bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase 1b/II study of durvalumab (D) and tremelimumab (T) plus PET-adjudicated chemoradiation (CRT) in patients (Pts) with esophageal adenocarcinoma.
Authors: Ku Geoffrey Yuyat , Wu Abraham Jing-Ching , Trivedi Nikhil , Maron Steven Brad , Joshi Smita Suhas , Ilson David H. , Janjigian Yelena Y. , Shcherba Marina , Li Jia , Tang Laura H. , Yeh Randy , Sihag Smita , Park Bernard J. , Jones David Randolph , Molena Daniela
Published: January 2024

355

Background: We previously evaluated adding D, an anti-PD-L1 antibody, to PET-directed CRT and found the combination to be safe and promising in terms of pathologic response and survival outcomes.1 Here, we add T to the combination. Methods: Pts with locally advanced esophageal/GEJ adenocarcinoma were enrolled. Pts received 2 cycles of mFOLFOX6 prior to repeat PET/CT. PET responders (≥35% reduction in SUV (PETr)) received 5-FU/capecitabine and oxaliplatin with RT, while induction PET non-responders (PETnr) received carboplatin/paclitaxel with RT. All Pts received T 300 mg ×1 and D 1,500 mg q4W ×2 starting 2 weeks prior to CRT. Esophagectomy was planned 6-8 weeks after CRT. Pts with R0 resections received adjuvant T 300 mg ×1 and D 1,500mg q4W ×6. The primary endpoint was the pathologic complete response (pCR) rate. Initially, 6 Pts were enrolled to evaluate for toxicity; they received RT to 50.4 Gy. Subsequently, RT was lowered to 41.4 Gy to decrease the length of preop treatment (tx). Results: 16 pts have been enrolled. All Pts had clinical ≥T3 and/or N+ disease. PD-L1 CPS was ≥1 in 9 (60%) of 15 tested. 1 Pt (6%) had a microsatellite unstable (MSI) tumor. 9 (56%) Pts were PETr; 3 Pts (19%) were PETnr but had improved clinical symptoms and other PET parameters (MTV/TLG) and also continued with 5-FU/capecitabine and oxaliplatin during RT. Significant tx-related adverse events (AEs) are shown in the Table. Immune-related AEs (irAEs) were: gd 3 enterocolitis (1 Pt), gd 3/4 colitis (2 Pts, 12%), gd 1 diarrhea (1 Pt), gd 2 pruritis (1 Pt), gd 1 and gd 3 dermatitis (1 Pt each) and gd 2 arthralgias in 1 Pt. 1 Pt died of aspiration pneumonia while being treated for gd 4 colitis during CRT; 1 Pt developed gd 3 enterocolitis and cholecystitis during CRT, achieved a clinical CR and did not undergo surgery. He developed local recurrence and had surgery off-study 16 months after start of tx; 1 Pt developed a bone metastasis after CRT. 4 Pts are awaiting restaging post-CRT. Of 9 Pts who had surgery, 4 achieved a pCR (44%, including the MSI Pt) and 3 (33%) had ypN0 tumors and ³90% tx response. All 9 Pts have initiated/completed adjuvant D+T. Conclusions: The addition of D+T to induction FOLFOX and PET-directed CRT prior to surgery is feasible, although irAEs seem numerically higher than in our prior study of D and CRT. Pathologic response data are promising. Accrual is ongoing and updated data will be presented. 1. Ann Surg 2023;278:e511. Clinical trial information: NCT02962063 . [Table: see text]
Short-term outcomes of pedicled jejunum reconstruction after esophagectomy for esophageal cancer.
Authors: Matano Mamoru , Kanetaka Kengo , Kobayashi Shinichiro , Kobayashi Kazuma , Inoue Yusuke , Soyama Akihiko , Adachi Tomohiko , Eguchi Susumu
Published: January 2024

