCL5. This process was achieved through the co‑stimulation of phorbol‑12‑myristate‑13‑​acetate, interleukin‑4 (IL‑4) and IL‑13. The nuclear factor‑κB (NF‑κB) signaling pathway was activated to regulate EMT, as well as the migration and invasion process of MCF‑7 cells, when co‑cultured with TAMs. We also reported that blocking the expression of CCL5 in vivo may significantly inhibit the growth of human breast cancer xenografts. Therefore, targeting CCL5 may be considered as a novel therapeutic strategy for suppressing the invasion and metastasis of breast cancer.

Human epidermal growth factor receptor (HER)‑2‑positive breast cancer accounts for ~25% of all breast cancer cases, has a high propensity for relapse, metastasis and drug resistance, and is associated with a poor prognosis. Therefore, it is necessary to develop more effective therapeutic targets for the treatment of HER‑2‑positive breast cancer. CD44+/CD24‑/low is currently the most commonly used marker for breast cancer stem cells (CSCs), which are considered the main cause of drug resistance, relapse and metastasis. In the present study, the ratio of CD44+/CD24‑/low cells was almost zero in SK‑BR‑3 cells; however, it was >90% in MDA‑MB‑231 cells, as determined by flow cytometry. Since SK‑BR‑3 and MDA‑MB‑231 cells both exhibit a strong propensity for invasion and migration, it was hypothesized that there may be other markers of CSCs in SK‑BR‑3 cells. Therefore, transcriptome sequencing was performed for SK‑BR‑3 and MDA‑MB‑231 cells. It was observed that several leukocyte differentiation antigens and other CSC markers were significantly more highly expressed in SK‑BR‑3 cells. Furthermore, the expression of aldehyde dehydrogenase (ALDH)1A3, CD164 and epithelial cell adhesion molecule (EpCAM) was higher in SK‑BR‑3 cells compared with in other subtypes of breast cell lines, as determined by reverse transcription‑polymerase chain reaction and western blot analysis. In addition, the expression levels of ALDH1A3, ALDH3B2 and EpCAM were higher in HER‑2‑positive breast cancer compared with in paracancerous tissues and other subtypes of breast cancer, as determined by immunohistochemistry. The expression of β‑catenin in the Wnt signaling pathway was lower in SK‑BR‑3 cells compared with in MDA‑MB‑231 cells, which may be used as a prognostic indicator for breast cancer. These findings may help identify novel CSC markers and therapeutic targets for HER‑2‑positive breast cancer.

2641 Background: HBM4003 is a fully human heavy chain only monoclonal antibody (HCAb) to CTLA-4, which has been engineered to deplete Treg cells by enhanced antibody-dependent cellular cytotoxicity (ADCC) activity. In the Phase 1 dose escalation part, HBM4003 showed favorable safety and efficacy profile in patients (pts) with advanced solid tumors. Here, we present the updated data from the dose escalation part and most recent safety and clinical activity data from three expansion cohorts of pts with advanced hepatocellular carcinoma (HCC), melanoma, and renal cell carcinoma (RCC). Methods: In the dose-escalation part, pts were enrolled into 3 dose levels (DL): 0.3mg/kg QW (28-day cycle), 0.45mg/kg Q3W (21-day cycle), and 0.6mg/kg Q3W (21-day cycle). In the dose-expansion part, pts with advanced HCC, melanoma, and RCC received 0.45 mg/kg Q3W (21-day cycle). Tumor measurements were performed every 6 weeks for up to 12 months and subsequently every 12 weeks per RECIST v1.1. Results: In total 60 pts were included for this analysis, including 24 pts with advanced solid tumors in the dose escalation part and 36 pts in the dose expansion part: 18 pts with HCC, 4 pts with melanoma, and 14 pts with RCC, from 12 sites in mainland China, 5 sites in Australia, and 1 site in Hong Kong. 46 pts (77%) received ≥ 2 lines of previous systemic therapies and 37 pts (62%) received previous PD-1/PD-L1 treatment. For the HCC cohort, 19 pts were treated in dose-escalation (1 pt, 0.45 mg/kg Q3W) and dose-expansion parts. All 19 pts received previous PD-1/PD-L1 therapy. 12 pts were evaluable for efficacy. Two had stable disease (SD), 2 pts had partial response (PR) as best response. For 12 evaluable pts, ORR was 16.7% and disease control rate (DCR) was 33.3%. For the RCC cohort, 19 pts were treated in dose-escalation and dose-expansion parts; 18 pts were evaluable for efficacy. Eight had SD as best response; the DCR was 44.4%. Overall, the most common treatment-related adverse event (TRAE) (incidence ≥ 10%) of all grades was rash (16 [26.7%] pts). At the 0.45 mg/kg Q3W DL, the most common TRAE of all grades was hepatic function abnormalities (12 [27.9%] pts) and rash (12 [27.9%] pts). 30 (69.8%) pts reported Gr 1 or 2 TRAEs. Gr ≥3 TRAEs occurred in 4 (9.3%) pts. 1 pt reported Gr 4 TRAE: blood creatine phosphokinase increased. No Gr 5 TRAE was reported. TRAE leading to discontinuation occurred in 4 pts. In mouse model, only tumor infiltrating lymphocytes Treg was depleted upon HBM4003 treatment while no Treg change in blood and spleen. In pts, Treg depletion was observed only in tumor tissue on day 21 post dosing. Overall, HBM4003 demonstrated dose proportional pharmacokinetics and low immunogenicity. Conclusions: HBM4003 showed a favorable safety profile, promising antitumor activity and intratumoral Treg depletion in pts with advanced solid tumors at the 0.45 mg/kg Q3W DL. Clinical trial information: NCT04135261.

