bluuebunny/crossref_metadata_2025_split huggingface dataset:
External validation of the ARCAD nomogram in a real-world cohort of patients with stage IV colorectal cancer (CRC).
Authors: Yu James , Li Jiannong , Schell Michael , Ginestet Pablo Gonzalez , Zalcberg John Raymond , Simes John , Marschner Ian , Kim Richard D. , Sjoquist Katrin Marie 
Published: January 2024

38 Background: The ARCAD CRC nomogram is designed to predict 1-yr survival in stage 4 CRC to assist with prognostication (Sjoquist, JNCI, 2018). However, this nomogram was developed using patients (pts) enrolled in clinical trials. We sought to externally validate these data in a real-world cohort. Methods: We used the Flatiron database from nationwide records collected from 2013-2020 to create a retrospective Flatiron real-world cohort (FRWC) of pts with histologically confirmed stage 4 CRC. Pts with baseline blood tests prior to treatment (Tx) who had received at least 1 line of Tx were included. Missing data (<8.5%) were imputed using R package MissForest. A multivariable Cox proportional hazards model for overall survival (OS) was applied to fit the reduced model derived from the published ARCAD nomogram as variables from the full model such as number and sites of metastasis were unavailable in Flatiron. The C-index was used to validate the fitted models. The area under a time-dependent ROC (AUROC) analysis was applied to indicate the model prediction performance. Results: A total of 9710 pts, 5740 of whom were deceased were analyzed. The FRWC was older (64 vs 61) and had a poorer ECOG-PS (2+ 14.7% vs 4.2%) compared to the ARCAD. A reduced ARCAD nomogram was derived from the full model (Table). The reduced nomogram calibration was as good as the full model (C-index 0.67 vs 0.68). The 1-yr OS prediction in FRWC using the reduced ARCAD nomogram was good with an AUROC of 0.74. The predictive and observed 1-yr OS using the reduced ARCAD nomogram in the FRWC was 0.640 (95% CI 0.637, 0.644) and 0.727 (95% CI 0.718,0.736). Conclusions: The ARCAD nomogram was validated in the very large FRWC. The observed underestimation of survival by the ARCAD nomogram in the FRWC is likely due to recent advances in Tx options for CRC including targeted- or immunotherapy as the FRWC is more recent compared to pts enrolled in the ARCAD cohort (1997-2012). Our findings indicate that the ARCAD nomogram is a promising decision-making tool for clinicians to predict 1-yr OS in real-world populations. [Table: see text]
A single-center, real-world experience of atezolizumab plus bevacizumab as first-line therapy in patients with unresectable hepatocellular carcinoma, including patients with advanced cirrhosis.
Authors: Parekh Jay , Abraham Soniya , Andanamala Haripriya , Rehman Asad , Ahearn Paul , Adjepong Yaw , Buller Gregory , Stein Stacey 
Published: January 2024

445 Background: Atezolizumab plus bevacizumab (A+B) is approved by the Food and Drug Administration (FDA) for treatment of advanced stage hepatocellular carcinoma (HCC) as first line systemic therapy following results of the IMBRAVE150 trial. Since its approval, limited real-world data is available. The benefit of this treatment in patients with advanced cirrhosis is still unclear, especially in patients with Child Pugh (CP) B cirrhosis. We aim to supplement the trial data with real world outcomes of individuals with unresectable HCC treated with (A+B) in the first line setting including patients with advanced cirrhosis. Methods: This was a single-center, retrospective analysis of patients with advanced HCC treated with A+B as first line systemic therapy between May 2020-January 2023. Patient characteristics, HCC stage, treatment information, adverse events and survival data were collected. Outcomes evaluated included progression free survival (PFS), overall survival (OS), overall response rate (ORR) using RECIST 1.1 and adverse events (AE) rate according to CTCAE v5. R v4.2.1 was used for analysis. Results: We identified a total of 41 patients with advanced stage HCC who received A+B as first line systemic therapy. The median age at diagnosis was 69 years (range 42 – 85). 34(83%) of the patients were males. 8(20%) of the patients were African American. 