bluuebunny/crossref_metadata_2025 huggingface dataset:
Nab-paclitaxel plus sintilimab as second-line therapy for advanced or metastatic gastric or gastroesophageal junction adenocarcinoma (G/GEJA): Preliminary results from an open-label, single-arm, phase 2 study.
Authors: Jiang Zhichao , Zhang Wen , Yang Lin , Sun Yongkun , Zhao Yun-Bo , Deng Wei , Zhou Ai-Ping
Published: January 2022

293

Background: Anti-PD-1 antibody showed some efficacy but was not superior to mono-chemotherapy in the second line (2L)-treatment of advanced or metastatic G/GEJA. The combination of chemotherapy and anti-PD-1 antibody has been demonstrated to have a synergistic effect. Nab-paclitaxel (nab-PTX) was one of the most common used 2L-regimens in Asia. Therefore, we aimed to assess efficacy and safety of nab-PTX plus sintilimab in patients (pts) with advanced G/GEJA in this study. Methods: This was an open-label, single-arm, phase 2 study undertaken at the National Cancer Center of China. Eligible patients were aged 18 to 75 years old with histological or cytological diagnosis of G/GEJA, had an ECOG PS of 0 or 1 and measurable disease according to the RECIST v 1.1 after 1L-chemotherapy with fluoropyrimidine and platinum. Patients received nab-PTX (125mg/m2, d1 & d8, ≤ 6 cycles) and sintilimab (200mg, d1, ≤ 2 years) every 3 weeks. The primary endpoint was objective response rate (ORR). The threshold 2L-therapy ORR was set to 13% and the expected ORR was 30%. Results: From Nov 4, 2019, to Sep 15, 2021, 36 pts were enrolled and 31 pts were eligible for response assessment. Median age was 58y and 58.1% were men. Median follow-up time was 7.8 months (95% CI 3.299-12.301). ORR was 41.9%. One patient (pt) achieved complete response and 12 pts acquired partial response. Disease control rate was 83.9%. Median progression free survival was 5.2 months (95%CI 3.556-6.848). The most common treatment-related adverse events (TRAEs) of grade 3-4 were neutropenia (19.4%), leukopenia (9.7%), aspartate aminotransferase increased (9.7%), thrombocytopenia (3.2%) and fatigue (3.2%). No treatment-related deaths occurred. The potential immune-related adverse events (irAEs) were hypothyroidism (3 pts [9.7%]), pneumonia (1 pt [3.2%]), myocardial enzyme elevation without any syndrome (1 pt [3.2%]) and isolated ACTH deficiency (1 pt [3.2%]). Most of the potential irAEs were grade 1 or 2. Only one patient developed grade 3 colitis. Furthermore, 3 pts (9.7%) with diabetes developed hyperglycemia of grade 3 and 1 pt (3.2%) endured acute myocardial infarction who had a history of coronary heart disease. Conclusions: Second-line nab-PTX plus sintilimab showed promising anti-tumour activity with a manageable safety profile in pts with advanced or metastatic G/GEJA preliminarily. These results warrant further accrual and evaluation. This study is still recruiting. Clinical trial information: NCT04140318. Research Sponsor: Innovent Biologics and CSPC Ouyi Pharmaceutical Co. Ltd. Clinical trial information: NCT04140318.
A first-in-human phase 1b study of a novel allosteric extracellular FGFR2 inhibitor alofanib in patients with refractory metastatic gastric cancer.
Authors: Tjulandin Sergei , Statsenko Galina , Artamonova Elena , Vladimirova Liubov Yu , Besova Natalia , Mochalova Anastasia , Rykov Ivan , Moiseyenko Vladimir , Utyashev Igor A. , Iugai Sergei , Kazey Vasily , Raskin Grigory , Dragun Nadezhda , Reznikov Dmitry , Gavrilova Evgenia , Tsimafeyeu Ilya
Published: January 2022

304

Background: FGFR2 promotes gastric cancer progression, suggesting that inhibition of FGFR2 may be an important therapeutic strategy. Alofanib (RPT835) is a small molecule, allosteric inhibitor that binds to the non-active extracellular site of IIIc and IIIb FGFR2 isoforms with IC50 < 10 nM. Methods: RPT835GC1B is a Phase 1b open-label study evaluating the safety and preliminary efficacy of alofanib in patients with metastatic gastric adenocarcinoma pretreated with ≥ 1 previous lines of therapy. The standard dose-escalation part (design 3+3) aimed to establish the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) as a primary endpoint. Secondary endpoints included pharmacokinetic (PK) parameters, rate of adverse events, progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). Alofanib was administered daily intravenously for 5-days followed by a 2-day interval (rest). There were five dose levels: 50, 100, 165, 250, and 350 mg/m2. All patients received alofanib until disease progression or unacceptable toxicity. Results: As of 20 September 2021, 21 patients have been enrolled in the study. Patients were Caucasian (100%), predominantly male (71%), 67% had 2 and more metastatic sites, including liver metastases (43%), 14% had ECOG PS 2, and were heavily pretreated (86% had previous 3 and more lines of therapy). All enrolled patients have been studied for safety and have not experienced any dose-limiting toxicities (DLTs) within the 28-day DLT-assessment window. 17 (81%) patients had at least one treatment-related adverse event (trAE). Grade 3 or higher trAEs (5/23.8%) have included raised ALT/AST at 50 mg/m2, neutropenia at 50 mg/m2, diarrhea at 165 mg/m2, headache at 165 mg/m2, increased serum amylase at 350 mg/m2, and reactions immediately after intravenous injections (facial flushing, dizziness, weakness, sweating, and sinus tachycardia) at 350 mg/m2. Three (14.3%) patients discontinued treatment due to trAEs. Most common Grade 1-2 adverse events included reactions immediately after intravenous injections, diarrhea, thrombocytopenia, arthralgia, and headache. Grade 1 hyperphosphatemia was found in 1 (4.8%) patient. Table summarizes efficacy data. Conclusions: The MTD has not been reached and dose of 350 mg/m2 has been declared as RP2D. Alofanib showed acceptable tolerability and preliminary signs of clinical activity in the late-line treatment of metastatic gastric cancer. Clinical trial information: NCT04071184. [Table: see text]
Lesion-level response to immune checkpoint inhibitor in patients with advanced gastric cancer.
Authors: Motoo Iori , Ando Takayuki , Kajiura Shinya , Ogawa Kohei , Tsukada Kenichiro , Ueda Akira , Suzuki Nobuhiro , Nakada Naokatsu , Nakashima Koji , Hosokawa Ayumu , Yasuda Ichiro
Published: January 2022

