bluuebunny/crossref_metadata_2025_split huggingface dataset:
Real-world experience on the efficacy and tolerability of biweekly trifluridine/tipiracil with or without bevacizumab in metastatic colorectal cancer.
Authors: Ang Choon Seong , Low Qin Jian , Ho Carol LF , Walsh Robert John , Asokumaran Yugarajah , Choo Joan RE , Chan Gloria HJ , Ho Jingshan , Ang Yvonne , Tan Hon Lyn , Yong Wei-Peng , Sundar Raghav , Chee Cheng Ean 
Published: June 2022

3584 Background: Trifluridine/tipiracil (TAS-102) is currently approved as third-line treatment in metastatic colorectal cancer (mCRC). However, there is paucity of real-world data on the tolerability and efficacy with biweekly dosing as monotherapy or in combination with bevacizumab. In this study, we present our center’s experience with biweekly TAS-102 with or without bevacizumab in mCRC patients (pts). Methods: We performed a single center retrospective observational study of pts receiving TAS-102 between 2018 and 2021. Results: A total of 83 pts were included (53 men, 30 women), with a median age of 64 years. Majority of pts were treated with TAS-102 in the 3rd-line (48.2%) and 4th-line (28.9%) setting. Almost all (94.0%) were of ECOG ≤ 1 at the initiation of treatment. The mean number of cycles administered was 3.8 and bevacizumab (5mg/kg on Day 1, every 2 weeks) was used in combination with TAS-102 in 18 pts (21.7%). Majority of pts (84.3%) were given TAS-102 using the biweekly regimen (35mg/m2 BD, on Day 1-5 and 15-19, q28 days) rather than standard regimen (35mg/m2 BD, on Day 1-5 and 8-12, q28 days) following a change in institutional practice. Fifteen pts (18.1%) had their initial dose reduced to 30mg/m2 BD at prescriber's discretion. Median PFS and OS were 2.37 and 10.15 months, respectively. In terms of tolerability, fatigue (any grade, 42.2%) and neutropenia (any grade, 44.6%) were the two most common adverse events reported. Grade 3 or higher neutropenia and febrile neutropenia were 16.9% and 3.6%, respectively. Dose reduction during treatment was required in 15 pts (18.1%), dose delay in 31 pts (37.3%) and six pts (7.2%) discontinued treatment due to toxicity. More than half (54.2%) had at least an additional line of therapy (regorafenib, clinical trials or re-challenge previous chemotherapy agents) following disease progression with TAS-102. Conclusions: We report the largest real-world experience with biweekly TAS-102. Our pts treated with TAS-102 had comparable median PFS to the RECOURSE cohort but with significantly better OS as more than half continued to receive treatment. Biweekly dosing of TAS-102 with or without bevacizumab is well tolerated with significantly lower rates of Grade 3 neutropenia compared to the published data in the literature.
Clinical outcomes following termination of immunotherapy due to long-term benefit in MSI-H colorectal cancer.
Authors: Simmons Kristen , Kee Bryan K. , Raghav Kanwal Pratap Singh , Johnson Benny , Kopetz Scott , Willis Jason , Dasari Arvind , Vilar Sanchez Eduardo , Ludford Kaysia , Parseghian Christine Megerdichian , Lee Michael Sangmin , Le Phat , Shen John Paul Y.C. , Overman Michael J. , Morris Van K. 
