bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety and efficacy of allogeneic natural killer cells in combination with pembrolizumab in patients with chemotherapy-refractory biliary tract cancer: A multicenter open-label phase 1/2a trial.
Authors: Leem Galam , Jang Sung Ill , Cho Jae-Hee , Jo Jung Hyun , Lee Hee Seung , Chung Moon Jae , Park Jeong Youp , Bang Seungmin , Yoo Da-Kyung , Cheon Hyo-Cheon , Kim Jae-Eun , Lim Kyeong-Pill , Jung In-Hye , Im Jung-Min , Chung Yong Yoon , Park Seung Woo
Published: June 2023

4080

Background: This study investigated the administration of combination therapy, allogeneic natural killer (NK) cells and pembrolizumab, in the treatment of advanced biliary tract cancer to determine the safety and tolerability (phase 1), and the efficacy and safety (phase 2a). Methods: Forty patients (phase 1, n=6; phase 2a, n=34) were enrolled between December 2019 and June 2021. The patients were inoperable and no further conventional chemotherapy was anticipated after finishing at least one chemotherapy. The patients received 3x106 NK cells/kg of highly activated allogeneic NK cells (“SMT-NK”) on weeks 1 and 2 and 200 mg of pembrolizumab (Keytruda) on week 1. No treatment was given in week 3. This 3-week schedule (1 cycle) was repeated until confirmed disease progression, intolerable adverse events (AEs), patient withdrawal of consent, or finishing the maximum treatment schedule. The tumor response was evaluated after every three cycles. Results: In phase 1, 4 patients (66.7%) experienced 7 AEs, but no severe AEs directly related to the combination of the two drugs was observed. In phase 2a, 126 AEs occurred in 29 patients (85.3%). Severe AEs (≥ grade 3) were reported in 16 patients (47.1%). No dose limiting toxicity was reported. The overall response rate (ORR) was 17.4% in the full-analysis set and 50.0% in the per-protocol set. Conclusions: SMT-NKs plus pembrolizumab resulted in no severe AEs directly related to the drug combination. The combination therapy also exerted antitumor activity with improved efficacy compared to recent monotherapy with pembrolizumab in patients with advanced biliary tract cancer. A multi-center, randomized, placebo-controlled, open-label, phase 2b clinical trials to evaluate the antitumor activity of combination therapy of SMT-NKs and pembrolizumab versus pembrolizumab monotherapy in patients with advanced biliary tract cancer is now ongoing with the aim of enrolling 128 patients (ClinicalTrials.gov identifier: NCT05429697). To date, 38 patients have been enrolled and randomly assigned to each group. Within the median follow up period of 5.3 months, the disease control rate (DCR, complete response + partial response) was 27.2% in the combination therapy of SMT-NKs and pembrolizumab group, and 7.1% in the pembrolizumab monotherapy group. The ORR was 54.5% in the combination therapy group and 42.9% in the monotherapy group. So far, no severe drug-related AEs was reported. Clinical trial information: NCT03937895 .
Economic evaluation for the US of durvalumab plus gemcitabine and cisplatin (DGC) in advanced biliary tract cancer (BTC).
Authors: Aqel Osama , Shen Yunrong , Alfayoumi Ibrahim , Abraham Ivo
Published: June 2023

4081

Background: BTCs are a group of relatively rare malignancies comprised of intrahepatic cholangiocarcinoma (CCA), extrahepatic CCA, and gallbladder cancer. The first-line standard of care of gemcitabine and cisplatin (GC) has remained unchanged for the past decade, highlighting the need for novel therapies. The TOPAZ-1 trial demonstrated improved progression-free (PFS) and overall survival (OS) with durvalumab added to GC. This trial-based economic evaluation estimated the cost-effectiveness/utility of DGC versus GC from a US payer perspective. Methods: A three state partitioned survival model (Progression-free, Progressed, Death) was developed to compare costs and overall survival outcomes associated with both treatments. PFS and OS curves were digitized, and parametric functions fitted. A 5-year time horizon with a 3% discount rate/year was considered. Costs of treatment (average sales price), administration, and monitoring parameters were sourced from Centers for Medicare & Medicaid Services databases; costs of adverse event management (grade 3/4 with rate ≥ 5%) were sourced from prior BTC economic evaluations. Life years (LY), quality adjusted life years (QALY), incremental cost-effectiveness and utility ratios (ICER/ICUR) were estimated in a base case (BCA) and probabilistic sensitivity analyses (PSA). A cost-effectiveness acceptability curve (CEAC) was plotted to determine the probability of either treatment being cost-effective over the other at different willingness to pay (WTP) thresholds. Results: Exponential regression was used to extrapolate DGC and GC survival curves. As shown in the table, the BCA (PSA) shows an incremental cost of DGC over GC of 131,350 (131,212), incremental LY of 0.38 (0.38), and incremental QALY of 0.26 (0.28). The BCA and (PSA) ICERs reveal an additional 345,658 (345,295) per LY gained (g) and an additional 505,192 (468,614) per QALYg. The CEAC curve shows that DGC treatment has a 50% probability of being cost-effective at a WTP threshold value of 525,000 and 100% probability at a threshold of 1,375,000 or above. Conclusions: This economic evaluation demonstrates that, in the setting of advanced BTC, DGC is associated with a slight improvement in LY and QALY, yet at a marked incremental cost, requiring a very high WTP threshold. [Table: see text]
Impact of risk factors on overall survival (OS) in patients (pts) with unresectable hepatocellular carcinoma (HCC) treated with first-line (1L) tislelizumab (TIS).
Authors: Kudo Masatoshi , Finn Richard S. , Meyer Tim , Boisserie Frederic , Li Songzi , Chen Yaxi , Abdrashitov Ramil , Zhu Andrew X. , Vogel Arndt , Qin Shukui
Published: June 2023