311

Background: The efficacy of anti-PD-1 monotherapy has been reported to be heterogeneous in each metastatic location in non-small cell lung cancer. Therefore, we analyzed the response of target lesions in each organ and the association between pattern of progression and survival in patients with gastric cancer (GC). Methods: We performed retrospective analysis, which include 148 patients with GC who received nivolumab or pembrolizumab treatment between 2017 and 2021 at eight institutions in Japan. Response rate (RR), progression free survival (PFS), and overall survival (OS) were evaluated in total patients. The percent change of target lesions of each organs was measured by CT using RECIST, and their best percent changes were compared. In the GC patients with best response of progression disease (PD), the association between pattern of progression and survival was analyzed. Systemic progression was defined as PD in two or more lesions including target or non-target lesions, and non-systemic progression was defined as PD in only one lesion. Results: Among 148 patients, the RR, median PFS, and median OS were 11.6%, 1.6 months (95%CI, 1.4-1.9), and 4.4 months (95%CI, 3.6-6.6), respectively. A total of 293 lesions from 112 patients with target lesions were examined. The median best percent change of lymph node (n = 76), liver (n = 62), peritoneum (n = 19) and lung (n = 8) was +2.3%, +27%, +12%, +8.5%, respectively. Liver had significantly the lowest responses compared with lymph node and peritoneum (p < 0.0001 and p = 0.016). The median OS in non-systemic and systemic progression group was 5.6 months (95%CI, 3.6-8.8) and 3.3 months (95%CI, 1.9-3.6) and survival of patients with non-systemic progression showed significantly longer than that of systemic progression (p = 0.012). According to univariate and multivariate analysis, poor performance status (PS) (HR 1.73, 95%CI, 1.00-2.87) and systemic progression (HR 3.09, 95%CI, 1.95-4.82) were associated with OS in total patients. Additionally, liver metastasis (OR 2.99, 95%CI, 1.04-8.58) was identified as a baseline factor associated with systemic progression in the univariate and multivariate analysis. Conclusions: The efficacy of immune checkpoint inhibitor (ICI) is dependent on the metastatic location. Moreover, pattern of progression has been associated with overall survival. Liver metastasis might be a predictive factor of systemic progression in ICI treatment for GC.
Exploratory analysis of the impact of prior immune checkpoint inhibitor (ICI) on trastuzumab deruxtecan (T-DXd; DS-8201) clinical outcomes and biomarkers (BM) in DESTINY-Gastric01 (DG-01), a randomized, phase 2, multicenter, open-label study in patients (pts) with HER2+ advanced gastric or gastroesophageal junction adenocarcinoma.
Authors: Shitara Kohei , Bang Yung-Jue , Iwasa Satoru , Sugimoto Naotoshi , Ryu Min-Hee , Sakai Daisuke , Chung Hyun Cheol Cheol , Omuro Yasushi , Kawakami Hisato , Yabusaki Hiroshi , Sakamoto Yasuhiro , Nishina Tomohiro , Inaki Koichiro , Kuwahara Yusuke , Suto Fumitaka , Sugihara Masahiro , Saito Kaku , Kojima Akihito , Yamaguchi Kensei
Published: January 2022

322

Background: T-DXd is a HER2-targeting antibody-drug conjugate. In primary analyses of DG-01 (NCT03329690), T-DXd showed clinically meaningful improvement in objective response rate (ORR) and overall survival (OS) vs chemotherapy in the primary cohort of pts with HER2+ advanced gastric cancer (AGC; IHC3+ or IHC2+/ISH+; Shitara K et al. NEJM 2020;382:2419). In the context of emerging first-line ICI-based regimens in AGC, we conducted a post hoc analysis of T-DXd clinical outcomes and baseline BMs in pts with or without prior ICI. Methods: DG-01 primary cohort enrolled pts who progressed on ≥2 prior lines with centrally confirmed HER2+ AGC. Efficacy and safety were assessed in pts with or without prior ICI (defined as any ICI-related treatment received prior to T-DXd). Exploratory BM analysis in the T-DXd arm assessed RNA sequencing (RNAseq) of tumor biopsies and ctDNA of liquid biopsies taken immediately before T-DXd treatment. A linear regression model and Wilcoxon rank-sum test were used to identify differentially expressed genes and signature scores between pts with or without prior ICI. Results: Prior ICI was received in 35.2% (44/125) of pts treated with T-DXd and 27.4% (17/62) treated with chemotherapy. The table shows efficacy in pts with or without prior ICI. Safety data in the T-DXd arm were similar between pts with or without prior ICI, including adjudicated drug-related interstitial lung disease/pneumonitis; 9.1% (4/44) of pts with prior ICI and 9.9% (8/81) of pts without prior ICI. Among 34 T-DXd-treated pts with RNAseq data, 12 received prior ICI. Searching for differentially expressing genes (fold change ≥2, P≤0.01) identified multiple genes with a higher trend for expression in tumors with prior ICI, including immune-oncology (IO)-related molecules, CXCL9 and PD-1 (log2 fold change 2.3 and 1.4, P=7.3e-05 and 2.8e-03, respectively). Furthermore, gene signature analysis showed a concurrent higher trend of multiple chemokine gene expressions in the prior ICI group. Conclusions: This exploratory analysis suggests that treatment with T-DXd results in better outcomes than chemotherapy regardless of prior ICI. Given a relatively small sample size, the relationship between changes in IO-related signatures and efficacy of T-DXd warrants further evaluation in larger cohorts. Clinical trial information: NCT03329690. [Table: see text]
Quantitative proteomic profiling of esophageal adenocarcinoma tumors to assess prevalence of approved targets and elucidate novel biomarkers.
Authors: Mittal Sumeet K. , Bansal Ajay , Abdo Joe , Driscoll Olivia , Oh Seyun , Thyparambil Sheeno P. , Liao Wei-Li , Heaton Robert , Hagen Catherine E. , Hartley Christopher
Published: January 2022