Published: June 2022

3585 Background: Immune checkpoint blockade therapy improves survival in patients (pts) with microsatellite instability-high (MSI-H) advanced colorectal cancer (CRC). Oncologists often discontinue immunotherapy after 2 years of disease control based on prior trial data. Recurrence outcomes following discontinuation of immunotherapy and clinicopathologic features associated with recurrence remain underreported given the recent advent of these agents for pts with MSI-H advanced CRC. Methods: Records from pts with MSI-H CRC from MD Anderson Cancer Center who received immunotherapy between 2015-2022 and stopped after clinical benefit were reviewed. Median survival was estimated according to the Kaplan-Meier method. Associations between the event of recurrence and coexisting mutations ( KRAS, NRAS, BRAFV600E, PIK3CA, APC, TP53, POLE/POLD), metastatic site (lung, liver, lymph nodes, or peritoneum), primary tumor sidedness (right vs. left colon), and prior immunotherapy (anti-PD-(L)1 alone or with anti-CTLA-4 antibodies) were measured by Fisher’s exact tests. Results: Thirty-six pts with MSI-H CRC without progression on immunotherapy were reviewed. Of these 29 and 7 received anti-PDL1 antibody alone or in combination with anti-CTLA-4 antibody, respectively. Median exposure to prior immunotherapy was 24 months (range, 5-43). After a median follow-up of 19 months (95% CI, 14-26) after stopping immunotherapy, 30 of 36 pts (83%) remained without disease progression. For the 6 patients with progression after stopping, median time to relapse was 13 months (range, 5-31). Median disease-free survival (DFS) was not reached. The estimated 1-year, 2-year, and 3-year DFS probabilities were 90% (95% CI, 79-100), 79.1% (95% CI, 64-98), and 68% (95% CI, 47-98), respectively. Median overall survival from the time that immunotherapy was stopped was 54 months (95% CI, 47-NA). Only 1 pt died due to unrelated illness. There were no observed associations between disease recurrence and co-existing mutations, metastatic organ involvement, primary tumor sidedness, or immunotherapy used. Conclusions: Most pts with MSI-H advanced CRC who achieve initial clinical benefit and do not progress on immunotherapy do not recur after treatment is stopped. Our data suggest that favorable outcomes do occur following cessation of immunotherapy in this setting even with concomitant prognostically unfavorable clinical features (RAS, BRAFV600E mutations; liver, peritoneal metastases).
Preliminary results of raltitrexed in Chinese patients with metastatic colorectal cancer: A prospective, multicenter, real-world study.
Authors: Li Jin , Qin Shukui , Zhou Ai-Ping , Zhang Yanqiao , Yuan Xianglin , Qin Baoli , Zeng Shan , Shen Lin , Yuan Ying , Zhu Liangjun , Wang Weibo , Zhang Xianwen , Liang Jun , Ye Feng , Chen Ping , Wang Huaizhang , Yu Zhengyan , Fang Yong , Yue Lu , Xiong Jianping 
Published: June 2022

3591 Background: Raltitrexed-based chemotherapy regimen is one of the common regimens for the treatment of metastatic colorectal cancer (mCRC). This prospective observational real-world study aimed to evaluate the safety and effectiveness of raltitrexed administered to Chinese patients with mCRC in real life setting. Methods: This is a prospective, multicenter, real-world study. Prospectively registered Patients received second-line treatment of raltitrexed plus irinotecan combined with or without target therapy until progression disease or unacceptable toxicity. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), quality of life (QOL) and safety. Totally,1000 patients were required for primary point testing. Results: Between May 2018 and December 2021,a total of 1039 patients from 57 centers were screened for enrollment,among which 271 patients were treated with raltitrexed plus irinotecan, 753 patients accepted target therapy (bevacizumab or cetuximab) additionally, and 15 patients combined with other drugs. Overall mPFS was 6.8 months (95%CI: 6.5-7.1),ORR was 20.2%, and DCR was 85.7%; The ORR of combined with or without target therapy were 21.6% and 16.2% ( p = 0.038),respectively, the DCR were 88.2% and 79.0% ( p < 0.001). The mPFS of combined without or with target therapy were 5.2 months (95% CI: 4.7 to 5.7) and 7.3 months respectively (95% CI: 7.0-7.7) [HR = 0.67, 95% CI 0.56̃0.80, p < 0.001], The mPFS of combined with bevacizumab or cetuximab were 7.4 months (95% CI: 7.0 -7.8) and 6.8 months (95% CI: 5.9-7.7) [HR = 1.15, 95% CI 0.88̃1.51, p = 0.3]. mOS has not yet reached. Majority of treatment-related adverse events (TEAEs) were grade I or II. The most common grade III or IV TRAEs reported by 116 patients (11.2%) were aspartate aminotransferase increased (4.0%), alanine aminotransferase increased (3.7%), neutrocytopenia (2.7%), glutamyltransferase increased (2.5%), leukocytopenia (1.1%). Conclusions: The real-world study confirmd that raltitrexed was an effective and safe regimen for the second-line treatment in Chinese patients with mCRC, especially combined with target therapy additionally, which was aligned with previous trials. Clinical trial information: ChiCTR1800016185.
