bluuebunny/crossref_metadata_2025_split huggingface dataset:
Landmark analysis of OS by response status in previously treated patients (pts) with advanced hepatocellular carcinoma (aHCC): Post hoc analysis of the KEYNOTE-394 study.
Authors: Ren Zhenggang , Chen Zhendong , Fang Weijia , Ou Shuangyan , Ryoo Baek-Yeol , Meng Zhiqiang , Bai Yuxian , Chen Xiaoming , Liu Xiufeng , Xiao Juxiang , Ho Gwo Fuang , Mao Yimin , Wang Xin , Jieer Ying , Hao Chunyi , Shen Hujia , Lin Jianxin , Hatogai Ken , Siegel Abby B. , Qin Shukui 
Published: June 2023

4074 Background: KEYNOTE-224 and KEYNOTE-240 landmark analyses showed that objective response (OR) in pembrolizumab (pembro)-treated pts was prognostic of longer OS after the landmark. Landmark analysis was performed using the KEYNOTE-394 study to determine whether response assessment before landmark is prognostic of longer OS after landmark time in pembro-treated pts. Methods: Adults with confirmed HCC, radiographic progression during or after treatment with or intolerance to sorafenib or oxaliplatin-based chemotherapy were eligible for KEYNOTE-394. Landmark analyses of OS for responders, pts with SD, and pts with other status in these analyses at 6, 12, 18, and 24 wk after randomization were performed on the pembro arm. Tumor imaging was performed every 6 wk after randomization. Responders (R) at each landmark were defined as pts with any response assessment of CR or PR before the landmark date; all other pts were defined as nonresponders (NR). SD at each landmark was defined as pts with a response assessment of SD and no better response before the landmark date. Other was defined as pts with responses of PD or a missing/not evaluable status. Response was assessed per RECIST v1.1 by blinded independent central review. HR and 95% CI for survival after the landmark are based on the Cox regression model with the Efron method for handling ties, with response status by the landmark time as a single covariate. Results: Median time from randomization to data cutoff date (June 30, 2021) was 33.8 mo (range, 18.7-48.8) for pembro. OS after landmark time was numerically longer for R vs NR, R vs pts with SD, and pts with SD vs pts with Other status. Conclusions: KEYNOTE-394 landmark analysis supports the prognostic association between OR with pembro before the landmark and OS after the landmark observed in KEYNOTE-224 and KEYNOTE-240 in previously treated pts with aHCC. Landmark analysis also suggested longer OS after the landmark for pts who achieved a better response to pembro before the landmark. Clinical trial information: NCT03062358 . [Table: see text]
Safety and efficacy of transarterial chemoembolization combined with tyrosine kinase inhibitors and camrelizumab in the treatment of patients with advanced unresectable hepatocellular carcinoma.
Authors: Li Jinpeng , Jia Yuntao , Han Huihui , Lin Yanyan , Song Jinlong 
Published: June 2023

4079 Background: Combined systemic and local therapy is a promising treatment strategy for patients with advanced hepatocellular carcinoma (HCC). Transarterial chemoembolization (TACE), tyrosine kinase inhibitors (TKI) and PD-1 antibodies are all recommended for patients with unresectable HCC (uHCC). This study was aimed to evaluate the efficacy and safety of TACE combined with TKIs and camrelizumab in the treatment of uHCC. Methods: In this multicenter, single-arm phase II trial (ChiCTR2000039508), patients with intermediate-stage uHCC who had a Child-Pugh score ≤ 7 and had not received prior systemic anti-cancer treatment would receive treatment with TACE followed by immunotherapy with camrelizumab 200 mg every 3 weeks plus a TKI agent selected from lenvatinib (12 mg/day for bodyweight ≥60 kg or 8 mg/day for bodyweight <60 kg), sorafenib 400 mg bid or donafenib 200 mg bid until intolerable toxicity or disease progression. During the study treatment, patients assessed as eligible for resection would undergo surgery. The primary endpoint was objective response rate (ORR) per modified RECIST. Secondary endpoints included progression-free survival (PFS), disease control rate (DCR), duration of response (DOR) and overall survival (OS). Results: From September 2020 to November 2021, 87 patients (81 men and 6 women; median age, 56 years) were enrolled. Among them, 43 (49.4%) patients had extrahepatic metastases, and 65 (74.7%) patients had HBV infection. As of September 28, 2022, the median duration of follow-up was 13.6 (0.83-24.9) months. A total of 34 patients (39.1%) died, and the median OS was not reached. The median PFS was 10.5 months (95% CI: 7.8-13.1). The ORR rate was 71.3% (62/87), and the DCR rate was 89.7% (78/87) per mRECIST. According to RECIST version 1.1, the ORR rate was 35.6% (31/87), and the DCR rate was 87.4% (76/87). The ORR and PFS showed consistent benefits in subgroups based on ECOG score, HBV infection, baseline alpha-fetoprotein level, combined TKI, and the number of TACE treatments. Ten patients (11.5%) successfully underwent conversion therapy and all achieved R0 resection. Two patients achieved a complete pathological response (pCR) and four achieved a major pathological response (MPR). The most common AEs were hypoproteinemia (92%), elevated lactate dehydrogenase (80.5%), elevated glutamic oxaloacetic transaminase (79.3%), elevated bilirubin (78.2%), abdominal pain (62.1%), nausea (33.3%), and RCCEP (26.4%). The incidence of grade 3-4 adverse reactions was 67.8%, and no treatment-related deaths occurred. Conclusions: TACE combined with TKI and camrelizumab showed promising clinical benefits. It can effectively control tumor progression and provide opportunities for resection with acceptable safety, which will bring great benefits to uHCC. Clinical trial information: ChiCTR2000039508 .
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.