4083

Background: TIS is a monoclonal antibody with high affinity and specificity for programmed cell death protein 1. In the phase 3 RATIONALE-301 trial (NCT03412773), TIS demonstrated non-inferior OS versus sorafenib (SOR) as 1L monotherapy for unresectable HCC (median [m] OS 15.9 [TIS] vs 14.1 [SOR] months [mo]; hazard ratio [HR] 0.85), with a favorable safety profile. Certain biomarkers are potential prognostic factors and may impact OS in 1L treatment of unresectable HCC; this exploratory analysis examined the effect of albumin-bilirubin (ALBI) grade, platelet count, platelet-lymphocyte ratio (PLR), and neutrophil-lymphocyte ratio (NLR) as predictors of OS in RATIONALE-301. Methods: Systemic therapy-naïve adults with histologically confirmed HCC (Barcelona Clinic Liver Cancer Stage C or Stage B that was not amenable to or progressed after loco-regional therapy; Child-Pugh A), with ≥1 measurable lesion per RECIST v1.1, and an ECOG performance status ≤1 were randomized 1:1 to receive TIS (200 mg IV Q3W) or SOR (400 mg orally BID) until disease progression, intolerable toxicity, or withdrawal. The primary endpoint was OS. Results: Overall, 674 pts were randomized (TIS n=342; SOR n=332). At data cutoff (July 11, 2022), minimum study follow-up was 33 mo. Demographic and baseline characteristics for biomarkers were generally balanced across arms. Numerically longer (≥2 mo) mOS was observed in biomarker subgroups ALBI grade 1 vs 2 and NLR ≤3 vs >3 with TIS or SOR, and PLR ≤141 vs >141 with TIS. Both platelet count threshold subgroups were accompanied by a smaller difference (<2 mo) in mOS between biomarker cutoffs, which may indicate limited prognostic value for this biomarker. TIS also demonstrated numerically longer OS versus SOR in the same subgroup categories: ALBI grade 1, PLR ≤141, and NLR ≤3. Conclusions: This analysis suggests that ALBI grade, PLR, and NLR could have prognostic value for OS, irrespective of treatment. TIS demonstrated numerically improved mOS compared with SOR for PLR ≤141 and NLR ≤3, suggesting higher benefit for pts with a more favorable balance between systemic inflammation and immunity. Clinical trial information: NCT03412773 . [Table: see text]
Sintilimab plus gemcitabine and cisplatin as a first-line treatment for patients with advanced biliary tract cancer: A biomolecular exploratory, phase II clinical trial.
Authors: Yuan Zhen-gang , Zeng Tian-mei , Yang Guang , Lou Cheng , Wei Wei , Tao Chen-jie , Chen Xi-yun , Han Qin , Cheng Zhuo , Shang Pei-pei , Dong Yu-long , Xu He-ming , Guo Lie-ping , Chen Dong-sheng , Song Yunjie , Qi Chuang , Deng Wanglong
Published: June 2023

4086

Background: The prognosis of biliary tract cancer (BTC) remains unsatisfactory. Thus, this study aimed to determine the efficacy, safety, and predictive biomarkers of the immune checkpoint inhibitor sintilimab in combination with gemcitabine and cisplatin (GemCis) in advanced BTCs. Methods: In this single-arm, phase II study (Trial registration number: ChiCTR2000036652), gemcitabine (1000 mg/m²) plus cisplatin (25 mg/m²) were administered on days 1 and 8, respectively, while 200 mg sintilimab was administered on day 1 of each 21-day cycle for 6–8 weeks, followed by sintilimab alone up to 2 years. The primary endpoint was overall survival (OS). The second endpoints were objective response rate (ORR), progression-free survival (PFS), and disease control rate, assessed using RECIST V.1.1. Multiomics biomarkers associated with clinical response were assessed as exploratory objectives. Results: Thirty patients were enrolled between August 2020 and May 2022. The median follow-up duration, OS, and PFS were 12.3 months (95% confidence interval [CI]: 9.1–16.0), 15.9 months (95% CI: 8.6–not reached), and 5.1 months (95% CI: 4.3–8.7), respectively. Here, 36.7% of patients were found to achieve an objective response. The most common grade 3 or 4 treatment-related adverse events were thrombocytopenia (33.3%), with no reported deaths nor unexpected safety events. Biomarker analysis indicated that patients with homologous recombination repair pathway gene alterations (median, PFS: 9.8 vs. 4.5 months, p = 0.023; OS: NR vs. 9.0 months, p = 0.014; ORR: 77.8% vs. 19%, p = 0.004) or loss-of-function mutations in chromatin remodeling genes (median, PFS: 8.7 vs. 4.2 months, p = 0.021; ORR: 63.6% vs. 21.1%, p = 0.046) presented better tumor response and survival outcomes. Furthermore, transcriptome analysis of the tumor immune microenvironment revealed a markedly longer PFS, and tumor response were associated with higher expression of 3-gene effector T cell signature (median, PFS: 7.8 vs. 4.3 months, p = 0.02; ORR: 64.2% vs. 7.1%, p = 0.004) and 18-gene inflamed T cell signature (median, PFS: 8.6 vs. 4.3 months, p = 0.01; ORR: 64.2% vs. 7.1%, p = 0.004). Moreover, our findings highlighted the adverse predictive value of mast cells in immuno-chemotherapy for BTCs for the first time. Conclusions: Sintilimab plus GemCis displayed a promising antitumor activity and acceptable safety profile as a first-line treatment in patients with advanced BTC. Multiomics potential predictive biomarkers are identified and warrant further verification. Clinical trial information: ChiCTR2000036652 .
Trastuzumab (T) plus gemcitabine-cisplatin (GC) for treatment naïve HER2 positive biliary tract adenocarcinomas (BTC): A multicentre open-label, phase II study (TAB).
Authors: Ostwal Vikas S. , Mandavkar Sarika , Bhargava Prabhat Ghanshyam , Srinivas Sujay , Nashikkar Chaitali , Shetty Omshree , Kaushal Rajiv Kumar , Yadav Subhash , Shah Aekta , Baheti Akshay Dwarka , Ankathi Suman Kumar , Mehta Daksha , Kapoor Akhil , Goel Mahesh , Patkar Shraddha , Chaugule Deepali , Ramaswamy Anant
Published: June 2023

