bluuebunny/crossref_metadata_2025 huggingface dataset:
Retrospective pilot study of regorafenib combined with ICIs in the third-line treatment of advanced colorectal cancer.
Authors: Zhang Hangyu , Zheng Yi , Tong Zhou , Liu Lulu , Zhu Xudong , Fu Qihan , Bao Xuanwen , Dai Xiaomeng , Fang Weijia , Zhao Peng
Published: June 2021

e15582

Background: An increasing number of patients with advanced colorectal cancer tend to receive third-line treatment. Although there are several treatment options, concerns about efficacy and adverse events still remained. Regorafenib seems to enhance the effect of immune checkpoint inhibitors (ICIs) by modulate tumor microenvironment. In the absence of stage III clinical trial data, the real-world study might show certain clinical value. Methods: From Aug 2019 to June 2020, 23 advanced MSS colorectal cancer patients underwent third-line treatment of regorafenib combined with ICI. All patients received regorafenib 80 mg QD for 21 days, as a 28-day cycle, combined with ICIs until disease progression or intolerable adverse events. We retrospectively collected the overall response data, survival data and adverse events data from these patients. Results: The characteristics of all 23 patients is shown in the table. All patients had received at least 2 lines of prior systemic chemotherapy, the median time from diagnosis to third-line treatment was 31 months. The overall response rate was 26% (6/23), including one complete response. Almost all the responders were male (5/6) and with pulmonary metastasis (5/6). The disease control rate was 60% (14/23). The progression free survival ranges from 0.69 month to 19.3 months (median 4.8 months), with 6 patients continued response and constantly treatment. Duration of response range from 6.4 months to 19.4 months. Serious adverse events were hepatitis occurred in two patients and lead to the termination of subsequent anticancer therapy, which was considered to be related to immunotherapy. Conclusions: Regorafenib combined with ICIs might favor a certain group of advanced colorectal cancer patients, with a acceptable response rate and comparatively long duration of response. Interestingly, this retrospective pilot study was in consistence with that of REGONIVO trials to some extent for that the male patients with pulmonary metastasis appeared to response better. Key words: colorectal cancer; regorafenib; immune check point inhibitors Clinical characteristics of 23 patients.[Table: see text]
A study on the genomic alterations of transformation from colorectal adenoma to colorectal cancer.
Authors: Chen Qingjian , Yang Pan , Luo Linna , Fan Wenhua , Wei Chen , Zhao Qi , Luo Huiyan
Published: June 2021

e15607

Background: Colorectal cancer is one of the most common malignancies worldwide. Approximately 85% of colorectal cancers are thought to result from adenoma. However, the molecular mechanism of adenoma transformation into colorectal cancer is still unclear. Methods: Ninety-nine adenoma patients aged from 25 to 78 years old were enrolled in this study. We collected tissue sample from each patient and 77 matched blood samples. Pathological subtypes included tubular villous adenomas, villous adenomas, tubular adenomas, high-grade intraepithelial neoplasia, and polyps. Eighty-one stage I colorectal cancer patients (CRC I) were also enrolled in this study. All samples underwent Next-generation sequencing with a panel of 405 cancer related genes. Results: Mutational profiles of adenoma and CRC I patients were compared. The top 5 most frequently mutated genes in adenoma were APC (71%), KRAS (41%), ATM (33%), RIF1 (31%), SYNE1 (28%). While in CRC I patients, top 5 mutated genes were APC (78%), TP53 (57%), TTN (35%), KRAS (33%) and TCF7L2 (22%). There were significant differences between TP53 and TTN by chi-square test. The frequency, number and TMB of mutations in stage I colorectal cancer patients were significantly higher than those in various adenoma subtypes. Stage I colorectal cancer patients have more mutated genes enriched in the Wnt and Notch pathways than adenoma patients. We analyzed mutation signatures in CRC I and adenoma patients, and CRC I were more focused on mutation signatures of mismatch repair such as signature 1, signature 6, signature 10, and signature 15. A total of 391 mutations were identified in tissue samples, while 130 mutations were found in plasma cell-free DNA, with 116 mutations shared between them. The two genes with the highest consistency between tissue and blood were PAX7 and KMT2D. Conclusions: TP53 and TTN are associated with the transition from CRC I to adenoma, and Wnt and Notch pathways may also be involved. PAX7 and KMT2D mutations frequently found in adenoma tissue and blood cfDNA demonstrate the diagnostic potential of these two genes in clinic.
Update results of paclitaxel and cisplatin in combination with anlotinib as first-line regimen for patients with advanced ESCC: A multicenter, single-arm, open-label phase Ⅱ clinical trial.
Authors: Wang Junsheng , Wu Tao , Luo Suxia , Li Ning , Hong Yonggui , Guo Yanzhen , Cheng Yufeng , Li Baosheng
Published: June 2021