7(17%) patients had CP B cirrhosis. Median PFS on A+B among all patients was 10.82 months (95% CI: 5.38 – 16.26). Median OS from time of A+B initiation was 14.01 months (95% CI: 10.67 – 17.34). Median OS and PFS were significantly shorter among CP B patients, 6.84(95% CI: NE – 19.36, p = 0.003) and 6.8(95% CI: NE -19.33, p = 0.016) respectively. Hazard ratio (HR) for death from any cause among CP B patients was 4.87(95% CI: 1.35 – 17.48, p <0.01) compared to others. ORR was 31.42%. 10/23(39.13%) patients with CP A had overall response, while 1/7(14.28%) patients with CP B had overall response. AE of any grade was observed in 30(73.2%) patients.10(24.4%) patients had grade 3 or more events, 2(28.5%) among CP B patients. 1(14.2%) had GI bleed among CP B patients, while 4(9.7) patients had GI bleed overall. Common adverse events included fatigue (26.8%), anorexia (26.8%), aspartate aminotransferase (AST) elevation (14.6%), proteinuria (17%), rash (21.9%). Conclusions: Efficacy profile of A+B appears to be sustained in the real world. While the efficacy is inferior in CP B liver disease, A+B remains a viable option for these patients with limited treatment options and acceptable tolerability. Our study adds to the body of evidence for real world data with A+B.
Organ-specific response with first-line atezolizumab-bevacizumab versus lenvatinib for patients with advanced hepatocellular carcinoma.
Authors: Park Young-Gyu , Kim Hyung-Don , Kim Sejin , Kim Kyu-Pyo , Park Sook Ryun , Ryu Min-Hee , Ryoo Baek-Yeol , Yoo Changhoon 
Published: January 2024

467 Background: Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer-related death worldwide. Immune checkpoint inhibitor (ICI)-based treatments have become the mainstay of first-line treatment for unresectable HCC, but there has been a concern that intrahepatic HCC lesions may be less responsive to ICI monotherapy. Methods: This retrospective study included 386 patients with Child-Pugh A unresectable HCC who were treated with first-line atezolizumab-bevacizumab (n = 217) or lenvatinib (n = 169). The organ-specific response was separately evaluated according to the site of the lesions: liver, lung, lymph node (LN), and intra-abdomen based on a radiological evaluation adopted from RECIST v 1.1. Up to 2 lesions were chosen as target lesions in each organ for the organ-specific response evaluation. Results: The median age was 60 years. The majority of study patients were male in both groups (83.4% and 85.8% in the atezolizumab-bevacizumab and lenvatinib groups, respectively). The etiology of HCC was similar between the two groups: hepatitis B virus infection was the most common etiology in both groups (73.3% and 65.7% in the atezolizumab-bevacizumab and lenvatinib groups, respectively), while 21.2% and 29.0% of patients had non-viral HCC, respectively. Extrahepatic spread was identified in 76.0% and 74.6% of patients in the atezolizumab-bevacizumab and lenvatinib groups, respectively: lung, LN, and intra-abdominal metastases were present in 39.6% vs. 39.1%, 30.0% vs. 33.1% and 16.6% vs. 15.4% of patients, respectively. The proportion of patients achieving a ≥ 30% reduction in the tumor burden for each organ category was higher overall in the atezolizumab-bevacizumab group than in the lenvatinib group: 20.2% vs. 11.8%, 23.0% vs. 12.2%, 27.9% vs. 17.9%, and 33.3% vs. 15.0% for intrahepatic, lung, LN and intra-abdominal lesions, respectively. The corresponding values for the subgroup with a viral etiology were 17.3% vs. 8.1%, 18.8% vs. 13.3%, 28.9% vs. 3.6% and 36.0% vs. 12.5%, respectively. Among patients with a non-viral etiology, atezolizumab-bevacizumab was not clearly associated with a better organ-specific response for the LN and intra-abdominal lesions: 20.0% vs. 54.5% and 20.0% vs. 25.0%, respectively, for a ≥ 30% reduction in the tumor burden. Conclusions: Compared to lenvatinib, atezolizumab-bevacizumab was associated with a favorable organ-specific response regardless of the site of the tumor lesions. Unlike anti-PD-1 monotherapy, atezolizumab-bevacizumab had a comparable organ-specific response between intrahepatic and extrahepatic lesions, especially for those with viral etiology HCCs.