PKUCH 04 trial: Total neoadjuvant chemoradiation combined with neoadjuvant PD-1 blockade for pMMR/MSS locally advanced middle to low rectal cancer.
Authors: WU Aiwen , Li Yingjie , Ji Dengbo , Zhang Li , Zhang Xiaoyan , Cai Yong , Zhang Yangzi , Yao Yunfeng , Wang Lin , Leng Jiahua , Zhan Tiancheng , Sun Ying-Shi , Li Zhongwu 
Published: June 2022

3609 Background: Total neoadjuvant therapy (TNT) with induction chemotherapy and chemoradiation is the standard of care for locally advanced rectal cancers. Incorporation of PD-1 blockade in the neoadjuvant setting is promising for mismatch repair deficient (dMMR) patients, yet the efficacy of TNT combined with PD-1 blockage for pMMR/MSS patients is little unknown. The purpose of this study is to evaluate the clinical benefit of neoadjuvant PD-1 blockade combined with TNT in pMMR/MSS locally advanced rectal cancer. Methods: We designed a prospective, single-arm, phase II study on locally advanced dMMR/MSS rectal cancer (PKUCH 04 trial). Patients will receiving neoadjuvant regimen (PD-1 inhibitor, camrelizumab, also called SHR01210, 200mg d1, oxaliplatin 130mg/m2 d1, capecitabine 1250mg/m2 bid1-14, for three cycles, then long course chemoradiation (IMRT, 1.8Gy/f*25f), then another two cycles of CapeOx (oxaliplatin 130mg/m2 d1, capecitabine 1250mg/m2 bid1-14, q3wks) if no disease progression occurs. The primary endpoint was pathologic complete response (pCR) rate, and the secondary outcome include adverse event and surgical complication. Tumor assessment was carried out after induction, chemoradiation, and before the decision of either surgery or watch and wait. Results: A total of 27 patients were screened and finally 25 patients were eligible for further analysis, with median age 58 years (range 31-70). The median distance from the anal verge was 5.3 cm (1.2-10). 76% were male, 76% had N2 disease, 56% positive MRF, 80% positive EMVI. All patients have completed the induction and chemoradiation phases. 21 patients underwent TME surgery, of which 7 had pathological complete response (33.3%). Four achieved clinical complete or near complete response and chose watch and wait. 7 had major pathological remission (over 90% remission). Another 7 had partial pathological remission. No progressive disease was found. 14 had LAR, 7 APR, and. The surgical complication rate was 14.3%, and the mortality rate was 0. The common adverse events included nausea (80%), lymphopenia (80%), paresthesia (76%), reactive cutaneous capillary endothelial proliferation (72%), neutropenia (68%). Grade 3 adverse events include lymphopenia (24%), diarrhea (8%), and thrombocytopenia (4%) and no grade 4 or 5 events were observed. Till January 2022, no recurrence or regrowth was found. Conclusions: Total neoadjuvant chemoradiation combined with neoadjuvant PD-1 blockade is safe and effective which can achieve good regression and sphincter preservation for pMMR/MSS rectal cancer. This suggests a potential new paradigm for treatment of pMMR/MSS locally advanced rectal cancer and necessitates further investigation. Clinical trial information: NCT04340401.