369

Background: The number of patients with esophageal cancer after gastrectomy and patients accompanied with simultaneous gastric cancer has gradually increased because of the prevalence of gastric in Japan. Pedicled jejunum is one of the choices for esophageal reconstruction when the stomach is not available. However, surgical outcomes of jejunal reconstruction and the effect of the timing of gastrectomy remain to be elucidated. Methods: This study was a retrospective, cohort study that included 24 patients who underwent supercharged pedicled jejunal conduit for esophageal reconstruction in our institution between May 2007 and July 2023. The patients were divided into two groups: gastrectomy was performed before esophagectomy (A group) and gastrectomy was performed simultaneously for accompanied gastric cancer (S group). Surgical outcomes and postoperative complications were compared between the two groups. As a nutritional assessment, perioperative change in body composition such as visceral fat area (VFA) with computed tomography was analyzed. Results: In 24 patients, the median operative time was 769 minutes and the median blood loss was 543 g. Severe postoperative complications developed in 6 cases (25%). The A group included 15 cases and the S group did 9 cases. There was no statistical difference in postoperative complication between the two groups, however, postoperative hospital stay was statistically longer in the S group than in that of the A group (37 days vs. 21 days, p=0.02). Although weight loss at 1 year after operation was almost identical in the two groups, the loss of VFA was more severe in the S group than in the A group (23 % of preoperative VFA vs. 77% of preoperative VFA, p=0.03). Conclusions: The use of a pedicled jejunal conduit after esophagectomy could be performed safely. Postoperative nutritional support is needed for patients especially those who underwent simultaneous gastrectomy.
Phase II trial of cabozantinib (cabo) plus durvalumab (durva) in chemotherapy refractory microsatellite stable (MSS) patients with advanced gastric and esophageal (G/E) adenocarcinoma: CAMILLA G/E cohort results.
Authors: Saeed Anwaar , Park Robin , Dai Junqiang , Kasi Anup , Barbosa Lori , Mulvaney Kelly , Rarden Jordan , Phadnis Milind A. , Saeed Azhar , Sahin Ibrahim Halil , Baranda Joaquina Celebre , Williamson Stephen K. , Sun Weijing , Al-Rajabi Raed Moh'd Taiseer
Published: January 2024

373

Background: Cabo is a multi-tyrosine kinase inhibitor harboring anti-VEGFR2, MET, AXL, MER and TYRO3 activity. Immunomodulatory and synergistic anti-tumor activity of cabo in combination with PD-1/L1 inhibitors have been demonstrated preclinically and in prior studies in various solid tumors. The phase Ib gastrointestinal (GI) basket CAMILLA trial evaluating cabo + durva confirmed manageable toxicity and anti-tumor activity, leading to the expansion into a multi-cohort phase 2 study. Herein, we report the results of the phase II G/E adenocarcinoma cohort. Methods: Patients (Pts) enrolled in the phase II G/E adenocarcinoma cohort were administered cabo + durva at the RP2D of 40mg QD and 1500mg IV Q4W respectively. Enrolled pts must have progressed on >1 line(s) of systemic therapy. Prior exposure to PD-1/L1 inhibitors was allowed. Those with HER2 positive disease must have progressed on anti-HER2 therapies. The primary outcome was objective response rate (ORR). Secondary outcomes were treatment-related adverse events (TRAEs), disease control rate (DCR), progression free survival (PFS), and overall survival (OS). Exploratory subgroup analyses were conducted in PD-L1 CPS >5. Results: 31 patients were enrolled, with 29 patients evaluable for efficacy. The median age was 61 years (range 32-79). 86% had an ECOG performance status of one. 48% had ≥ 2 prior lines of systemic therapies (range 1-4). Of the 29 pts evaluable for efficacy, 6 pts had confirmed objective responses (5 PR + 1 CR = ORR 20.69%). The most common TRAEs were fatigue (65%), anorexia (58%), elevated liver enzymes (39%), and diarrhea (35%). Grade >3 TRAEs occurred in 19% of pts. Grade >3 immune-related adverse events (irAE) rate was 6%. DCR was 86.2% (25/29). Median PFS and OS were 4.4 (95% confidence interval (CI) 2.2-5.4) and 5.6 months (95% CI 3.6-8.3) respectively. In patients with PD-L1 CPS >5 (12/29), ORR was 25%, and median PFS and OS were 5.5 months (95% CI 1.8-12.4) and 19.3 months (95% CI 2.3-28.2) respectively. Conclusions: Cabo + durva showed anti-tumor activity and manageable toxicity in advanced chemotherapy refractory G/E adenocarcinoma. Further evaluation in patients with high PD-L1 CPS ≥ 5 is warranted in a future randomized trial. Clinical trial information: NCT03539822 .
Genomic analysis of oesophageal carcinoma (EC) to identify recurrent mutations in histone methyltransferases as a distinctive subset.
Authors: Wang Jingyuan , Xiu Joanne , Oberley Matthew James , Battaglin Francesca , Arai Hiroyuki , Soni Shivani , Zhang Wu , Goldberg Richard M. , Shields Anthony F. , Grothey Axel , Hwang Jimmy J. , Marshall John , Astsaturov Igor A. , Weinberg Benjamin Adam , Lou Emil , Hall Michael J. , Shroff Rachna T. , Khushman Moh'd M. , Sohal Davendra , Lenz Heinz-Josef
Published: January 2024