e16013

Background: Paclitaxel combined with cisplatin regimen has been the standard first-line therapy in advanced Esophageal Squamous Cell Carcinoma (ESCC) for almost two decades. However, the 5-year survival rate was only 4.8% in advanced ESCC. Therefore, more effective therapeutic treatments were needed to prolong the survival urgently. Anlotinib was demonstrated to be an effective second-line monotherapy for patients with advanced or recurrent ESCC in China. And the preliminary results of our trial had been reported in 2020 ESMO (Abs 1448) and 2021 ASCO-GI Symposium (Abs 181). Consequently, this study was to investigate the efficacy and safety of paclitaxel and cisplatin combined with anlotinib as first-line therapy in advanced ESCC and report the update results regularly. Methods: Pts with previously untreated metastatic or unresectable, locally advanced ESCC, who had not received (neo) adjuvant therapy/radical surgery within 6 months were recruited in this study. Eligible patients were given paclitaxel (135mg/m2, iv, q3w) and cisplatin (60̃75mg/m2, iv, d1̃3, q3w) plus anlotinib (10mg, po, d1̃14, q3w) for 4̃6 cycles as initial therapy. For those who did not have disease progression, maintenance treatment was treated with anlotinib monotherapy (10mg, po, d1̃14, q3w) until progression or unacceptable toxicity. The tumor response was assessed by investigator according to RECIST version 1.1 criteria using computed tomography scans every two cycles. The predefined sample size was 47. The primary endpoint was PFS and secondary endpoints included safety, ORR, DCR and DOR. Results: From Oct 2019 to Dec 2020, a total of 45 patients were enrolled. Among 34 pts who were available for efficacy and safety evaluation. there were 1 confirmed CR (2.9%), 26 confirmed PR (76.5%), 2 unconfirmed PR (5.9%) and 5 SD (14.7%). Consequently, ORR was 79.4% (95%CI: 62.1̃91.3) and DCR was 100.0% (95%CI: 89.7̃100.0). At the data cut-off date, 11 patients discontinued treatment due to PD, the preliminary prognostic result indicated that the median PFS of the 34 patients was 9.76 months (95%CI: 8.44-13.08). And the median OS was not yet available. Additionally, safety profile exhibited that the common drug-related adverse events were myelosuppression, gastrointestinal reaction, fatigue, hypertension, constipation, hypokalemia, hepatotoxicity and hemoptysis. And the common grade ≥3 adverse events were myelosuppression (20.6%), hypertension (8.8%), nausea and vomit (5.9%), fatigue (5.9%) and hypokalemia (5.9%). Conclusions: The update results suggested that the regimen of paclitaxel and cisplatin combined with anlotinib as first-line therapy for advanced ESCC exhibited encouraging efficacy and tolerable safety profile. And the conclusions needed to be confirmed in trials continued subsequently. Clinical trial information: NCT04063683.
CO-STAR: Surgical conversion feasibility trial of sintilimab (PD-1 inhibitor) combined with Nab-PTX, S-1 and apatinib for the first-line treatment of stage IV gastric cancer (GC).
Authors: Xue Qiang , Wang Baogui , Wang Xiaona , Ding Xuewei , Liu Yong , Wang Xuejun , Liu Ning , Zhan Hongjie , Ke Bin , Li Bin , Cai Mingzhi , Deng Jingyu , Wu Liangliang , Huang Wenbai , Liu Hongmin , Sun Yan , Liang Han
Published: June 2021

e16041

Background: Chemotherapy and PD-1 inhibitor have shown significant clinical benefits in first-line treatment of GC, overall survival was still dismal. The surgical intervention with curative or life prolonging intention was evaluated as feasible for stage IV GC from clinical trials and retrospective cohorts. Our previous study of cytotoxic chemotherapy (S-1 & PTX) in combination with multi-targets anti-angiogenic TKIs illustrated increased response and R0 resection rate. Given the enhanced response from chemo, PD-1 and TKIs regimens, this trial was designed to assess the feasibility of surgical conversion from this combination in stage IV GC. Methods: This is a prospective, single-arm, single-center, phase II trial. Eligible criteria were treatment naïve, histopathologically confirmed stage IV (AJCC8th) and ECOG PS 0-1 GC adenocarcinoma. Pts were given with sintilimab (200mg, iv, d1) combined with Nab-PTX (w/o peritoneal spread: 260 mg/m2, iv, d1; w/ peritoneal spread: 180 mg/m2, iv, d1 and 80 mg/m2, ip, d1), S-1 (60mg, po, bid, d1-14), and apatinib (250mg, po, qd) every 3 wks. Tumor response was assessed every 2-4 cycles by radiologic imaging and MDT was employed to determine surgical feasibility. Safety run-in was employed in the first 3+3 pts by DLTs to determine the tolerability. The primary endpoint was ORR and R0 surgical conversion rate. Results: 42 pts were enrolled up to 2/2021. The median follow-up was 3.5m (range 0.7-11.3). The median age was 56 yrs (range 31-72), male was 47.6%, and PS 1 was 31.0%. The metastatic factors were characterized as No.16 lymph nodes 54.8% (23), liver 23.8% (10), peritoneum 40.5% (17), Krukenberg 2.4% (1), and extensive metastases (≥2 organs) 42.9% (18). No DLT occurred in initial 6 pts. Of 36 evaluable pts, ORR was 61.1% and DCR was 97.2%. Surgical conversion was currently identified in 18 pts with 94.4% (17) R0 resection, and the R0 surgical conversion rate was 47.2% (17/36). Median treatment cycle in converted pts was 4. 22.2% (4/18) pts achieved pathological complete response (TRG 0), and 27.8% (5/18) pts had major response (TRG 0-1). The most common AEs were grade 1-2, and 1 SAE of hemorrhage grade 4 occurred. No increase of anastomotic leakage, hemorrhage, and abdominal infection, and no surgery caused death and complication caused second operation occurred. The median postoperative length of stay was 9.5d (range 6-16). Conclusions: These preliminary results showed favorable tumor response and acceptable tolerability for potential surgical resection. Sintilimab, doublet chemotherapy, and apatinib might offer an opportunity of cure for stage IV gastric cancer. Trial ID: NCT04267549. Clinical trial information: NCT04267549. [Table: see text]
Impact of PD-L1 combined positive score (CPS) on clinical response to nivolumab in patients with advanced esophageal squamous cell carcinoma.
Authors: Matsubara Yuki , Toriyama Kazuhiro , Kadowaki Shigenori , Ogata Takatsugu , Nakazawa Taiko , Kato Kyoko , Nozawa Kazuki , Narita Yukiya , Honda Kazunori , Masuishi Toshiki , Bando Hideaki , Ando Masashi , Tajika Masahiro , Hosoda Waki , Muro Kei
Published: June 2021