e16197 Background: Donafenib (Dona), a multikinase inhibitor recently marketed in China for advanced HCC with its superiority in overall survival (OS) over Sorafenib from a large head-to-head Phase 3 study. The clinical experience of triple therapy (TKIs + ICIs + TACE) in the treatment of patients (pts) with uHCC is limited. We assessed the safety and efficacy of triple therapy [Dona +anti-PD-1+ TACE] in uHCC in this Phase 1 study. Methods: The objective of this Phase 1, open-label, multicenter, dose-escalation and expansion study was to assess the MTD/recommended dose for Dona in combination of a fixed-dose anti-PD-1 plus TACE in uHCC. The primary endpoint was DLT occurring in the first treatment cycle. Secondary endpoints included the overall safety and tolerability, ORR and PFS by mRECIST. Qualified pts (age 18-75) were enrolled if uHCC without macrovascular invasion (VP3/4) or extrahepatic spread; measurable disease by mRECIST; ECOG 0 to 1; Child-Pugh A; systemic therapy naive. Results: At the cut-off date (Dec 31 2021), data of 25 pts who underwent triple therapy from 6 cancer centers in China were analyzed (Table). The median duration of follow-up was 105 days (1-358 days). No DLTs were observed [Dona 50 mg Bid (n=3); 150 mg Qd (n=3); 100 mg Bid (n=6)]. Additional 13 pts were treated with the recommended dose of Dona 100 mg Bid. Treatment-related adverse events (TRAE) occurred in 24 pts (Grade 3, 36%; no Grade 4). 16 pts had at least one response assessment, the ORR was 62.5%; in 12 pts with BLCL B, the ORR was 83.3%. mPFS was not reached. Conclusions: Combination of Dona, anti-PD-1 and TACE showed a high rate of tumor response and good safety profile in uHCC. Clinical trial information: NCT04605185. [Table: see text]

Zinc finger protein family is the largest transcription factor family in the human genome. Studies have shown that the aberrant expression of zinc finger protein (ZNF) had a potential role in tumorigenesis. However, due to the high complexity of the ZNF family genes, the role of the ZNF family genes in breast cancer (BRCA) is still lacking in systematic understanding.In the study, we aim to understand the expression profile, prognostic value, immune invasion pattern, tumor microenvironment, epigenetic and pathway relationships, and drug sensitivity of ZNFs using multi-omics data from public databases.We focused on six members of ZNFs, which were upregulated in a variety of cancers. Notably, ZNF750 and ZNF224 were lower expressed in BRCA, and their expressions were significantly associated with BRCA prognosis. We confirmed the observations obtained by analyzing the clinic-pathological data. Otherwise, the expressions of ZNFs were significantly related to stromal and immune scores, and was significantly different among different immune subtypes in BRCA. Here, we found down-regulated methylation of ZNF217 and ZNF750. The relationship between methylation and survival showed the survival was worse for hypo-methylation of ZNF750 in BRCA, which is consistent with the correlation of high expression of ZNF750 in BRCA with worse survival.Collectively, our results provide clues for a better understanding of the characterization of ZNF family genes in BRCA from a multi-omics perspective and show their potential for use as new tumor markers and therapeutic targets.

