bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of RAS status and prior targeted therapy on the activity of aflibercept plus FOLFIRI in patients with metastatic colorectal cancer (mCRC) in daily practice. Final results of the QoLiTrap prospective non-interventional study.
Authors: Hofheinz Ralf Dieter , Kröning Hendrik , Zahn Mark-Oliver , Scholten Felicitas , Derigs Hans-Günter , Pederiva Stefanie , Anchisi Sandro , Bohanes Pierre Oliver , Gruenberger Birgit , Windemuth-Kieselbach Christine , Piringer Gudrun , Thaler Josef , Moos Roger von
Published: June 2021

e15570

Background: The anti-angiogenic fusion protein aflibercept targets VEGF-A, VEGF-B and PIGF. It is approved in combination with FOLFIRI for treatment of mCRC previously treated with an oxaliplatin-containing regimen. We evaluated the influence of RAS status and prior targeted therapy on the efficacy and safety of aflibercept plus FOLFIRI in daily practice. Methods: QoLiTrap is a large international (Germany, Austria, Switzerland), non-interventional study evaluating the quality of life (QoL), efficacy and safety of aflibercept plus FOLFIRI in daily clinical practice. The primary endpoint was QoL assessed by EORTC QLQ-C30 questionnaire. Secondary endpoints included overall survival (OS), progression-free survival (PFS), tumor response and safety. Patients were evaluable for primary and secondary endpoint analysis if they had a QoL questionnaire at baseline and at least 2 post baseline. Safety was analyzed in all patients exposed to at least one dose of study drug. We report here the results by RAS status and prior targeted therapy received. Results: 1277 patients with mCRC were treated (median age 66 years, males 64.8%, right colon tumor 27.6%, liver metastases 53.2% , ECOG 0-1 84.7%) mainly in second-line (50.3%) but also in third-line (23.1%) and fourth-line (11.9%) setting. Median duration of treatment was 12 weeks. Overall, 872 patients were evaluable for the efficacy analysis. At baseline, the global health (mean) score was 58.7 and the mean change from baseline over 12 weeks was -4.6%. A clinically meaningful decline of -10 points was not reached, regardless of RAS status and prior targeted therapy. Secondary endpoints are provided in the Table below. Most common all grade adverse events were diarrhea (34.2%), nausea (17.9%), fatigue (17.2%), stomatitis (17.2%) and hypertension (11.6%). Conclusions: Aflibercept plus FOLFIRI administered in daily practice shows no deleterious effect on QoL and retains its activity irrespective of RAS status and prior targeted therapy. The safety profile was manageable. Clinical trial information: AIO-LQ-0113. [Table: see text]
The importance of maintenance chemotherapy in the first and second lines of treatment of metastatic colorectal cancer.
Authors: Gridnev Danila , Popov Anatoly , Islamova Dina , Makarov Vladislav , Vozny Edouard , Kudryavtseva Anna
Published: June 2021

e15583

Background: The first and second lines of CT is decisive in the treatment of colorectal cancer. Choosing the right one allows you to increase PFS and improve long-term results. Surgical treatment and maintenance chemotherapy (MT) increase PFS and OS, as they can be prescribed at any stage of treatment. Methods: The analysis included 192 patients diagnosed with metastatic colorectal cancer (mCRC) who received treatment between 2014 and 2019. The average age of the patients was 62 years. At the beginning of treatment, the overall condition of all patients was ECOG1. Primary mCRC had 129 (67%) patients. In 63 (33%) patients, locally advanced disease was first diagnosed, which were included in the study after progression. PFS and OS for all patients were calculated from the start of the 1st line. Localization of the primary tumor in 42 (22%) patients was on the right side of the colon and on the left side in 149 (78%) and 1 patient did not show primary tumor. Among the patients with primary metastatic disease, 100 (52%) had isolated metastases, while the remaining 92 (48%) had 2 or more localizations. Different types of surgical treatment of metastases in the liver occurred in 41 (21%) patients. 119 patients never received MT (with any number of lines) and made a comparison group(A). 73 patients received MT in at least one of the CT lines (B). 12 patients received MT in the 1st and 2nd CT (C). These groups were homogeneous in terms of gender, age, ECOG, accessibility of surgical treatment of distant metastasis, mutational status of the tumor, and accessibility of biotherapy. Evaluation of the effect was performed using RECIST criteria, at intervals of 3 months or the appearance of clinical symptoms of progression. The treatment was carried out before the progression. At the time of analysis, 94 patients are alive and continue to receive treatment. Results: We compared in all three groups: In group A: OS - 12.9 months, PFS 1-line CT - 9.5 months, PFS 2-line CT - 4.5 months In group B: OS - 27.6 months, PFS 1-line CT - 13.6 months, PFS 2-line CT - 9.1 months In group C: OS - 38.3 months, PFS 1-line CT - 14.2 months, PFS 2-line CT - 9.1 months. “Five-year” survival (In those patients who were observed from the start of the study for all 5 years) in group A was 5,8 %, in group B 15 %, and in group C 16 %. Conclusions: Increase of PFS and OS in patients who received MT at least at one of the stages of treatment, and continues to increase in patients receiving MT in the first two lines CT. Thus, MT is a necessary component of the treatment of mCRC.
Effect of hyperlipidemia in patients with a history of colon cancer.
Authors: Tarar Zahid , Zafar Muhammad Usman , Ghous Ghulam , Farooq Umer , Ahluwalia Arjan
Published: June 2021

