bluuebunny/crossref_metadata_2025 huggingface dataset:
Ant-PD-1/PD-L1 inhibitors in metastatic gastroesophageal cancers (GEC): A systematic review and meta-analysis.
Authors: Parmar Kanak , Subramanyam Sai , Appiah Duke , Mukherjee Sarbajit
Published: January 2022

323

Background: CheckMate 649 and KEYNOTE 590 studies established the role of immune checkpoint inhibitors (ICI) in the frontline setting for unresectable, advanced, or metastatic GEC. However, many GEC patients do not benefit from ICI. The purpose of the study was to evaluate the efficacy of ICI in various subgroups of GEC patients. Methods: We searched MEDLINE/PubMed, Embase, ESMO, and ASCO Meeting Abstracts for phase II or III randomized clinical trials (RCTs) testing ICI in metastatic/advanced gastric or gastroesophageal junction or esophageal cancer. Outcome measures included overall survival (OS) and progression-free survival (PFS). Subgroup analysis was performed for histology (squamous vs. adenocarcinoma), cancer location (gastric, gastroesophageal junction, and esophageal), age (< 65 years vs. > = 65 years), race (Asians vs. non-Asians), and sex (male vs. females). Random-effects meta-analysis was conducted using the R software. Results: Fourteen RCTs were included for the final analysis with total of 9102 patients. RCTs were divided into three groups: 5 RCTs for ICI+ chemotherapy vs. chemotherapy (Group A), 9 RCTs for ICI vs. chemotherapy (Group B), and 2 RCTs for ICI vs. placebo (Group C). OS was improved in Groups A (HR 0.78, 95% CI 0.71-0.86) and B (HR 0.82, 95% CI 0.73-0.91), but the results were not statistically significant in Group C. PFS was improved in Groups A(HR 0.70 95% CI 0.63-0.78) and C(HR 0.69 95% CI 0.56-0.86) but not statistically significant in Group B. On subgroup analysis for Group A, a statistically significant difference in OS was seen across all subgroups: histology, cancer location, age, and race except gastroesophageal junction cancer (HR 0.83 95% CI 0.66-1.04) and females (HR 0.86 95%CI 0.73-1.01). In Group B, statistically significant differences were only seen in esophageal cancer (HR 0.73 95% CI 0.66-0.81), squamous histology (HR 0.74 95% CI 0.67-0.82), Asian race (HR 0.77 95% CI 0.67-0.88) and men (HR 0.84 95% CI: 0.77-0.92). Conclusions: This study shows evidence for the use of ICI+ chemotherapy in the frontline setting for the management of GEC. While comparing ICI against chemotherapy, esophageal cancer, squamous histology, and the Asian race seemed to benefit more from ICI. Similarly, males, in general, benefited more from ICI than females. We plan to present an updated analysis at the meeting, which will include pending publications of some ongoing clinical trials.
Effect of adding immunotherapy to standard of care on survival in patients with esophageal cancer: Analysis of NCDB database.
Authors: AMIN SABER Ali , Lin Chi
Published: January 2022

325

Background: Combined immuno-chemotherapy has been shown to be more effective than chemotherapy alone in advanced esophageal cancer. However, the association of immunotherapy and overall survival (OS) of patients with esophageal cancer, regardless of stage and combined therapy, is unknown. The objective is to explore the association of immunotherapy with OS in patients with all stage esophageal adenocarcinoma or squamous cell carcinoma who received any treatment. Subset analysis was conducted on OS for patients who received chemoradiation with and without immunotherapy. Methods: This study included 85,900 adult patients in the National Cancer Database diagnosed between 2004 and 2017 with stage I-IV esophageal adenocarcinoma or squamous cell carcinoma. The association of immunotherapy with OS was assessed with Cox proportional hazards regression, adjusted for age at diagnosis, race, sex, stage, histology, Charlson score, education, income, insurance, hospital type, place of living, region, distance to facility, year of diagnosis and treatment modality. Results: Of 85,900 patients, 69,264 (81%) were men, 85,159 (88%) were White and 7,875 (9%) were Black. The median (range) age at diagnosis was 64 (18-90) years. Overall, 1990 (2.3%) received immunotherapy. Immunotherapy did not improve median OS in stage I-II (31 vs 27M, p >.05) but improved median OS in stage III (from 18 to 30 M, p <.0001) and IV (from 8 to 14 M p <.0001). In the multivariable COX analysis, patients who received immunotherapy had significantly improved OS compared with no immunotherapy (HR 0.756; 95% CI 0.713-0.801; P =.001). Treatment with CRT without surgery plus immunotherapy was associated with significantly improved OS compared with CRT alone (HR 0.817; 95% CI 0.745-0.896; P =.001). Interestingly, addition of immunotherapy to CRT with surgery did not improve OS compared with CRT and surgery. After stratified by stage, immunotherapy was found to be associated with improved OS only in stage IV patients either in all patients (HR 0.685; 95% CI 0.641-0.731, p < 0.001) or in patients who received CRT without surgery (HR 0.758; 95% CI 0.682-0.841). Conclusions: In this study, the addition of immunotherapy to standard of care, especially chemoradiation without surgery was associated with improved OS compared with standard of care (or chemoradiation) alone in patients with advanced stage esophageal cancer.
Induction FOLFOX prior to CROSS chemoradiotherapy and surgery in patients with locally-advanced esophageal and gastroesophageal junction cancer: A phase II study.
Authors: Dunne Richard Francis , Badri Nabeel , Nicolais Maria , Noel Marcus Smith , Baran Andrea M. , Wang Wenjia , Ramsdale Erika E. , Zittel Jason , Qiu Haoming , Katz Alan W. , Jones Carolyn E. , Peyre Christian G. , Lada Michal J. , Hezel Aram F , Tejani Mohamedtaki Abdulaziz
Published: January 2022