343

Background: Esophageal adenocarcinoma (EAC) continues to have extremely poor prognosis despite advances in surgical and oncological regimens. Targeted and immune therapy hold promise to improve outcomes in solid tumors including EAC. At present HER-2 and anti-PD-L1 therapies are approved by the FDA for EAC. Additionally, off-label use of EGFR directed therapy has been reported. The aim of this study is to measure expression of 80+ oncoproteins in EAC using multiplexed mass spectrometry to elucidate expression of currently approved-drug targets and explore promising new targets for drug development. Methods: After Institutional Review Board approval (Mayo Clinic and KUMC), EAC patients whose tumors were resected via esophagectomy before chemotherapy and/or radiation were identified. Normal esophageal mucosa samples with no history of EAC were also retrieved for analysis. Tissue sections were microdissected to exclude stroma from adenocarcinoma cells. Isolated EAC cells were solubilized for mass spectrometry-based quantitation of more than 80 clinically relevant tumor markers. Results: 55 EAC tissues were analyzed. HER2, PD-L1 and EGFR were overexpressed only in 16.3%, 0%, and 0% of patients, respectively. New oncoproteins #2 and #6 were noted to have high (7,634.0 and 27,222.6 attomoles/ug) and consistent (98.1% and 94.5%) overexpression in EAC samples. Expression of HER2, oncoproteins #2 and #6 were significantly higher in EAC compared to normal esophageal mucosa. There was no statistical difference in the expression of PD-L1 and EGFR between EAC and normal samples. Conclusions: Mass spectrometry revealed a very low prevalence of target oncoproteins in EAC for currently used drugs. Our study potentially reveals alternate markers which are near universally present at high levels and should be further explored for targeted treatment.[Table: see text]
Brain metastasis in gastroesophageal adenocarcinoma: Outcomes and molecular features.
Authors: Tsai Charlton , Nguyen Bastien , Luthra Anisha , Chou Joanne F. , Tang Laura H. , Strong Vivian E. , Molena Daniela , Jones David Randolph , Coit Daniel G. , Ilson David H. , Ku Geoffrey Yuyat , Moss Nelson S. , Beal Kathryn , Capanu Marinela , Schultz Nikolaus , Janjigian Yelena Y. , Maron Steven Brad
Published: January 2022

347

Background: Brain metastases (BrM) rarely occur in patients with metastatic gastroesophageal adenocarcinoma (GEA) and represent a unique therapeutic challenge. We describe the unique clinical, molecular, and genomic factors associated with mGEA cancer and BrM development in order to help guide future clinical management. Methods: Patients (pts) with GEA seen at Memorial Sloan Kettering Cancer Center (MSKCC) from 2008-2019 and who had consented for genomic tumor profiling with MSK-IMPACT, a capture-based next-generation sequencing platform that detects mutations, copy-number variations, and select fusions, were retrospectively identified. Clinical and pathologic characteristics were reviewed. BrM were identified via International Classification of Diseases (ICD) billing codes and electronic medical record problem lists, and then manually validated. Survival was calculated from the time of BrM diagnosis until date of death or last follow up and estimated using the Kaplan-Meier method. Results: Fifty pts with GEA metastatic to the brain were identified. Most pts were male (86%) and white (80%), with primary tumor of the esophagus/gastroesophageal junction (82%) and intestinal-type Lauren histology (90%). Twenty-three pts (46%) were HER2 positive (defined as IHC 2+/FISH+ or IHC 3+). Frequencies of PTEN (16%) and EGFR (22%) alterations in primary or metastatic sites were enriched in pts with BM compared to that seen across the MSKCC retrospective cohort and the GEA Cancer Genome Atlas (TCGA) cohort. The majority (68%) of pts had stage IV disease at initial diagnosis, and 4 pts were found to have BrM within 1 month (mo) of stage IV diagnosis, while 27 pts developed BrM during therapy. Median time to BrM diagnosis was 18.3 mos (IQR 11.5-28.9) and 15.1 mos from stage IV diagnosis (IQR 4.8-25.5). Median survival was 7.6 mos from BrM diagnosis and 15.6 (95% CI 10.0-NR, n = 19), 7.6 (95% CI 2.5-NR, n = 13), and 4.3 (95% CI 3.5-12.3, n = 18) mos for pts with 1, 2-3, or 4+ BrM, respectively. Conclusions: GEA pts with BrM had increased frequency of HER2 positivity, as well as PTEN and EGFR alterations, compared to GEA pts overall historically. Further correlation between BrM development, molecular characteristics, and survival in a larger cohort will be presented.
Association of an immunosuppressive macrophage transcriptional signature derived from peripheral blood macrophages with gastric cancer prognosis.
Authors: Sullivan Kevin , Mahuron Kelly , Li Haiqing , Paz Isaac Benjamin , Fong Yuman , Woo Yanghee
Published: January 2022