e16045

Background: The ATTRACTION-3 trial showed that nivolumab (Nivo) significantly improved overall survival (OS) of patients (pts) with previously treated advanced esophageal squamous cell carcinoma (ESCC) regardless of tumor programmed cell death ligand-1 (PD-L1) expression assessed with tumor proportion score (TPS). On the other hand, pembrolizumab prolonged OS in advanced esophageal carcinoma pts with combined positive score (CPS) of ≥ 10 in the KEYNOTE-181 trial. Whether CPS can predict clinical outcome of Nivo in advanced ESCC pts remains unclear. Methods: We retrospectively evaluated advanced ESCC pts who received Nivo at a single institution between January 2014 and September 2020. The main eligibility criteria were as follows: refractory or intolerant to fluoropyrimidines and platinum, no prior anti-PD-1/PD-L1 antibody treatment, no comorbid malignancies, and available tissue specimens obtained before initiation of Nivo. PD-L1 immunostaining was performed using PD-L1 IHC 22C3 pharmDx assay, and the tumors were classified into three groups depending on CPS (≥ 10, 1–10, < 1). The adjusted hazard ratios (aHRs) for progression-free survival (PFS) and OS were calculated using a multivariate Cox model that contained variables with p values < 0.05 in the univariate analysis. Results: Among 69 pts, 50 were eligible (CPS ≥ 10/CPS 1–10/CPS < 1, 23/18/9). Patient characteristics were as follows (CPS ≥ 10/CPS 1–10/CPS < 1): age, ≥ 65, 70/67/67%; male, 83/67/78%; PS ≥ 1, 61/72/44%; second-line treatment, 65/61/56%; disease status, recurrent, 61/33/78%; prior esophagectomy, 65/33/44%; prior radiotherapy, 57/56/56%; prior taxane, 52/28/44%; the number of metastatic sites, ≥ 2, 48/61/89%; lymph node metastasis, 78/83/89%, lung metastasis, 26/22/56%; liver metastasis, 17/17/44%. Among 42 pts (84%) with disease progression after Nivo treatment, 24 pts received salvage-line chemotherapy. The adjustment factor for PFS was liver metastasis, while that for OS was not detected. The median PFS was 4.1 months (mo) in CPS ≥ 10 and 2.5 mo in CPS 1–10 (HR vs. CPS ≥ 10, 1.06; 95% CI, 0.51–2.17; p = 0.864; aHR, 1.15; 95% CI, 0.54–2.36; p = 0.713), and 1.4 mo in CPS < 1 (HR vs. CPS ≥ 10, 3,78; 95% CI, 1.53–8.92; p = 0.005; aHR, 1.91; 95% CI, 0.67–5.39; p = 0.223). The median OS was 12.3 mo in CPS ≥ 10, 10.2 mo in CPS 1–10 (HR vs. CPS ≥ 10, 1.72; 95% CI, 0.75–4.00; p = 0.201), and 9.0 mo in CPS < 1 (HR vs. CPS ≥ 10, 2.31; 95% CI, 0.92–5.69; p = 0.075). Objective response rate (CPS ≥ 10/CPS 1–10/CPS < 1) in 40 pts who had measurable lesions were 32/25/0%, respectively. Conclusions: The pts with CPS of < 1 did not respond to Nivo. Our study suggests that CPS is useful for predicting response to Nivo in pts with advanced ESCC.[Table: see text]
A phase 1 multicenter, dose expansion study of ARX788 as monotherapy in patients with HER2-positive advanced gastric and gastroesophageal junction adenocarcinoma (ACE-Gastric-01).
Authors: Zhang Yang , Qiu Miaozhen , Wang Jufeng , Zhang Yanqiao , Yuan Xianglin , Zhang Tao , Yan Jinchun , Xiong Gaozhun , Ji Yanping , Liang Xuejun , Xia Gang , Xu Rui-hua
Published: June 2021

e16059

Background: ARX788 is a novel antibody drug conjugate (ADC) that consists of human epidermal growth factor receptor 2 (HER2) targeted monoclonal antibody (mAb) linked to a cytotoxic payload, AS269, a highly potent tubulin inhibitor. In a phase 1 study of ARX788 in HER2-positive advanced breast cancer (CTR20171162/ACE-Breast-01), the objective response rate (ORR) was 74 % (14/19) at 1.5 mg/kg Q3W. Here we present the safety, tolerability, and antitumor activity of ARX788 in HER2-positive advanced gastric and gastroesophageal junction (GEJ) cancer in the phase 1 (ACE-Gastric-01) study. Methods: participants with HER2+ gastric/GEJ cancer were administrated with ARX788 intravenously at dose levels of 1.3, 1.5, and 1.7 mg/kg Q3W to determine the maximum tolerated dose and recommended phase 2 dose; and to evaluate the antitumor activity. Efficacy endpoints included objective response rate (ORR) and disease control rate (DCR) per RECIST v1.1. Results: As of Jan 29, 2021, a total of 23 participants including 9 at the 1.3 mg/kg and 14 at the 1.5 mg/kg received at least one dose of ARX788. All patients were heavily treated previously. The confirmed ORR was 42.9% and 46.2% at the 1.3 and 1.5 mg/kg, respectively. As of the cut-off date, six participants were still under treatment with two of them were treated for longer than 12 months. Most AEs were grade 1 or 2 and were manageable. There were 2 drug-related grade 3 AEs and no grade 4 or 5 AEs occurred. No DLT was observed and the MTD was not reached. The dose expansion at the 1.7 mg/kg Q3W cohort is still ongoing and the mature data will be presented later. Conclusions: ARX788 was well tolerated with promising antitumor activity in patients with HER2-positive advanced gastric and GEJ adenocarcinoma. Clinical trial information: CTR20190639. [Table: see text]
HERIZON: A phase 1B/2 open-label study of imu-131 HER2/neu peptide vaccine PLUS standard of care chemotherapy with randomization in phase 2 in patients with HER2/neu overexpressing metastatic or advanced adenocarcinoma of the stomach or gastroesophageal junction.
Authors: Laeufle Rita , Maglakelidze Marina , Bulat Iurie , Ryspayeva Dinara , Zoran Andric , Chawla Tanuj , Nikolic Ivan , Nagarkar Rajnish , Venkata Giri , Choudhary Vaibhav , Radosavljevic Davorin , Singh Rajesh Kumar , Wiedermann Ursula , Good Anthony J , Ede Nick , Chong Leslie Mi Ok
Published: June 2021