327

Background: In the CROSS trial, neoadjuvant chemoradiotherapy (CRT) prior to surgery for esophageal (E) and gastroesophageal junction (GEJ) cancers was found to improve survival. However, 10-year data did not show benefit in reducing isolated distant metastases. Addition of full-dose induction chemotherapy (CT) prior to CRT could provide early systemic disease control in addition to enhanced local control. We evaluated induction CT with FOLFOX followed by CRT and surgery in patients with E/GEJ cancers. Methods: This single-arm, phase II clinical trial investigated trimodality therapy in clinically staged II/III resectable cancers of the E/GEJ (NCT03110926). Treatment schedule was: 6 weeks of mFOLFOX-6 (5-fluorouracil, leucovorin, and oxaliplatin) followed by 5.5 weeks of CRT with weekly paclitaxel and carboplatin and 41.4-45 Gy of radiation (RT) and surgery. Primary endpoint was 2-year relapse-free survival (RFS) measured from time of surgery to date of first recurrence or death and was calculated by the Kaplan-Meier method. Overall survival (OS) and key pathologic findings were secondary outcomes. Results: In total, 41 patients enrolled with mean age of 63.1 years; 78% were male. Almost all (95%) were adenocarcinoma. Median duration of follow-up was 2.08 years. Most primary tumors were located in the GE junction (68.3%). Treatment was well tolerated: 95% patients completed all FOLFOX cycles, 98% received the pre-specified RT dose, and 36 of 41 (87.7%) went on to have surgery (1 elected observation after complete clinical response). R0 resection occurred in 97% of those that went on to have surgery. At least partial pathologic response was found in 30 of 36 (83.3%); 8 of 36 (22%, CI 10.1-39.2%) had a pathologic complete response (pCR) and 20 of 36 (55%) had pCR or near-complete response (NCR). At the time of analysis, 2-year RFS was 71.5% (CI 52.1-84.2) and the median RFS was 3.1 years; median OS was not reached. At time of follow-up, 85% (17 of 20) of those with NCR and PCR were relapse-free. Conclusions: Our study demonstrates a high treatment completion rate when FOLFOX was administered prior to CRT and surgery for E/GEJ cancers. Almost all patients had R0 resection and over half had NCR or pCR response. Short-term follow-up RFS and OS demonstrate promising efficacy for this approach in a sample almost exclusively of adenocarcinoma tumors. Strategies to implement induction FOLFOX or FLOT either with or without CRT should continue to be explored in larger studies. Clinical trial information: NCT03110926.
Preclinical evaluation of a dual magnetic and fluorescence-guided approach for sentinel lymph node biopsy in the stomach.
Authors: Shetty Anil , Cousins Aidan , Krishnan Shridhar , Pham Nguyen , Milanova Valentina , Krishnan Giri , Nelson Melanie , Ikoma Naruhiko , Thierry Benjamin
Published: January 2022

337

Background: Gastrectomy with extended (D2) lymphadenectomy is considered as a standard of care for gastric cancer to provide best possible outcomes and pathologic staging. However, D2 gastrectomy is technically demanding operation and reported to be associated with increased complications, including bleeding, pancreatitis, abscess, chylous ascites, and mortality. Application of sentinel lymph node mapping in gastric cancer has the potential to reduce patient morbidity, while facilitating detailed pathology processing required to accurately identify nodal metastases. However, sentinel lymph node biopsy techniques are not established for gastrectomy because of a lack of practical tracers; an effective and convenient tracer that exclusively accumulates in sentinel lymph nodes is critically needed. Methods: A lymphotropic tracer solution consisting of mannose-labelled magnetic nanoparticles (SPIONs) and a fluorescent dye (indocyanine green, ICG) was injected laparoscopically into the stomach submucosa of 6 healthy female domesticated pigs while under general anaesthesia. Intraoperative laparoscopic fluorescence imaging was used to highlight draining lymphatic pathways containing ICG, while a combination of T2-weighted MRI and magnetometer probe detection were used to identify nodes containing SPIONs. Results: Mixing the ICG dye and SPIONs ensured concurrence of fluorescent and magnetic signals in the sentinel nodes. Average tracer accumulation time before dissection was 5 hours. On average 4.5 fluorescent nodes (range 2–7) were removed, of which 2 (average) were also magnetic (range 1–4). Magnetic nodes could be identified using both preoperative MRI and intraoperative magnetometer probe. The mannose label of the SPIONs produced a strong binding affinity to macrophages, and in combination with particle size (80 nm) results in enhanced retention in the sentinel nodes. On average, after 5 hours accumulation time, the sentinel nodes contained 4.1% of the SPION injected dose and 88% of the magnetometer counts. Conclusions: Through the co-injection of fluorescent and mannose-labelled magnetic tracers, lymphatic drainage pathways can be determined preoperatively with MRI, visualised with intraoperative fluorescence cameras, and SLNs confirmed with magnetometer. Although ICG flows through multiple echelons, in doing so it creates a lymphatic roadmap to guide surgeons. The addition of magnetic particles provides sentinel node discrimination, so in combination, these two tracers could greatly enhance the capability to detect SLNs in gastric cancer.
Association of magnitude and consistency of PD-L1 expression and other variables associated with benefit from immune checkpoint inhibition (ICI): Systematic review and meta-analysis of 14 phase 3 trials in advanced gastroesophageal cancer (GEC).
Authors: Yoon Harry H. , Jin Zhaohui , Kour Oudom , Shitara Kohei , Gibson Michael K. , Prokop Larry , Kang Yoon-Koo , Shi Qian , Ajani Jaffer A.
Published: January 2022