4089

Background: HER2 over-expression or amplification is seen in 4%-16% of BTCs and is a therapeutic target of interest. Gemcitabine-cisplatin (GC) is one of the standard regimens of choice in advanced BTCs. We aimed to evaluate the clinical activity of GC plus anti-HER2 antibody trastuzumab as initial treatment in HER2-positive BTC. Methods: This study was an investigator-initiated, open-label, single-arm, multi institutional, phase II trial in patients (pts) aged 18 years or older with HER2-positive (defined as IHC 3+ or IHC 2+ and FISH positive), treatment naïve BTCs. Patients received GC (Gem 1000 mg/m2 IV and Cisplatin 25mg/m2 IV on day 1 and 8, q 3 weeks) combined with Trastuzumab at 8mg/kg as initial dose followed by 6mg/kg q 3 -weekly till disease progression (PD) or unacceptable toxicities. The primary end-point of the study was an improvement in 6-month progression free survival (PFS) from 40% (historical cohort) to 60% in the study arm. Next generation sequencing to evaluate HER2 and other mutations was conducted on the tissue samples of the patients screened for this study. Results: From March 2020 to August 2022, of the 876 patients were screened for HER2 status, 118 (13.4%) were found to have HER2 positive status and 90 of them were enrolled into the study. A majority of patients had GBC (95.6%) and at-least 2 sites of metastatic disease beyond primary (77.8%). With a median follow up of 8.5 months, 72 patients had PD and the median PFS was 7.95 months (95% CI: 6.84 -9.06; median overall survival (OS) was 9.95 months (95% CI: 9.25 – 10.66). Partial responses (PR) were seen in 8 patients (8.9%) and 61 had stable disease (67.7%) for a disease control rate of 76.6%. Common chemotherapy-related grade 3 or 4 adverse events were anemia [26 (28.9%)], neutropenia [18(20%)] and thrombocytopenia [8(8.9%)] while one patient has Trastuzumab related asymptomatic fall in cardiac ejection fraction (>=10%). The presence of isolated TP53 mutations predicted for inferior PFS compared to patients with other mutations (TERT promoter, HER2, PIK3CA etc) or no detected mutations (6.51 months vs. 12.02 months vs. 10.58 months; p<0.001). Conclusions: The combination of GC and trastuzumab shows near doubling of survival in treatment naive HER2 positive BTC in a prospective manner for the first time and sets the stage for a larger phase III trial with the combination. Evaluating mutations like TP53, HER2, TERT promoter and PIK3CA along with HER2 testing could be considered as a preferred modality to select these patients for anti HER2 therapy. Clinical trial information: CTRI/2019/11/021955 . [Table: see text]
Individual patient-level data validation of surrogate and modified endpoints for immunotherapy in advanced hepatocellular carcinoma: Post-hoc analysis of IMbrave150 and real-world observations.
Authors: Lim Mir , Muquith Maishara , Miramontes Bernadette , Lee Chieh-Ju , Huang Yi-Hsiang , Hsiehchen David
Published: June 2023

4090

Background: Immune checkpoint inhibitors (ICIs) have become the preferred treatment for advanced hepatocellular carcinoma (HCC). Surrogate endpoints including overall response rate (ORR) and progression-free survival (PFS) are preferred outcome measures in early-phase trials. However, ICIs can induce atypical patterns of response and progression, calling into question the validity of surrogate endpoints as predictive of overall survival (OS) benefit. We performed a post-hoc analysis of a large, randomized phase 3 clinical trial (IMbrave150) and cross-sectional analysis of a multi-institution real-world environment (RWE) to assess the OS surrogacy of ORR and PFS using Response Evaluation Criteria in Solid Tumors (RECIST), modified RECIST (mRECIST), or immune-modified RECIST (imRECIST) in patients treated with ICIs. Methods: The IMbrave150 cohort in our analysis included 279 out of 336 patients treated with atezolizumab and bevacizumab in the intent-to-treat population. The RWE cohort included 328 patients with Child-Pugh A or B disease treated in the first or subsequent-line setting with anti-PD-1/L1 therapies. RECIST, mRECIST, and imRECIST ORR and PFS data for the IMbrave150 cohort was determined by investigators and central review, while RECIST ORR and PFS data for the RWE cohort was determined by treating providers or retrospective review. Results: In the IMbrave150 and RWE cohorts, Child-Pugh A patients treated in the first-line setting with CR/PR showed greater OS versus patients with SD/PD (IMbrave150: HR 0.16, 95% CI 0.10-0.26; RWE: HR 0.25, 95% CI 0.15-0.43). CR was associated with the greatest OS benefit, followed by PR, SD, and PD. Patients treated in the second-line setting or with Child-Pugh B disease showed that ORR was able to discriminate OS benefit but hazard ratios were closer to the null. In both cohorts, there was a positive rank correlation between RECIST PFS and OS (IMbrave150: Kendall's τ = 0.44, p < 0.001); RWE: Kendall's τ = 0.52, p < 0.001). However, only 31-46% of the variance in OS rankings was explained by PFS rankings. mRECIST PFS and imRECIST PFS showed a positive rank correlation with OS, with an explained variance of 30% and 38% for mRECIST and imRECIST, respectively. Conclusions: Our results suggest that RECIST ORR is a robust surrogate endpoint in HCC treated with ICIs. In contrast, the explained variance between RECIST PFS and OS in both the IMbrave and RWE cohorts was limited. This may reflect the impact of ICIs on response to subsequent therapies which may extend OS benefit. Although prior studies have proposed that modifications to RECIST may lead to more accurate surrogate markers, mRECIST and imRECIST ORR or PFS in HCC treated with ICIs were not associated with greater predictive performance compared to RECIST.
Salvage ipilimumab plus nivolumab in advanced hepatocellular carcinoma after prior anti-PD-(L)1 blockade.
Authors: Alden Stephanie Leigh , Lim Mir , Kao Chester , Shu Daniel , Singal Amit G. , Noonan Anne M. , Griffith Paige , Baretti Marina , Ho Won Jin , Kamel Ihab R. , Yarchoan Mark , Hsiehchen David
Published: June 2023