e16065

Background: The phase 2 part of the study hypothesizes HER-Vaxx (IMU-131) will provide treatment benefits consistent with traditional monoclonal antibodies that target HER2 in patients with confirmed Her2+ advanced or metastatic gastric cancer with a corresponding adaptive immune response without added toxicity. In the phase 1b dose finding part of the study tumor response of patients who received 50ug dose strongly correlated with antibody levels with 50ug selected as the phase 2 dose (Wiedermann et. al., 2019). Phase 2 is a randomized two arm study of either HER-Vaxx plus standard chemotherapy or standard chemotherapy alone. The primary endpoint is overall survival, with progression-free survival, safety and immune related changes in humoral and cellular immunogenicity secondary endpoints. Methods: Patients received SOC chemotherapy for a maximum of 6 cycles with the HER-Vaxx group also receiving 50ug dose of IMU-131 at Baseline/Day 0, Day 14, Day 35, Day 77 and then every 63 days until disease progression. The per protocol pre-planned first interim analysis (OS, PFS and safety) in a total of 27 patients after 15 progression events was reviewed by the independent data monitoring committee (IDMC). Results: Within ITT analysis, 8 of 27 patients died on the control arm and 4 on the HER-Vaxx plus SOC chemotherapy arm with an overall survival HR of 0.418 (2 sided 80% CI: 0.186, 0.942) and a 1-sided p-value of 0.083. Out of 27 patients, 9 patients progressed on the control arm while 6 patients progressed on the HER-Vaxx plus SOC chemotherapy arm with a HR of 0.532 (2 sided 80% CI: 0.267, 1.060) and a 1-sided p-value of 0.086. A robust HER2 specific antibody response developed in the HER-Vaxx arm compared to the control arm whereas there was no difference in safety between the two treatment arms. Conclusions: The IDMC confirmed that the safety of the study was favorable with no added toxicity of HER-Vaxx and SOC chemotherapy with a favorable risk-benefit for the combination. The study has completed enrollment and final data is expected in late 2021. Clinical trial information: NCT02795988.
Neoadjuvant programmed death-1 blockade plus chemotherapy in locally advanced esophageal squamous cell carcinoma.
Authors: Zhang Xu , Yang Guozhen , Su Xiaodong , Luo Guangyu , Cai Peiqiang , Zheng Yating , Bei Ting , Gao Chan , Huang Mengli
Published: June 2021

e16076

Background: Immunotherapy is effective in treating advanced esophageal squamous cell carcinoma (ESCC), but little is known about its role in the setting of neoadjuvant therapy. Methods: Data from a retrospective cohort and a prospective cohort of locally advanced ESCC patients were analyzed. All patients included had received neoadjuvant camrelizumab plus nab-paclitaxel and S1 capsule followed by radical esophagectomy. The main purpose of this study was to evaluate the safety and feasibility of the neoadjuvant treatment. In addition, pathological response and the relationship between tumor immune microenvironment features (TIME)/tumor mutational burden (TMB) and treatment response were also explored. Results: A total of 25 locally advanced ESCC patients from both cohorts were included, of which 12 from the retrospective cohort and 13 from the prospective cohort. Only two patients experienced grade 3 or 4 adverse events, including onehad anemia and the other (4%) had limb numbness. No surgical delay or perioperative death was reported. Sixteen patients (64%) responded to the treatment, eight (32%) with a complete pathological response and eight (32%) with a major pathological response. Neither programmed death-ligand 1 expression nor TMB was correlated with treatment response. In terms of TIME analysis, patients with better pathological response in the primary tumor had significantly higher abundance of CD56dim natural killer cells (109 vs 32, P= 0.01), while lower density of M2-tumor-associated macrophages was associated with numerically better pathological response in the lymph nodes (47 vs 163.1, P= 0.55). Conclusions: Neoadjuvant camrelizumab plus nab-paclitaxel and S1 is safe, feasible and effective, and the efficacy could be predicted by TIME, which is worthy of further investigation. Clinical trial information: ChiCTR2000029807.
Improved lymph node metastasis prediction from preoperative esophageal squamous cell cancer CT by graph attention convolutional neural network (GACNN).
Authors: Ding Mingjun , Cui Hui , Li Butuo , Zou Bing , Xu Yiyue , Fan Bingjie , Li Wanlong , Yu Jinming , Wang Linlin
Published: June 2021

e16093

Background: Lymph node (LN) metastasis is the most important factor for decision making in esophageal squamous cell carcinoma (ESCC). A more accurate prediction model for LN metastatic status in ESCC patients is needed. Methods: In this retrospective study, 397 ESCC patients who took Contrast-Enhanced CT (CECT) within 15 days before surgery between October 2013 and November 2018 were collected. There are 924 (798 negative and 126 positive) LNs with pathologically confirmed status after surgery. All LNs were randomly divided into a training set (n = 663) and validation set (n = 185). Data augmentation including shifting and rotation was performed in the training set, resulting in 1326 negative and 1140 positive LN samples. The GACNN model was trained over CT volumetric patches centred at manually segmented LN samples. GACNN was composed of a 3D UNet encoder to extract deep features, and a graph attention layer to integrate morphological features extracted from segmented LN. The model was validated using the validation set (135 negative and 50 positive) and measured by area under ROC curve (auc), sensitivity (sen), and specificity (spe). Results: GACNN achieved better auc, sen, and spe of 0.802, 0.765, and 0.826, when compared to 3 other models including CT radiomics model (auc 0.733, sen 0.689, spe 0.765), 3D UNet encoder (auc 0.778, sen 0.722, spe 0.767), and our model without morphological features (auc 0.796, sen 0.754, spe 0.803). The improvement was statistically significant (p < 0.001). Conclusions: Our prediction model improved the prediction of LN metastasis, which has the potential to assist LN metastasis risk evaluation and personalized treatment planning in ESCC patients for surgery or radiotherapy.
Correlation of patient characteristics with clinical outcomes of camrelizumab combined with apatinib for unresectable hepatocellular carcinma (uHCC): An observational retrospective analysis.
Authors: Liu Gang , Gong Liansheng , Zhou Wenxuan , Li Xiaoli , Wang Fei , He Tingting , Zhao Juan
Published: June 2021