Tinengotinib (TT-00420) in combination with atezolizumab in Chinese patients (pts) with biliary tract carcinoma (BTC): Preliminary efficacy and safety results from a phase Ib/II study.
Authors: Zhang Panpan , Gong Jifang , Niu Zuoxing , Cheng Ying , Fan Jean , Peng Peng , Sun Caixia , Wang Hui , Yu Yingying , Zhu Yujia , Wu Yingtong , Li Qing , Huang Peng , Wu Frank , Shen Lin 
Published: January 2024

473 Background: Programmed Cell Death Ligand 1 (PD-L1) inhibitor durvalumab in combination with gemcitabine and cisplatin has been approved as first-line therapy for BTC. However, the efficacy of subsequent standard of care is limited. Tinengotinib is a spectrum-selective multi-kinase inhibitor that targets cell proliferation, angiogenesis, and immune-oncology pathways by inhibiting Aurora kinases A/B, Janus kinases and receptor tyrosine kinases (FGFRs and VEGFRs). Tinengotinib combined with PD-L1 has demonstrated promising antineoplastic activity in preclinical study. Here we present the preliminary data of tinengotinib in combination with atezolizumab (atezo) in pts with advanced BTC from a phase Ib/II trial in China. Methods: In combination therapy, eligible pts with advanced/metastatic BTC were enrolled and treated with tinengotinib plus atezo 1200 mg/20 mL in 21-day cycle. Dose escalation (Phase Ib) and dose expansion (Phase II) were designed. Dose escalation followed a standard 3+3 design. Primary objectives in phase Ib were safety, tolerability, and determination of the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Results: As of 17-Aug-2023, six pts (5 cholangiocarcinoma, 1 gallbladder carcinoma) were enrolled and treated with tinengotinib 8 mg QD plus atezo (n=3) or tinengotinib 10 mg QD plus atezo (n=3). Median age was 62.0 years (range 47-75), 83.3% had ECOG performance status of 1, 83.3% had stage IV disease, 50% had ≥ 3 lines of prior antineoplastic therapies, and 50% had prior immunotherapy. No DLT was observed in these two dose levels. Treatment-related adverse events (TRAEs) were reported in 6 (100%) pts, including Grade (Gr)1-2 for 6 pts, Gr 3 in 2 pts. No Gr 4-5 TRAE. The most common TRAEs (≥ 50%) included hypertension, palmar-plantar erythrodysesthesia syndrome, blood bilirubin increased, proteinuria, hypertriglyceridemia and platelet count decreased. Two pts achieved partial response (PR). One prior immunotherapy naïve pt had a tumor reduction of 48.0% lasting for more than 5 months (tinengotinib 8 mg QD plus atezo). Another pt with prior immunotherapy (sintilimab), target therapy (donafenib) and chemotherapy had a tumor reduction of 39.1% (tinengotinib 10 mg QD plus atezo). Three pts had stable disease (SD). Conclusions: Tinengotinib in combination with atezo was well-tolerated for the treatment of Chinese BTC pts. Preliminary encouraging efficacy of tinengotinib in combination with atezo was observed in pts with heavily pre-treated BTC. The ongoing study is to further evaluate the safety and efficacy of tinengotinib in combination with atezo in pts with BTC who had prior immunotherapy and/or chemotherapy. Clinical trial information: NCT05253053 .