379

Background: Histone-lysine N-methyltransferase 2 (KMT2) family proteins methylate lysine 4 on the histone H3 tail at important regulatory regions in the genome and thereby impart crucial functions through modulating chromatin structures and DNA accessibility, which is associated with tumorigenesis and immune tolerance, indicating its possible correlation with the efficacy of immunotherapy. Recurrent mutations of KMT2 have been identified in EC, but data addressing the molecular features of KMT2 mutated (MT) EC are lacking. We aimed to understand the molecular profile of KMT2 -MT EC. Methods: A total of 787 oesophageal carcinoma [adenocarcinoma (EAC), N=604; squamous cell carcinoma (ESCC), N=183] were analyzed using next-generation sequencing (NGS) and immunohistochemistry (Caris Life Sciences, Phoenix, AZ). Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous mutations, and mismatch repair deficiency (dMMR)/microsatellite instability-high (MSI-H) status was evaluated by a combination of IHC, Fragment analysis and NGS. Results: The mutation spectrum of KMT2A/C/D was significantly different between ESCC and EAC ( KMT2A, 2.7% vs. 1.2%; KMT2C, 3.8% vs. 1.2%; KMT2D, 14.2% vs. 2.0%, P <0.05). KMT2-MT EAC tumors showed significantly higher mutation rates in CIC (13% vs 1.1%), NF1 (12.5% vs 2.2%), FBXW7 (12% vs 3.4%), ATM (11.5% vs 2.6%) and BRCA1 (11.5% vs 1%, all q<0.05), compared to KMT2-WT tumors. However, in ESCC there were no significant differences in gene mutations between the KMT2-MT and WT groups. Significantly higher rates of dMMR/MSI-H (19.2% vs 1.0% in EAC, 5.4% vs. 0% in ESCC, both p<0.01) were seen in both KMT2-MT ESCC and EAC, compared to KMT2-WT cohorts, respectively. TMB was significantly higher in both KMT2-MT ESCC (median: 10 vs 8.6 mut/Mb, P=0.042) and EAC (23.9 vs 8.0 mut/Mb, P<0.0001), compared to KMT2-WT cohorts, respectively. A numerically longer immune-related overall survival was observed in KMT2 -MT EC patients, compared to KMT2 -WT EC patients (9.05 vs 6.98 months, HR=0.744, 95%CI: 0.52-1.07, P =0.11). Conclusions: This is the largest study to investigate the distinct genomic landscapes between KMT2 -MT and WT EC to date. Our data showed the KMT2 -MT EC has a distinctive genetic profile, indicated by higher TMB, and higher frequency of dMMR/MSI-H and gene mutations involved in DDR and epigenetic regulation. Understanding these molecular characteristics may be informative in the development of effective treatment strategies in KMT2 -MT EC.
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]
Impact of baseline liver function on survival outcomes in patients with unresectable hepatocellular carcinoma (uHCC) treated with camrelizumab + rivoceranib vs sorafenib: A post hoc analysis of study CARES-310.
Authors: Vogel Arndt , Cheng Ann-Lii , Shi Wei , Jang Seong , Alexander Laura , Meng Xianzhang , Raphael Natalia , Chan Stephen Lam
Published: January 2024