e15603

Background: The most common cancer of the digestive system is colorectal cancer. 5-year survival rate of early-stage colon cancer is > 90% whereas it is only 10% for patients with distant metastases. Recent studies have shown that lipids influence a tumor’s metastatic capabilities. High fat diet has also been linked with colon cancer. In this study, we try to understand the effect of hyperlipidemia in patients with a history of colon cancer. Methods: This is a retrospective study examining data from the National Inpatient Sample (NIS) Database of the year 2018. We identified patients with any history of Colon cancer using their specific ICD-10 codes. Additionally, we queried for ICD10 codes for hyperlipidemia. Primary outcome was inpatient mortality. Secondary outcome was hospital length of stay and total charge. Utilizing STATA MP 16.1 we performed multivariate logistic regression analysis. Various comorbidities including previous history of coronary artery disease, peripheral artery disease, stroke, smoking, diabetes, hypertension and chemotherapy were incorporated into the analysis. Additionally, hospital demographics were included in the analysis as well including race, hospital bed size teaching status, location, region, insurance and patient income. Data was considered statistically significant if p-value was < 0.05. Results: The total number of patients included in this study were 34,792. They were all adults age > 18 years. Approximately 49% were females. Mean age was 67 years and average hospital length of stay was 6.5 days. After running multivariable analysis for inpatient mortality, we noted that patients with hyperlipidemia had lower odds of mortality (Odds Ratio (OR) 0.64, 95% Confidence Intervals (CI) 0.56 – 0.73). Higher odds of mortality were seen in patients with coronary artery disease (OR 1.23, 95% CI 1.05 – 1.44). Among racial distributions, Blacks had higher odds of mortality when compared with White (OR 1.3, 95% CI 1.1 – 1.5). Hispanics had lower odds of inpatient mortality compared to Whites (OR 0.8, 95% CI 0.6 – 0.9). The odds of mortality were higher with increasing age (OR 1.025, 95% CI 1.02 – 1.031) and lower among females (0.82, 95% CI 0.73 – 0.91). Among secondary outcomes, hyperlipidemia did not affect the hospital length of stay or cost. Several factors increased the hospital length of stay which included any history of coronary artery disease, peripheral artery disease, or diabetes. In addition, patients admitted over the weekend had a higher length of stay. Conclusions: In this study, we find that hyperlipidemia is associated with lower mortality in patients with colon cancer. This could be possible because patients with hyperlipidemia are on statin therapy. This indirectly could point to a potential benefit of statins in colon cancer. Hyperlipidemia does not affect hospital length of stay or cost.
The anti-cancer effect of statins in obese esophageal cancer patients undergoing esophagectomy.
Authors: Abdelfatah Eihab N , Kukar Moshim , Mukherjee Sarbajit , Groman Adrienne , Yendamuri Saikrishna S.
Published: June 2021

e16012

Background: In addition to lowering lipid levels and treating atherosclerotic disease, statins have demonstrated anti-inflammatory and anti-tumor activity in various cancer types. We evaluate this effect in esophageal cancer patients undergoing esophagectomy. Methods: All patients undergoing esophagectomy for esophageal cancer at Roswell Park Comprehensive Cancer Center between March 2007 and December 2015 were included. The association between pre-surgery statin use with overall survival (OS), disease-specific survival (DSS) and recurrence-free survival (RFS) was analyzed using Cox proportional hazards regression, with age, sex, American Society of Anesthesia (ASA) score, neoadjuvant therapy, surgical technique, tumor stage, histology, and grade considered in multivariable analyses. Survival analyses were independently performed for body mass index (BMI)-based patient subgroups. Results: 212 patients met inclusion criteria for this study. Median follow up period was 36 months. Estimated five-year RFS for the patient cohort overall was 55.7% and estimated five-year DSS was 53.9%. Estimated five-year OS was 45.4%. There was no significant association between statin use and outcomes of esophagectomy patients overall. However, in subgroup analysis analyzing patients by BMI category, there was a significant association between statin use and outcomes in patients with BMI ≥ 30 (n = 95 patients). Multivariate analysis in obese patients demonstrated an association of statins with improved OS (HR 0.52, p = 0.049), DSS (HR 0.46, p = 0.034) and RFS (HR 0.43, p = 0.036). The other variables significantly associated with outcome measures were stage ≥ 2 (OS HR 2.36, p = 0.010; RFS HR 2.50, p = 0.018; DSS HR 2.51, p = 0.011) and ASA score ≥ 3 (RFS HR 2.26, p = 0.037; DSS HR 2.33, p = 0.019). Conclusions: Statin use is associated with improved RFS, DSS and OS of obese patients undergoing esophagectomy for esophageal cancer. This novel finding suggests an interaction between the pathophysiologic state of obesity and the pleiotropic effects of statins. BMI could be explored as a potential biomarker for adjunctive statin use in future trials.[Table: see text]
Discovery and validation of methylation signatures in circulating cell-free DNA for early detection of esophageal cancer: A case-control study.
Authors: Zhuang Weitao , Ben Xiao-song , Li Chengcheng , Xu Jiayue , Tian Dan , Zhou Zihao , Chen Gang , Deng Cheng , Tang Jiming , Shi Ruiqing , Xie Liang , Zhang Dongkun , Zhou Haiyu , Li Bingsi , Zhang Zhihong , Liu Hao , Wang Guoqiang , Cai Shangli , Qiao Gui-Bin
Published: June 2021

