bluuebunny/crossref_metadata_2025_split huggingface dataset:
Camrelizumab plus chemotherapy as neoadjuvant therapy for resectable, locally advanced esophageal squamous cell carcinoma (NIC-ESCC2019): A multicenter, open-label, single-arm, phase 2 study.
Authors: Li Jingpei , Liu Jun , Li Zhuoyi , Cui Fei , Zeng Yuan , Liang Wenhua , Liang Hengrui , Wang Wei , Xu Ke , Cai Weipeng , Fu JunHui , He Jianxing 
Published: June 2021

4028 Background: Despite multidisciplinary therapies, prognosis of pts with resectable esophageal squamous cell carcinoma (ESCC) remains poor. Combining PD-1 blockade to neoadjuvant chemotherapy might be a feasible and effective strategy. Camrelizumab (an anti-PD-1 antibody) was approved for advanced or metastatic ESCC in the second-line setting and showed improved anti-tumor activity and survival benefit when combined with chemotherapy in multiple advanced tumors. Methods: In this NIC-ESCC2019 phase 2 study, histologically or cytologically confirmed ESCC pts (stage II-IVA) were enrolled to receive two cycles of neoadjuvant chemoimmunotherapy (NIC) with camrelizumab (200 mg on day 1) plus nab-paclitaxel (260 mg/m² in total on day 1 and day 8) and cisplatin (75 mg/m² in total on days 1-3) of each 21-day cycle, followed by esophagectomy. The primary endpoint was complete pathologic response (CPR) rate in the primary tumor. Besides, we also explored the relationship between the tumor genomic profile or primary-tumor microenvironment and the pathological response. Results: Between Jan 17, 2020 and Dec 8, 2020, 56 pts were enrolled. 51 pts underwent surgical resection, and all had complete tumor resection. CPR was achieved in 18 (35.3%; 95% CI, 21.7%-48.9%) pts; 12 (23.5%) pts had major pathologic response (MPR), and 21 (41.2%) had incomplete pathological response (IPR). Of note, 16 (31.4%) pts achieved CPR in both primary tumor and lymph nodes. The objective response rate was 66.7% (95% CI, 40.0-70.4). No in-hospital mortality occurred. The most common treatment-related adverse events (TRAEs) were decreased WBC (20 [36%] of 56 pts), vomiting (19 [34%]), and alopecia (18 [32%]). Grade 3 TRAEs only occurred in 6 (11%) pts, and there were no grade 4 or 5 TRAEs. The most common immune-related AEs included grade 1-2 rash maculo-papular (7 [13%]) and reactive cutaneous capillary endothelial proliferation (5 [9%]). Presence of mutations in CREBBP and KMT2D at treatment-naïve time-point was correlated with non-response group (IPR and stable disease) (CREBBP, p = 0.046; KMT2D, p = 0.047). Among the immune populations, CD8+, CD8+PD-1+ and CD8+PD-L1+ T cells increased significantly after two doses of NIC, especially in the CPR+MPR group (CD8+, p = 0.013; CD8+PD-1+, p < 0.001; CD8+PD-L1+, p = 0.068). Conclusions: The addition of camrelizumab to neoadjuvant chemotherapy in ESCC demonstrated promising efficacy with acceptable toxicity, supporting the further investigation in a randomized phase 3 clinical trial. Clinical trial information: NCT04225364. [Table: see text]
SHARED: Efficacy and safety of sintilimab in combination with concurrent chemoradiotherapy (cCRT) in patients with locally advanced gastric (G) or gastroesophageal junction (GEJ) adenocarcinoma.