344

Background: ICI with anti-PD-1 therapy was approved by the US FDA as 1st/2nd-line treatment of advanced GEC regardless of PD-L1 status. It is argued that patients (pts) with PD-L1-low GEC do not benefit from ICI. To avoid spurious exclusion of pts, we systematically reviewed phase 3 trials to assess the magnitude and consistency of PD-L1 to predict benefit from ICI. We also examined other potential predictive factors to understand their magnitude and consistency in comparison with PD-L1 status. Methods: MEDLINE, Embase, Scopus, Web of Science, and Cochrane Central Register were searched for all randomized clinical trials (RCT; 2000-2021) in advanced GEC comparing ICI, alone or with chemotherapy, vs standard of care (SOC). The primary endpoint was overall survival (OS). Study screening, data abstraction, and bias assessment were done independently by two reviewers per PRISMA guidelines. The mean HR for ICI vs SOC was calculated by random effects model. The predictive value of a factor was quantified using relative magnitude and consistency (table). Results: 14 RCTs at low risk of bias were included (N = 9,210 pts; KN62, CM649, CM648, ESCORT1st, KN590, ATT4, JAV100, KN181, KN61, ATT3, ESCORT, RATIONALE302, JAV300, ATT2). 6 trials were 1st-line, 8 were after 1st-line. Treatment comparisons were ICI + chemo vs chemo (6 trials), ICI vs chemo (9 trials), and ICI vs placebo (1 trial). ICI was always anti-PD-1/-L1 (1 trial also had anti-CTLA-4). Table shows primary results. To enable head to head comparisons, subgroup analyses of trials containing both levels of a factor or having similar design were done and generally yielded consistent results. Conclusions: PD-L1 CPS is the strongest predictive biomarker, after MSI, for OS benefit from ICI-containing therapy vs SOC. Additional research on gender is warranted.[Table: see text]
Distinct differences in genomic profile of gastric and gastroesophageal junction adenocarcinoma.
Authors: Nakauchi Masaya , Walch Henry S. , Chatila Walid Khaled , Tran Thinh , Vos Elvira Lise , Sihag Smita , Tang Laura H. , Coit Daniel G. , Stadler Zsofia Kinga , Janjigian Yelena Y. , Maron Steven Brad , Ku Geoffrey Yuyat , Ilson David H. , Solit David B. , Schultz Nikolaus , Molena Daniela , Strong Vivian E.
Published: January 2022

345

Background: Gastroesophageal junction cancer (GEJC) and gastric cancer (GC) are frequently studied together as one disease. Genomic profiles between the two disease sites have not been well characterized. We aimed to characterize molecular differences between the two disease sites. Methods: We collected data between January 2010 and December 2019 from a prospectively maintained database of GEJC and GC at our center. GEJC was defined according to the Siewert type 1 to 3 classification. Patients who underwent surgical resection and had MSK-IMPACT (MSK-Integrated Mutation Profiling of Actionable Cancer Targets) sequencing performed on their primary tumor were included in this analysis. Results: Two hundred and seventy-four samples were analyzed; 156 (56.9%) GEJC and 118 (43.1%) GC patients. Regarding molecular subtypes, the GEJC group had a higher frequency of chromosomally instable tumors compared to the GC cohort (55.1% vs. 25.4%, p < 0.001). The fraction of genome altered (FGA) was significantly higher in the GEJC group (p < 0.001). TP53 (75.3% vs. 31.9%, p < 0.001, q < 0.001), CDKN2A (17.1% vs. 4.3%, p = 0.002, q = 0.02), and MDM2 (6.8% vs. 0%, p = 0.007, q = 0.033) were more frequently altered in the GEJC group, whereas CDH1 (2.7% vs. 9.6%, p = 0.037, q = 0.118) and RHOA (0% vs. 6.4%, p = 0.003, q = 0.02) were more frequently altered in the GC group. The GEJC group also had a higher frequency of alterations in the cell cycle pathway compared to the GC patients (36.3% vs. 11.7%, p < 0.001, q < 0.001). Conclusions: There are distinct differences in genomic profiles between GEJC and GC with a higher frequency of mutations in TP53, CDKN2A, MDM2, and cell cycle pathway in the GEJC patients, that may have potential implications in evaluating optimal treatment strategies with targeted therapy.
Analysis of the gastric microbiome in gastric cancer patients and in non-tumorous patients.
Authors: Bang Eun Joo , Choi Hyuk Soon , Lee Jae Min , Kim Eun Sun , Keum Bora , Jeen Yoon Tae , Chun Hoon Jai
Published: January 2022

349

Background: Gastric cancer is the fifth most common cancer worldwide and it is the most commonly diagnosed cancer in Korea. The most clearly known microbiologic risk factor is Helicobacter pylori infection. Chronic inflammation of gastric mucosa accelerates a cascade of chronic active gastritis, multifocal atrophy intestinal metaplasia, gastric dysplasia and gastric adenocarcinoma. Studies proved H. pylori reduces microbial diversity, but it is reversible with H. pylori eradication. Thus, we could assume gastric carcinogenesis may not solely depend on H. pylori. In this study, we analyzed and compared gastric microbiome in gastric cancer patients and non-cancer patients to find changes between the two groups. Additionally, we analyzed microbial diversity of cancerous lesions and para-cancerous lesions in the cancer group in an effort to reveal the role of microbiome in carcinogenesis. Methods: Gastric mucosa collected by biopsy during esophagogastroduodenoscopy (EGD) from 10 patients with gastric cancer and 18 non-cancer patients. Gastric biopsies were obtained from the margin of cancer and para-cancerous lesions in cancer patients. In control group, samples were obtained from antrum with normal mucosal morphology. DNA was extracted from the gastric mucosal tissues and 16s rRNA genes were amplified. Then they were analyzed by microbiome analysis program. Results: Higher number of species was detected in the control group (average of 97.75 species) compared to the cancer group (average of 73.4 species). The gastric cancer microbiome was showed reduced microbial diversity compared to that of control group. Fusobacteria was more dominant in cancer group and Rhodobacterales was found more prominent in control group. We compared microbial diversity of the cancer lesion and the para-cancerous lesion within the cancer group and higher number of species was detected in non-tumorous lesion. Conclusions: Gastric microbiome of non-tumorous patients was more diverse and the composition of species was different between the two groups. These results suggest that microbial dysbiosis may be involved in gastric carcinogenesis. Further studies should include more detailed analysis of spatial and temporal composition and the comparison between different pathologic types and tumor location are necessary. Better understanding of microbial differences and changes in healthy and gastric cancer patients could verify the carcinogenesis of gastric cancer.
Survival prediction using radiomic signatures in metastatic gastric and esophageal adenocarcinoma (GEA).
Authors: Allen Michael J , Sertic Andrew , Liu Zhihui (Amy) , Liu Zijin , Suzuki Chihiro , Panov Elan David , Ma Lucy Xiaolu , Bach Yvonne , Jang Raymond Woo-Jun , Chen Eric Xueyu , Darling Gail Elizabeth , Yeung Jonathan , Swallow Carol Jane , Brar Savtaj Singh , Kalimuthu Sangeetha , Wong Rebecca , Veit-Haibach Patrick , Elimova Elena
Published: January 2022