509

Background: CARES-310 study (NCT03764293) evaluated the combination of camrelizumab, an anti-PD-1 inhibitor, and rivoceranib, a highly selective VEGFR-2 tyrosine kinase inhibitor, (cam + rivo) vs sorafenib (sora) for the treatment of uHCC. Cam + rivo significantly improved median overall survival ([mOS] 22.1 months [mo] vs 15.1 mo) and median progression-free survival ([mPFS] 5.6 mo vs 3.7 mo) compared to sora. This post-hoc analysis evaluated the impact of baseline albumin-bilirubin (ALBI) grade and Child-Pugh (CP) class on survival outcomes. Methods: In this randomized, open-label, international, multicenter, phase 3 study, patients were randomized 1:1 to receive cam 200 mg IV Q2W + rivo 250 mg PO QD (n=272) or sora 400 mg PO BID (n=271). Median overall survival (mOS), median progression free survival (mPFS), objective response rate (ORR), disease control rate (DCR), and safety were assessed by baseline ALBI grade and CP class. Results: mOS, mPFS, DCR, and ORR improved with cam + rivo vs sora regardless of baseline liver function (Table). Although treatment-related grade 3/4 AEs occurred at a greater rate in the cam + rivo arm vs the sora arm, the rate of these events was similar for patients with baseline ALBI grade 1 and grade 2 (cam + rivo, 82.1% and 81.7% vs sora, 53.9% and 54.0%, respectively). Median time-to-deterioration (mTTD) to CP class B was similar between treatment arms for ALBI grade 1 (not evaluable [NE], NE) and grade 2 (cam + rivo, 10.1 mo; sora, 10.6 mo; HR, 0.99). Conclusions: In this post-hoc analysis of Study CARES-310, the efficacy of cam + rivo was superior to sora regardless of baseline liver function as measured by both ALBI grade and CP class. Despite a higher rate of grade 3/4 AEs, there was no detrimental effect of cam +rivo on liver function in patients with both well- and moderately- preserved liver function compared to sora. These results support cam + rivo as a potential new first-line treatment option for patients with uHCC regardless of baseline liver function. Clinical trial information: NCT03764293 . [Table: see text]
Novel GPC3-targeting radiopharmaceutical therapy for hepatocellular carcinoma.
Authors: Lin Fanching , Clift Renee , Ehara Takeru , Yanagida Hayato , Horton Steven , Salvador Katrina , Richardson Samantha , Guest Matt , Noncovich Alain , Bhat Abhijit , Han Guangzhou , Song Ken , Rearden Jessica , Li Gary
Published: January 2024

525

Background: Glypican-3 (GPC3) is a membrane-anchored oncofetal protein whose expression is largely absent in normal tissues. Significant upregulation of GPC3 protein has been observed in approximately 75% of hepatocellular carcinomas (HCC), and is associated with poor prognosis. The differential expression of GPC3 between tumor and normal tissues provides an opportunity for targeted radiopharmaceutical therapy (RPT) to treat HCC, a leading cause for cancer-related deaths worldwide. Methods: RAYZ-8009 comprises a novel macrocyclic peptide binder to GPC3, a linker, and a chelator that can be complexed with different radioisotopes. The affinity of peptide binders to GPC3 was determined by surface plasma resonance (SPR) and radioligand binding assays. Target-mediated cellular internalization was radiometrically measured at multiple time points. In vivo biodistribution, monotherapy and combination treatments with 177Lu or 225Ac were performed in HCC xenografts. Results: RAYZ-8009 showed high binding affinity (KD=0.7 nM) to human GPC3, with comparable affinity to GPC3 of human, mouse, canine and monkey origins, and no binding to other GPC family members. Potent cellular binding was confirmed in GPC3+ HepG2 cells, and was not affected by isotope switching. RAYZ-8009 achieved efficient internalization upon binding, with 42% internalized by 20 minutes in HepG2 cells. Biodistribution study of 177Lu-RAYZ-8009 showed sustained tumor uptake and fast renal clearance, with minimal or no uptake in other normal tissues. Exquisite tumor-specific uptake was also demonstrated in orthotopic HCC tumors with no uptake in surrounding normal liver tissue. Therapeutically, significant and durable anti-tumor effect and survival benefit were achieved with 177Lu- and 225Ac-labeled RAYZ-8009, as monotherapy or in combination with lenvatinib, in GPC3+ HCC xenografts. Conclusions: Preclinical in vitro and in vivo data demonstrate the potential of RAYZ-8009 as a theranostic agent for the treatment of patients with GPC3+ HCC.
Progression pattern and post-progression survival following atezolizumab and bevacizumab treatment in advanced hepatocellular carcinoma.
Authors: Kobayashi Satoshi , Fukushima Taito , Ueno Makoto , Chuma Makoto , Numata Kazushi , Tsuruya Kota , Arase Yoshitaka , Hirose Shunji , Kagawa Tatehiro , Hattori Nobuhiro , Watanabe Tsunemasa , Matsunaga Kotaro , Uojima Haruki , Hidaka Hisashi , Kusano Chika , Morimoto Manabu , Maeda Shin
Published: January 2024