Authors: Wei Jia , Lu Xiaofeng , Liu Qin , Fu Yao , Liu Song , Yang Ju , Wang Meng , Zheng Liming , Yang Yang , Fan Xiangshan , Zhao Yang , Guan Wenxian , Liu Baorui 
Published: June 2021

4040 Background: PD-1 inhibitor and chemotherapy have shown significant clinical benefits in 1L-treatment of G/GEJ. While it is not clear for locally advanced stage. The aim of this single-arm phase Ib trial is to assess the feasibility of sintilimab (PD-1 inhibitor) in combination with cCRT in locally advanced GC. Methods: Patients (pts) with initial histopathologically confirmed G/GEJ adenocarcinoma, diagnosed as locally advanced III-IVA per AJCC 8th and ECOG PS of 0-1 were eligible. Sintilimab (200mg, iv, Q3W) was given with CRT sandwich in sequence of one induction chemotherapy (S-1+Nab-PTX), weekly Nab-PTX(80-100mg/m2, d1, d8, d15, d22), concurrent radiotherapy (45Gy/1.8Gy*25f), and one consolidation chemotherapy (S-1+Nab-PTX). Pts received three additional combinations of sintilimab and chemotherapy after surgery or investigator’s best choice for unresectable pts after planned therapy. The primary endpoint was pCR and a Simon two-stage was employed at first 9 pts. This interim analysis was pre-planned after finishing stage I assessment. Accrual is ongoing with another 25 in next stage. Results: In the first stage, 5 out of 9 pts achieved pCR and passed to next stage. As of 7th Feb 2021, 28 pts met inclusion criteria with median age 67 yrs (range 47-81), men 86%, PS 1 25%, cT3/4a/4b 28%/54%/18%, cN1/N2/N3 7%/50%/43% and Borrmann II/III/IV 57%/18%/25%. The location on GEJ and G was 14% and 86%. Of 23 pts completed neoadjuvant, all were evaluated as D2-surgery feasibility. 19 pts had completed gastrectomy (4 pts waiting for surgery) with pCR 42.1% (8/19), MPR (≤10% viable tumor cells) 73.7% (14/19) and R0 resection 94.7% (18/19). Down-staging to pT0 and pN0 were both observed in 42.1%. The median follow-up was 5.8m unavailable for survival evaluation at present. Grade (gr) 3-4 TRAE occurred in 39.3% (11/28) pts with most common events as myelosuppression (39.3%) and increased transaminase (10.7%). IrAEs occurred in 21.4% (6/28) pts with one gr 4 hepatitis and others gr 1-2. Peri-operative complications occurred in 3 pts with gr 1-2 pneumonia, increased transaminase, and ileus. No death or unexpected toxicity observed. Conclusions: SHARED interim analysis demonstrated a promising feasibility of sintilimab in combination with cCRT with preliminary impressive pCR & MPR and acceptable toxicity in phase III-IVA G/GEJ cancer. These results warrant further accrual and evaluation. Clinical trial information: ChiCTR1900024428.
Relationship between Helicobacter pylori and development of hepatocellular carcinoma: A systematic review and meta-analysis.
Authors: Madala Samragnyi , MacDougall Kira , Surapaneni Balarama Krishna , Park Robin , Kasi Anup , Girotra Mohit 
Published: June 2021

4091 Background: The relationship between Helicobacter pylori (H.pylori) and hepatocellular carcinoma (HCC) was first proposed in 1994. Since then, several studies have been performed to explore the association. The role of Hepatitis C (HCV) viruses coexisting with H.pylori in causing HCC was also studied. With the emergence of data in this regard, a causal relationship has been postulated, but not confirmed, and hence the relationship remains controversial. Our meta-analysis aims to summarize the research on this topic and investigate if there exists a relationship between H. pylori infection and the development of HCC and if the presence of HCV along with H.pylori plays a role in liver carcinogenesis. Methods: Following PRISMA guidelines, we performed a systematic review of all relevant studies published in the literature using keywords “Helicobacter pylori” and “Hepatocellular carcinoma” on major literature databases, including PubMed, EMBASE, Web of Science, and Cochrane controlled trials register. A total of 656 studies were identified between 1994 to March 2020, out of which 26 studies qualified under our selection criteria. Patients positive for HCC are included as cases and patients that did not have HCC under control group. In both groups, H.pylori positive patients and their HCV status, was identified. Results: Out of the 26 studies included in the final analysis, the prevalence of H. pylori infection was 64.78% (561 of 866) amongst HCC cases and 47.92% (1718 of 3585) in the non-HCC control group. The summary odds ratio for the association of H. pylori infection with the risk for HCC using the random-effects model was determined to be 4.75 (95% CI, 3.06-7.37), I²=63%. Subgroup analysis to determine the odds of developing HCC in the presence of H.pylori and HCV coinfection, was 13.97 (95% CI, 3.94-49.61), I²=81%. Whereas, the odds of developing HCC in the presence of only HCV without H.pylori was found to be 2.21 (0.70-6.94), I²=79. Subgroup analysis by study design showed no significant difference between the study groups (P= 0.5705). Conclusions: Our meta-analysis showed a positive association between H. pylori infection and the development of HCC. It showed a significantly higher risk of developing HCC in the presence of HCV infection along with H.pylori. Further prospective cohort studies are needed to prove the causal relationship, especially in cases of Hepatitis B, C coinfection, and cirrhotic patients.[Table: see text]
The cost effectiveness of lenvatinib versus atezolizumab and bevacizumab or sorafenib in patients with unresectable hepatocellular carcinoma (uHCC) in Canada.