4091

Background: Combination PD-(L)1/CTLA-4 blockade is approved in patients with advanced hepatocellular carcinoma (HCC) in the first line or after treatment with sorafenib, but it is unclear if combination therapy has efficacy after treatment with anti-PD-(L)1 alone or in combination with a multikinase inhibitor. We evaluated responses to ipilimumab plus nivolumab in patients with advanced HCC who previously received anti-PD-(L)1 to assess the efficacy and safety of this regimen. Methods: We performed a multi-center retrospective review of patients 18 years of age or older with a diagnosis of HCC based on histology or imaging who had received at least one dose of anti-PD-(L)1 therapy prior to receiving ipilimumab plus nivolumab as a subsequent line of therapy. All patients had imaging and/or laboratory monitoring to monitor for disease progression. Results: Our cohort contained 32 patients, with a majority being male (88%, n = 28) and a median age of 67 years. All patients were Child Pugh A (66%, n = 21) or B (34%, n = 11) at the start of treatment, with most having an ECOG performance status of 0-1 (84%, n = 27). The median number of prior lines of therapy was 2 (range 1-8). Prior anti-PD-(L)1 containing regimens included atezolizumab plus bevacizumab (50%, n = 16), other VEGF plus anti-PD-(L)1 combination (31%, n = 10), and anti-PD-(L)1 monotherapy (19%, n = 6). The objective response rate (ORR) was 22% (1 CR, (3%), 6 PR (19%)), with remaining responses including 8 SD (25%), 16 PD (50%), and 1 NE (3%). Among patients who had an objective response to ipilimumab plus nivolumab, none had an objective response to prior anti-PD-(L)1 treatments. Response rates were similar across major clinical (obese vs. non-obese) and etiological (viral vs. non-viral) subsets of HCC. Response to ipilimumab plus nivolumab was associated with improved PFS and OS: median PFS for PD/SD/NE 2.4 months (95% CI: 2.1-NR) vs. PR/CR not reached (NR) (95% CI: 7.5-NR), p = 0.004, and OS for PD/SD/NE 5.9 months (95% CI: 3.1-NR) vs. PR/CR NR (95% CI: NR-NR), p = 0.02. Immune related adverse events (irAEs) were reported in 13 patients (41%), and 6 patients experienced grade 3-4 irAEs (19%). One patient in our cohort experienced a fatal irAE (autoimmune hepatitis), and 5 patients discontinued therapy due to irAEs. Conclusions: This study demonstrates that ipilimumab plus nivolumab has clinical activity in patients with advanced HCC who previously received anti-PD-(L)1 therapy with an acceptable safety profile, supporting this regimen as second line immune checkpoint inhibitor therapy in advanced HCC. Further studies are required to determine the optimal sequence of therapies in advanced HCC.
Efficacy and safety of first-line treatments for patients with advanced hepatocellular carcinoma: A systematic review and network meta-analysis.
Authors: Li Danni , Li Jingyi , Liu Yunpeng , Qu Xiujuan
Published: June 2023

4094

Background: In recent years, the first-line treatment options for advanced HCC has been increasingly abundant, including transarterial therapies, combination of the immune checkpoint inhibitors (ICIs) and the anti-vascular endothelial growth factor (VEGF) inhibitor, ICIs combined with ICIs, and tyrosine kinase inhibitors. However, it remains to be confusing which treatment pattern would benefit people most, especially for different subgroups. Methods: A systematic literature search was conducted on PubMed, Embase, Cochrane Central Register of Controlled Trials, and American Society of Clinical Oncology and European Society of Medical Oncology meeting proceedings for III phase randomized clinical trials (RCTs) investigating first-line treatments for HCC compared with sorafenib. The survival outcomes and toxic effects of RCTs should be reported, including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs) of grade 3 or higher. This systematic review was performed in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines. The random-effects model was used to calculate the summary hazard ratios (HRs) of OS and PFS. The likelihood of ORR, and AEs of grade 3 or higher was performed by odds ratios (ORs) using a random-effects model. Results: A total of 13 phase III RCTs involving 8505 patients were included in this study. Hepatic arterial infusion of oxaliplatin combined with fluorouracil (FOHAIC-1) showed OS, PFS, and ORR benefit over all other first-line therapies, except for the regimen of sorafenib plus HAIC of FOLFOX (OS: HR, 0.88; 95% CI, 0.37-2.09; ORR: OR, 1.53; 95% CI, 0.29-8.13). More importantly, we found that sorafenib combined with FOLFOX was superior to other regimens in patients with HBV infection regarding OS except FOHAIC-1 (HR, 0.57; 95%CI, 0.21-1.52) and tremelimumab-durvalumab (HR, 0.42; 95%CI, 0.16-1.11). While in HCV-infected subgroup, ICIs combined with anti-VEGF inhibitor improved OS benefit compared with tremelimumab-durvalumab (HR, 0.31; 95% CI, 0.11-0.84) and sorafenib (HR, 0.38; 95% CI, 0.16-0.88). HAIC-FO also showed significant OS benefits to other therapies in patients with portal invasion or extrahepatic metastasis. The probability of adverse events of grade 3 or higher was significantly lower with HAIC-FO than with others except for nivolumab (RR, 0.96; 95%CI, 0.51-1.82) and tislelizumab (RR, 0.57; 95%CI, 0.30-1.08). Conclusions: This network meta-analysis supports arterial infusion as the first-line treatment for patients with HCC. In portal invasion and extrahepatic metastasis subgroups, HAIC-FO may be a preferred option, with sorafenib combined with FOLFOX as an additional option in those with HBV infection. Besides, novel combination therapy should be focused on in patients with certain subgroups.
A prospective, open-label, randomized, controlled trial of radiofrequency ablation versus stereotactic body radiation therapy for recurrent small hepatocellular carcinoma.
Authors: Zhang Yaojun , Xi Mian , Chen Minshan , Xu Li , Liu Shi-Liang , Liu Mengzhong ,   Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center
Published: June 2023