e16081 Background: REACH-2 and REACH were two global, randomized, double-blind, placebo (PL)-controlled phase 3 studies of Ramucirumab (RAM) versus PL in patients with HCC after prior sorafenib. REACH-2 confirmed the RAM treatment benefit for patients with baseline AFP ≥ 400 ng/mL, consistent with results in a prespecified subgroup of patients in REACH with AFP ≥ 400 ng/mL. A pooled analysis was performed to evaluate the efficacy and safety of RAM in Chinese patients (including patients from mainland China, Hong Kong, and Taiwan) from REACH-2 and REACH with baseline AFP ≥400 ng/mL. Methods: Except for AFP level requirement, REACH-2 and REACH were similar in study design and included patients who had advanced HCC (BCLC stage C or B disease refractory or not amenable to locoregional therapy), Child-Pugh A, ECOG PS 0-1, and prior sorafenib. Patients were randomized to RAM (8 mg/kg) I.V. or PL Q2W, plus best supportive care, until disease progression or unacceptable toxicity. Individual patient data were pooled from REACH-2 and REACH (AFP ≥400 mg/mL). Overall survival (OS) and progression-free survival (PFS) were evaluated using Kaplan-Meier method and Cox proportional hazard model. Objective response rate (ORR), disease control rate (DCR), and safety were reported. Efficacy analyses were stratified by study to account for any potential difference in the two studies. Results: Data from 155 Chinese patients were pooled from REACH (51) and REACH-2 (104) (N = 98 RAM vs N = 57 PL). Baseline characteristics were generally balanced between arms in pooled data set; however, lower median level of AFP was noted in the RAM arm. In the pooled population, RAM treatment numerically improved OS over PL (median OS 7.1 months vs 4.7 months; HR = 0.735 [95% CI: 0.512, 1.055]). Improvements in PFS (median PFS 2.6 months vs 1.5 months; HR = 0.666 [95% CI: 0.459, 0.967]), ORR (3.1% vs 0%), and DCR (44.9% vs 29.8%) were also observed. Hypertension (6.1% vs 1.8%), pneumonia (5.1% vs 1.8%), and hyponatremia (5.1% vs 1.8%) were the Grade ≥3 treatment-emergent adverse events (TEAEs) among ≥ 5% patients that was more frequently observed in the RAM arm compared with the PL arm. Conclusions: Pooled analysis of two phase 3 trials of RAM as second-line treatment in patients with HCC following sorafenib demonstrated a clinically meaningful benefit with a manageable safety profile in Chinese HCC patients with baseline AFP ≥ 400 ng/mL. Treatment benefits in OS observed in the pooled Chinese population were consistent with the entire population from REACH/REACH-2 (AFP ≥ 400 ng/mL). Clinical trial information: NCT01140347, NCT02435433.

Introduction: Atezolizumab plus bevacizumab significantly improved overall survival (OS) and progression-free survival (PFS) versus sorafenib in patients with unresectable hepatocellular carcinoma (HCC) in IMbrave150. Efficacy and safety data from the Chinese subpopulation are reported. Methods: IMbrave150, a global, randomized, open-label, phase 3 study in patients with systemic treatment-naive unresectable HCC, included an extension phase that enrolled additional patients from mainland China. Patients were randomized (2:1) to receive intravenous atezolizumab 1,200 mg plus bevacizumab 15 mg/kg once every 3 weeks or sorafenib 400 mg twice a day until unacceptable toxicity or loss of clinical benefit. Co-primary endpoints were OS and independent review facility-assessed PFS per Response Evaluation Criteria in Solid Tumors version 1.1 in the intention-to-treat population. Results: Of 194 Chinese patients enrolled from April 16, 2018, to April 8, 2019 (137 in the global study and 57 in the China extension phase), 133 received atezolizumab plus bevacizumab and 61 received sorafenib. At the data cutoff (August 29, 2019), the stratified hazard ratio for OS was 0.44 (95% CI, 0.25–0.76) and for PFS was 0.60 (95% CI, 0.40–0.90). The respective median OS and PFS with atezolizumab plus bevacizumab were not reached (NR; 95% CI, 13.5 months to NR) and 5.7 months (95% CI, 4.2–8.3) versus 11.4 months (95% CI, 6.7 to NR) and 3.2 months (95% CI, 2.6–4.8) with sorafenib. Grade 3–4 adverse events (AEs) occurred in 78 of 132 (59.1%) atezolizumab plus bevacizumab-treated and 27 of 58 (46.6%) sorafenib-treated patients. The most common grade 3–4 AE with atezolizumab plus bevacizumab was hypertension, occurring in 15.2% of patients; however, other high-grade AEs were infrequent. Conclusion: Clinically meaningful improvements in OS and PFS observed with atezolizumab plus bevacizumab versus sorafenib suggest that atezolizumab plus bevacizumab may become a practice-changing treatment for Chinese patients with unresectable HCC.