357

Background: Radiomic characterisation of tumour phenotypes can generate image-driven biomarkers that potentially aid in clinical decision-making. We sought to identify radiomic features in metastatic GEA that may be predictive for survival outcomes. Methods: A retrospective analysis between 2009-20 identified patients (pts) with metastatic GEA. All pts received chemotherapy (CTx), with a ‘baseline’ and 8-12 week ‘on-treatment’ contrast-enhanced CT chest/abdomen/pelvis performed. Radiomic analysis was performed with LIFEx (livexsoft.org). Population demographics and clinical outcomes were recorded. Univariable Cox proportional hazards model (UVA) assessed clinical variables (n=26) predictive of overall survival (OS) and progression-free survival (PFS) with p=0.05 indicating significance. Multivariable Cox model (MVA) was used to assess radiomic features (n=78) in the presence of clinical variables. Concordance index (C-index) was calculated to assess model performance (≥0.7 = high predictive accuracy). A ‘validation’ cohort analysis was performed to validate the model. Results: 166 pts were identified (primary cohort n=143; validation cohort n=23). 123 had de-novo metastatic disease, 43 recurrence following curative-intent therapy. In the primary cohort the median age was 58.1y, 101 (71%) were male, 120 (84%) were non-Asian and 131 (92%) were ECOG 0-1. Similar demographics were observed in the validation cohort. Both ‘baseline’ and ‘on-treatment’ scans UVA identified Her2 status, ethnicity, and the number of CTx cycles as predictive of PFS, while ECOG, brain metastases, neutrophil count (ANC), albumin and number of CTx cycles were predictive of OS. ‘Baseline’ model analysis for PFS and OS identified consistent radiomic features (HUskewness; HUpeakSphere), with an observed C-index 0.6 and 0.657 respectively. No radiomic features were identified on ‘on-treatment’ PFS analysis. ‘On-treatment’ OS analysis is shown in the table with 3 radiomic features (SHAPE Surface; SHAPE Compacity; PARAMS ZSpatial-Resampling) predictive for OS. The C-index is 0.76. Analysis of the validation cohort supported the model (C-index 0.815) for ‘on-treatment’ OS. Conclusions: Radiomic analysis identified a number of features associated with PFS and OS. The features specifically identified on ‘on-treatment’ scans were highly predictive for OS. Our analysis suggests radiomic features in addition to clinical variables can be predictive of outcome in patients with metastatic GEA receiving CTx.[Table: see text]
Definitive chemoradiation for oligometastatic esophageal cancer patients.
Authors: Puckett Lindsay , Matoska Thomas , Jurkowski Lauren , Banerjee Anjishnu , Martinez Enrique , Kodali Divya , Shukla Monica , Linsky Paul , Gasparri Mario , Chakrabarti Sakti , George Ben , Shreenivas Aditya V.
Published: January 2022

359

Background: When esophageal cancer (EC) is metastatic at diagnosis, prognosis is poor, with 5-year survival of ̃5%. NCCN guidelines recommend palliative treatment or best supportive care. However, guidelines do not stratify by the extent of metastatic disease. Oligometastatic (oligo) disease has been shown in some cancers to portend better survival and more aggressive treatment options may be appropriate. Preliminary data has shown this may be the case for oligo EC, however, consensus recommendations remain palliative in intent. This study aims to compare overall survival (OS) in oligo EC patients treated with a definitive approach (chemoradiotherapy [CRT]) to those treated with purely palliative intent. Methods: Patients with oligo (any histology, ≤5 metastatic foci) EC treated in a single academic hospital between 2009-2020 were retrospectively analyzed in 2021. Patients were divided into definitive and palliative treatment groups; definitive CRT was defined as radiation therapy >40 Gy and >2 cycles of chemotherapy (CT) (+/- induction CT). OS was calculated by measuring the time from the date of diagnosis to the date of death or last follow-up. Survival curves between groups and by various prognostic factors were compared using the log rank test. Results: Of 77 Stage IVB patients, 35 met the pre-specified oligo definition. Of these, 18 received definitive CRT, and 17 palliative treatment (Table). With a median follow-up of 60.8 months, median OS for definitive CRT and palliative groups were 91.4 and 8.2 months, (p<0.01), translating into 5-year OS of 57.7% (95%CI: 33.5-82.0%) vs. 7.5% (95%CI: 0.0-21.6%), respectively. Prognostic factors correlated with increased OS included lower ECOG performance status (PS) (p<0.01), induction CT (p<0.01), N stage (p<0.01), adenocarcinoma (vs. squamous cell carcinoma) (p<0.05), diagnosis in 2013 or later (p<0.05), younger age (p<0.05), and > lymphocyte-to-monocyte ratio (p<0.05). Factors not associated with OS included neutrophil-to-lymphocyte ratio (p=0.39), T-stage (p=0.9), primary site (GEJ, distal, mid, or cervical) (p=0.07), tumor grade (p=0.83), type of spread (hematogenous, lymphatic, or local invasion) (p=0.69), sex (p=0.22), and HER2 status (p=0.07). Conclusions: Within our population, oligo EC patients treated with definitive CRT had significantly improved OS as compared to those treated with palliative only intent. These results suggest there may be a sub-population of oligo EC that would benefit from more aggressive treatment paradigms; thus, further evaluation is warranted.[Table: see text]
A phase 3 randomized, double-blind, placebo-controlled study of durvalumab in combination with gemcitabine plus cisplatin (GemCis) in patients (pts) with advanced biliary tract cancer (BTC): TOPAZ-1.
Authors: Oh Do-Youn , He Aiwu Ruth , Qin Shukui , Chen Li-Tzong , Okusaka Takuji , Vogel Arndt , Kim Jin Won , Suksombooncharoen Thatthan , Lee Myung Ah , Kitano Masayuki , Burris III Howard A. , Bouattour Mohamed , Tanasanvimon Suebpong , Zaucha Renata , Avallone Antonio , Cundom Juan , Rokutanda Nana , Xiong Julia , Cohen Gordon , Valle Juan W.
Published: January 2022