Authors: Trueman David , Liu Yifeng , Geadah Marc , Hon Nicholas , Sabapathy Suthakar , Kamboj Laveena , Li Huimin , Lucero Melanie , Meier Genevieve 
Published: June 2021

4098 Background: Hepatocellular carcinoma (HCC) represents 72% of liver cancers in Canada. In the phase III REFLECT trial, lenvatinib met the primary endpoint of non-inferiority in overall survival (OS) versus sorafenib and demonstrated superiority in secondary endpoints of progression free-survival (PFS), time to progression and objective response rate. Based on the REFLECT trial, lenvatinib has become the standard of care in the treatment of Canadian patients with unresectable HCC (uHCC). In the Phase III IMbrave150 trial, the use of the combination of atezolizumab and bevacizumab (atezo+bev) resulted in statistically significant improvement in OS and PFS versus sorafenib for patients with uHCC. The aim of this analysis was to estimate the cost-effectiveness of lenvatinib versus atezo+bev or sorafenib as first-line treatment for patients with uHCC from the perspective of Ministry of Health in Canada. Methods: A cost-utility analysis was conducted using a partitioned survival analysis. Health state membership for lenvatinib and sorafenib were estimated based on patient level data and clinical inputs from REFLECT and extrapolated using parametric survival models. Relative efficacy for atezo+bev was estimated from a de novo network meta-analysis. In the base-case analysis, estimates from REFLECT used in the NMA were adjusted for imbalances in baseline characteristics. Sensitivity analyses included the use of alternative approaches to determine relative efficacy. Health state utility values were determined with EQ-5D data collected in REFLECT. Drug acquisition costs were obtained from publicly available sources and medical resource utilization was based on a survey of Canadian clinicians. The time horizon was 10 years. Results of the incremental analysis were calculated sequentially. Results: In the base case lenvatinib was associated with cost savings of CAD$4,640 and CAD$120,095 and a QALY difference of 0.15 and -0.28 vs sorafenib and atezo+bev, respectively. The base case deterministic analysis resulted in lenvatinib being dominant over sorafenib and cost-effective vs. atezo+bev (sequential ICER for atezo+bev was CAD$425,754 per QALY). Results of the probabilistic sensitivity analysis (PSA) were consistent with the base case findings with lenvatinib being the optimal treatment strategy in >99% of iterations. Conclusions: Results of this analysis demonstrate that lenvatinib represents the optimal use of healthcare resources as a first-line treatment for uHCC in Canada.
Tumor-informed assessment of circulating tumor DNA and its incorporation into practice for patients with hepatobiliary cancers.
Authors: Kasi Pashtoon Murtaza , Budde Griffin , Dayyani Farshid , Botta Gregory P. , Diehl Adam , King Gentry Teng , Malla Midhun , Abdelrahim Maen , Hanna Diana L. , Schafer Liudmila N. , Tejani Mohamedtaki Abdulaziz , Krainock Michael , Billings Paul R. , Olshan Perry , Aushev Vasily N. , Aleshin Alexey 
Published: June 2021

4103 Background: Hepatocellular carcinoma (HCC) and biliary tract cancers [BTC - including cholangiocarcinoma (CCA) and gall bladder cancers (GBC)] represent a heterogeneous group of diseases. Glycoprotein-based tumor markers like alpha-fetoprotein (AFP) or carbohydrate antigen 19-9 (CA-19-9) though part of standard-of-care (SOC), lack sensitivity, and specificity. A fair proportion of these cancers do not produce these glycoproteins. Circulating tumor DNA (ctDNA) testing can fill this void and be used for the assessment of molecular residual disease (MRD), as well as for surveillance purposes in patients with HCC or BTC. Prospective evaluation of this methodology in clinical practice has been limited to date. Methods: A personalized and tumor-informed multiplex PCR assay (Signatera bespoke mPCR NGS assay) was used for the detection and quantification of ctDNA. Serial time points were collected on a subset of patients to monitor their ctDNA levels in response to treatment. Results: Here we analyzed 200 plasma samples from a total of 90 patients with HCC (n=27) and BTC (n=63), comprising 46 patients with CCA and 17 patients with GBC. Sample-level ctDNA positivity rates, determined using a tumor-informed assay are presented in table. ctDNA detection was significantly associated with the stage of disease (Wilcoxon rank-sum test, p<0.05). Serial time point analysis was performed on a subset of patients (n=56) that had 2-7 time points available and correlations between ctDNA levels and clinical response were noted and will be presented. Conclusions: Our study is the first to set the benchmark for the utility and feasibility of using a tumor-informed assay in this cohort of hepatobiliary cancers. With adjuvant chemotherapy already a SOC for BTC, and immunotherapy being studied for HCC alongside other novel agents for CCA and GBC, assessment of MRD or ctDNA clearance on therapy would be of value as an additional tool in identifying patients at high risk for recurrence/metastasis. The utility of this study would also lie in incorporation in clinical trials to enrich and study those who are at the highest risk of recurrence i.e. ctDNA positive.[Table: see text]
Modified FOLFIRINOX versus S-1 as second-line chemotherapy in patients with gemcitabine-failed metastatic pancreatic cancer: A randomized phase III trial (MPACA-3).