e16120

Background: There is limited data on clinical parameters to evaluate the therapeutic effects on immune checkpoint inhibitors (ICIs) combined with anti-angiogenic agent for uHCC. Here, we assessed efficacy and safety of camrelizumab combined with apatinib for uHCC from real-world data, and performed the retrospective subgroup analysis to investigate the potential factors related to therapy response and patients survival as well. Methods: We evaluated clinical data and outcome of 26 uHCC patients who received camrelizumab 200 mg intravenously every 2 weeks combined with apatinib 250 mg qd between May 2019 and Jul 2020. Objective response rate (ORR), disease control rate (DCR), progression free survival (PFS) and overall survival (OS) were evaluated using independent central review mRECIST and RECIST 1.1. Treatment related adverse events (TRAEs) and immune-related adverse events (irAEs) were evaluated. Results: The patients’ characteristics of our cohort are summarized in Table. Overall, our study shows that ORR was 57.7% (mRECIST), DCR was 84.62% (mRECIST), median PFS (mPFS) and OS (mOS) were 11 months and 18.2 months, respectively. For subgroup analysis, patients with first-line therapy (n=22) had dramatically better mPFS than non-first-line (15.0 vs. 4 months; p=0.01). Patients with baseline serum alpha-foetoprotein (AFP) > 400 ng/ml shows better therapeutic efficacy ( p<0.001). The patients with decreased AFP level after treatment had significantly longer mPFS (15.0 vs. 4 months; p<0.001) and mOS (NR vs. 5.7 months; p<0.001) than others. Overall, 14 (53.85%) patients had grade≥3 TRAEs, only 3 (11.54%) patients had grade≥2 irAEs. Conclusions: The first up-to-date real-world evidence indicates that both the baseline and post-treatment AFP level might be independent prognostic factors to evaluate the therapeutic efficacy and clinical outcome on the combination therapy of camrelizumab and apatinib. While larger sample sizes and longer follow-up study are needed to verify reliability of statistical results.[Table: see text]
Landmark analysis of overall survival (OS) by objective response (OR) in previously treated patients (pts) with advanced hepatocellular carcinoma (aHCC): Post hoc analysis of the randomized, phase 3 KEYNOTE-240 study.
Authors: Zhu Andrew X. , Cattan Stéphane , Merle Philippe , Daniele Bruno , Chan Stephen Lam , Yau Thomas , Bouattour Mohamed , Lim Ho Yeong , Chao Yee , Knox Jennifer J. , Ogasawara Sadahisa , Garrido Marcelo , Cheng Ann-Lii , Edeline Julien , Finn Richard S. , Siegel Abby B. , Rahman Ahmadur , Liu Chih-Chin , Kudo Masatoshi
Published: June 2021

e16122

Background: Studies have shown that OR is prognostic of OS in pts with HCC. KEYNOTE-224 (NCT02702414) evaluated pembrolizumab (pembro; anti–PD-1) in sorafenib (sora)-treated pts with aHCC and showed an ORR of 17% that was durable in responders receiving pembro, ultimately leading to FDA approval. In KEYNOTE-224, a landmark analysis showed that OR in pembro-treated pts was prognostic of longer OS. The KEYNOTE-240 (NCT02702401) study evaluated pembro + best supportive care (BSC) vs placebo (pbo) + BSC in sora-treated pts with aHCC. Although clinical benefit was observed in KEYNOTE-240 with pembro vs pbo, prespecified statistical significance criteria for OS and PFS were not met. This post hoc analysis of KEYNOTE-240 was performed to determine whether OR at landmark is prognostic of longer survival after landmark time. Methods: Eligible pts were aged ≥18 y, had confirmed aHCC, and experienced progression during or after sora treatment or intolerance to sora. Landmark analyses of OS according to OR at 6, 12, and 18 wk after randomization were performed on the pembro arm to evaluate the association between survival after the landmark with response achieved before the landmark. OR was assessed by blinded independent central review per RECIST v1.1. Responders at each landmark were defined as pts with any response assessment of CR or PR before the landmark date; all other pts were defined as nonresponders. HR and 95% CI for survival after the landmark were calculated from the Cox proportional hazards model using Efron method of tie handling, with responder status as a single covariate. Analysis was performed on the ITT population. Results: As of Jan 2, 2019, median time from randomization to data cutoff was 21.2 mo (range 13.4-30.4) for pembro. In the pembro arm, 51 pts (18.3%) had a best OR of CR or PR and 6 pts (4.4%) in the pbo arm had a best OR of PR (no CR) (excluded from landmark analyses). OS after landmark time was longer for responders than nonresponders at the wk 6, 12, and 18 time points (Table). The HR for OS after landmark time for responders vs nonresponders was 0.37 (95% CI 0.18-0.75), 0.39 (95% CI 0.23-0.66), and 0.37 (95% CI 0.21-0.63) at wk 6, 12, and 18, respectively. Conclusions: This post hoc analysis showed that pts with sora-treated aHCC who achieved OR by landmark time with pembro have longer OS after the landmark time, confirming the prognostic association between OR with pembro and OS observed in KEYNOTE-224. Clinical trial information: NCT02702401. [Table: see text]
Trends in primary gallbladder cancer incidence and incidence-based mortality in the United States, 1973 to 2015.
Authors: Low Soon Khai , Giannis Dimitrios , Dinh Thuong Nguyen , Nam Nguyen Hai , Alshareef Abdulmueti , Moris Dimitrios , Lee Shin Yin , Ammad Ud Din Mohammad , Huy Nguyen Tien
Published: June 2021