378

Background: BTC is a rare, heterogenous cancer with poor prognosis. Reports on immunogenic features of BTC suggest checkpoint inhibition may result in antitumor immune responses, and limited clinical activity has been seen with single agents in advanced settings. Durvalumab (PD-L1 inhibitor) + GemCis showed promising antitumor activity in advanced BTC in a phase 2 study. TOPAZ-1 (NCT03875235) is the first global phase 3 study to evaluate first-line immunotherapy + GemCis in advanced BTC. Methods: In this double-blind study, pts previously untreated for unresectable locally advanced, recurrent, or metastatic BTC were randomized 1:1 to receive durvalumab (1500 mg every 3 weeks [Q3W]) or placebo + GemCis (Gem 1000 mg/m2 and Cis 25 mg/m2 on Days 1 and 8 Q3W) for up to 8 cycles, followed by durvalumab (1500 mg Q4W) or placebo until disease progression or unacceptable toxicity. Randomization was stratified by disease status (initially unresectable, recurrent) and primary tumor location (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer). The primary objective was to assess overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. Results: At data cutoff for this interim analysis (11 August 2021), 685 pts were randomized to durvalumab + GemCis (n=341) or placebo + GemCis (n=344; Table). The primary objective was met: durvalumab + GemCis significantly improved OS vs placebo + GemCis (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.66–0.97; p=0.021). PFS was also significantly improved with durvalumab vs placebo (HR, 0.75; 95% CI, 0.64–0.89; p=0.001). ORR was 26.7% with durvalumab and 18.7% with placebo. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 62.7% of pts receiving durvalumab and 64.9% of pts receiving placebo. TRAEs led to discontinuation of any study medication in 8.9% of pts receiving durvalumab and 11.4% of pts receiving placebo. Conclusions: In pts with advanced BTC, durvalumab + GemCis significantly improved OS and PFS vs placebo + GemCis with manageable safety, indicating durvalumab + GemCis may be a new first-line standard of care regimen. Clinical trial information: NCT03875235. [Table: see text]
Phase 3 randomized, open-label, multicenter study of tremelimumab (T) and durvalumab (D) as first-line therapy in patients (pts) with unresectable hepatocellular carcinoma (uHCC): HIMALAYA.
Authors: Abou-Alfa Ghassan K. , Chan Stephen Lam , Kudo Masatoshi , Lau George , Kelley Robin Kate , Furuse Junji , Sukeepaisarnjaroen Wattana , Kang Yoon-Koo , Dao Tu V. , De Toni Enrico N. , Rimassa Lorenza , Breder Valeriy Vladimirovich , Vasilyev Alexander , Heurgue Alexandra , Tam Vincent , Mody Kabir , Thungappa Satheesh Chiradoni , He Philip , Negro Alejandra , Sangro Bruno
Published: January 2022