e16027

Background: The pivotal goal of esophageal cancer (ESCA) screening is to identify early-stage cancer or precancerous lesions when curable treatments are available. Methylation of circulating-free DNA (cfDNA) has shown promising results in the early detection of multiple tumors recently. Here we conducted a prospective study to investigate the performance of cfDNA methylation in the early detection of ESCA. Methods: Specific methylation markers for ESCA were identified and optimized based on 24 esophageal tumor and its corresponding adjacent tissues. Age-matched participants with ESCA (n = 136), benign esophageal disease (n = 21) and healthy controls (n = 126) were randomized into the training and testing sets to develop an early-detection classifier. Results: In total, 921 differentiated methylation blocks (DMBs) between tumor and adjacent tissues were identified, of which 679 (73.7%) showed higher methylation level and 242 (26.3%) had lower methylation level in tumor tissues. In the training set, the specificity of the model built with these DMBs was 94.1% (95% CI, 85.5%−98.4%) and the sensitivity was 86.0% (95% CI, 72.2%−94.8%). The sensitives increased with stages, which were 77.8% (95% CI, 39.8%−97.2%), 90.9% (95% CI, 58.7%−99.8%), 83.3% (95% CI, 51.7%−97.9%) and 100.0% (95%CI, 63.1%−100.0%) for stage I-IV, respectively. Similar results were observed in the testing set with area under curve (AUC) of 0.932 (95% CI, 0.887−0.977). Conclusions: The cfDNA methylation profiles distinguished ESCAs from healthy individuals and benign esophageal diseases with promising sensitivity and specificity. Consideration of the potential value of early detection in ESCAs, further evaluation in larger prospective studies is warranted.
Camrelizumab combined with paclitaxel and nedaplatin as neoadjuvant therapy for locally advanced esophageal squamous cell carcinoma (ESPRIT): A phase Ⅱ, single-arm, exploratory research.
Authors: Ma Jianqun , Zhang Jinfeng , Yang Yingnan , Zheng Dayong , Wang Xiaoyuan , Liang Hao , Zhang Luquan , Xin Yanzhong , Ling Xiaodong , Fang Chengyuan , Jiang Hao , Zheng Wei
Published: June 2021

e16033

Background: Camrelizumab has been approved as a standard therapy in the second-line treatment of esophageal squamous cell carcinoma (ESCC). This study aimed to explore the efficacy and safety of camrelizumab combined with commonly used neoadjuvant chemotherapy (paclitaxel and platinum) in neoadjuvant treatment of ESCC. Methods: In this single-arm, phase Ⅱ study, patients with advanced ESCC who were expected to receive neoadjuvant therapy followed by radical surgery were recruited. The patients received 2-4 cycles of camrelizumab (200mg, iv, q3w) in combination with paclitaxel (155mg/m2, iv, q3w) and nedaplatin (80mg/m2, iv, q3w) as neoadjuvant therapy, and the therapeutic effects were determined every 2 cycles. The radical surgery was performed on patients whose tumors were evaluated as resectable. The primary endpoint was pCR, and the secondary endpoints were objective response rate (ORR) and disease control rate (DCR). Results: From May 2020 to January 2021, 24 patients with a median age of 60.5 years (50-73) were enrolled. Among them, 21 patients were available for efficacy analysis, of which 1 achieved complete response (CR), 7 achieved partial response (PR), and 13 had stable disease (SD). The ORR was 38.1% and DCR was 100%. The tumor in 10 patients shrank significantly after neoadjuvant therapy and these patients preferred radiotherapy instead of surgery as the radical therapeutic method. 2 patients abandoned surgery because of personal reasons. 2 patients were in the process of neoadjuvant therapy and had not undergone surgery yet. The remaining 7 patients underwent radical surgery and 4 patients (57.14%) achieved pCR (pT0N0M0). The main treatment-related grade 3/4 adverse event (AE) was neutropenia (1/21). All the AEs were manageable. The average intraoperative blood loss was 221mL and the average hospitalization time after operation was 12.7 days (range 8-19 days). No anastomotic leakage and treatment-related death occurred. Conclusions: Camrelizumab in combination with paclitaxel and platinum as a neoadjuvant therapy was well tolerated. The pCR rate of 57.14% was higher than the expected 40%. This encouraging result promoted us to continue this phase Ⅱ study. Clinical trial information: ChiCTR2000033761.
Clinical effectiveness of apatinib at different doses in patients with advanced gastric cancer as the third-line or further treatment: Results from a post-marketing phase IV study.
Authors: Li Jin , Qin Shukui , Wen Lu , Wang Junsheng , Deng Wenying , Guo Weijian , Jia Tongfu , Zhao Qun , Zhang Guifang , He Yifu , Zhong Haijun , Ba Yi , Lin Xiaoyan , Yang Jianwei , Zhao Jun , Bai Yuxian , Sun Guogui , Wu Yongjuan , Wang Meng , Sun Ying
Published: June 2021

e16037

Background: Apatinib, a highly selective VEGFR2 inhibitor, has shown a clinical benefit as third-line or further-line treatment in patients with gastric cancer in a randomized phase III study with the initial dose of 850mg. However, the study was conducted in a small scale (n = 267) under standardized conditions. Here, we assessed exposure and effectiveness of apatinib at different doses using data collected from a post-marketing phase IV study that included a broader patient population with a larger sample size. Methods: Patients with advanced or metastatic advanced gastric cancer or gastroesophageal junction adenocarcinoma who were aged 18-75 with ECOG performance status of 0-2 and failed at least two lines of chemotherapy were enrolled. Apatinib was recommended with an initial dose of 850 mg q.d orally, while the initial dose was determined at the discretion of the investigators. Administration of apatinib regarding the initial dose, duration of treatment, dose modification, average daily exposure dose (ADED) and its effect on progression-free survival (PFS) and overall survival (OS) were analyzed. Results: A total of 2004 patients were included in the intention-to-treat population. The median age was 59 (range, 19-85) years, 71.8% of patients were male, 84.2% had ECOG performance status of 0-1; 96.4% had stage IV disease, and 98.8% had metastases, among which 34.2% with more than 2 metastases. Five patients did not receive therapy. Compared to 5.5% of patients with the initial dose > 500mg, 94.1% was given at the initial dose≤500mg; 8.6% had ADED > 500mg and 91.1% had ADED ≤500mg. The median duration of treatment was 56 days. Treatment interruption and discontinuation, and dose reduction occurred in 34.4%, 24.5%, and 13.7% of patients due to adverse events, respectively. Survival analyses in the initial dose ≤500mg/ > 500mg subgroups showed median PFS of 2.6 months (95%CI 2.20-2.79) vs 2.7 months (95% CI 1.91-3.32), median OS of 5.6 months (95% CI 5.26-5.95) vs 5.9 months (95% CI 4.40-6.87). In the ADED ≤500mg/ > 500mg subgroups, the median PFS was 2.6 months (95% CI 2.14-2.76) vs 3.0 months (95% CI 2.27-3.61), and median OS was 5.7 months (95% CI 5.32-6.08) vs 6.1 months (95% CI 5.36-7.72). Conclusions: In conclusion, more than 90% of the patients received a lower dose regimen, which indicate dosage of 500mg or lower is a tolerated exposure. Furthermore, dose at 500mg or lower produced similar efficacy to that more than 500mg. Clinical trial information: NCT02426034.
Effects of formula composed of active monomers of removing heat and phlegm prescription on malignant phenotypes and growth signaling in esophageal carcinoma cells.
Authors: Si Fuchun , Wang Wenbin
Published: June 2021