4096

Background: Effective treatments are urgently needed to improve the prognosis of patients with recurrent hepatocellular carcinoma (HCC). Previous studies demonstrated that both radiofrequency ablation (RFA) and stereotactic body radiation therapy (SBRT) were promising therapies for recurrent small HCC. This trial was designed to compare the efficacy and safety of RFA versus SBRT in patients with recurrent small HCC. Methods: This is a prospective, open label, randomized controlled trial, in which patients aged between 18 and 75 years with recurrent small HCC (occurred more than 3 months after hepatectomy or RFA, a solitary HCC ≤5.0 cm in diameter without vascular invasion or extrahepatic metastasis), KPS score ≥90, Child-Pugh score ≤6, adequate organ function, and estimated life expectancy ≥6 months were considered eligible. All patients were assigned 1:1 to RFA or SBRT group, and stratification was performed according to tumor size (≤ 2.0 cm or 2.1-5.0 cm). The primary endpoint was 2-year local progression-free survival. Secondary endpoints were progression-free survival, locoregional control, overall survival, and safety. Results: A total of 170 patients were recruited during August 2019 to May 2022 (83 in RFA arm and 87 in SBRT arm). In the ITT population, median age was 56 (range, 33-75) and 15 were female. Baseline characteristics were well balanced between treatment arms. Adverse events occurred in RFA and SBRT were mainly grade 1 or grade 2 in severity, and were gastrointestinal and constitutional symptoms, or abnormal laboratory investigations. The most common adverse events were bilirubin increase（14.6%）and AST increase (13.3%) in RFA group vs ALT increase (20.0%) and AST increase (15.3%) in SBRT group. No Grade 3-4 adverse events or mortality were noted. Late adverse events were hardly observed after 3 months. The follow-up of survival data is ongoing. Conclusions: Both RFA and SBRT are tolerable and safe for patients with recurrent small HCC. This randomized controlled trial will report the survival outcomes in 2024, which will make an important contribution in clinical decision-making for recurrent small HCC. Clinical trial information: NCT04047173 .
A phase II study of olaparib and durvalumab in patients with IDH-mutated cholangiocarcinoma.
Authors: Tsang Erica S. , O'Kane Grainne M. , Knox Jennifer J. , Chen Eric X
Published: June 2023

4099

Background: IDH1/2 mutations (m) occur in approximately 25% of cholangiocarcinomas (CCAs) (20% intrahepatic, < 5% extrahepatic) and result in the accumulation of R-2-hydroxyglutarate (R2HG). R2HG, suppresses homologous recombination repair and as a result IDH1/2m are hypothesized to predict PARP inhibitor sensitivity. PARP inhibition upregulates PD-L1 and the combination is thought to be synergistic. We conducted a phase II trial of olaparib with durvalumab for patients with IDH-mutated cholangiocarcinoma. Methods: Patients with advanced IDHm CCA were enrolled in this phase II open-label study (NCT03991832). Patients received olaparib 300 mg twice daily continuously and durvalumab 1500 mg IV every 4 weeks. Simon’s optimal two-stage design was used, with an interim analysis planned for efficacy. 10 patients were accrued in the first stage, with a plan for expansion if ≥2 responses were observed. The primary objective was to determine the overall response rate (RECIST 1.1) and disease control rate (DCR). Secondary objectives included progression-free survival, overall survival, and safety of the olaparib and durvalumab combination. Results: 10 patients with IDH1m were enrolled in this study between January 2020-August 2021. Median age was 63.5 years (range 49-78), and 50% were female. All patients had a baseline ECOG PS of 0-1. 40% of patients had prior surgical resections and subsequently developed recurrent disease. 20% of patients had ³2 lines of prior chemotherapy, with 90% receiving prior platinum. Median duration of treatment was 1.95 months (range 1.8-13.5). There were no treatment-related grade 3-4 toxicities. Any grade toxicities included fatigue (100%), nausea (60%), anemia (20%), hypothyroidism (20%), elevated liver enzymes (20%). We did not observe any complete or partial responses. The DCR was 30% with 3 patients demonstrating stable disease. One patient remained on treatment for 13.5 months, and was eventually taken off study due to clinical progression. The median PFS was 1.97 months (95% CI 1.73-3.93). Given that no responses were seen in the initial 10 patients, the study did not proceed to Stage 2. Conclusions: While the combination of olaparib and durvalumab was well-tolerated, this study was discontinued after Stage I due to lack of efficacy. IDH1/2m may not induce a BRCAness phenotype and further correlative studies are planned to evaluate this. Clinical trial information: NCT03991832 .
Ex-vivo analysis of programmed cell death on fibrolamellar carcinoma.
Authors: Ajay Olutani-Grace , Kent Paul , Nagourney Robert Alan , Stockwell Tom , Ellison Jessica , Swasey Susanne M. , Tasse Jordan C , Schadde Erik , Humar Abhinav , Kato Tom , Yamashiro Darrell
Published: June 2023