Background GLS-010, a novel engineered fully human immunoglobin G4 monoclonal antibody, can specially block the PD-1/PD-L1/2 axis and reactivate the antitumor immunity. Aim This phase Ia/Ib study was carried out to evaluate the safety, recommended phase II dose (R2PD), and primary antitumor effects of GLS-010 in patients with advanced, refractory lymphoma and solid tumors. Methods In phase Ia study, patients with refractory solid tumors and lymphoma enrolled and received GLS-010 at a dose of 1, 4, or 10 mg/kg Q2W; 240 mg Q3W or Q2W. The primary objective was to assess the dose-limiting toxicity (DLT). In phase Ib study, doses were expanded in 9 specific tumors to ensure the R2PD and explore the efficacy. Tumor mutation burden level and PD-L1 expression were also assessed with whole-exome sequencing and immunohistochemistry (SP263), respectively. Results Up to April 18, 2020, a total of 289 patients (n = 24, phase Ia; n = 265, phase Ib) were enrolled. DLT was not observed in phase Ia part. The T1/2, CLss, and Vd were similar among all dose groups and different tumors. The most common treatment-emergent adverse events (TEAEs) were anemia, leukopenia, elevated alanine aminotransaminase/asparate aminotransferase (ALT/AST), and elevated bilirubin. And hypothyroidism was the most common immune-related adverse event (irAE). The incidence of grade ≥3 TEAE was 39.8%, while grade ≥3 irAE was only 4.5%. Based on safety studies, pharmacokinetics/pharmacodynamics, and preclinical data, 240-mg Q2W was recommended as the expansion dose. The overall objective response rate was 23.6%, with 10 patients achieving complete response. Patients with a high PD-L1 expression level (31.3% Versus. 13.7%, p = 0.012) or t-issue tumor mutation burden level (31.3% Versus. 5.6%, p = 0.009) showed a significantly better response. Conclusion GLS-010 showed acceptable safety profile and favorable clinical response. The dose of 240 mg Q2W was an optimal recommended dose as monotherapy.

TPS487 Background: In 2020, there were ̃905,000 new cases and ̃830,000 deaths from liver cancer globally, and a respective 410,038 and 391,152 in China (5-year overall survival [OS]: 14.1%).1,2,3 Hepatocellular carcinoma (HCC) accounts for 75%–85% of liver cancers.1 Transarterial chemoembolization (TACE) is the preferred treatment for patients with intermediate-stage unresectable HCC (uHCC); however, there are issues with the need for repeated dosing and the heterogenous target population (median OS: 13–43 mo). Treatment with TACE + systemic therapy may improve this. Although several trials reported negative results for TACE + sorafenib (sor) vs TACE alone in patients with uHCC, the TACTICS trial showed improved untreatable (unTACEable) progression-free survival (PFS) (25.2 vs 13.5 mo; P= 0.006).4 While promising, the unmet need for combination therapies remains. The recent IMbrave150 trial showed significantly improved OS with atezolizumab (atezo) + bevacizumab (bev) vs sor (19.2 vs 13.4 mo; P= 0.0009) in patients with uHCC5, making it an attractive option for combination with TACE. Methods: TALENTACE (NCT047126430) is a phase III, open-label, randomized study to evaluate the efficacy and safety of TACE + atezo + bev or TACE alone in patients with uHCC. Key inclusion criteria are ≥18 years old, HCC diagnosis, no prior systemic treatment, no prior locoregional treatment of target lesions, eligible for TACE treatment, tumor max diameter + tumor number ≥6, and not a candidate for curative therapy. Patients with tumors that have macrovascular invasion (MVI) or extrahepatic spread (EHS) are excluded. Patients will be randomized (1:1) to receive TACE + atezo + bev or TACE alone. TACE will be performed by clinical demand; atezo (1200 mg) and bev (15 mg/kg) will be administered by intravenous infusion on Day 1 of each 21-day cycle. Co-primary endpoints are independent review committee-determined TACE-PFS (randomization to unTACEable progression, TACE failure/refractoriness, or death) and OS. Secondary endpoints include investigator-determined TACE-PFS; time to unTACEable progression, progression, MVI, EHS, and MVI/EHS; objective response rate, duration of response, patient reported outcomes, and incidence of adverse events. References: Sung, H., et al. CA Cancer J Clin. 2021;71(3):209–249. World Health Organisation: Globocan 2020 – China Factsheet. Available at: https://gco.iarc.fr/today/data/factsheets/populations/160-china-fact-sheets.pdf [accessed 1 June 2021] Allemani, C., et al. Lancet. 2018, 391(10125): 1023–1075. Kudo, M., et al. Gut. 2020;69(8):1492–1501. Finn, RS., et al. J Clin Oncol. 2021;39(no. 3_suppl):267–267. Clinical trial information: NCT04712643.