e16051

Background: Esophageal carcinoma (EC) ranks seventh in the incidence of malignant tumors and the sixth mortality worldwide. Removing heat and phlegm prescription(RHPP, composed of Rhizoma Dioscoreae Nipponicae, Rhizoma Paridis, Saponin, Rhizoma Bolbostemmae) was an effective formula screened from 531 Chinese herbs for treating EC in our previous study. The purpose of this study is to further track, isolate, purify and identify the active monomers of RHPP, study the effect of each active monomer on Eca109, EC9706, EC-1, TE-1 four EC cells and the signaling mechanism, then optimize and compose new active monomers formula and study its mechanism on EC cells. Methods: The active monomer of RHPP was extracted, separated and identified by ethanol extractioncolumn, chromatography, recrystallization, HPLC, spectroscopic method,etc. The effects of four kinds of active monomers and their composed formula on the proliferation, migration, clone formation, cell cycle and signal pathway proteins expression of Eca109 cell, EC9706 cell and TE-1 cell were investigated by MTT assay, RTCA assay, soft agar assay, flow cytometry and western blot analysis. Results: Four active monomers were identified from Rhizoma Dioscoreae Nipponicae (CSL), Saponin (ZJ), Rhizoma Bolbostemmae (TBM), Rhizoma Paridis (CL) respectively with molecular weights of 868, 1003, 1365, 854.5, and corresponding molecular formulas of C45H72O16, C50H82O20, C64H100O31 and C44H70O16(China patient No. ZL202010136431.6). Four active monomers significantly affected the cell morphology, proliferation, migration, cloning ability, cell cycle of four EC cells. The IC50 values of the active monomer of CSL, ZJ, TBM and CL for Eca109 were 1.29±0.12, 2.42±0.09, 1.93±0.09, 3.04±0.28μg/ml respectively; for EC9706 were 1.41±0.02, 5.94±0.45, 1.97±0.09, 0.63±0.04μg/ml respectively; for TE-1 were 3.72±0.28, 35.58±0.58, 7.90±0.41, 1.85±0.09μg/ml respectively; for EC-1 were 1.11±0.14, 3.56±0.28, 1.23±0.02, 0.61±0.02μg/ml respectively. Four active monomers could downregulate EGFR, PLC-γ1, and PKCα protein expression. Using the baseline proportional increase and decrease design method to compose new removing heat prescription(RH), removing phlegm prescription(RP) and removing heat and phlegm prescription (RHPP), the ratio of each drug monomer in RH, RP and RHPP were mCSL: mCL = 6: 4, mZJ: mTBM = 3: 7, mCSL: mCL: mZJ: mTBM = 48: 32: 6: 14. RH, RP and RHPP all could inhibit the proliferation, migration, cloning ability, cell cycle of four EC cells. Conclusions: The four active monomers and new composed RHPP all can inhibit the proliferation of EC9706, Eca109, TE-1, EC-1 four EC cells, which have close relationship with EGFR, PLC-γ1, and PKCαproteins expression. This study provides new formula and basis for the development of anti-esophageal carcinoma drugs in traditional Chinese medicine.
A noninvasive gastric cancer Her2 test using surrogate methylation markers.
Authors: Liu Xin , Ye Gengtai , Cui Chunhui , Li Hui , Yang Ting , Lei Xuetao , Zhang Guofan , Zheng Boyang , Xie Lang , Lei Xiaotian , Wu Chaorui , Song Xinjian , Yu Jiang , Chen Zhiwei , Fan Jianbing
Published: June 2021

e16084

Background: There are 10-20% of gastric cancer (GC) with overexpressed Her2. Her2 status remains an essential biomarker for guiding the trastuzumab (Herceptin) therapy, a monoclonal antibody approved for the first-line treatment of late-stage Her2-positive GC. Although IHC, together with FISH, is comprehensively applied to verify Her2 status on tissue samples, an accurate blood test is highly desirable due to the inaccessibility of tissue samples, especially in very late stage GC patients as well as tumor heterogeneity of tissue biopsy. Detecting copy number aberration of Her2 gene in cell-free DNA (cfDNA) gains a lot of interest for its non-invasive approach. However, the limited signal-to-noise ratio poses a great challenge for the accuracy and robustness of the tests (either targeted sequencing or ddPCR). Here, we report a non-invasive test for Her2 status verification based on novel surrogate DNA methylation markers. Methods: Genome-wide DNA methylation sequencing was performed in 30 Her2-negative (IHC 0/1+) and 44 Her2-positive (IHC 3+) tissue samples to identify Her2-overexpression-specific methylation markers. Then we analyzed the performance of these candidate markers using methylation-specific quantitative PCR (qMSP) in plasma samples collected from 102 GC patients before surgical treatment. A Her2-status diagnostic model was built and further validated in a multi-center, prospective cohort (n = 150). The concordance of Her2 status between GC plasma and matching tissue samples (IHC/FISH) was determined. Results: We first discovered 102 statistically significant methylation markers of Her2 status in tissue. Out of these candidate markers, a 3-marker diagnostic model was built and validated on plasma samples, which could discriminate Her2-positive from Her2-negative GC patients with high sensitivity (86.7%) and specificity (96.8%). The overall plasma-tissue concordance of this liquid biopsy test was 95.3%. Furthermore, the Her2-status test was able to classify Her2 2+ status (IHC) into either Her2-negative or Her2-positive status, which was confirmed by conventional FISH test. Conclusions: Overall, the cfDNA-based test is a novel, accurate and noninvasive approach for determining Her2 status in GC patients. The high concordance with IHC/FISH results of this blood test holds great promise as an auxiliary method for guiding Her2-targeted therapy in GC patients. A clinical trial is undergoing to validate this test in the phase-2 clinical trial of a Her2-targeted drug (for GC) in China.
Combining radiation therapy with anti-PD-1 for patients with advanced hepatocellular carcinoma: An open-label, single-center, single-arm clinical study.
Authors: Li Jian-Xu , Su Ting-Shi , Lin Xiao-Feng , Chen Yi-Tian , Liang Shi-Xiong , Xiang Bang-De
Published: June 2021