4103

Background: Fibrolamellar carcinoma (FLC) is a rare liver cancer with surgery as the only established treatment. Relapse is common (>80%) and with 40% unresectable, there is a need for rationale systemic therapy. Empiric combinations, especially with lenvatinib (LEN) and gemcitabine (GEM), show promise, but are lacking a CLIA licensed laboratory rationale. Ex-Vivo Analysis of Programmed Cell Death (EVA-PCD), from Nagourney Cancer Institute, is an attempt to meet this need. Methods: Nagourney Institute analyzed FLC tissue (as previously described), with a panel of 34 single/26 combinations of available/promising agents from 18 drug classes. Drug concentration with 50% cell death (LC50), below, within, or above 1-standard deviation of the mean (n ≥ 15), define Highly-Sensitive/Intermediate/Resistant, respectively. Active/Moderate/Inactive are similarly defined but with n < 15. Actionable defines clinically available drug(s), not resistant/inactive and ≥ 6 assays. Results: Forty-four samples from 40 patients (17M,23F, age 6-56, 23 states/4 countries) were analyzed: 80% were viable and 69% of high quality for a total of 378 assays (avg 12/patient). However, all patients had actionable agents, and 78% of the assays showed activity in at least some patients. All the universally resistant/inactive assays (22%) were single agent. 76% of assays were actionable in at least one patient (100% for combinations compared to 62% for single agents). EVA-PCD replicate FLC studies and experience, such as the failure of monotherapy and the importance of LEN. Of 11 patients who had treatment that matched testing, 72% responded as predicted, including 6 with 100% response to LEN and/or QUE as predicted. Overall LEN/QUE, LEN/EVE, TRE, REG, QUE, 5FU/INF performed the best, while single agent ALP, CAB, LAR, VOR, GEM, DAS and IBR all showed 0% activity when tested > 5 times. The largest challenge is the need for an adequate amount of viable tissue to arrive within 24 hours. However our experience demonstrates that it is feasible from other countries and across the US. Conclusions: This is the first demonstration of CLIA approved human FLC tumor testing. Data are in line with literature and correlates clinically. Prospective data are needed to fully incorporate EVA-PCD testing into the clinic. [Table: see text]
Alteration of gut microbiota composition in patients with cholangiocarcinoma with non-responsiveness to first-line chemotherapy: A pilot study.
Authors: Ketpueak Thanika , Sriwichaiin Sirawit , Suparan Kanokphong , Kerdphoo Sasiwan , Charoentum Chaiyut , Suksombooncharoen Thatthan , Chewaskulyong Busyamas , Chattipakorn Nipon , Chattipakorn Siriporn
Published: June 2023

4104

Background: Gut microbiota established crucial roles in host metabolism and several diseases, particularly cancers. Distinct bacterial profiles from intestine are found to be a potential factor in carcinogenesis, while some of those are associated with detrimental treatment to the responsiveness in various types of cancer. Association of gut microbiota and treatment outcome has been thoroughly investigated in intrahepatic cholangiocarcinoma (ICCA). The present study aimed to compare gut microbiota profiles between chemotherapy responder and non-responder in ICCA patients. Methods: Unresectable or metastatic ICCA patients were recruited in the study. The criteria of all patients were naïve to chemotherapy. All patients received first line combination of cisplatin 25 mg/m2 and gemcitabine 1000 mg/m2 at day1 and day 8 in every 21-day cycle and were given up to 8 cycles. The primary endpoint was to evaluate the association between gut microbiota and the objective response rate. Bacterial genomic DNA samples were extracted from the stool using a commercial genomic DNA isolation kit (Qiagen, Hilden, Germany) and then underwent next-generation sequencing. Data analyses were conducted by using QIIME2 and Analysis of Compositions of Microbiomes with Bias Correction (ANCOM-BC). Results: Seventeen ICCA patients were recruited. The objective response rate was 23.5% comparable to historical study. Chemotherapy responder group was defined as partial response patients (N = 4) and chemotherapy non-responder group included stable of disease and progressive disease (N = 13). Baseline characteristics were similar including age, sex, ECOG performance status, numbers of metastatic organ and CA 19-9 in two groups. Median Age were 63 years old (60-70) and 61 (45-73), respectively. Alpha-diversity and beta-diversity were not different between two groups. In chemotherapy non-responder group, some taxa were dominantly observed including Ruminococcaceae, Oribacterium, Oxalobacter, Peptostreptococcus, Aggregabacter, which had been previously reported increasing in ICCA patients. Interestingly, Ruminococcaceae, which was previously documented to be correlated with vascular invasion, was significantly increased abundance in non-responder group. Moreover, the median progression-free survival (PFS) was improved in chemotherapy responder group compared to non-responder group 11.8 and 6.6 month, respectively. Large sample sizes study to confirm this study result should be developed. Conclusions: Distinct bacteria from gut microbiota such as Ruminococcaceae has inversely associated with chemotherapy response in ICCA patients receiving first line cisplatin and gemcitabine combination, suggesting the possibility of the poorer PFS.
Application of the albumin-bilirubin (ALBI) grade as predictive marker of atezolizumab plus bevacizumab (A+B) treatment outcomes for patients with advanced hepatocellular carcinoma (HCC): Real-world retrospective analysis at Veterans Health Administration (VHA).
Authors: Alkadimi Munaf , Fierro Maria Elena , Boyle Lauren Diaz , Lucero Kana , Franklin Kathleen , Mader Michael , Nooruddin Zohra
Published: June 2023