379

Background: A single priming dose of T (anti-CTLA-4) added to D (anti-PD-L1) in the STRIDE (Single T Regular Interval D) regimen, formerly T300+D, showed encouraging clinical activity and limited toxicity in a phase 2 uHCC study (Study 22, NCT02519348), suggesting single exposure to T is sufficient to improve upon D activity. HIMALAYA (NCT03298451) evaluated the efficacy and safety of STRIDE or D vs sorafenib (S) in uHCC. Methods: HIMALAYA is an open-label, multicenter, phase 3 study, in which pts with uHCC and no prior systemic therapy were initially randomized to STRIDE (T 300 mg plus D 1500 mg [one dose] plus D 1500 mg every 4 weeks [Q4W]), D (1500 mg Q4W), S (400 mg twice daily), or T 75 mg Q4W (4 doses) plus D 1500 mg Q4W (T75+D). Recruitment to T75+D ceased after a planned analysis of Study 22 showed T75+D did not meaningfully differ from D. The primary objective was overall survival (OS) for STRIDE vs S. The secondary objective was OS noninferiority (NI) of D to S (NI margin: 1.08). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR; RECIST v.1.1), duration of response (DoR), and safety. Results: In total, 1171 pts were randomized to STRIDE (N=393), D (N=389), or S (N=389). At data cutoff (DCO), the primary objective was met: OS was significantly improved for STRIDE vs S (hazard ratio [HR], 0.78; 96% confidence interval [CI], 0.65–0.92; p=0.0035; Table). D met the objective of OS NI to S (HR, 0.86; 96% CI, 0.73–1.03). ORRs were higher for STRIDE (20.1%) and D (17.0%) than for S (5.1%). No new safety signals were identified. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 25.8% (STRIDE), 12.9% (D), and 36.9% (S) of pts. Grade 3/4 hepatic TRAEs occurred in 5.9% (STRIDE), 5.2% (D), and 4.5% (S) of pts. No TRAE of esophageal varices hemorrhage occurred. Rates of TRAEs leading to discontinuation were 8.2% (STRIDE), 4.1% (D), and 11.0% (S). Conclusions: HIMALAYA was the first large phase 3 trial with a diverse, representative uHCC population and extensive long-term follow-up to assess both mono- and combination immunotherapy. D was noninferior to S with favorable safety. The combination of a single priming dose of T plus D in STRIDE displayed superior efficacy and a favorable benefit-risk profile vs S. STRIDE is a proposed, novel, first-line standard of care systemic therapy for uHCC. Clinical trial information: NCT03298451. [Table: see text]
Lenvatinib combined with transarterial chemoembolization as first-line treatment of advanced hepatocellular carcinoma: A phase 3, multicenter, randomized controlled trial.
Authors: Peng Zhenwei , Fan Wenzhe , Zhu Bowen , Li Jiaping , Kuang Ming
Published: January 2022

380

Background: LAUNCH is a multicenter, randomized, open-label, parallel-group phase 3 trial, aiming to assess the efficacy and safety of lenvatinib plus TACE compared with lenvatinib alone as first-line therapy in patients with advanced hepatocellular carcinoma (HCC). Methods: Patients with advanced HCC were randomly assigned in a 1:1 ratio to receive either lenvatinib plus TACE (LEN-TACE group) or lenvatinib alone (LEN group). Randomized stratification factors include: Eastern Cooperative Oncology Group performance status score (0 vs. 1), tumor thrombus (presence vs. absence), body weight (<60 vs. ≥60kg) and site. In both Len group and LEN-TACE group, patients received oral lenvatinib after randomization within 3 days. The initial dose is 12 mg/day for patients weighing ≥ 60 kg, and 8 mg/day for patients weighing < 60 kg. TACE was started one day after initial lenvatinib in LEN-TACE group and then performed on-demand according to the condition of the tumor and liver function. The primary endpoint were overall survival (OS). The secondary endpoints were progression-free survival (PFS), objective response rate (ORR, the proportion of patients with complete response or partial response according to mRECIST), and adverse events. The deadline for interim analysis of data is September 20, 2021. Results: Overall, 338 patients from 12 hospital in China were randomly assigned to receive either lenvatinib plus TACE (n = 170) or lenvatinib (n = 168). The median follow-up duration was 18.4 months (95% confidence interval [CI] 13.7-23.1 months) in the LEN-TACE group and 17.0 months (95% CI 14.2-19.8 months) in the LEN group. The median OS was 17.8 months (95% CI 16.1–19.5) for the lenvatinib-TACE group and 11.5 months (95% CI 10.3–12.7) for the lenvatinib group (stratified hazard ratio [HR] for death = 0.45, 95% CI 0.33–0.61, P<0.001). The median PFS was significantly longer in the LEN-TACE group than in the LEN group (10.6 vs. 6.4 months, HR[hazard ratio]=0.43, P<0.001). Lenvatinib plus TACE improved ORR compared to lenvatinib alone (54.1% vs. 25.0, P<0.001). The following grade 3–4 AEs were more frequently in the lenvatinib-TACE group than in the lenvatinib group: ALT increased (30 [17.6%] vs. 2 [1.2%], P<0.001), AST increased (39 [22.9%] vs. 3 [1.8%], P<0.001), hyperbilirubinemia (16 [9.4%] vs. 5 [3.0%], P=0.014). Conclusions: In conclusion, this trial showed that the combination of lenvatinib plus TACE can improve clinical outcomes and may be the new first-line treatment for patients with advanced hepatocellular carcinoma. Clinical trial information: NCT03905967.
Responses to immunotherapy in hepatocellular carcinoma patients with nonalcoholic steatohepatitis cirrhosis.
Authors: Chang Jeremy , Ryan Joseph S , Ajmera Veeral , Ting Stephanie , Tamayo Pablo , Burgoyne Adam
Published: January 2022

389

Background: Hepatocellular carcinoma (HCC) is the most rapidly growing cause of cancer-related mortality in the United States. Recent preclinical studies suggest that immunotherapy agents targeted at programmed cell death protein 1 (PD-1) do not lead to tumor regression in HCC with underlying nonalcoholic steatohepatitis (NASH). However, further clinical studies are needed to clarify the impact of immunotherapy on patients with NASH-related HCC. Methods: This was a single center, retrospective study analyzing the best responses to immunotherapy in patients with HCC and underlying cirrhosis due to NASH. Patients were divided into 2 groups: those with HCC related to NASH cirrhosis and those with HCC without NASH cirrhosis. All patients received immunotherapy, either as a single agent or in combination with other cancer-directed therapy, with response assessments conducted during their treatment courses. Results: A total of 79 patients were included in this study. There were 15 patients in the NASH cirrhosis-related HCC group and 64 patients in the HCC group without NASH cirrhosis. When analyzing the best disease responses to immunotherapy, 7 patients (46.7%) with HCC and NASH cirrhosis were found to have disease progression as their best responses compared to 7 patients (10.9%) who had HCC without NASH cirrhosis (risk ratio 4.27, p = 0.004). In addition, for the group without NASH cirrhosis, 57 patients (89.1%) experienced disease control (stable disease, partial response, or complete response) from immunotherapy versus 8 patients (53.3%) in the NASH cirrhosis-related HCC group (risk ratio 1.67, p = 0.004). There were no notable differences in patient age, gender, or immunotherapy agents received between the two groups, but there was a significantly greater proportion of patients of Hispanic ethnicity in the HCC group with NASH cirrhosis (p = 0.006, full patient characteristics listed in the table). However, when looking at all individuals in the study, patients of Hispanic ethnicity were not found to have a significantly higher risk of disease progression compared to non-Hispanic patients (p = 0.07). Conclusions: There were significantly higher rates of disease progression as the best response to immunotherapy in patients with HCC and NASH cirrhosis compared to those without NASH cirrhosis. With the expanded use of immunotherapy in HCC patients, further prospective studies are needed to clarify the impact of underlying liver disease etiology on immunotherapy response.[Table: see text]
Treatment of hepatocellular carcinoma with tyrosine kinase inhibitors: Real-world outcomes from the West of Scotland.
Authors: Naylor Gregory , McLaren Alistair , Graham Janet , Evans T.R. Jeffry
Published: January 2022