e16117

Combining radiation therapy with anti-PD-1 for patients with advanced hepatocellular carcinoma: an open-label, single-center, single-arm clinical study Jian-Xu Li, Ting-Shi Su, Xiao-Feng Lin, Yi-Tian Chen, Shi-Xiong Liang, Bang-De Xiang; Guangxi Medical University Cancer Hospital, Nanning, China Abstract Research Funding: Jiangsu Hengrui Pharmaceuticals Co., Ltd., Shanghai, China. Guangxi Medical and Health Appropriate Technology Development and Application Project (No. S2019039), Guangxi, China. Background: Based on the results of recent studies, the PD-1 monoclonal antibodies have been approved to treat the patients with advanced hepatocellular carcinoma (HCC) by the FDA. Radiation therapy (RT) can enhance responsiveness to PD-1 monoclonal antibody by potential mechanisms. A phase Ⅱa study was conducted to assess the safety and the efficacy of combining RT with anti-PD-1 for patients with advanced hepatocellular carcinoma. Methods: Patients with advanced HCC were eligible. Stereotactic body radiation therapy (SBRT) were adopted, and the dose of radiation were Dt-PGTV 30-50 Gy/10fractions. Camrelizumab (200mg) were given intravenously every 3 weeks since the first day of RT until disease progression, or intolerable toxicity. Adverse events (AEs) and objective response rate (ORR) were summarized to assess the safety and efficacy. Results: From April 2020 to November 2020, 17 patients were enrolled (median age 54, range 32-69). 15 (88%) patients were male. 14 (82%) had ECOG performance score of 0. All the patients had Child-Pugh score A. 16 patients staged as Barcelona Clinic Liver Cancer staging C or China Liver Cancer staging Ⅲ. Extrahepatic metastases were identified in 11 (65%) patients. 13 (77%) patients were Hepatitis B virus infected. 15 (88%) patients had previously 2 lines or more chemotherapy. 9 (53%) patients had Alpha-fetoprotein level≥400 ng/ml. The ORR was 47%. The best response assessed by RECIST 1.1 was partial response (8 patients). Four patients had grade 3 immune-related adverse events (irAEs), including increased aspartate aminotransferase and alanine transaminase (n =1)，decreased hemoglobin (n =1)，decreased platelet count (n =1)，decreased neutrophil count (n =1). All grade 3 irAEs were mitigated with proper treatment. None treatment-related deaths occurred. Conclusions: In this study, RT combined with anti-PD-1 had an acceptable safety profile and indicated an effective treatment option in patients with unresectable HCC. Clinical trial information: NCT04193696. Clinical trial information: NCT04193696.
A single-arm, multicenter, open-label phase 2 trial of surufatinib in patients with unresectable or metastatic biliary tract cancer.
Authors: Bai Yuxian , Xu Jianming , Sun Huichuan , Bai Chunmei , Jia Ru , Li Yi , Zhang Wenjie , Liu Lei , Huang Cheng , Guan Mei , Zhou Jinghong , Su Weiguo
Published: June 2021

e16123

Background: Several clinical studies of vascular endothelial growth factor/vascular endothelial growth factor receptor (VEGF/VEGFR) therapy as second-line treatment for biliary tract cancer (BTC) has demonstrated moderate efficacy. In this study, surufatinib was evaluated as a second-line VEGFR therapy in BTC patients. Methods: This was a single-arm, multi-center, open-label phase 2 study conducted in China. The study enrolled eligible BTC patients who progressed after fist-line chemotherapy. Patients received surufatinib monotherapy as second-line treatment, at doses of 300 mg, once daily, in 28-day cycles. Tumor assessments were performed every 8 weeks ± 7 days according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Results: As of Nov. 30, 2018, a total of 39 BTC patients, including 29 (74.4%) with intrahepatic cholangiocarcinoma, 5 (12.8%) with extrahepatic cholangiocarcinoma, and 5 (12.8%) with gallbladder cancer, were enrolled and treated with surufatinib. Sixteen-week progression-free survival (PFS) rate was 46.33% (95% confidence interval [CI], 24.38‒65.73), with median PFS of 3.7 months and median overall survival (OS) of 6.9 months. In addition, results from subgroup and post-hoc analyses suggested the trends of better clinical efficacy in patients with tumor locations inside the liver, or with lower baseline values of CA19-9 (≤ 1000 IU/mL) and CEA (≤ 3 ng/mL). The top three treatment-related adverse events (TRAEs) with severity of Grade ≥ 3 included blood bilirubin increased (20.5%), hypertension (17.9%), and proteinuria (12.8%). Conclusions: When applied in the treatment of BTC patients, surufatinib monotherapy has offered moderate clinical efficacy and has demonstrated favorable tolerability and safety profiles. Moreover, surufatinib further boosting the antitumor effects of cancer immunotherapy is desirable. Clinical trial information: NCT02966821.
Efficacy and biomarker analysis of neoadjuvant carrizumab plus apatinib in patients with local advanced biliary tract cancers.
Authors: Rao Jian-hua , Wu Chen , Zhang Hui , Wang Xuehao , Lu Ling , Cheng Feng , Chen Dongsheng
Published: June 2021