4107

Background: Most clinical trials use Child-Pugh (CP) for patient selection; this subjective scale was originally developed to assess liver function in cirrhosis, thus cannot be applied to HCC patients with non-cirrhotic background. Alternatively, ALBI grade is an objective and validated prognostic system that has demonstrated improved accuracy to predict survival and liver function decline in HCC patients. Our real-world study aims to assess the ALBI grade as a predictive marker of treatment response in patients with advanced HCC who received (A+B) within the VHA. Methods: VHA patients with HCC receiving 1st line therapy with A+B were identified through EMR using ICD-9 or ICD-10 codes between 1 Jan 2007 and 31 Dec 2021. Patients were followed from their A+B initiation date through the earliest of the last VHA visit, loss to follow up, death, or end of study on Jan 31, 2023. Structured electronic health record and chart review data were retrospectively collected to determine patient baseline characteristics, treatment response, overall survival (OS), and progression-free survival. Survival rates were based on patients with at least 6 months or 1 year of time (as indicated) from A+B initiation until the chart was reviewed; patients without a scan or known date of scan were excluded from PFS calculations. The Chi-Squared test was used to compare rates. Results: 332 patients were included in the study. The median age was 67 yrs, 99% were males, 63% non-Hispanic White, 26% Black, 86% with ECOG < 1, 84% had CPS class A, 16% had CPS class B and C, 56% had viral hepatitis-caused HCC, 20% had no cirrhosis present, and 60% had prior local therapies. There was a statistically significant difference in progression free survival (PFS) and over survival (OS) amongst different ALBI grades as shown. Conclusions: In our retrospective cohort, it was clear that patients with ALBI grade 1 had improved PFS and OS compared to ALBI score grade 3. Patients with ALBI score grade 2 also had a moderate response to treatment with modest OS and PFS compared to patients with ALBI score grade 3. Utilizing stratification ability ALBI grade in future clinical trials may improve prognostic power facilitating ideal patient selection. [Table: see text]
Adjuvant immune checkpoint inhibitors and association with recurrence-free survival in postoperative hepatocellular carcinoma (PREVENT): A prospective cohort study.
Authors: Li Le , Liang Xiu-Mei , Chen Kang , Zhang Guan-Lan , Huang Shan , Ma Liang , Zhong Jian-Hong
Published: June 2023

4119

Background: Adjuvant therapy may improve survival of patients with hepatocellular carcinoma (HCC) after curative resection, yet no such therapy is universally recommended. This study compared safety and efficacy outcomes between patients at high risk of recurrence who received different types of adjuvant therapy or no such therapy after hepatic resection for HCC. Methods: Recurrence-free survival (RFS), overall survival, and adverse events were compared among patients who received adjuvant immune checkpoint inhibitors (ICIs) alone, ICIs with tyrosine kinase inhibitors (TKIs), or no adjuvant therapy at our medical center between 13 March 2019 and 19 March 2022. In some analyses, patients who received adjuvant therapy were matched based on propensity scores to patients who did not, in order to reduce confounding due to baseline differences. This study was registered on ClinicalTrials.gov (NCT05221398). Results: Of the 492 patients in our final analysis, 410 (83.3%) received no adjuvant therapy, 50 (10.2%) received ICIs alone, and 32 (6.5%) received adjuvant ICIs and TKIs. During median follow-up of 23.3 months (IQR 15.6 to 31.1 months), HCC recurred in 221 (53.9%) of patients who received no adjuvant therapy, compared to 22 (44.0%) of patients who received ICIs and 18 (56.3%) of patients who received ICIs and TKIs. RFS was significantly longer among patients who received either type of adjuvant therapy (23.9 months, 95%CI 14.0-33.7) than among those who received none (16.8 months, 95%CI 13.2-20.3), and this difference remained significant after propensity score matching (HR 0.61, 95%CI 0.39-0.94, P = 0.033). However, overall survival was unaffected by either type of adjuvant therapy, even after propensity score matching. The rate of grade 3 or 4 adverse events was similar between the two types of adjuvant therapy. Conclusions: ICIs alone or with TKIs may improve RFS of patients at high risk of recurrence after curative resection. Clinical trial information: NCT05221398 .
Machine learning-based multimodal prediction of prognosis in patients with resected intrahepatic cholangiocarcinoma.
Authors: Schmauch Benoit , Brion Eliott , Ducret Valérie , Nasar Naaz , McIntyre Sarah , Sin-Chan Patrick , Maussion Charles , Jarnagin William R. , Chakraborty Jayasree
Published: June 2023

4121

Background: Intrahepatic cholangiocarcinoma (iCCA) is an aggressive malignancy and the second most common primary liver cancer. About a third of patients may benefit from surgery but recurrence is common and the overall survival is low. Accurate prognosis modeling that can predict response to treatment and outcome remains an unmet clinical need. Deep learning methods provide a new opportunity to better predict prognosis by extracting distinguishing characteristics interrogating multiple data sources, which appears to be superior to unimodal modeling. This study aimed to construct a predictive model of patient outcome and identify predictive biomarkers based on a combination of clinical, genomic, histological and radiological data. Methods: We analyzed 83 patients with iCCA that underwent surgery and designed a multi-modal model to predict overall survival (OS) and progression-free survival (PFS). Among these patients, each had one to three hematoxylin/eosin histology slides. As a pre-processing step, each histology slide was decomposed into patches, each patch was fed into a ResNet feature extractor to extract a feature representation of the patch, and the features across patches were aggregated with maximum pooling to yield a 2048-dimensional vector representation for each slide. Among these 83 patients, 76 patients had their tumors profiled for somatic genomic alterations using MSK-IMPACT, a deep targeted-sequencing assay. A binary matrix across altered genes and samples was created as an input to the prediction model. Cox proportional hazard models specific to each modality (clinical data, histological slides, and altered genes) were then designed and their predictions were averaged to produce the final log-risk score. The models were validated using a 5-fold, 5-repeat cross-validation with patient-level splits. Results: A model using only clinical and routine histological data achieved a concordance index of 0.74 (95% confidence interval, 0.64-0.82) for OS and 0.73 (0.64-0.78) for PFS. Adding information about genetic alterations improved performance for OS (0.80, 0.70-0.88) and similar performance for PFS (0.72, 0.64-0.79). Both models outperform a staging-based patient stratification. Conclusions: This study demonstrates that machine learning models can improve survival prediction using multi-modal data after resection of intrahepatic cholangiocarcinoma. Such models have the potential to improve risk stratification and treatment recommendations. [Table: see text]
Efficacy and safety of HepaSphere drug-eluting bead transarterial chemoembolization combined with hepatic arterial infusion chemotherapy in advanced hepatocellular carcinoma.
Authors: Liu Baojiang , Gao Song , Guo Jianhai , Kou Fuxin , Liu Shaoxing , Zhang Xin , Feng Aiwei , Wang Xiaodong , Cao Guang , Chen Hui , Liu Peng , Xu Haifeng , Gao Qinzong , Yang Renjie , Zhu Xu
Published: June 2023