e16133

Background: Primary gallbladder carcinoma (GBC) is the most common biliary tract cancer with poor survival despite aggressive treatment. The purpose of our study was to investigate the trends of GBC incidence and incidence-based mortality (IBM), as well as to identify the factors responsible for any observed changes. Methods: GBC cases diagnosed between 1973 and 2015 were retrieved from the Surveillance, Epidemiology, and End Results database (SEER) database. Incidence and IBM rates age-adjusted to the 2000 US standard population were calculated and were stratified according to population and tumor-associated characteristics. Joinpoint Regression Analysis program was used to calculate the annual percent changes (APCs) for trend analysis. Results: Among the 10,792 patients with GBC, there was a predominance of white (81%) and female (71%) patients. The overall incidence rate was 1.086 (95% CI: 1.065 to 1.106) and the overall IBM rate was 0.995 (95% CI: 0.976 to 1.015). GBC incidence decreased by 1.645% (95% CI: 1.448 to 1.842, p < 0.001) per year, but the decreasing trend was only statistically significant from 1973 to 2002, after which the incidence rates stabilized. Conversely, IBM decreased by 1.689% (95% CI: 1.217 to 2.159, p < 0.001) per year from 1980 to 2015; the degree of decline in IBM rates during 1997-2015 (-1.194, 95% CI: -1.680 to -0.705, p < 0.001) was lower compared to that during 1980-1997 (-3.132, 95% CI: -3.682 to -2.578, p < 0.001). Mortality rates of GBC decreased in all age groups and in all races except for African American. There was a significant decrease in IBM in all SEER stages of GBC, except for distant stage GBC. Conclusions: GBC incidence and IBM rates have been decreasing over the last 40 years. However, the decrease in incidence and IBM appeared to have plateaued in the last two decades. The roles of increasing widespread use of laparoscopic cholecystectomy and use of newer treatment modalities, such as adjuvant chemotherapy and radiation, need to be investigated further.[Table: see text]
The PATH score based on pathological grade predicts survival of patients with advanced hepatocellular carcinoma after hepatic arterial infusion chemotherapy.
Authors: Lai Jinfa , Lyu Ning , Zhao Ming
Published: June 2021

e16134

Background: Hepatic arterial infusion chemotherapy (HAIC) is an emerging and effective therapeutic strategy for advanced hepatocellular carcinoma (HCC). We developed a practical prognostic score for patients undergoing HAIC to determine who can benefit from it. Methods: Between 2014 and 2019, 482 treatment-naïve patients with advanced HCC undergoing HAIC were included from two independent treatment departments. Patients were randomly divided into training (n = 337) and validation (n = 145) cohorts. Pathological grade, ALBI grade, and TNM stage were selected and developed a simple score to evaluate HAIC treatment (PATH) by Cox regression model, subsequently confirmed in the validation cohort and compared with other prognostic scores. Results: According to the PATH score, patients were divided into three groups; low-risk (0-1 point), moderate-risk (2-3 points), and high-risk (4-6 points). The median survival in the low-risk group was significantly longer than those in the other two groups (34.9 [95% CI: 25.8-44.0] vs. 13.6 [95% CI: 11.3-15.9] vs. 8.0 [95% CI: 6.8-9.2] months; p <0.001). The PATH score was fairly confirmed in the validation cohort and consistently performed better than other existing models in the training and validation cohorts. Conclusions: PATH score may be a simple and practical tool, which has good discrimination ability to screen HAIC sensitive populations and effectively predict individual survival outcomes. Calculation method of the PATH score.[Table: see text]
Computational extraction and analysis of de-identified medical records to characterize hyperammonemia in patients with fibrolamellar carcinoma (FLC).
Authors: Zack Travis , Maisel Samantha , O'Neill Allison Frances , La Quaglia Michael P. , Herman Michael , Knox Jennifer J. , Yaqubie Amin , Venook Alan P. , Mayer Robert J. , Gordan John Dozier , Abou-Alfa Ghassan K.
Published: June 2021

e16169

Background: Rare cancers including FLC make up 25% of adult tumors, but are difficult to study due to low incidence and incomplete case identification. FLC occurs in adolescents and young adults without liver dysfunction. Hyperammonemia has been frequently reported in FLC patients, but is poorly understood. Methods: Data from three clinical trials allowed us to establish the incidence of hyperammonemia (serum ammonia value > 75 µmol/L) in FLC. In these studies, FLC patients received everolimus, estrogen deprivation therapy (EDT) with leuprolide + letrozole or everolimus + EDT (Oncologist. 2020 25(11):925-e1603), ENMD-2076 (Oncologist. 2020 25(12):e1837-e1845), or neratinib (J Clin Oncol 39, 2021 (suppl 3; abstr 310); ammonia was tested prospectively in the latter two studies. To assess impacts of cancer therapy or liver dysfunction, we studied hyperammonemia in FLC and non-FLC patients at UCSF in parallel. Using Natural Language Processing (NLP) of pathology reports and oncology notes from > 2300 liver cancer patients from the last 12 years of UCSF records, we identified a cohort of patients with FLC, contrasting their laboratory data to all UCSF patients with ammonia testing for the last 10 years. We used leiden clustering and umap dimensionality reduction to contrast FLC and other patients to assess the clinical context of hyperammonemia. Results: Data from the 3 trials showed hyperammonemia in 10 of 32 (31.3%) FLC patients during study participation, independent of the therapy received. These patients exhibited hyperammonemia with varying levels, and at different points in their treatment. NLP identified 37 patients with FLC ( < 0.1% of liver cancer patients), with 33% showing hyperammonemia. Across all UCSF patients, we found 24,000 independent visits where ammonia was tested, with > 2400 demonstrating hyperammonemia. Using leidan clustering on all encounters with ammonia > 75 µmol/L, we found distinct subsets of hyperammonemia corresponding to known metabolic and physiologic processes (e.g., fulminant liver failure, tumor lysis syndrome, etc). FLC patients clustered separately from hepatocellular carcinoma patients with hyperammonemic encephalopathy due to cirrhosis. Conclusions: NLP of large EMRs is a valuable tool to study FLC, a rare cancer. Herein, we have defined hyperammonemia as a frequent event in FLC, not directly linked to hepatic dysfunction or individual therapies. Further investigation may determine whether hyperammonemia is related to FLC tumor biology.
Immune related biomarkers in biliary tract cancers (BTC).
Authors: Sandhu Zoya , Sanchez-Garcia Jorge , Barker Tyler , Raghunath Sharanya , Shortt Katherine , Hwang Su-Ho , Fulde Gail , Zendejas-Ruiz Ivan R , Haslem Derrick S. , Yeatman Timothy Joseph , Thota Ramya
Published: June 2021