e16126

Background: Camrelizumab (anti-PD-1 antibody) plus apatinib (VEGFR2 inhibitor) as combination therapy is highly effective in advanced osteosarcoma, hepatocellular carcinoma and extensive-stage SCLC. This study aimed to access the efficacy, safety and explore predictive biomarkers of neoadjuvant carrizumab plus apatinib in local advanced biliary tract cancers (BTCs) (ChiCTR2000034283). Methods: This single-arm, phase II trial enrolled patients with local advanced BTCs. Patients received camrelizumab 200 mg every 2 weeks plus apatinib 250 mg once per day for two cycles, clinical response was then evaluated. Gene expression profiling (GEP), using the 289-gene immune-related RNA panel sequencing, was performed on baseline tumor samples. Differential gene expression analysis was performed between responder (partial response and complete response) and non-responder (stable disease and progressive disease) using Wilcoxon rank-sum test. Results: Across these patients with local advanced BTCs, neoadjuvant camrelizumab plus apatinib demonstrated antitumor activity. Seventeen (n = 13 gallbladder carcinoma; n = 4 cholangiocarcinoma) response-evaluable patients received two cycles of combination therapy, of whom 12 (70.5%) patients achieved objective response, including 2 (11.7%) with complete response, and the DCR was 76.4%. To further assess the impact of the tumor microenvironment on the combination therapy response, we sequenced baseline tumor samples performed biomarker analyses using the 289-gene immune-related RNA panel. Of all enrolled patients with evaluable responses, 16 (94.1%) patients had available GEP data. Baseline tumor samples on differential genes revealed a significantly higher S100A8 (P = 0.004), IL1B (P = 0.002), KIR2DL3 (P = 0.007) expression in non-responders compared with responders. Extensive analyses on immune cell types were also performed. ECMES positive exhausted CD8 T cells (P = 0.009) and SIGLEC5 positive neutrophils (P = 0.0014) were significantly increased in baseline non-responders. In contrast, no significant differences of CD8 positive T cells, B-cells, cytotoxic cells, dendritic cells, macrophages cells or NK cells were found at baseline between groups. Meanwhile, signature scores were calculated using the Gene Set Variation Analysis package with publicly available gene signatures between responder and non-responder groups, and no noteworthy differences were found in TILs score, Cytolytic activity score, IFN-γ signature and Teff score. Conclusions: Neoadjuvant camrelizumab plus apatinib exhibited promising antitumor activity in patients with local advanced biliary tract cancers. Elevated S100A8, IL1B, KIR2DL3 expression levels may indicate resistance in clinical response. Increased ECMES positive exhausted CD8 T cells and SIGLEC5 positive neutrophils were predictive of response in non-responder tumors.
Updated results of the phase II ALTER-H003 trial: Anlotinib plus toripalimab as a first-line treatment for patients with unresectable hepatocellular carcinoma.
Authors: Lin Haifeng , Ma Jie , Zhuo Manyun , Zhang Chengsheng , Luo Jingru , Zhuang Xiaohong , Zeng Zhiming , Yang Lihua
Published: June 2021

e16130

Background: The combination therapy of anti-angiogenic with anti-PD-1 /L1 agents has represented superior efficacy over sorafenib in the first-line treatment for unresectable HCC (uHCC). There are unmet medical needs due to limited options. Anlotinib is a novel oral multi-targeted tyrosine kinase inhibitor for tumor angiogenesis and proliferation, and has been approved for treatment of several malignancies in China. Toripalimab is a humanized IgG4 mAb against PD-1. Now we present the updated results with more patients enrolled and longer follow-up of ALTER-H003 to evaluate the efficacy and safety of anlotinib plus toripalimab as the first-line regimen for uHCC. Methods: This was a single-arm, multicenter, phase II trial. 30 patients (pts) with uHCC, previously untreated, Child-Pugh ≤7 and ECOG PS <2 will be enrolled. Pts received anlotinib (12 mg, p.o., qd, d1-14, q3w) and toripalimab (240 mg, iv, d1, q3w) until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) assessed by investigator according to mRECIST and irRECIST. Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response (DoR) and safety. Results: By the cutoff date of January 21, 2021, 18 pts were enrolled and durations of treatment ranged from 0.1+ to 7.4+ months, 13 pts were still on treatment. 14 pts were evaluable, confirmed ORR and DCR was 21.4% (95% CI 4.7%-50.8%) and 92.9% (95% CI 66.1%-99.8%) respectively according to mRECIST. one patient achieved a complete response (CR), and one additional patient remained on treatment with unconfirmed PR. The median duration of response (DoR) has not been reached and DoRs ranges from 2.4m to 4.9m. 14 of 18 pts (77.8%) experienced treatment-related adverse events (TRAEs), Grade 3 TRAEs occurred in 7 pts (38.9%). Immune-Related TRAEs (irTRAEs) occurred in 10 pts (55.6%), few grade 3 irTRAEs were observed. No grade 4 or higher (ir)TRAEs occurred. More detailed (ir)TRAEs information were shown in Table. Conclusions: Anlotinib in combination with toripalimab showed promising anti-tumor efficacy and manageable toxicity in the first-line treatment for uHCC patients. This study is still ongoing and more data is being updated. Most common (ir)TRAEs in enrolled pts (n=18). Clinical trial information: ChiCTR1900028295. [Table: see text]
Radiological response as a predictor of pathological response to combined tyrosine kinase inhibitor (TKI) and anti-PD-1 antibodies in hepatocellular carcinoma (HCC).
Authors: Sun Hui-Chuan , Huang Cheng , Zhu Xiao-Dong , Shen Ying-Hao , Wu Dong , Ji Yuan , Ge Ning-Ling , Chen Yi , Tan Chang-Jun , Zhou Jian , Fan Jia
Published: June 2021