421 Background: Immune checkpoint inhibitors (ICI) targeting PD-1/L1 or in combination with CTLA-4 have shown therapeutic benefit in patients with advanced hepatocellular carcinoma (aHCC). This study aimed to evaluate the safety, tolerability, and preliminary efficacy of IBI310, an anti-CTLA-4 monoclonal antibody (mAb), combined with sintilimab, in patients with aHCC who failed or intolerant to previous systemic therapy. Methods: Three cohorts were pre-designed to explore recommended dose of IBI310 in de-escalation order: sintilimab 200 mg plus IBI310 3, 2 or 1 mg/kg every 3 week (q3w). Patients will receive the combined treatment up to 4 cycles, followed by sintilimab 200 mg q3w up to 24 months. Primary endpoint was safety. Key secondary endpoints included objective response rate (ORR), disease control rate (DCR), progress free survival (PFS) and overall survival (OS) by RECISTv1.1 per investigators. Results: 9 subjects were initially treated with sintilimab 200 mg plus IBI310 3 mg/kg q3w without predefined adverse event (AE) observed. 3 mg/kg was determined as recommended dose of IBI310 and no subject was assigned to other cohorts. As of the data cut-off of August 30, 29 subjects were enrolled (median age 51.4 years, 86.2% male, 96.6% BCLC C, 24.1% ICI treated). The average treatment cycles of IBI310 and sintilimab were 2.8 and 5.7. The most frequent treatment related adverse events (TRAEs) of any grade were alanine transaminase increases (34.5%), aspartate transaminase increases (34.5%), thrombopenia (24.1%), and lipase increases (24.1%). Grade ≥3 TRAEs occurred in 34.5% of subjects (including one grade 5 immune-mediated pneumonitis). Dose interruption and discontinuation rates due to AE were 55.2% and 6.9%. With a median follow-up of 9.89 months, investigator confirmed ORR and DCR were 17.2% (all partial response, including one anti-PD1 mAb failed) and 72.4%. The median PFS was 3.9 months (95% CI: 2.6, NR) and median OS not reached (95% CI: 11.4, NR). The 6-month PFS and OS rates were 45.8% (95%CI 25.2%, 64.2%) and 93.1% (95%CI 75.1%, 98.2%) respectively. 6 patients remain on treatment at cutoff date. Conclusions: The combination of sintilimab and IBI310 shows promising efficacy and managable safety profile in aHCC patients. Our results are comparable to that have been published in the same setting. This regimen is currently being evaluated in phase II study. Clinical trial information: NCT04401813.

Thymoquinone (TQ, 2‐methyl‐5‐isopropyl‐1,4‐benzoquinone), a bioactive constituent extracted from the seeds of Nigella sativa, has been proved to exert anti‐tumor efficiency in various cancers. Autophagy is a self‐digestion phenomenon, and its role in tumor formation and progression remains controversial. In the present study, we investigated the effects of TQ on renal cell cancer (RCC) cell lines (786‐O and ACHN) using wound healing assay, transwell assay and western blot analysis. We found that TQ effectively inhibited the metastatic capacity of RCC cells in vitro, which was also verified in a xenograft model. Meanwhile, we observed LC3 puncta and detected the expression of LC3 in TQ‐treated RCC cells, and then found that autophagy was induced by TQ in 786‐O and ACHN cell lines. In addition, TQ inhibited the migration and invasion as well as the EMT in RCC cells in an autophagy‐dependent manner. To further explore the underlying mechanism, we detected the AMPK/mTOR signaling pathway. The results indicated that TQ inhibited the metastasis of RCC cells by inducing autophagy via AMPK/mTOR signaling pathway. In conclusion, our findings provide a novel therapeutic strategy that aims at TQ‐induced autophagy in RCC treatment.