Authors: Go Se-Il , Lee Sang-Cheol , Bae Woo Kyun , Zang Dae Young , Lee Hyun Woo , Jang Joung Soon , Ji Jun Ho , Kim Jung Hoon , Park Sanggon , Sym Sun Jin , Yang Yaewon , Jeon So Yeon , Oh Sung Yong , Kang Jung Hun 
Published: June 2021

4119 Background: Modified FOLFIRINOX (mFOLFIRINOX) consisting of 5-fluorouracil/leucovorin, irinotecan, and oxaliplatin has been assessed as second-line treatment of patients with advanced pancreatic cancer in retrospective and phase II studies. However, the result was not confirmed by randomized controlled trial. Methods: A randomized, open-label, phase III trial was conducted at 9 institutions in Korea. Patients with metastatic pancreatic adenocarcinoma (mPAC) and Eastern Cooperative Oncology Group performance status of 0-1 who failed to first-line gemcitabine-based chemotherapy were randomly assigned to receive mFOLFIRINOX or S-1. The primary endpoint was overall survival. Results: A total of 80 patients were enrolled from March 2017 to December 2019. The accrual of patients was early terminated due to clear difference of efficacy in the interim analysis and expectation of poor recruitment due to conflicting adjuvant regimens. Objective response and disease control rates were 15.4% vs. 2.4% ( p= 0.041) and 66.7% vs. 36.6% ( p= 0.007) in the mFOLFIRINOX and S-1 arms, respectively. The median progression-free survival was 5.2 and 2.2 months in the mFOLFIRINOX and S-1 arms, respectively ( p= 0.002). The median overall survival was 9.2 and 4.9 months in the mFOLFIRINOX and S-1 arms, respectively ( p= 0.048). The adjusted hazard ratio of the mFOLFIRINOX arm to the S-1 arm for overall survival was 0.402 (95% confidence interval 0.223-0.725, p= 0.002). All grade 3-4 adverse events occurred in 56.5% and 17.1% in the mFOLFIRINOX and S-1 arms, respectively ( p< 0.001). However, only one patient in each arm prematurely discontinued treatment due to toxicity and there was no treatment-related mortality in both arms. Minimally important differences in the health-related quality of life were not observed in both arms. Conclusions: mFOLFIRINOX as second-line treatment in mPAC patients failed to gemcitabine-based chemotherapy demonstrated a survival benefit versus S-1 alone with acceptable toxicities. Clinical trial information: KCT0003534.
First-line pembrolizumab (pembro) in cisplatin-ineligible patients with advanced urothelial cancer (UC): Response and survival results up to five years from the KEYNOTE-052 phase 2 study.
Authors: O'Donnell Peter H. , Balar Arjun Vasant , Vuky Jacqueline , Castellano Daniel , Bellmunt Joaquim , Powles Thomas , Bajorin Dean F. , Grivas Petros , Hahn Noah M. , Plimack Elizabeth R. , Xu Jin Zhi , Godwin James Luke , Homet Moreno Blanca , De Wit Ronald 
Published: June 2021

4508 Background: Pembro was approvedfor cisplatin-ineligible patients with untreated advanced UC based on initial results of the phase 2 KEYNOTE-052 study (NCT02335424), which showed an ORR of 29%. Updated results after up to 5 years of follow-up are presented. Methods: KEYNOTE-052 is a single-arm, multi-site, open-label trial. Patients had advanced or metastatic UC, were cisplatin ineligible (criteria: ECOG PS 2, CrCl ≥30 to ̃60 mL/min, grade ≥2 peripheral neuropathy/hearing loss, NYHA class III heart failure), and had not previously received chemotherapy for advanced/metastatic disease. Patients received pembro 200 mg IV Q3W until progression, unacceptable toxicity, withdrawal, or 24 mo of therapy, whichever occurred first. PD-L1 status was determined by combined positive score (CPS, number of PD-L1–staining cells [tumor cells, lymphocytes, macrophages] divided by the total number of viable tumor cells, multiplied by 100); PD-L1–positive was CPS ≥10. The primary end point was confirmed ORR (RECIST v1.1, independent central review). Key secondary end points were duration of response (DOR), OS, and safety. Results: Among 370 enrolled patients, median age was 74 y, 315 (85.1%) had