4122

Background: Transarterial chemoembolization (TACE) is widely applied and shows good efficacy in advanced hepatocellular carcinoma (HCC). Recently, hepatic arterial infusion chemotherapy (HAIC) has also gained popularity in the treatment of HCC. Several studies have described the comparison between HAIC and TACE or TACE combined with HAIC. However, the evaluation between TACE plus HAIC and HAIC is rarely reported. Here, we observed the performance of HepaSphere DEB-TACE combined with HAIC (Hepa-HAIC) comparing to HAIC in patients with advanced HCC. Methods: 167 patients diagnosed as advanced HCC and treated in Peking University Cancer Hospital from May 2018 to May 2022 were enrolled in this retrospective study, composed of 74 patients received HepaSphere DEB-TACE combined with HAIC-FOLFOX (Hepa-HAIC) and 93 patients received HAIC-FOLFOX. More than 60% patients experienced other treatments before the enrollment. To avoid the selection bias, propensity score matching (PSM) was conducted and applied for the efficacy and safety analysis between these two cohorts. The primary endpoints are progression-free survival (PFS) and overall survival (OS); the secondary endpoint includes objective response rate (ORR), disease control rate (DCR) and safety. Results: Propensity-matching yielded 48 pairs and the baselines were almost equal in Hepa-HAIC and HAIC cohorts after matching. Median PFS and median OS were both higher in matched Hepa-HAIC cohort (median PFS:8.9 vs. 5.8 months, P=0.035; median OS:22.4 vs. 9.5 months, P=0.027), which were consistent with pre-matching analysis. The ORR in Hepa-HAIC and HAIC cohorts was 75.0% and 37.5%, respectively; DCR was 93.8% after Hepa-HAIC and 81.3% after HAIC. There was no treatment-related death. Serious adverse events were similar in these two groups, except alanine aminotransferase (ALT) and vomiting. There was more frequency of Grade 3–4 ALT elevation in Hepa-HAIC (33.3% vs. 8.3%, P=0.003) while more incidence of vomiting in HAIC group (29.2% vs. 12.5%, P=0.044). Conclusions: All of the observed PFS, OS, ORR and DCR in Hepa-HAIC group are superior to HAIC group, which indicates the combination of HepaSphere DEB-TACE and HAIC may lead to improved outcomes with comparable safety profile in advanced HCC. [Table: see text]
Preliminary results of sequential transarterial chemoembolization and stereotactic body radiotherapy followed by immunotherapy using single tremelimumab regular interval durvalumab in locally advanced, unresectable hepatocellular carcinoma (START-FIT using STRIDE): A single-arm, phase II study.
Authors: Chiang Chi Leung , Chang Stephen Lam , Chan Sik-Kwan , Lee Ann Shing , Chiu Keith Wan Hang , Yeung Vanessa Ting Yan , Wong Natalie Sean Man , Lee Venus Wan Yan , Lau Vince Wing Hang , Man Nancy Kwan , Kong Feng-Ming Spring , Chan Albert Chi Yan
Published: June 2023

4124

Background: Sequential transarterial chemoembolization and stereotactic body radiotherapy followed by immunotherapy (IO) (START-FIT) using anti-PD-L1 has demonstrated promising efficacy in locally advanced HCC (laHCC). We aimed to evaluate START-FIT activity using anti-PD-L1 and anti-CTLA-4 IO backbone. Methods: Adult patients with laHCC not suitable for curative resections were recruited. Each with tumor at least 5cm, maximum three tumors, and child-Pugh A5-B7 liver function. Patients had single TACE, 5-SBRT 28 days after, then single Tremelimumab (300mg) and regular 4-week interval Durvalumab (1500mg) at 7 days upon SBRT completion. Primary endpoint was overall response rate (ORR) per modified Response Evaluation Criteria in Solid Tumors (mRECIST); secondary endpoints included progression-free survival (PFS), overall survival (OS), and treatment-related (TR) adverse event (AE) [NCT04988945]. Results: During 11 Dec, 20 and 3 Oct, 22, 16 patients were enrolled with median age 66 (range (r): 51–84 years), 14 (87.5%) were male, the lesion(s) diameter median sum was 11.2 cm (r: 5.8–15cm), and 11 (68.8%) had macrovascular invasion (n=6, hepatic vein, n=4, branched portal vein, n=1 both). With median 11.3 months (r: 3.7–24.5 months) follow-up time, the best ORR was 81.3% (95% CI: 54.4–96.0%) (Complete response CR: n=7, 43.8%; partial response PR: n=6, 37.5%; static disease SD + progressive disease PD: n=3, 18.7%). The 6 and 12-month PFS rates was 86.7% (95% CI: 69.3–100%) and 58.7% (95% CI: 33.6–84.4%), while 6 and 12-month OS rates was 100% (95% CI: 91.7–100%) and 83.3% (95% CI: 62.2–100%) respectively. The 12-month OS with CR vs. PR vs. SD+PD was 100%, 75%, and 50% respectively. Four (25%) and one patient (6.3%) experienced TRAEs and immune-related AE of grade 3 or worse respectively. Conclusions: START-FIT using STRIDE is safe and effective in unresectable laHCC resulted in 43.8% CR rate and promising survival. Clinical trial information: NCT04988945 . [Table: see text]