Surgical and pathological outcome, and pathological regression, in patients receiving perioperative atezolizumab in combination with FLOT chemotherapy versus FLOT alone for resectable esophagogastric adenocarcinoma: Interim results from DANTE, a randomized, multicenter, phase IIb trial of the FLOT-AIO German Gastric Cancer Group and Swiss SAKK.
Authors: Al-Batran Salah-Eddin , Lorenzen Sylvie , Thuss-Patience Peter C. , Homann Nils , Schenk Michael , Lindig Udo , Heuer Vera , Kretzschmar Albrecht , Goekkurt Eray , Haag Georg Martin , Riera Knorrenschild Jorge , Bolling Claus , Hofheinz Ralf-Dieter , Angermeier Stefan , Ettrich Thomas Jens , Siebenhuener Alexander , Kopp Christina , Pauligk Claudia , Goetze Thorsten Oliver , Gaiser Timo 
Published: June 2022

4003 Background: DANTE evaluates atezolizumab in the perioperative treatment of resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma in combination with FLOT. Here, we report interim results. Methods: DANTE is a multicenter, investigator-initiated, phase IIb trial. Patients (pts) with resectable adenocarcinoma of the stomach and GEJ (≥cT2 and/or N+) were randomized to receive 4+4 cycles of periop. FLOT chemotherapy (arm B) or the same regime with additional atezolizumab at 840 mg, q2w, followed by atezolizumab monotherapy for 8 cycles at 1200 mg, q3w (arm A). The primary endpoint is progression-free survival. The secondary endpoints surgical outcome (pTNM, R0 resection rate and periop. morbidity/mortality), path. regression and safety are reported here. TNM stage was evaluated by local pathologists and path. regression (Becker-Classification) by local and central pathologists. PD-L1 and MSI status were centrally evaluated. Results: In total, 295 pts were randomized (A, 146; B, 149) with baseline characteristics as follows: median age 61y, male 74%, intestinal type 42%, GEJ 61%, cT3/4 77%, N+ 78%. Twenty-five pts (8.5%) were MSI; 50% had PD-L1 CPS ≥1, 23% PD-L1 CPS ≥5 and 15% PD-L1 CPS ≥10. Pre-op FLOT cycles were completed in 93% of pts and post-op cycles in 43% of pts, with no difference between arms. Surgical morbidity (A, 45%; B, 43%) and mortality (overall 2.5%) were comparable between arms, as were R0-resection rates (arm A, 92% vs. arm B, 91%). Downsizing favored arm A vs B (pT0, 23% vs 15%; pN0, 68% vs 54%). Increases in path. regression rates were seen, particularly with higher PD-L1 expression (Table). Conclusions: The analysis shows beneficial effects of atezolizumab combined with FLOT vs FLOT alone on path. stage and path. regression that seem to be more pronounced with higher PD-L1 expression. Sponsor: Institut für Klinische Krebsforschung IKF am Krankenhaus Nordwest. EudraCT: 2017-001979-23. Clinical trial information: NCT03421288. [Table: see text]
The association of B7-H6 expression to the immune microenvironment in gastric cancer.