ZSAB-TOP: A phase 2 trial of tislelizumab (TIS) and ociperlimab (OCI) combined with gemcitabine and cisplatin (GemCis) as the first-line treatment for advanced biliary tract cancer (BTC).
Authors: Fan Jia , Zhou Jian , Shi Guoming , Huang Xiaoyong , Ma Liang , Wang Jun-Ye , Gao Qiang , Qiu Shuangjian , Sun Huichuan , Shi Yinghong , Huang Xiao-Wu , Wang Xiaoying , Yi Yong , Zhu Xiaodong , Huang Cheng , Ding Zhenbin , Chen Yi , He Yi-Feng , Shen Yinghao , Sun Qiman 
Published: January 2024

475 Background: GemCis has long been the standard-of-care for advanced BTC, however the prognosis remains poor. Combinations with immunotherapy and GemCis are being explored in BTC. This study aimed to evaluate the efficacy and safety of TIS (an anti-PD-1 antibody) and OCI (a TIGIT inhibitor) combined with GemCis as the first-line treatment for advanced BTC. Herein, the primary analysis results of this study were reported. Methods: In this open-label, single-arm, multicenter phase 2 study, systematic treatment-naïve pts with unresectable advanced BTC received TIS (200 mg, day1, Q3W), OCI (900 mg, day1, Q3W), and GemCis (Gem 1000 mg/m2 and Cis 25 mg/m2 on days 1 and 8 Q3W, up to 8 cycles). The primary endpoint was investigator-assessed objective response rate (ORR) per RECIST v1.1. Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. A binomial exact test with a one-sided α of 0.05 was performed in the analysis of the primary endpoint to test the historical ORR of 25% with GemCis. If p≤0.05, the statistical superiority of the study treatment would be claimed. Results: A total of 45 pts were enrolled, with 75.6% having intrahepatic cholangiocarcinoma and 60.0% metastatic disease. As of 24 Aug 2023 (median follow-up, 8.0 months), 24.4% (11/45) pts remained on study treatment. Among the 41 pts in efficacy analysis set, confirmed ORR (cORR) was 48.8% (20/41, 95% CI, 32.9-64.9, p=0.0009), with 1 complete response. The statistical superiority was achieved. The subgroups of TIGIT+ pts tended to have numerically higher cORR (Table). Median PFS was 7.7 months, with 6-month PFS rate of 67.6%. Median OS was not reached, and 6-month OS rate was 86.2%. Grade ≥3 treatment-related adverse events rate was 60% (27/45). Immune-mediated adverse events rate was 37.8% (17/45), which were mostly grade 1 and 2. Conclusions: The combination of TIS and OCI plus GemCis showed promising anti-tumor activity with manageable safety as the first-line treatment for advanced BTC. Clinical trial information: NCT05023109 . [Table: see text]
Understanding the efficacy of frontline therapies for hepatocellular carcinoma through etiologic stratification.