539

Background: Although the combination of atezolizumab and bevacizumab (ATZ + BEV) is a standard treatment for advanced hepatocellular carcinoma (HCC), strategies for addressing treatment failure and prognostic factors of post-progression survival remain unestablished. Methods: We conducted a multicenter retrospective study to evaluate post-progression survival following ATZ + BEV treatment in patients with advanced HCC. We classified the patients into four groups: BCLC stage B with or without new intrahepatic lesions (BCLCp-B1 and BCLCp-B2, respectively) and BCLC stage C without or with new extrahepatic lesions (BCLCp-C1 and BCLCp-C2, respectively) at the time of progression. Results: Of the 204 patients who started ATZ + BEV treatment between October 2020 and September 2022, 110 showed disease progression, with 25, 8, 55, and 22 showing the BCLCp-B1, BCLCp-B2, BCLCp-C1, and BCLCp-C2 stages of the disease, respectively. Specifically, patients with the BCLCp-B1 stage of the disease showed better overall survival than those with the BCLCp-B2, BCLCp-C1, and BCLCp-C2 stages (hazard ratios: 2.19 (95% confidence interval [CI], 0.61–7.86), 2.16 (95% CI, 1.13–4.11), and 2.97 (95% CI, 1.42–6.23) for HCC stages BCLCp-B2, BCLCp-C1, and BCLCp-C2, respectively). Via multivariable analysis, we identified the BCLCp-C1 and BCLCp-C2 stages, as well as performance status, Child-Pugh class, and alpha-fetoprotein as poor prognostic factors for post-progression survival. Conclusions: BCLCp-B1 stage was identified as a better prognostic factor for post-progression survival following ATZ + BEV treatment compared with BCLCp-B2 stage as well as BCLCp-C1 and BCLCp-C2 stages. This may help in making decisions regarding subsequent treatment after ATZ + BEV.
Extrahepatic cholangiocarcinoma: Genomic variables associated with anatomical location and outcome.
Authors: Preston William A , Drill Esther N. , Boerner Thomas , Harding James J. , Cercek Andrea , O'Reilly Eileen Mary , Abou-Alfa Ghassan K. , Park Wungki , Balachandran Vinod P. , Drebin Jeffrey A. , Soares Kevin , Wei Alice Chia-Chi , Kingham T. Peter , D'Angelica Michael Ian , Jarnagin William R.
Published: January 2024

554

Background: Genomic determinants of outcome in intrahepatic cholangiocarcinoma have become clear but remain ill-defined in extrahepatic cholangiocarcinoma (ECA). We aimed to clarify the genomic alterations that define ECA, analyze differences between perihilar (PCA) and distal (DCA) disease, and determine clinicopathologic and genomic factors associated with survival. Methods: Patients with EHC with tissue available for targeted next-generation sequencing at Memorial Sloan Kettering Cancer Center were identified. Differences between PCA and DCA were compared, stratified by disease extent and treatment. Associations between genomic alterations and clinicopathologic features and outcomes were analyzed. Univariable and then multivariable cox proportional hazards regression were used to compare survival, which was reported from operation in resected patients and from diagnosis in non-resected patients. Results: Two-hundred-twenty-four patients (n=127 PCA, n=97 DCA, 2006-2022) met inclusion criteria. Median survival was 29 months (IQR [25, 35]; 43 months [35, 48] resection, 17 months [13, 19] without). Compared to PCA, DCA was enriched in TP53mut (67 [69%] vs. 42 [33%]), Q<0.01) and epigenetic pathway alterations (44 [45%] vs. 37 [29%], Q=0.041) and had more altered pathways (3 vs. 2, Q<0.01). KRASmut was similar between PCA (46 [36%]) and DCA (36 [37%]); however, PCA was enriched in KRAS G12V (16 [13%] vs. 4 [4%]) and Q61H (11 [9%] vs. 3 [3%], P=0.002). No other clinicopathologic or genomic variables distinguished PCA from DCA (Table). MDM2mut occurred in 19/141 (13%) patients with nodal/metastatic disease compared to 1/83 (1%) patients with local disease ( Q=0.03), but conferred no survival disadvantage. In resected patients, survival was similar between PCA and DCA and no genomic alterations were associated with outcome. By contrast, in patients without surgery, CDKN2Adel (HR 2.59, 95% CI [1.48, 4.52]) and APCmut (HR 5.11, 95% CI [1.96, 13.3]) were associated with survival disadvantages. Lack of resection (HR 3.13, 95% CI [2.25, 4.36]), CDKN2Amut (HR 1.80 [95% CI 1.80, 2.68), and APCmut (HR 2.00 [95% CI 1.04, 3.87]) were associated with poor survival in the entire cohort. Conclusions: In this study, aside from a higher incidence of TP53mut in DCA and some differences in KRAS subtype alteration patterns, genomic alterations were comparable between PCA and DCA. CDKN2Amut and APCmut were associated with poor survival in all patients but no biomarkers provided significant prognostic information when tumors were resected. [Table: see text]
Surrogate endpoints for overall survival in advanced hepatocellular carcinoma: A meta-analysis.
Authors: Saleh Yacob , Baskurt Zeynep , Farooq Abdul Rehman , Goodwin Rachel Anne , Knox Jennifer J. , Chen Eric X
Published: January 2024