Authors: Chen Jian , Li Deqin , Sun Dengjun , Song Shujie , Zhang Weiwei , Luo Ningning , Ge Minghui , Li Mengmeng , Qi Yingxue , Zhu Xiaofeng , Sun Tingting , Qi Chuang 
Published: June 2022

4025 Background: B7-H6, also known as NCR3LG1, is a promising molecule in B7 family and a ligand of natural killer (NK) -cell-activating receptor NKp30. B7-H6 can bind NKp30 and induce NK activation and cytokine secretion to exert anti-tumor effects. Studies have reported that the B7-H6 expression is significantly correlated with post-operative prognosis and distant metastasis status in patients with cancer. In patients with gastric cancer, B7-H6 high expression is significantly associated with longer OS. However, the effects of B7-H6 on immunotherapy and immune microenvironment are unknown. Herein, we used the data from TCGA database of gastric cancer to analyze the influence of B7-H6 expression on immune microenvironment. Methods: The gene expression profile and clinical data in gastric cancer were extracted from TCGA database ( http://cancergenome.nih.gov ). According to the previous reported article, 15 was chosen as the cutoff value for the expression of B7-H6, and the expression of B7-H6 is divided into two groups, high group (B7-H6 expression＞15) and low group (B7-H6 expression≤15). Kaplan-Meier analysis was used to verify the influence of B7-H6 expression on OS prognosis. “Cell Type Identification by Estimating Relative Subsets of RNA Transcripts” (CIBERSORT) algorithm was used to analyze the proportion of immune-related cells in the two groups. “Estimation of STromal and Immune cells in Malignant Tumours using Expression data” (ESTIMATE) algorithm was used to analyze stromal and immune scores in the two groups. The differences of immune-related signatures between the two groups were calculated according to previous reports. Results: Kaplan-Meier survival analysis showed that high group was significantly associated with longer overall survival (p value = 0.016), which was consistent with previous reports. The result of CIBERSORT algorithm showed that the proportion of activation immune correlation CD8(+) T cells and NK active cells was significantly higher in low group than in high group (p＜0.05). Meanwhile, the proportion of immune suppressive correlation CD4 resting memory T cell was significantly lower in low group than in high group (p＜0.05). The result of ESTIMATE algorithm showed that the stromal score, immune score, and ESTIMATE score in low group were significantly higher than in high group (p＜0.01). The immune-related signatures, including immune signature, expanded immune signature, TLS signature, myeloid cell chemotaxis, tertiary lymphoid structure, were significantly higher in low group than in high group (p＜0.05). Conclusions: The low B7-H6 expression was correlated with better immune microenvironment. The effect of B7-H6 expression on immunotherapy needs to be further explored.
Choice of PD-L1 immunohistochemistry assay influences clinical eligibility for gastric cancer immunotherapy.
Authors: Tay Ryan Yong Kiat , Yeong Joe Poh Sheng , Lum Jeffrey , Teo Chong Boon , Tan Benjamin Kye Jyn , Chan Yiong Huak , Choo Joan RE , Jeyasekhran Anand , Miow Qing Hao , Loo Lit-Hsin , Yong Wei-Peng , Sundar Raghav 
Published: June 2022

4026 Background: Immune checkpoint inhibitors (ICI) are now standard-of-care treatment for patients with metastatic gastric cancer (GC). To guide patient selection for ICI therapy, programmed death ligand-1 (PD-L1) biomarker expression is routinely assessed via immunohistochemistry (IHC). Regulatory approval for ICIs is granted based on PD-L1 expression status, scored using metrics such as the combined positive score (CPS). However, with an increasing number of approved ICIs, each paired with a different PD-L1 antibody IHC assay used in their respective landmark trials, there is an unmet clinical and logistical need for harmonization. We thus investigated the interchangeability between the Dako 22C3, Dako 28-8 and Ventana SP-142 assays in GC PD-L1 IHC. Methods: In this cross-sectional study, samples were obtained via biopsy or resection of gastric cancer at the National University Hospital, Singapore. We scored 362 GC samples for PD-L1 CPS, tumor proportion score (TPS) and immune cells (IC) using a multiplex immunohistochemistry/immunofluorescence technique. 