visceral disease, and 43 (11.6%) completed 24 mo of therapy. Median time from enrollment to data cutoff (Sep 26, 2020) was 56.3 mo (range, 51.2-65.3) for all patients and 56.0 mo (range, 51.4-65.2) for the 110 patients (29.7%) with CPS ≥10. Confirmed ORR for all patients was 28.9% (95% CI, 24.3-33.8); complete response, 9.5% (n=35); partial response, 19.5% (n=72). Median DOR was 33.4 mo (range, 1.4+ to 60.7+); 44.8% and 39.4% of patients had DOR ≥36 and ≥48 mo, (Kaplan-Meier estimates). Median OS was 11.3 mo (95% CI, 9.7-13.1); 24- and 36-mo OS rates were 31.5% and 22.1%. Patients with CPS ≥10 had better outcomes than patients with CPS <10 (Table). Treatment-related adverse events (AEs) occurred in 67.3% of patients; 21.1% of treatment-related AEs were grade ≥3, including 1 death (myositis). Conclusions: After up to 5 y of follow-up, pembro continued to elicit clinically meaningful, durable antitumor activity in cisplatin-ineligible patients with advanced UC. These effects were more pronounced in patients with CPS ≥10. Clinical trial information: NCT02335424. [Table: see text]
RC48-ADC combined with toripalimab, an anti-PD-1 monoclonal antibody (Ab), in patients with locally advanced or metastatic urothelial carcinoma (UC): Preliminary results of a phase Ib/II study.
Authors: Zhou Li , Xu Huayan , Yan Xieqiao , Chi Zhihong , Cui Chuanliang , Si Lu , Tang Bixia , Mao Lili , Lian Bin , Wang Xuan , Li Siming , Bai Xue , Guo Jun , Sheng Xinan 
Published: June 2021

4534 Background: RC48-ADC is a novel humanized anti-HER2 antibody-drug conjugate (ADC), which showed promising data in HER2-positive and even negative patients (pts). Anti-PD-1 Abs have durable antitumor effect for mUC especially in PD-L1 positive patients. The combination may have synergistic antitumor effect. This phase 1b/II study evaluated the safety and activity of RC48-ADC combined with toripalimab in mUC. Methods: In dose-escalation cohort, pts received 1.5 or 2 mg/kg RC48-ADC + 3mg/kg toripalimab with the traditional 3+3 escalation design. In expansion cohort, patients received the recommended dose of RC48-ADC + toripalimab every 2 weeks. The primary endpoints were safety/tolerability and recommended RC48-ADC dose; secondary endpoints included pharmacokinetics, ORR per RECIST 1.1, PFS, and OS stratified by HER2 and PD-L1 expression. HER2 positivity was determined by IHC and in situ hybridization (ISH). PD-L1 expression was tested with IHC 22C3 pharmDx assay. Results: As of 8 Jan 2021 (data cutoff), 14 mUC pts (9 males, median age 66 y [52-76]) were enrolled. Most pts were systemic treatment naïve (57%) in the locally advanced or metastatic setting. The primary site was in upper tract UC in 50%; 50% had visceral metastases (mets), including 36% with liver mets; HER2 expression was positive (IHC 3+ or 2+ ISH+) in 28%, and 43% PD-L1 CPS≥10. A total of 36 pts is anticipated to be enrolled by Apr 2021. No dose limiting toxicity was reported and the recommended dose for RC48-ADC was 2mg/kg. At data cutoff, 10/14 patients were evaluable for response, with 8 PR, 1 SD (tumor shrinking), and 1 PD. The objective response rate (ORR) was 80%, and disease control rate (DCR) was 90%. All responsive patients have durable efficacy and are still on treatment. Follow-up continues for PFS and OS. Most common treatment-related AEs were grade 1-2, including aminotransferase level increased (7/14, 50%), weight loss (6/14, 43%), alopecia (6/14, 43%), asthenia (4/14, 29%), anemia (3/14, 21%), leukopenia (21%), peripheral sensory neuropathy (21%), hypothyroidism (21%), blood triglycerides increased (21%), and creatine phosphokinase increase (21%). One pt had G3 intestinal obstruction attributed to study drug and went back to treatment after recovery. Conclusions: RC48-ADC in combination with toripalimab had a good tolerance and promising anti-tumor activity in pts with mUC. Further evaluation of safety and efficacy is ongoing. Clinical trial information: NCT04264936.