354

Background: Gastric cancer (GC) is the fourth most common cause of cancer death worldwide. Studies have shown an association of higher macrophage density in the tumor microenvironment with worse outcomes in GC. The presence of M2 specific gene signatures in the peripheral blood of cancer patients are associated with poor prognosis. However, it is unknown whether these immunosuppressive M2 markers are prognostic when found in the primary GC tumors. Methods: Based on previously published differential gene expression profiles that distinguish M1 versus M2 macrophages in the peripheral blood, we used the UCSC Xena webtool to analyze the TCGA Stomach Cancer cohort for tumor-associated immune signatures for their prognostic value. We excluded null entries, normal tissue, and entries with incomplete data. We investigated both M1- and M2-macrophage signatures (M1 signature: CCR7, IL2RA, CXCL11, CCL19, CXCL10, PLA1A, PTX3 and M2 signature: MRC1, MS4A4A, CD36, CCL13, CCL18, CCL23, SLC38A6, FGL2, FN1, MAF); as well as a T cell cytolytic signature defined by genes with cytolytic functions ( GZMA, GZMB, GZMH, GZMM, PRF1). We analyzed the impact of transcriptional gene expression with relation to stage, histological subtype, overall survival (OS), and disease free interval (DFI). The UCSC Xena webtool uses log-rank test to compare Kaplan-Meier curves. Results: A total of 341 entries were analyzed with age ranging from 30-90 and 39.4% female. Increased CD168 expression was associated with increased stage of GC (p = 0.017). Higher expression of the M2-macrophage signature was associated with diffuse type adenocarcinoma and mucinous type intestinal adenocarcinoma, compared to tubular and papillary type intestinal adenocarcinoma (p < 0.001). In addition, higher M2-macrophage signature expression was associated with late stage (Stage II or above) compared to early stage (stage I) (p = 0.022). A low M2-macrophage signature was associated with improved 5-year OS (p = 0.029), and a significantly improved 5-year DFI (p = 0.042). CD8A, cytolytic T cell signature, and M1 macrophage signature were not associated with stage of disease or survival. Conclusions: A transcriptional signature derived from peripheral blood immunosuppressive M2 macrophage phenotype is found in GC primary tumors and associated with higher pathologic staging and with worse outcomes. These M2 defining molecular biomarkers of GC has the potential to serve as targets of novel immune-therapeutic strategies.
Impact of race/ethnicity and socioeconomic status on emergency department visits in patients with hepatocellular carcinoma.
Authors: Lin Daniel , Tan Amie , Kilgore Karl M. , Teigland Christie , Hernandez Sairy , Slay Dayne L. , Schroeder Amy L. , Kim Seung
Published: January 2022

385

Background: Despite advances in diagnosis and treatment of hepatocellular carcinoma (HCC), disparities in care utilization and health outcomes persist. Few studies have evaluated the impact of race/ethnicity and socioeconomic status (SES) on incidence of emergency department (ED) visits, which may reflect access to and quality of cancer care. We investigated this relationship among patients (pts) with HCC. Methods: Using 100% Medicare Fee-for-Service claims and a commercial multi-payor claims database, pts diagnosed with HCC between 2014-2018 were identified. Using 9-digit ZIP code from enrollment records, pts were matched to near-neighborhood social determinants of health (SDOH) characteristics, including income, education, English language ability, living alone, vehicle ownership, rurality, and primary care shortages. We defined SES according to income level: low (≤2 times [x] federal poverty level [FPL]), middle (2-3x FPL), and high (>3x FPL). We used generalized linear regressions to evaluate the effect of race/ethnicity on incidence rate ratios (IRR) of ED visits, adjusting for SDOH variables and demographic and clinical characteristics. We further stratified ED IRR by income level to examine how racial/ethnic differences in ED visits differ by SES. Results: 22,247 pts with HCC were identified (median age 69; 63% male; 69% White, 14% Black, 7% Hispanic, 6% Asian, 4% Other). The table summarizes adjusted IRR of ED visits for each racial/ethnic group compared with whites, overall and by income level. Overall, ED visits were higher for Blacks (IRR 1.27) and Hispanics (IRR 1.17) and lower for Asians (IRR 0.67). When stratified by income, Blacks and Hispanics had larger incidence of ED visits compared with Whites at higher income levels; these differences became insignificant at low income level. Asians had lower rate of ED visits regardless of income. Conclusions: Black and Hispanic pts with HCC demonstrated higher rates of ED visits compared with Whites. These differences were more pronounced at higher income levels, particularly for Blacks, suggesting racial disparities may differ by SES. Further research is needed to understand the intersectionality between race/ethnicity, SES and other SDOH, to guide structural-level interventions to address these disparities. [Table: see text]
Atezolizumab plus bevacizumab in Child-Pugh B advanced hepatocellular carcinoma patients.
Authors: Kim Hyeyeong , Cheon Jaekyung , Ha Yeongjung , Kim Han Sang , Kim Chang Gon , Kim Ilhwan , Kim Chan , Jung Sang-hoon , Chon Hong Jae
Published: January 2022