e16191

Background: Biliary tract cancers are aggressive tumors with limited treatment options. Several ongoing clinical trials are currently exploring role of immune therapy in advanced BTC. Programmed death-ligand 1 (PD-L1), tumor mutational burden (TMB), and microsatellite instability (MSI) are commonly used immune related-biomarkers. Herein, we analyzed the TMB, MSI and PD-L1 expression in advanced BTC. Methods: We retrospectively evaluated the association of TMB, MSI and PD-L1 expression with survival and related treatment outcomes. Results: The immune mediated biomarkers were reported in a total of 62 BTC patients (pts). The mean age of the pts is 73 (range 32-83) years, with predominant females (59%) and Caucasians (82%). The most common histology noted was intrahepatic cholangiocarcinoma (67%) followed by extrahepatic cholangiocarcinoma (18%) and gallbladder carcinoma (15%). Approximately, 40% received 2 or more lines of therapy while 20% of patients didn’t receive any treatment and over. The treatment regimen included gemcitabine-based regimen (35%), 5FU based regimen (18%), immune therapy (15%) and targeted therapy (6%). The TMB was low in 52 pts (83%), intermediate 7 pts (11%) and high in 2 pts (3%). MSI is stable in 55 pts (89%) and PD-L1 expression is negative in 29 pts (47%) and positive in 23 pts (37%). Conclusions: Our data suggests the BTC’s have in general low TMB, are microsatellite stable and have low PD-L1 expression. The potential prognostic and predictive value of these immune related- biomarkers need to be validated in larger studies.
Study of microsatellite instability in neuroendocrine tumors of pancreas and colon.
Authors: Trifanov Vladimir S. , Timoshkina Natalya N. , Gvaldin Dmitry Yu. , Mesheryakova Milana Yu. , Kolesnikov Evgeniy N. , Gaziev Umar M. , Sanamyants Sergey V. , Mezentsev Stanislav S. , Duritskiy Maksim N. , Gabrichidze Petr N. , Kit Oleg I.
Published: June 2021

e16196

Background: Microsatellite instability (MSI), as an acquired feature of malignant tumors, is a predictive and prognostic marker. The less aggressive nature of MSI-positive tumors has been associated with high immunogenicity. In the present study, MSI was assessed in NET samples of different localizations. Methods: The sample included 50 patients with a diagnosis of pancreatic NET (G1-G3) and NET of colon (G2-G3). MSI was analyzed by fragment analysis of five microsatellite loci (Bat25, Bat26, NR21, NR24, NR27). The level of MLH1 methylation was detected by pyrosequencing. Results: MSI was noted in 25.8% cases of the NET of colon and in 13.3% cases of the NET of the pancreas. In the case of pancreatic NET, only MSI low level was identified (instability at 1/5 loci), while in the case of NET of colon, most cases were classified as MSI high level. The incidence of MSI of pancreatic NET was consistent with literature data for small intestinal NET (14%), unlike MSI NET and BRAF V600 mutated adenocarcinomas of colon, MSI-positive pancreatic NET were not associated with hypermethylation of the MLH1 promoter. MSI was more often detected in women over 60 years old, at stages of the tumor process without distant metastases (p = 0.49). The sample size did not allow us to determine significant differences in the studied clinical and pathological groups of NETs, however, we note that in all cases of an unfavorable course of the disease (progression, death), was noted MSS status of tumors. Conclusions: Thus, MSI-positive NET of colon resembles MSI-positive adenocarcinomas of colon in frequency and pathogenetic mechanisms, while in terms of the identified frequency of MSI in pancreatic NET resembles the NET of the small intestine.
Surufatinib in combination with toripalimab in patients with advanced neuroendocrine carcinoma: Results from a multicenter, open-label, single-arm, phase II trial.
Authors: Shen Lin , Yu Xianjun , Lu Ming , Zhang Xing , Cheng Ying , Zhang Yanqiao , Li Zhiping , Xu Jianming , Weng Desheng , Wu Chunjiao , Ma Yue , Cheng Ke , WANG Wenquan , Gao Heli , Li Yi , Zhou Jinghong , Shi Haiyan , Tan Panfeng , Su Weiguo
Published: June 2021