390

Background: Sorafenib, lenvatinib and regorafenib have proven efficacy in patients with HCC in randomised clinical trials. First line sorafenib significantly improves overall survival (OS) and disease control rates vs. placebo (SHARP) whilst lenvatinib (REFLECT) is non-inferior to sorafenib in terms of OS. Second line regorafenib improves OS versus placebo (RESORCE). Real world outcomes are often inferior to randomised controlled trial data. Consequently we investigated the outcomes of real world patients with HCC treated with multi-kinase inhibitors in our regional tertiary-referral centre. Methods: All patients with advanced HCC treated with sorafenib, lenvatinib or regorafenib as monotherapy from 4 December 2015 to 16 September 2020 were included. The Information Governance (Caldicott) guardian approved access to patients records. Median OS (mOS) and treatment duration (mDoT) were calculated using Kaplan-Meier estimate; baseline patient characteristics and information on dosing regimen, dose interruptions and modifications, were also collected. Results: The SHARP trial achieved mOS and mDoT of 10.7 and 5.3 months. 26% required dose reductions and 44% dose interruptions. Our patients achieved mOS of 7.98 and mDoT 2.62 months; 35% required a dose reduction and 48% a dose interruption. Mean daily dose (MDD) was not given in SHARP but was 663.8mg in REFLECT; 728mg sorafenib was achieved in West of Scotland (WOS). In REFLECT, lenvatinib patients had mOS and mDOT of 13.6 and 5.7 months; our patients had a mOS of 9.55 and mDoT of 3.68 comparatively. 37% and 40% had dose reductions and interruptions in REFLECT vs. 50% and 44% in WOS. Our patients had a MDD of 10.9 mg (12mg/day) and 6.88mg (8mg/day) lenvatinib vs. 10.5mg and 7.0mg in REFLECT. In RESORCE, mOS and mDOT of 10.6 and 3.6 months was acheived in regorafenib patients vs. 9.52 and 3.42 months in WOS. 68% needed drug interruption or reduction vs. 53% in WOS and MDD of regorafenib was 144·1mg vs. 148.3mg in our population. Conclusions: Consistent with other real world experiences our data demonstrate reduced mOS and mDoT times compared to trials. This is despite maintaining good dose intensity. On average, mOS was 2.6 months less in our population vs. trial data. This may be explained by etiological differences of underlying liver disease or treatment of less highly selected patients. Our patients tended to be older, have poorer PS and Child Pugh scores compared with trials. Our data lack control arms, preventing interpretation of whether improved survival outcomes over placebo are maintained. Interestingly our data mirror the results of REFLECT where lenvatinib treatment was maintained for longer periods compared to sorafenib, despite higher numbers of dose interruptions. Our data also confirm that observed within RESORCE where, remarkably, patients treated with second line regorafenib achieved mOS similar to those treated in the first line setting.
Effect of immune checkpoint inhibitor (ICI) treatment in hepatocellular carcinoma (HCC) based on underlying liver disease.
Authors: Wu Linda , Bagiella Emilia , Rudshteyn Michelle , Cohen Deirdre Jill
Published: January 2022

396

Background: While treatment of unresectable HCC remains challenging, ICI either alone or in combination with bevacizumab, has become a standard therapy. Overall, HCC outcomes are improved with the use of ICI, but only a small percentage of patients respond. As a result, there remains a need for biomarker discovery for optimal patient selection. Emerging evidence suggests that patients with non-viral causes of HCC, including nonalcoholic steatohepatitis (NASH) and alcohol use, may not derive the same benefit from ICI as patients with viral causes of HCC. A recent study by Pfister et al. (2021) demonstrated in preclinical models that NASH-related aberrant T cell activation and impaired immune surveillance play a role in reducing responsiveness to ICI. Our study aimed to use real-world data to evaluate whether there is a difference in overall survival (OS) following treatment with ICI in patients with viral-induced compared to those with non-viral-induced HCC. Methods: We conducted a retrospective chart review of all patients with unresectable HCC at Mount Sinai Health System who received ICI from 1/2017 to 6/2021. The primary outcome investigated was OS of patients with viral etiologies compared to non-viral etiologies of HCC. Results: A total of 349 patients were included. The cohort was predominantly male (84%), with median age of 63 years. 86% of patients were cirrhotic. 246 (70%) patients had HCC with a viral etiology, with the majority (67.5%) due to hepatitis C infection. 103 patients (30%) had non-viral causes of HCC, with 47% due to NASH and 39% due to alcohol. At the time of ICI initiation, most patients (66%) had Child Pugh (CP) class A liver disease and performance status (PS) ECOG 0 (71%). Nivolumab was the most common ICI given (87%) and 79% of patients received ICI as first-line therapy. The viral and non-viral HCC groups were evenly matched in terms of sex, age, cirrhosis, ECOG PS, type of ICI, and line of therapy. With a median duration of follow-up of 10.5 months (range: 1.4-62.4 months), the median OS (mOS) of patients with viral HCC was 19.3 months (95% CI: 14.2-26.6) and mOS of patients with non-viral HCC was 11.4 months (95% CI: 9.3-17.7; P = 0.08). The hazard ratio, adjusted for CP class and stage, for viral HCC treated with ICI was 0.81 (95% CI: 0.583-1.127; P = 0.21). Conclusions: Patients with viral-induced HCC appear to have improved OS when treated with ICI compared to patients with non-viral-induced HCC, but the difference is not statistically significant. Further studies are required to better understand the mechanisms underlying response to ICI in HCC.
Outcomes of beta blockers (BB) in hepatocellular carcinoma (HCC) treated with immune checkpoint inhibitors (ICIs).
Authors: Wu Linda , Ozbek Umut , van Hyfte Grace , Reincke Marlene , Gampa Anuhya , Abugabal Yehia I. , Nishida Naoshi , Wietharn Brooke , Amara Suneetha , Balcar Lorenz , Pinter Matthias , Vogel Arndt , Weinmann Arndt , Saeed Anwaar , Rimassa Lorenza , Naqash Abdul Rafeh , Muzaffar Mahvish , Huang Yi-Hsiang , Pinato David James , Ang Celina
Published: January 2022