397

Background: Atezolizumab plus bevacizumab (Ate/Bev) demonstrated promising efficacy and safety in patients with advanced hepatocellular carcinoma (aHCC) in the phase III IMbrave 150 trial. However, despite the high unmet need in Child-Pugh B patients, this subgroup of patients was not included in this study. Therefore, we aimed to investigate the efficacy and safety of Ate/Bev in Child-Pugh B HCC patients. Methods: This multicenter retrospective study included 27 HCC patients classified as Child-Pugh B who received Ate/Bev at four cancer referral centers between May 2020 and August 2021. Comparative analyses were performed with an independent cohort of Child-Pugh A patients from the same registry (n=130). Results: All patients received Ate/Bev as first-line systemic treatment for aHCC. The objective response rates of patients in Child-Pugh groups B and A were 14.8% and 32.3%, and the disease control rates were 55.5% and 76.1%, respectively. The median progression-free survival (PFS) and overall survival (OS) were 3.0 months (95% CI, 1.6-4.3) and 6.0 months (95% CI, 4.9-7.0) in Child-Pugh B patients, while the median PFS was 6.0 months (95% CI, 4.6-13.4) and the median OS was not-reached (95% CI not available) in Child-Pugh A group. Compared to Child-Pugh A group, grade 3-4 adverse events (AEs) were more common in the Child-Pugh B group (48.1% vs 17.7%, p=0.001), with the most frequent grade 3-4 AEs being thrombocytopenia (11.1%) and AST elevation (11.1%). The rate of treatment discontinuation due to AEs was higher in the Child-Pugh B group (14.8% vs 3.1%, p=0.030), and the reasons for discontinuation were gastrointestinal (GI) bleeding (n=2), GI perforation (n=1) and interstitial pneumonitis (n=1). Conclusions: In the Child-Pugh B subgroup of patients with aHCC, Ate/Bev treatment showed modest clinical activity. However, due to the increased frequency of serious AEs, careful evaluation of treatment response and AE management is required in this subgroup patients. [Table: see text]
Effect of a cancer tracking system on timeliness of liver cancer care at a Veteran's Hospital.
Authors: Ivatorov Amanda , Mezzacappa Catherine , Taddei Tamar Hamosh
Published: January 2022

406

Background: Hepatocellular carcinoma (HCC) requires complex care coordination with opportunities for care delays and untimely follow-up of abnormal liver imaging results. An electronic medical record-linked abnormal imaging identification and tracking system was implemented at a Veterans Affairs Hospital. The system reviews all liver radiology reports, generates a queue of abnormal cases for care coordinator review, and provides a tracking feature to monitor each patient’s care. Methods: This is a pre-/post-intervention study to evaluate whether implementation of this tracking system reduced (1) time between HCC diagnosis and treatment and (2) time from first suspicious image to first specialty care appointment, diagnosis, and treatment. Patients diagnosed with HCC in the 37-months before tracking system implementation (pre-intervention) were compared with patients diagnosed with HCC in the 71-months (less an 11-month grace period) after tracking system implementation (post-intervention). Linear regression was used to calculate mean change in relevant intervals of care pre- and post-intervention adjusted for patient age, race, ethnicity, BCLC stage at diagnosis, and indication for first suspicious image. Results: There were 60 patients in the pre-intervention period and 127 in the post-intervention period. The post-intervention group had a greater proportion of HCC diagnosed at earlier BCLC stages (p<0.03). Compared to the pre-intervention cohort, the post-intervention cohort had an adjusted mean reduction of 36 days from diagnosis to treatment (p=0.007), 51 days from suspicious imaging to diagnosis (p=0.21), and 87 days from suspicious imaging to treatment (p=0.05). Stratified by indication for first suspicious imaging, patients whose imaging was performed for HCC screening had the greatest decreases in time from diagnosis to treatment (63 days, p=0.02) and from first suspicious image to treatment (179 days, p=0.03). Conclusions: Our tracking system improved timeliness of HCC diagnosis and treatment. We anticipate it may improve HCC care coordination and delivery, including when added to HCC screening protocols.[Table: see text]
Regorafenib plus nivolumab as first-line therapy for unresectable hepatocellular carcinoma (uHCC): Multicenter phase 2 trial (RENOBATE).
Authors: Yoo Changhoon , Ryoo Baek-Yeol , Kim Hyung-Don , Ryu Min-Hee , Kang Beodeul , Chon Hong Jae , Hong Jung Yong , Lim Ho Yeong
Published: January 2022

415

Background: The immunomodulatory effect of regorafenib may enhance the anti-tumor activity of nivolumab in patients with uHCC. We report results from a phase 2 study of regorafenib plus nivolumab as first-line therapy in patients with uHCC. Methods: In this open-label, multi-center, single-arm study, patients with >19 years, ECOG PS 0 or 1, BCLC stage B or C, and no prior systemic therapy were eligible. Patients received intravenous nivolumab 480 mg, every 4 weeks, and oral regorafenib 80 mg daily, 3 weeks on/1 week off, every 4 weeks. Tumor response was evaluated per RECIST v1.1, every 8 weeks (fixed schedule). Primary endpoint was overall response rates (ORR) per RECIST v1.1. Secondary endpoints were progression-free survival (PFS), overall survival (OS), ORR per mRECIST, and safety profile per NCI-CTCAE v5. Results: A total of 42 patients were enrolled between JUL-2020 and JAN-2021. Median age was 61 years (range, 40-79), and 31 patients (73.8%) were male. Most patients had BCLC C stage (n=38, 90.5%) and hepatitis B virus infection (n=30, 71.4%). Extrahepatic metastasis was noted in 36 patients (85.7%) and baseline serum AFP levels were >400 ng/mL in 17 patients (40.5%). With median follow-up duration of 9.2 months (95% CI, 8.5-9.9 months), 21 patients were ongoing in this study. ORR per RECIST v1.1 was 31.0% (CR 1 [2.4%] and PR 12 [28.6%]), and ORR per mRECIST was 35.7% (CR 4 [9.5%] and PR 11 [26.2%]). Median PFS was 5.5 months (95% CI, 1.8-9.1 months) and median OS was not reached. The 6-months PFS and OS were 49.9% and 90.4%. Most common adverse events were hand-foot skin reaction (n=14, 33.3%), skin rash (12, 28.5%), and alopecia (10, 23.8%). Conclusions: Regorafenib plus nivolumab shows promising efficacy outcomes in uHCC. There was no unexpected safety signals and most of toxicities were manageable. Clinical trial information: NCT04310709.
Transcatheter arterial chemoembolization therapy in combination strategy with lenvatinib in patients with unresectable hepatocellular carcinoma (TACTICS-L) in Japan: Final analysis.
Authors: Ueshima Kazuomi , Ishikawa Toru , Saeki Issei , Morimoto Naoki , Aikata Hiroshi , Tanabe Nobukazu , Inaba Yoshitaka , Wada Yoshiyuki , Kondo Yasuteru , Tsuda Masahiro , Nakao Kazuhiko , Ikeda Masafumi , Moriguchi Michihisa , Ito Takanori , Kobayashi Masahiro , Koga Hironori , Hino Keisuke , Suzuki Yoshiyuki , Yoshimura Kenichi , Kudo Masatoshi
Published: January 2022