e16199

Background: Patients with advanced neuroendocrine carcinoma (NEC) have a poor prognosis and limited treatment option after first-line treatment. Surufatinib, a multi-kinase inhibitor of VEGFR 1-3, FGFR 1 and CSF-1R, has been approved in patients with advanced or metastatic extra-pancreatic neuroendocrine tumors in China. Toripalimab is a monoclonal humanized IgG4 PD-1 antibody. Surufatinib modulates tumor immune microenvironment and has shown promising antitumor activity in combination with toripalimab in solid tumors, including neuroendocrine tumor and neuroendocrine carcinoma. Herein, we reported the efficacy and safety of surufatinib in combination with toripalimab in a cohort of advanced NEC patients. Methods: The multicenter, open-label, single-arm phase II clinical trial enrolled advanced NEC patients refractory to first-line chemotherapy, and received surufatinib 250 mg once a day orally plus toripalimab 240 mg intravenously on day 1 of a 21-day cycle. The primary end point is objective response rate (ORR) per RECIST 1.1. Results: Twenty-one patients enrolled and received combination therapy. At data cut-off (December 31, 2020), the average treatment cycles were 5.1±3.69 for surufatinib and 5.0±3.68 for toripalimab. Among 20 tumor evaluable patients, 4 patients achieved confirmed PR and 10 patients achieved stable disease. The ORR and disease control rate (DCR) are 20 % (95%CI: 5.7%-43.7%) and 70% (95%CI: 45.7%-88.1%) respectively. The median PFS is 3.94 months (95%CI: 1.31- unknown). OS is not mature till data cut-off. Adverse events (AEs) reported as related to treatment (TRAE) occurred in 100% of patients, of which Grade≥3 TRAEs occurred in 33.3% of patients. The reported Grade≥3 TRAEs were hypertension in 2 (9.5%) patients, and upper abdominal pain, oral mucositis, neutrophil count decreased, leukocyte count decreased, dermatitis, anemia and backache in 1 (4.8%) patient each. Immune related Grade ≥3 AEs, Gamma-glutamyl transpeptidase increased and dermatitis, occurred in 2 (9.5%) patients, respectively. TRAE caused surufatinib or toripalimab interruption occurred in 6 (28.6%) and 4 (19%) patients respectively. There were neither serious AEs nor AEs inducing treatment discontinuations or deaths. Conclusions: As there is no standard second-line treatment, this combination of surufatinib and toripalimab might offer a new promising choice to treat NEC as second-line treatment due to good efficacy and manageable treatment related toxicities. Clinical trial information: NCT04169672.
Neutrophil extracellular traps (NETs) and thrombosis (Thr) in pancreaticobiliary cancer (PBC).
Authors: Fountzilas Christos , Yu Han , Khan Anm Nazmul , Giridharan Thejaswini , Khorana Alok A. , Iyer Renuka V. , Segal Brahm H.
Published: June 2021

e16230

Background: NETs are linked to tissue damage, Thr and cancer progression. Detection of NETs in pancreatic cancer (PC) tissue and NET products in plasma, such as citrullinated Histone 3 (cit-H3) and myeloperoxidase (MPO), can predict survival. A robust biomarker to identify PC patients that may benefit from prophylactic antithrombotic interventions is still lacking. We hypothesized that NET products can predict PC patients at risk of poor outcomes. Methods: Frozen plasma collected on diagnosis from a cohort of 117 patients with HPBC (69% with PC) with known tissue factor (TF) levels was analyzed for MPO and cit-H3 by ELISA. Plasma MPO is a marker of neutrophil degranulation while cit-H3 is a more specific marker of NETosis. Univariate association of clinical variables, TF, cit-H3, MPO with overall survival (OS) was performed. For multivariable analysis, Cox proportional hazards regression model and backward stepwise selection based on the Bayesian information criterion (BIC) were used. Results: We observed a strong correlation between MPO and cit-H3. MPO also correlated with TF. Only TF showed a trend with association with the risk of Thr (p=0.053). Results of the multivariable model for OS are presented in the table (all patients and stratified by Thr status). High absolute neutrophil count (ANC) predicted worse OS only in patients without Thr. Increased cit-H3 was associated with worse OS. Higher MPO predicted worse OS in stage IV patients, which is in contrast to their relationship in stage I-III patients, where increased MPO was associated with improved OS. This interaction effect is stronger in patients with thrombosis. Conclusions: Plasma cit-H3, a systemic marker of NETosis, was associated with worse OS in PBC. Significant MPO by stage interaction implies a differential association of MPO with the OS among patients in different cancer stages. The activation status of neutrophils, including degranulation and NETosis, may be an important predictive biomarker for OS in patients with HPBC with interactions with both stage and Thr. Prospective studies to confirm and extend our findings are ongoing.[Table: see text]
Molecular subtypes of pancreatic adenocarcinoma stratified based on copy number variation profile.
Authors: Zhan Qian , Wen Chenlei , Yi Zhao , Zhang Henghui , Shen Baiyong
Published: June 2021

e16232

Background: Pancreatic adenocarcinoma (PAAD) is one of the most lethal carcinomas all over the world, with an estimate of 60,430 new cases and 48,220 deaths in United States according to the cancer statistics of 2021. It is important and urgent to identify molecular subtypes for stratifying PAAD into different groups with respective genomic footprint, appropriate treatment and prognosis status. Methods: We profiled a comprehensive landscape of genomic alterations for 608 PAAD patients in a Chinese cohort, including somatic mutations, pathogenic germline variants and copy number variations (CNVs). 233 out of 608 PAAD had disease-free survival (DFS) information with at least 6-month follow-up. Focusing on this subset of PAAD, we explored prognostic values for several kinds of genomic alterations and finally identified four molecular subtypes based on CNV profile. Results: For point mutations in highly mutated genes ( KRAS, TP53, CDKN2A and SMAD4) or homologous recombination repair (HRR) genes ( ATM, ATR, BARD1, BLM, BRCA1/2, BRIP1, CDK12, CHEK1/2, NBN, PALB2, RAD50/ 51B/ 51C/ 51D/54L and MRE11A), we found no associations between them and prognosis of PAAD patients. Instead, PAAD could be stratified into four molecular subtypes based on CNV profile through unsupervised clustering and CNV score defined by principle component analysis (PCA). According to amplification and deletion pattern of genes in DNA repair and receptor tyrosine kinase related signaling pathways, we named these four subtypes as repair-deficient, proliferation-active, repair-proficient and repair-enhanced ones. Among them, repair-deficient PAAD had the best prognosis with median DFS of 410 days, repair-proficient and proliferation-active one had median DFS of 239 and 197 days, respectively, while repair-enhanced one had the worst prognosis with DFS of 48 days. Genomic footprint analysis showed that both of repair-deficient and proliferation-active subtypes of PAAD possessed higher copy number instability (CNI), while both of repair-proficient and repair-enhanced subtypes possessed higher tumor mutational burden (TMB), implying that the former two subtypes suited for DNA damage therapies (such as platinum-based chemotherapy and PARPi) and the latter two subtypes suited for immunotherapy. Conclusions: We identified four molecular subtypes for PAAD based on CNV profile and found their respective genomic footprint, suited treatment and prognosis status, pacing key steps to precision medicine in PAAD field.