399

Background: Portal hypertension increases intestinal permeability, dysbiosis, and bacterial translocation, leading to a pro-inflammatory state, which can in turn promote progression of liver disease. However, multiple studies have shown that BB use in patients with cirrhosis can reduce the risk of developing HCC, and in patients with HCC, BB can improve overall survival (OS). In recent years, ICIs have become first-line therapy for patients with unresectable HCC, and we aimed to evaluate whether BB use conferred survival benefits in patients treated with ICIs using real-world data. Methods: We conducted a retrospective chart review of HCC patients treated with ICI from 2017 to 2019 at 13 institutions across North America, Europe, and Asia in order to evaluate the association between BB use and OS, as well as BB use and overall response rate (ORR). Univariable and multivariable logistic regression models were used to evaluate associations, and survival analyses were performed using the Kaplan-Meier method. Results: A total of 578 patients were evaluated. The median age of the cohort was 65 years, and 80% of patients were male. The majority of patients (70%) were cirrhotic. The causes of underlying liver disease were as follows: HBV (22%), HCV (36%), alcohol (20.8%), and NASH (13%). Most patients (73.5%) had Child Pugh (CP) class A liver disease, and good performance status with ECOG score either 0 (52%) or 1 (45%). The majority of patients (75%) treated with ICIs received a PD-1 inhibitor alone. There were 360 deaths (62% of patients) with a median follow-up of 30.8 months (Quartiles: 17.2-40.3 months). Two hundred and three (35%) patients had BB use at any point during ICI therapy. Fifty-one percent of these patients were on a nonselective BB whereas 49% were taking a cardio-selective BB. BB use was not significantly correlated with OS (hazard ratio, 1.12; 95% CI, 0.9-1.39; P = 0.298) or ORR (odds ratio, 0.84; 95% CI, 0.54-1.31; P = 0.451) in univariate or multivariate analyses. Conclusions: Patients who used BB while on immunotherapy for unresectable HCC did not have statistically significant differences in OS or ORR compared to patients who did not use BB. More studies are required to elucidate the effect of beta blockade on the microbiome, immune activation, and HCC.
Provider- and system-level barriers to surveillance for hepatocellular carcinoma among patients with chronic liver disease.
Authors: Beal Eliza W. , Gorji Leva , Volney Jaclyn , Sova Lindsey , Tsung Allan , McAlearney Ann Scheck
Published: January 2022

404

Background: Most cases of hepatocellular carcinoma (HCC) occur in patients with known risk factors. Expert society guidelines recommend HCC surveillance with ultrasound with or without serum alpha fetoprotein every 6 months for these patients, but less than 20% undergo recommended surveillance. The objective of this study was to identify provider- and system-level barriers to surveillance from the provider perspective and to examine the role of provider knowledge and attitudes. Providers’ suggestions for potential interventions to improve HCC surveillance were also elicited. Methods: Qualitative research methods were employed. Purposive sampling was used to invite providers from the Departments of Internal Medicine and Family and Community Medicine who provide primary care, and from the Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition to participate. A semi-structured interview guide was used. Transcribed interviews were analyzed to reveal emergent themes. Results: 22 providers were interviewed including primary care providers, general gastroenterologists and hepatologists. These providers spend a median of 70% (range 20% - 100%) of their time in clinical practice, versus research and administrative responsibilities, and have been in practice a median of 7 years (range 1.8 – 25 years). Provider-level barriers to HCC surveillance identified by participants included variable provider comfort managing chronic liver disease; relationships between primary care, gastroenterology, infectious disease and hepatology; if/how providers discuss HCC surveillance with high-risk patients; provider knowledge of guidelines and outcomes from HCC surveillance; and specific provider-level barriers including time in clinic, competing issues in clinic, deferral of responsibility to another provider, the provider-patient relationship, and time spent on patient education. System-level barriers to HCC surveillance included the absence of relevant technology tools, insurance denial of surveillance imaging, difficulty scheduling surveillance studies and the COVID-19 pandemic. Provider suggestions for interventions included patient navigation, use of technology, education for patients and primary care providers, partnering with primary care practices, and media campaigns. Conclusions: Important barriers to HCC surveillance and opportunities for intervention to improve HCC surveillance rates in high-risk patients were identified. Future research should focus on the design, testing and implementation of interventions to target provider- and system-level barriers.