417

Background: Treatment options for hepatocellular carcinoma (HCC) include surgical resection, percutaneous ablation therapy, transcatheter arterial chemoembolization (TACE), and liver transplantation, etc., and TACE is indicated for unresectable HCC (uHCC) that is not eligible for curative therapy. Combination therapy with TACE and molecular targeted agents has been reported to have higher antitumor efficacy than respective monotherapies. This study aims to evaluate safety and efficacy of combination of TACE and lenvatinib in uHCC patients. Methods: Phase II, prospective, multicenter, single-arm study was conducted in 19 Japanese sites. Lenvatinib was administered orally once daily for 14 to 21 days prior to TACE at a dose of 12 mg (body weight ≥60 kg) or 8 mg (< 60 kg). The first TACE was performed after a 2-day lenvatinib withdrawal period. This combination therapy was repeated until the time to untreatable progression (TTUP). The primary endpoint was progression-free survival (PFS). Secondary endpoints included TTUP, objective response rate (ORR), overall survival (OS), and safety. Results: Between February 2019 and April 2020, 62 patients were enrolled. Median age was 72.0 years (< 65 years, 13 [21.0%]; ≥65 years, 49 [79.0%]). Number of patients with Child-Pugh score 5 and 6 was 51 (82.3%) and 11 (17.7%); Eastern Cooperative Oncology Group Performance Status 0 and 1 was 59 (95.2%) and 3 (4.8%); and Barcelona Clinic Liver Cancer Stage A and B was 25 (40.3%) and 37 (59.7%). The number of previous TACE procedures was 0 in 35 patients (56.5%) and 1 to 3 in 27 patients (43.5%). The estimated median PFS, OS, and TTUP were more than 2 years. The ORR was 88.7% (90% CI 79.8 – 94.6 with complete response (CR) rate of 66.1%). Treatment emergent adverse events (AEs) occurred in 98.4% of patients, and the most common AEs were hypothyroidism (58.1%), hypertension (53.2%), decreased appetite (50.0%), and fatigue (48.4%). Grade 3 and 4 AEs occurred in 71.0% and 4.8%, and serious AEs occurred in 40.3%. One death not causally related to the protocol treatment was observed. Conclusions: In this final analysis, the combination of TACE and lenvatinib showed promising therapeutic efficacy in patients with uHCC. No new safety signal was observed. Future phase III studies are required to validate this combination therapy. Clinical trial information: jRCTs031180074.
Clinical outcomes associated with tislelizumab in patients (pts) with advanced hepatocellular carcinoma (HCC) who have been previously treated with sorafenib (SOR) or lenvatinib (LEN) in RATIONALE-208.
Authors: Edeline Julien , Merle Philippe , Fang Weijia , Assenat Eric , Pan Hongming , Rimassa Lorenza , Li Zhiwei , Blanc Jean-Frederic , Yen Chia-Jui , Ross Paul J. , Hu Sheng , Zhang Tao , Tran Albert , Shao Guoliang , Bouattour Mohamed , Chen Yajin , Wu John , Li Bai , Chica-Duque Sandra , Ren Zhenggang
Published: January 2022

420

Background: Tislelizumab, an anti-PD-1 monoclonal antibody, demonstrated clinical activity and was well tolerated in pts with previously treated advanced HCC in the phase 2 RATIONALE-208 study (NCT03419897). At the time of this study, SOR and LEN were recommended first-line treatments for pts with advanced HCC and continue to have an important role in the first-line treatment of HCC despite the recent approval of new immuno-oncology-based combinations (atezolizumab and bevacizumab) in some regions. We report the clinical outcomes of pts with advanced HCC who were previously treated with SOR/LEN. Methods: Pts who had received ≥1 prior line of systemic therapy for advanced HCC received tislelizumab 200 mg intravenously once every three weeks. Objective response rate (ORR) by independent review committee (IRC) (ORRIRC), duration of response by IRC (DORIRC), progression-free survival by IRC (PFSIRC), overall survival (OS), and safety were evaluated in pts who had been previously treated with SOR/LEN. Results: As of February 2020, 249 pts were enrolled and 235 pts had received prior treatment with SOR/LEN, of whom 126 and 109 pts had received 1 or ≥ 2 prior lines of systemic therapy, respectively. At study entry, 211 (89.8%) pts had BCLC stage C and 187 (79.6%) pts had extrahepatic spread. Median follow-up duration for pts previously treated with SOR/LEN was 12.5 months and ORRIRC was 13.6% (95% CI: 9.5, 18.7), including 2 complete responses and 30 partial responses. Median DORIRC was not reached. Median PFSIRC and OS of pts previously treated with SOR/LEN was 2.7 months (95% CI: 1.6, 2.8) and 13.5 months (95% CI: 10.9, 15.8), respectively. Tislelizumab was generally well tolerated in pts previously treated with SOR/LEN (Table), and the most common treatment-emergent adverse events were increased aspartate aminotransferase (n=70; 28.1%) and alanine aminotransferase (n=52; 20.9%). Conclusions: Tislelizumab was investigated beyond the first-line setting, as effective second- and third-line treatment options are limited for pts with advanced HCC and there is an unmet medical need. This analysis indicates that tislelizumab is clinically active and well tolerated in pts with advanced HCC who have received prior systemic treatment with SOR/LEN. Clinical trial information: NCT03419897. [Table: see text]
A study of pembrolizumab (pembro) in combination with Y90 radioembolization in patients (pts) with poor prognosis hepatocellular carcinoma (HCC) with preserved liver function.
Authors: McRee Autumn Jackson , Helft Paul R. , Harris William Proctor , Sanoff Hanna Kelly , Johnson Matthew , Yu Menggang , O'Neil Bert
Published: January 2022