Authors: Goryachok Maksym , Hu Junxiao , Lentz Robert William , Messersmith Wells A. , Leal Alexis Diane , Kim Sunnie S. , Baiyee Toegel Emily , Lieu Christopher Hanyoung , Davis S. Lindsey 
Published: January 2024

491 Background: Despite significant advancements in recent years, hepatocellular carcinoma (HCC) treatment options remain limited for patients who progress on locoregional therapy. Given increasing interest in personalized cancer care for HCC, analysis was done to understand whether the etiology of HCC influenced the efficacy of four common first-line FDA approved systemic therapy regimens. Methods: This study used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database from 1/1/2003 to 8/1/2021 with 3519 HCC patients who have received either atezolizumab-bevacizumab (AB), nivolumab, sorafenib, or lenvatinib as a first-line systemic therapy. Information on demographics (age, gender, sex race, ethnicity, ECOG, SES Index), cancer stage, and treatment type was collected. In addition, comorbidities of hepatitis B, hepatitis C, alcohol use, diabetes, and obesity were collected as surrogates for disease etiology: viral hepatic disease, alcohol induced hepatic dysfunction or non-alcoholic fatty liver disease (NAFLD). Patients with missing data in any of the population stratifying variables were excluded. Overall survival (OS), Progression-free-survival (PFS) and time to treatment discontinuation (TTTD) were analyzed for each systemic therapy stratified by etiology as endpoints. Kaplan-Meier (KM) univariate analysis was performed along with the log-rank test for the primary outcome. Multivariate analysis (MVA) was conducted on all three endpoints via cox proportional hazard model to adjust for possible covariates in the patient population. Results: After exclusion criteria, 548 patients with complete data were included (AB N=124, Sorafenib N=324, Lenvatinib N=61, Nivolumab N=39) with variable etiologic presence (hepatitis B N=14, hepatitis C N=50, alcohol use N=41, diabetes N=50, Obesity N=44). When comparing patients across all recorded systemic therapies stratified by the etiologic variables, there was no statistically significant difference in OS, PFS, or TTTD. When stratified by presence of Hepatitis B, patients treated with atezolizumab-bevacizumab trended towards improved outcomes but did not reach statistical significance (P = 0.064). Other treatments showed mixed results in relation to specific etiologies, but no clear trend in efficacy emerged. Conclusions: This early retrospective study suggests that systemic therapy for HCC is not significantly impacted by factors associated with the etiology of disease, such as hepatitis C, alcohol use, and obesity. However, small population sizes and potential nonrandom covariate missingness in this study may obscure effects. Future studies are needed to further elucidate this trend along with subpopulation effects of other systemic therapies.
Phase II results of circulating tumor DNA as a predictive biomarker in adjuvant chemotherapy in patients with stage II colon cancer: NRG-GI005 (COBRA) phase II/III study.
Authors: Morris Van K. , Yothers Greg , Kopetz Scott , Puhalla Shannon L. , Lucas Peter C. , Iqbal Atif , Boland Patrick M , Deming Dustin A. , Scott Aaron J. , Lim Howard J , Jacobs Samuel A. , Hong Theodore S. , Wolmark Norman , George Thomas J. 
Published: January 2024

5 Background: For patients (pts) with colon cancer (CC), the detection of circulating tumor DNA (ctDNA) is associated with persistent disease after resection and outperforms traditional clinical and pathological features in prognosticating recurrence risk. We hypothesized that for pts with low-risk stage II CC, a positive ctDNA status after resection may identify those who benefit from adjuvant chemotherapy. Methods: In this prospective phase II/III clinical trial, pts with resected stage II CC without traditional high risk features and whom the evaluating oncologist deems suitable for active surveillance (i.e., not needing adjuvant chemotherapy) were randomized 1:1 to two arms: standard-of-care/observation (Arm A), or ctDNA assay directed therapy (Arm B). Postoperative blood was analyzed for ctDNA with the Guardant LUNAR assay, covering CC-relevant mutations and CC-specific methylation profiling. Arm B pts with ctDNA detected were treated with 6 mos of adjuvant (CAPOX or FOLFOX) chemotherapy. Primary endpoint for the phase II study was clearance of ctDNA at the 6-mo timepoint. A 1-sided Fisher exact test was used to compare ctDNA clearance between Arm A and Arm B among the first 16 pts with ctDNA detected at baseline. If p>.35, the study would be stopped for futility of ctDNA clearance but would otherwise continue to phase III if p≤.35. We present the results of the pre-planned phase II analysis. Results: 635 pts were randomized (Arm A: 318; Arm B: 317). One pt with ctDNA detected in Arm B declined protocol-directed chemotherapy but was included in the intention to treat analysis. Among the first 16 pts with ctDNA detected at baseline for the primary endpoint analysis, clearance of ctDNA after 6 mos was observed in 3/7 pts (43%, 95% CI 10-82%) in the control arm and in 1/9 pts (11%, 95% CI 0.3-48%) in the experimental arm after chemotherapy (p=.98). There were no unanticipated toxicities in those treated with chemotherapy. Conclusions: The phase II endpoint was not met and further enrollment has been halted based upon pre-specified study stopping rules utilizing the original assay. No improvement in ctDNA clearance was observed after 6 mos of chemotherapy for pts with ctDNA detected following resection of stage IIA CC. Future trials evaluating ctDNA as an integral biomarker for minimal residual disease determination must account for assay specificity in this pt population. Support: U10CA180868, -180822; UG1CA189867; Guardant Health. Clinical trial information: NCT04068103 .