563

Background: Recent advances in systemic therapies have resulted in improved overall survivals (OS) for patients with advanced hepatocellular carcinoma (aHCC). The most commonly utilized primary endpoint for phase III trials in aHCC is OS. A robust surrogate endpoint (SEP) can reduce time and financial costs of future trials and accelerate regulatory approvals of new therapies. We conducted a literature-based meta-analysis to evaluate SEPs for OS in aHCC. Methods: Randomized controlled trials evaluating systemic therapies in aHCC published 2007 - 2023 were identified through a systemic literature search of Cochrane and Medline databases as well as of abstracts presented at ASCO and ESMO meetings. Hazard ratios (HR) for OS and progression-free survival (PFS) and time to progression (TTP) were extracted. ΔORR was calculated as the difference in overall response rates (ORR) between control and experimental arms. Pearson correlation and mixed-effects meta-regression analyses were performed. Surrogate threshold effect (STE) was determined for each comparison when possible. A p < 0.05 was considered to be statistically significant. Results: 26 trials were identified in the first-line setting with 14,827 patients and 11 trials in the subsequent-line setting with 5,316 patients. In first-line trials, immunotherapy (IO) is associated with higher ORR than other agents (p=0.003). There are statistically significant correlations between HRs of PFS/TTP/ΔORR and OS (Table). The relationship between HR-PFS and HR-OS persists in trials with or without IO, but only in trials enrolling < 30% patients of non-viral aetiologies. In subsequent-line trials, there are statistically significant correlations between HRs of PFS/TTP and OS (Table). STE for HR PFS is 0.68 and 0.87 respectively for 1st and subsequent line trials. Conclusions: There are moderate to strong correlations between PFS and OS in aHCC in first-line and subsequent line trials. STE for HR-PFS of 0.68 in first-line and 0.87 in subsequent-line settings can guide sample size calculation in future clinical trials. [Table: see text]
Preoperative weight loss program for hepatocellular carcinoma patients with high body mass index in hepatectomy.
Authors: Saito Yu , Morine Yuji , Yamada Shinichiro , Teraoku Hiroki , Ikemoto Tetsuya , Shimada Mitsuo
Published: January 2024

565

Background: This study aimed to investigate the usefulness of a weight-loss program (WLP) in patients with a high body mass index (BMI) prior to liver resection (Hx) for hepatocellular carcinoma (HCC). Methods: Among 445 patients with HCC who underwent initial Hx between 2000 and 2020, 19 with a high BMI (≥25.0) were enrolled in our WLP since 2014. For calorie restriction, the amount of energy consumed was calculated as the standard body weight (SBW) kg × 20–25 kcal/day. Protein mass was calculated as SBW kg × 1.0–1.2 g/day to maintain skeletal muscle mass. Patients also performed both aerobic and resistance exercises. The before-and-after changes were compared, and the effect of WLP on the short- and long-term results was investigated. Results: The average length of WLP was 21 days, and weight loss was successfully achieved in all patients. Body fat mass was reduced during the program, while skeletal muscle mass was maintained. WLP led to improvements in liver function and fibrotic markers, without tumor progression. There were no postoperative complications (≥Clavien–Dindo [CD] III). A retrospective comparison of postoperative outcomes revealed that those in the WLP group showed a significantly shorter operation time and improved postoperative morbidity rate (≥CD III) with decreased postoperative hospital stay. There were no significant differences in long-term prognosis based on participation in the WLP. Conclusions: WLP with multidisciplinary intervention improved short-term outcomes after Hx in patients with HCC and a high BMI.