422

Background: HCC is an aggressive cancer that is challenging to treat due to the concomitant diagnosis of cirrhosis. For HCC pts with no extrahepatic metastases and well-compensated liver function, Y90 radioembolization is a standard therapy. In observational studies, pts with multifocal disease or portal vein thrombosis (PVT) had worse outcomes with short disease control intervals of less than 6 months. Pembro is an anti-PD-1 monoclonal antibody that is FDA-approved for advanced HCC pts who have progressed on sorafenib. Given pre-clinical evidence that radiotherapy can increase PD-L1 expression and enhance tumoral T-cell recruitment, this study explored the safety and efficacy of pembro with Y90 radioembolization in pts with poor prognosis HCC. Methods: GI15-225 was a multi-center, single-arm study in poor prognosis HCC pts, defined as having multifocal disease, branch PVT and/or diffuse disease (NCT03099564). Pts with extrahepatic metastatic disease were excluded; eligible pts had disease amenable to 1-2 embolization procedures. Pts had Child Pugh A/B7 cirrhosis with no prior Y90 treatment; previous TAE, TACE, SBRT, liver resection or ablation were allowed. Treatment consisted of pembro 200mg every 3 weeks with Y90 radioembolization performed 7-10 days after first dose of pembro. The primary objective was to estimate the progression free survival (PFS) rate at 6 months per RECIST 1.1; secondary endpoints included safety, time to progression (TTP), overall response rate (ORR) and overall survival (OS). Results: A total of 29 pts were enrolled 10/23/17 to 11/24/20. Median age 66 years, 89% male, and 47% with PVT. 26 pts were evaluable for primary endpoint having received Y90 and at least one dose of pembro. The 6 month PFS rate was 57.7% (95% CI 36.9 – 76.6). Median PFS was 8.6 months (95% CI 4.1 – 13.4) and median TTP was 9.9 months (95% 4.2 – NR). Median OS was 22 months (95% CI 8.4 – 32.0). The ORR was 27% (Table). Most common treatment related grade 3-4 AEs were decreased lymphocytes (18%), increased bilirubin (11%), hypertension (11%), ascites (7%), and AST/ALT elevation (7%). One pt experienced grade 5 toxicity of hepatic failure after receiving one dose of pembro and Y90 that was attributed to Y90 and disease progression. Conclusions: Concurrent administration of pembro with Y90 radioembolization in pts with poor prognosis HCC demonstrated promising clinical activity with median TTP and OS that exceeds historical data reported in similar patients treated with Y90 alone. With a 6 month PFS rate of 57.7% and a favorable toxicity profile, the combination of immune checkpoint blockade and Y90 deserves further evaluation in larger randomized clinical trials. Clinical trial information: NCT03099564. [Table: see text]
Radio-immunotherapy for advanced HCC: A pilot study of irradiation dose.
Authors: Su Ting-Shi , Li Jian-Xu , Li Li-Qing , Xiang Bang-De , Liang Shi-Xiong
Published: January 2022

426

Background: Preclinically, radiation therapy for tumors was well known to reverse the immunosuppressive state by reprograming the tumor microenvironment. The combination of radiotherapy and immune checkpoint inhibitors (radio-immunotherapy) has renewed interest in clinical practice, and different irradiation dose may contribute diversely to immune response and abscopal effect. This pilot study aimed to assess the antitumour activity of the anti-PD-1 inhibitor Camrelizumab combined with different irradiation dose in patients with advanced hepatocellular carcinoma (HCC). Methods: Between April 2020 and January 2021, 20 patients with advanced HCC were prospectively enrolled in this pilot study. Five patients were treatment-naive and 15 patients were diagnosis as progressive diseases after previous treatment. For each patient, one to 3 intrahepatic and/or extrahepatic lesions were selected to irradiate. Camrelizumab was concurrently administered with 200mg on the first day of radiation and then every 3 weeks until disease progression, or unacceptable toxicity. Eligible patients were randomly assigned to receive 3 irradiation doses: low-dose group of 30Gy/10 fractions(3Gy/fx), intermediate-dose group of 40Gy/10 fractions (4Gy/fx), and high-dose group of 50Gy/10 fractions (5Gy/fx). Results: Nine patients had intrahepatic lesions (8 of macrovascular invasion) and 11 had extrahepatic metastases. The median number of treatment lines receiving immunotherapy of Camrelizumab was 2 (range 1-5). Enrolment to the 30Gy group was halted after 2 patients due to the poor clinical response. Finally, 2, 11, and 7 patients received the irradiation dose of 30, 40, and 50Gy, respectively. Twenty-eight selected lesions were irradiated (partial lesions in 12 patients and all lesions in 8 patients). Grade 3 treatment-related adverse events were observed in 4 patients, including 2 thrombocytopenia and 1 anaemia in the 40Gy group, and 1 anaemia in the 50Gy group. The median follow-up time was 12 months (range 7.0–18.0 months). There was a significant difference in PFS, but no difference in OS between the three groups. The median, 6- and 12-months PFS for the 30, 40, and 50 Gy groups were 1.7 months, 0% and 0% vs. 4.0 months (95%CI 1.7-6.3 months), 27.3% and 18.2% vs. 7.8 months (95%CI 4.1-11.5 months), 57.1% and 38.1%, respectively (P = 0.027). The median, 12-months OS were 11.4 months and 50% vs. 11.8 months and 34.6% vs. not reached and 66.7%, respectively (P = 0.229). The disease control rates were statistically different between the 30, 40, and 50Gy groups (50% vs. 54.5% vs. 100%, P = 0.039), whereas objective response rates were not significant different (0% vs. 45.5% vs. 71.4%, P = 0.123). Conclusions: Higher irradiation dose with 50 Gy in 10 fractions plus Camrelizumab may augment the radio-immunotherapy activity in advanced HCC with favorable PFS. The present study offers guidance for the dose selection of subsequent clinical trials. Clinical trial information: ChiCTR2000032375.
Nivolumab (NIVO) and drug eluting bead transarterial chemoembolization (deb-TACE): Updated results from an ongoing phase 1 study of patients (pts) with liver limited hepatocellular carcinoma (HCC).
Authors: Harding James J. , Yarmohammadi Hooman , Reiss Kim Anna , Chou Joanne F. , Capanu Marinela , Do Richard K. G. , Khalil Danny , El Dika Imane H. , Ferrer Christine S. , Heffernan Olivia , Giardina J Daniel , Merghoub Taha , Jarnagin William R. , Nadolski Gregory , Erinjeri Joseph Patrick , Soulen Michael C. , Tan Benjamin R. , Abou-Alfa Ghassan K.
Published: January 2022