Phase 1 trial of navitoclax and sorafenib in patients with refractory solid tumors with a hepatocellular carcinoma expansion cohort.
Authors: Emiloju Oluwadunni Eunice , Yin Jun , Koubek Emily , Reid Joel M. , Borad Mitesh , Lou Yanyan , Seetharam Mahesh , Edelman Martin Joseph , Jiang Yixing , Kaseb Ahmed Omar , Posey James , Davis S. Lindsey , Gores Gregory J , Roberts Lewis R. , Takebe Naoko , Wahner Hendrickson Andrea Elisabeth , Kaufmann Scott H. , Hubbard Joleen , Costello Brian Addis 
Published: January 2024

507 Background: Navitoclax (ABT-263) is an oral Bcl-2 homology-3 mimetic that binds with high affinity to pro-survival Bcl-2 proteins, resulting in apoptosis. Sorafenib, an oral multi kinase inhibitor inhibits tumor angiogenesis and also promotes apoptosis. The efficacy of either agent alone is limited; however, preclinical studies demonstrate synergy with the combination of navitoclax and sorafenib. Methods: In this phase 1 pharmacokinetic and pharmacodynamic study (NCT01364051), we evaluated the combination of navitoclax and sorafenib in a dose escalation cohort of patients with refractory solid tumors, with an expansion cohort in hepatocellular carcinoma (HCC). The study agents were provided by the Cancer Therapy Evaluation Program at National Cancer Institute under CRADA. Navitoclax and sorafenib were administered continuously on days 1 through 21 of 21-day cycles. The maximum tolerated dose (MTD) was determined using the continual reassessment method. Results: Ten patients were enrolled in the dose escalation cohort and 15 patients with HCC were enrolled in the expansion cohort. Two dose levels were tested, dose level 1 (navitoclax 150 mg daily plus sorafenib 400 mg twice daily) and dose level 2 (navitoclax 200 mg daily plus sorafenib 400 mg twice daily). At dose level 1, one dose limiting toxicity (DLT) [grade 3 aspartate aminotransferase elevation] was observed among 6 patients treated at this dose level. In a cohort of 3 patients treated at dose level 2, two DLTs were observed (grade 3 hypertension, and grade 3 rash), hence dose level 1 was identified as the MTD. Among all patients, the most common grade 3 toxicity was thrombocytopenia (5 patients, 20%): there were no grade 4 or 5 toxicities (Table). Patients received a median of 2 cycles (range 1-36 cycles) and all patients were off study treatment at data cut off. Six patients in the expansion cohort had stable disease, 5 had progressive disease and 4 with unavailable data. There were no partial or complete responses. Drug-drug interaction between navitoclax and sorafenib was not observed. The combination of navitoclax and sorafenib did not increase induction of apoptosis compared with navitoclax alone. Conclusions: Navitoclax plus sorafenib resulted in manageable, but not ideal toxicities for continuous oral administration which precluded dose escalation. The lack of clinical benefit in the HCC expansion cohort does not support further development of this combination for the treatment of advanced HCC. Clinical trial information: NCT01364051 . [Table: see text]