e16144

Background: Pathological complete response (CR) and major pathological response (MPR) are associated with long-term survival after neoadjuvant/conversion surgery of HCC. The relationship between imaging and histopathological evaluations of response to combined TKI plus anti-PD-1 antibody treatment is unclear. Methods: This retrospective analysis included 23 patients with an initial diagnosis of unresectable HCC who underwent resection after combined TKI/anti-PD-1 antibody treatment between March 2019 and December 2020 at Zhongshan Hospital of Fudan University. MRI was performed before and after treatment and objective response rate (ORR; CR or partial response [PR]) was evaluated using RECIST 1.1 and mRECIST by investigator assessment (INV) and independent imaging review (IIR). Histopathological response was evaluated in resected tumor tissue using residual viable tumor (RVT; RVT area/total tumor bed surface area under 100X microscopy). MPR was defined as <10% RVT. The relationship between radiological reduction in tumor size and MPR was investigated using a receiver operating characteristic (ROC) curve. Results: Patients had a median age of 54.0 years, 91% were male and the average pre-treatment tumor diameter was 11.5±4.6 cm. Three had Barcelona Clinic Liver Cancer (BCLC) Stage A disease (China Liver Cancer Stage [CNLC] Ib, n=3), six had BCLC Stage B (CNLC IIa, n=1 and IIb n=5) and 14 had BCLC Stage C (CNLC IIIa, n=10 and IIIb, n=4). Patients received lenvatinib (n=19) or apatinib (n=4) plus anti-PD-1 antibodies (pembrolizumab [n=5], sintilimab [n=5], camrelizumab [n=10], treprizumab [n=2] or nivolumab [n=1]) followed by resection. Radiological responses are summarized in Table. An MPR or pathologic CR was achieved by 52.2% (12/23) and 39.1% (9/23) of patients, respectively. A correlation was observed between radiological responses using RECIST 1.1 and mRECIST and MPR (Fisher’s exact test; P=0.089 and 0.037, respectively). Using RECIST 1.1, the optimum diagnostic cutoff for MPR was a 26% reduction in tumor size, by both INV (area under ROC (AUC)=0.780, 95% CI: 0.580–0.981, sensitivity 83.3%, specificity 72.7%) and IIR (AUC=0.739, 95% CI: 0.527–0.951, sensitivity 75.0%, specificity 72.7%). Using mRECIST, the optimum cutoff for MPR was a 78% reduction in tumor size by INV (AUC=0.746, 95% CI: 0.538–0.954, sensitivity 58.3%, specificity 90.9%) and IIR (AUC=0.742, 95% CI: 0.532–0.953, sensitivity 66.7%, specificity 81.8%). Conclusions: Radiological response showed a degree of correlation with MPR in patients with advanced HCC receiving combined TKI and anti-PD-1 antibody therapy. Therefore, imaging evaluation may be used to predict a pathological response and further guide clinical treatment decisions. Response rates (n=23).[Table: see text]
First-in-human phase I, pharmacokinetic (PK), and pharmacodynamic (PD) study of oral GNS561, a palmitoyl-protein thioesterase 1 (PPT1) inhibitor, in patients with primary and secondary liver malignancies.
Authors: Harding James J. , Awada Ahmad , Decaens Thomas , Roth Gael , Merle Philippe , Kotecki Nuria , Dreyer Chantal , Ansaldi Christelle , Rachid Madani , Mezouar Soraya , Menut Agnes , Bestion Eloine , Paradis Valerie , Halfon Philippe , Raymond Eric , Abou-Alfa Ghassan K.
Published: June 2021

e16175

Background: GNS561 belongs to a novel generation of drug blocking cancer cell proliferation by inhibiting late-stage autophagy and dose-dependent accumulation of enlarged lysosomes by interacting with palmitoyl-protein thioesterase-1 (PPT1). Methods: This phase I, multicenter, open-label, dose-escalation trial (3+3 design) explored two dosing schedules: one single oral intake three times a week and twice daily (BID) continuous oral intake of GNS561 in patients with advanced primary and secondary liver cancers (NCT03316222). The primary objective was to determine recommended phase II dose (RP2D) and schedule for further clinical development. The secondary objectives included a preliminary evaluation of the safety, pharmacokinetic (PK), pharmacodynamics (PD), and antitumor activity of GNS561. Results: Nineteen treatment-refractory patients were enrolled and were evaluable for primary endpoint: intrahepatic cholangiocarcinoma (iCCA) (9), hepatocellular carcinoma (HCC) (7), pancreatic ductal adenocarcinoma (PDAC) (2) and colorectal cancer (CRC) (1). Median age was 60, 89% were male and 37% had received 3 or more lines as prior cancer therapies. Dose escalation ranged from 50 mg three times a week to 200 mg BID. No dose-limiting toxicity were observed. Treatment-related adverse events were grade 1-2 gastrointestinal toxicity, primarily nausea/vomiting, occurring in 8 patients (42%) and diarrhea in 4 patients (21%). Occurrence of nausea/vomiting despite antiemetic prophylaxis prevented increasing doses above 200 mg BID. GNS561 displayed favorable bioavailability with interpatient variability (CV%: 13 to 223% and 21 to 98.2% on plasma concentrations on cycle 1 day 1 and cycle 2 day 1 respectively), and dose proportional exposure in plasma. GNS561 concentrations accumulated after multiple administration (2.60 - 9.00-fold) and exhibited a long half-life. Plasma and liver concentrations at doses ranging 100-200 mg BID were comparable to therapeutic exposures in preclinical models. Five patients (3 HCC and 2 iCCA) experienced tumor stabilization according to RECIST 1.1 criteria, including a minor response (-23%). Conclusions: GNS561 RP2D single agent was set at 200 mg BID based on this favorable safety profile and plasma exposure, GNS561 will be next further evaluated in monotherapy and in combination with checkpoint inhibitors considering the autophagic activity restriction of major histocompatibility complex-1 promotion of immune invasion. Clinical trial information: NCT03316222.
Pancreatic hormones response-generated machine learning model to help distinguish sporadic pancreatic cancer from new-onset diabetes cohort.
Authors: Bao Jiantong , Sun Chenyu , Zhang Yidi , Li Ling , Pandol Stephen Jacob , Kozma Kelly
Published: June 2021