437

Background: TACE is a standard of care for liver limited HCC and impacts the immune microenvironment, potentially augmenting the effects of immune checkpoint inhibitors. Methods: This is a multicenter phase 1 study of NIVO and deb-TACE in unresectable HCC pts and Child Pugh A cirrhosis (NCT03143270). The primary objective is to assess safety. Secondary objectives include response rate by RECIST v1.1, progression-free and overall survival by Kaplan-Meier methodology, and blood/tumor immune correlates. A 3 + 3 design with expansion cohort sequentially evaluates 3 cohorts of differing schedules of NIVO relative to deb-TACE. Deb-TACE (75mg of doxorubicin) is administered on Day 0. NIVO is dosed at 240mg IV every 14 days for 1 year (Cohort 1: NIVO begins day +14 after deb-TACE; Cohort 2, interrupted NIVO dosing begins at Day -28 but is held on the Day 0 then restarted on Day +14; Cohort 3, continuous NIVO dosing begins on Day -28 without interruption). Results: As of September 2021, 19 pts were treated [median 67 years (range: 54-78), male (80%), ECOG PS 0 (47%), Child Pugh A (100%), 3 pts in each cohort 1 and 2, 13 pts in cohort 3]. No cases of treatment related liver failure or Grade 5 adverse events (AEs) were observed. 1 DLT of Grade 3 transaminitis was observed in cohort 3 and resolved without intervention and did not recur with drug rechallenge. Median ALT at baseline, day 28, day 56, and end of treatment (EOT) were 27, 43.5, 36.5, and 29 U/L. Median bilirubin at baseline, day 28, day 56, and EOT were 0.6, 0.6, 0.5, and 0.6 mg/dL. Mean ALBI score at baseline (N=19) and EOT (N=14) were -2.75 ± 0.48 vs. -2.55 ± 0.50. The most common treatment-related AEs of any grade were fatigue (53%), ALT/AST increase (42%), fever (37%), and pruritis (32%). The objective response rate by RECIST v 1.1 was 21% (Table). 5/19 pts remained on study with SD or better for ≥12 (range 12-43) months. Updated survival analysis will be presented at the meeting; correlatives at a separate venue. Conclusions: Nivolumab administered with deb-TACE is safe with antitumor activity. This study provides a needed benchmark for the safety of embolization along with anti-PD1 therapy in liver limited HCC. The clinical question of combining immunotherapy with embolization to improve outcome over embolization alone remains investigational and several, pivotal, phase 3 studies are ongoing. Clinical trial information: NCT03143270. [Table: see text]
The safety and efficacy of transarterial chemoembolization (TACE) + lenvatinib + programmed cell death protein 1 (PD-1) antibody of advanced unresectable hepatocellular carcinoma.
Authors: Zhang Xiaoyun , Zhu Xinrui , Liu Chang , Lu Wusheng , Li Qiu , Chen Weixia , Li Zhiping , Lu Qiang , Peng Wei , Li Chuan , Yan Lvnan , Yang Jiayin , Wen Tianfu
Published: January 2022

453

Background: More than 70% of hepatocellular carcinoma (HCC) patients are in the intermediate or advanced stages at the time of diagnosis. TACE, TKI and PD-1 antibody are all recommended for patients with unresectable HCC (uHCC) according to Chinese HCC guidelines. There are few scientific trials to back up the safety and effecacy of TACE+TKI+PD-1 antibody for the treatment of uHCC and conversion resection. In this study, we explored the safety and efficacy of the TACE+TKI+PD-1 antibody in uHCC. Methods: This is a prospective, multicenter, cohort study (NCT04997850). Key Eligibility Criteria:18 years old ≤ age ≤ 70 years old; HCC confirmed by histopathology or cytology; No systemic treatment history. ECOG PS score 0-1; Child-Pugh A/B; BCLC stage B/C.Experience group: TACE + Lenvatinib (12mg when≥ 60kg/8mg when < 60kg QD) + Camrelizumab/ Sintilimab (200 mg ivgtt Q3W);Control group: TACE. Results: From Sep 2020 to May 2021, 38 patients were enrolled in experimental group (Table). At the cutoff date (Sep 10 2021), the median follow-up was of 33.34 weeks (Table). The conversion resection rate was 50% (19/38), and the conversion success rate was 52.6% (20/38). Among the 19 patients, 5 cases achieved complete pathological response and 1 case achieved major pathological response. The 48 weeks’ OS rate and PFS were 96.4% (95%CI 92.9% to 99.9%) and 91.7%(95%CI 85.8% to 97.4%).22 patients had level 3 treatment related adverse events (TRAE), there were no level 4 and 5 TRAEs. At the last follow-up, the ORR rate based on mRECIST was 84.2%, and the DCR rate was 94.7% (Table). Conclusions: TACE + Lenvatinib + PD-1 antibody is safe and effective, and conversion resection after the triple-treatment is feasible for uHCC. Clinical trial information: 04997850.[Table: see text]