344 samples were developed into a tissue microarray (TMA), while 18 samples were used as whole slides for orthogonal validation. The samples selected for whole slide analysis were obtained from GC patients treated with ICI therapy. Results: The percentage of PD-L1 positive samples at clinically relevant CPS ≥1, ≥5 and ≥10 cut-offs (Table) for the 28-8 assay were approximately two-fold higher than that of the 22C3 (CPS≥1: 70.3% vs 49.4%, p<0.001; CPS≥5: 29.1% vs 13.4%, p<0.001; CPS≥10: 13.7% vs 7.0%, p=0.004). The mean CPS score on 28-8 assay was nearly double that of the 22C3 (6.39 ±14.5 vs 3.46±8.98, p<0.001). At the clinically important CPS≥5 cut-off, there was only moderate concordance between the 22C3 and 28-8 assays. Conclusions: Our findings suggest that scoring PD-L1 CPS with the 28-8 assay may result in higher proportion of PD-L1 positivity and higher PD-L1 scores compared to assessment with the 22C3 and other assays. Clinically, this could lead to a larger number of patients eligible and approved for ICI therapy. If assays are viewed and used interchangeability, a substantial number of patients may be inaccurately denied or granted treatment with ICIs based on the assay chosen. As such, until stronger evidence of inter-assay concordance is found, we urge caution in treating the assays as equivalent.[Table: see text]
VOYAGER (KSCC1902): A single-arm, multicenter, phase II study of early induction of nivolumab during second-line treatment with taxane ± ramucirumab for advanced gastric or gastro-esophageal junction cancer.
Authors: Katsuya Hiroo , Makiyama Akitaka , Kashiwada Tomomi , Shinohara Yudai , Hu Qingjiang , Otsu Satoshi , Yoneda Akira , Emi Yasunori , Ishibashi Nobuya , Kojiro Eto , Nakamura Masato , Shimokawa Mototsugu , Oki Eiji , Saeki Hiroshi , Mori Masaki 
Published: June 2022

4028 Background: Although nivolumab prolonged overall survival in 3rd or later line treatment for advanced gastric cancer in the ATTRACTION-2 study, only a small number of patients respond or achieve stable disease. Previous reports have shown that low tumor burden at the start of treatment was potentially associated with efficacy to immunotherapy in some types of tumors, but it has not been studied in advanced gastric cancer. We conducted a clinical trial to evaluate the early induction of nivolumab. Methods: Eligible patients were unresectable advanced or recurrent gastric or gastro-esophageal junction cancer, histologically confirmed to be adenocarcinoma regardless of PD-L1 expression. Patients who were refractory to or intolerant of fluoropyrimidines had a complete or partial response after at least three cycles of taxane ± ramucirumab, and were confirmed to be either of the following conditions; disease progression by imaging tests, an increase of tumor markers, exacerbation of symptoms, and intolerant of pretreatment. Patients received 240mg/body nivolumab every 2 weeks. The primary endpoint was the rate of progression-free survival (PFS) at 6 months (M), and the secondary endpoints included safety, overall survival (OS), response rate (RR), time to treatment failure (TTF), and duration of response (DOR). Based on assuming a threshold PFS at 6M of 16% and an expected PFS of 30% with the early induction of nivolumab, 39 patients were required for a power of 0.8 with a one-sided α of 0.1. Results: Between September 2019 and February 2021, 42 patients were enrolled in this study. The characteristics of patients were male/female: 28/14, median age: 71 years (range: 39-87), and performance status 0/1/2: 21/19/2. The PFS at 6M was 35.7% (80% confidence interval 26.4-45.1%), which means this trial met the primary endpoint. The median PFS and OS were 4.0M (95%CI:2.3–5.7) and 10.9M (95%CI:9.9–16.0), respectively. Of 34 patients with baseline target legions, RR was 17.5% (all confirmed partial response) and the rate of stable disease was 41.2%. TTF, and DOR were 3.6M (95%CI:2.2–5.1), and 14.3M (95%CI:3.9–14.3), respectively. No new safety signals were observed. Conclusions: This study demonstrated an improvement of PFS at 6M in patients with advanced gastric cancer and might justify the strategy of early induction of nivolumab. Clinical trial information: jRCTs071190025.