e16235

Background: Diabetes mellitus (DM), a paraneoplastic phenomenon, can develop earlier than other symptoms in pancreatic cancer (PaC) patients. Enhanced surveillance is encouraged on all elderly patients with new-onset DM. However, it is a challenge to differentiate newly developed PaCDM from type 2 DM (T2DM). Thus, we investigated the differences of pancreatic hormones responses and functions between PaCDM and T2DM patients, and developed discriminative model by machine learning algorithms. Methods: PaC patients with normal blood glucose (PaCNG) or with new-onset DM (PaCDM) were recruited. For each case, age and gender matched newly developed T2DM patients and healthy volunteers were selected as controls. After ≥10 hours fasting, all participants underwent a mixed meal stimulation test (MMTT). Blood samples were collected at 0, 15, 30, 60 and 120 min to measure insulin, C-peptide, glucagon, and pancreatic polypeptide (PP). Indices of insulin sensitivity (HOMA-IS, HOMA-IR) and insulin secretion (HOMA-β, insulinogenic index 30’ and 120’) were calculated. Increases in hormone levels were compared among groups with repeated measure analysis. Four machine learning algorithms (Random Forest, Logistic Regression, Support Vector Machines, Naïve bayes) were used to develop quadri-separated discriminative models of PaCDM based on baseline characteristics, pancreatic hormones and insulin indices listed above. Results: Insulin and C-peptide responses to MMTT were blunted in PaCDM patients compared to T2DM. The AUC of insulin were comparatively lower in PaCDM; between-group differences were observed at the fasting (197.15 ± 16.59 pg/mL to 537.96 ± 118.69 pg/mL; P = 0.040) and 15 min (523.94 ± 81.15 pg/mL to 1182.51 ± 219.35 pg/mL; P = 0.036) time-points. No statistical differences among groups were found for glucagon. The mean peak PP concentration after MMTT in PaCDM group (466.67 ± 79.05 pg/mL) was higher than control group (258.54 ± 31.36 pg/mL, P = 0.034), but not statistically different to T2DM patients (452.34 ± 62.96 pg/mL, P = 0.892). PaCDM patients had lower insulin secretion capacity but better insulin sensitivity compared to T2DM patients. Eight indices (age, HbA1c, CA19-9, peak concentration of glucose, area above basal of PP, HOMA-IR, HOMA-IS, HOMA-β) were recruited for model development. And the discriminative model generated by random forest algorithm obtained best performance (AUC = 1.000, CA = 0.963, F-1 = 0.941, Precision = 0.889, Recall = 1.000, Specificity = 0.947; model verified). Conclusions: PaCDM patients tend to present with lower β-cell function and better insulin resistance compared to T2DM patients. As our model based on machine learning algorithm generates a good result for discrimination, the above findings may help with early screening for sporadic PaC in new-onset DM. Clinical trial information: ChiCTR1800018247.
A phase 1 study of neoadjuvant chemotherapy followed by concurrent chemoradiation with gemcitabine, sorafenib, and vorinostat in pancreatic cancer.
Authors: Poklepovic Andrew Stewart , Fields Emma Charlotte , Bandyopadhyay Dipankar , Tombes Mary Beth , Kmieciak Maciej , McGuire William P. , Gordon Sarah W. , Kaplan Brian J. , Myers Jennifer Lynn , Matin Khalid , Patel Bhaumik , Kothadia Sejal , Dent Paul
Published: June 2021

e16268

Background: The multi-kinase inhibitor sorafenib (S) and HDAC inhibitor vorinostat (V) demonstrated synergism against preclinincal pancreatic cancer (PaCa) models. The combination of S & V also potently radiosensitized pancreatic cancer cells and enhanced the activity of gemcitabine (G). This led to a phase 1 trial to determine the doses and schedule appropriate for phase 2 study of S & V with weekly G and intensity modulated radiotherapy (IMRT) as neoadjuvant treatment of PaCa following chemotherapy. Methods: Using a 3+3 dose-escalation design, adult patients with resectable, borderline resectable, unresectable, and lymph node positive PaCa were enrolled to 6 dose levels. Enrolled patients had completed at least 8w of neoadjuvant chemotherapy prior to IMRT. The schedule of administration was weekly 200mg/m2 G weekly during IMRT, S & V were dosed either 3x or 5x weekly during IMRT. Primary endpoint was to identify the dose and schedule for S & V with G based chemoradiation. Key secondary endpoints included antitumor activity, R0 resection rate, OS. Correlative studies to evaluate a variety of biomarkers and Nanostring expression analysis on pre- and post-therapy tumor specimens were also performed. Results: 22 patients were enrolled and 21 treated at 6 dose levels. Due to thrombocytopenia limiting drug exposure, the trial was modified to reduce G to 200mg/m2/wk and S & V to 3 d/wk instead of 5 d/wk. 13 patients were eligible for surgery, and 9 had R0 resections. Conclusions: Our findings indicate that the study regimen was well tolerated, typical toxicities of S (hand foot syndrome) were not observed with intermittent dosing. Uncomplicated cytopenias limited drug exposure, which was improved with intermittent S&V dosing. The RP2D of the combination is S (400mg po BID 3d/wk), V (200mg po qd 3d/wk), G 200mg/m2 IV weekly, with IMRT (50.4 Gy over 28 fractions, 5d/wk). Antitumor activity was observed across dose levels, with an encouraging R0 resection rate. These results warrant further investigation of combining S and V with G and IMRT as neoadjuvant treatment of PaCa following chemotherapy. Analyses of correlative studies and OS are underway. Clinical trial information: NCT02349867. [Table: see text]