bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risk factors for recurrence in each pattern after curative gastrectomy for pStage II/III gastric cancer: An exploratory analysis of a randomized controlled trial (JCOG1001).
Authors: Toriumi Tetsuro , Terashima Masanori , Mizusawa Junki , Sato Yuya , Kurokawa Yukinori , Takiguchi Shuji , Doki Yuichiro , Kawachi Yasuyuki , Shinohara Hisashi , Choda Yasuhiro , Ito Seiji , Yoshikawa Takaki , Sano Takeshi , Sasako Mitsuru 
Published: June 2021

4052 Background: Peritoneal, lymph node, and hematogenous recurrence are frequently observed as patterns of recurrence after surgery for gastric cancer. However, the clinicopathological characteristics associated with each recurrence have rarely been comprehensively reported in a multicenter study. Understanding the risk factors for each pattern of recurrence would be helpful for the early detection of recurrence and the initiation of optimal treatment. This study investigated the risk factors for the first recurrence in each pattern after curative gastrectomy, using data from a multicenter randomized controlled trial (JCOG1001) that was designed to investigate the efficacy of bursectomy. Methods: Patients of 20-80 years of age, with cT3(SS)-T4a(SE) gastric carcinoma according to the 14th Japanese Classification of Gastric Carcinoma, with an ECOG PS of 0-1, and a body mass index of < 30 kg/m2, and without bulky lymph nodes, Borrmann type 4 or large type 3 carcinoma were eligible for inclusion in JCOG1001. Of the 1204 patients who were enrolled in JCOG1001, 932 pStage II/III patients with a common histological type were included in this study. Risk factors for hematogenous, lymph node, and peritoneal patterns of recurrence were estimated by a multivariable Fine and Grey model considering death or site of recurrence other than the first site of recurrence as competing risks. Results: The overall rate of recurrence was 27.1%. Hematogenous recurrence was the most frequent pattern (12.3%), followed by peritoneal (11.2%) and lymph node (7.5%) recurrence. Differentiated type (HR, 1.818; 1.237-2.674; p = 0.0024), pT4 (in comparison to pT1-3, HR, 1.511; 95% CI, 1.011-2.257; p = 0.0440), and pN3 (in comparison to pN0-2, HR, 2.431; 95% CI, 1.635-3.616; p < 0.0001) were associated with an increased incidence of hematogenous recurrence. Conversely, more than D2 lymphadenectomy reduced this pattern of recurrence (in comparison to D1+or D2 lymphadenectomy, HR, 0.575; 95% CI, 0.364-0.907; p = 0.0174). Peritoneal recurrence was significantly associated with large (≥5 cm) tumor (HR, 1.649; 95% CI, 1.034-2.629; p = 0.0356), pT4 (in comparison to pT1-3, HR, 3.222; 95% CI, 2.086-4.976; p < 0.0001), pN3 (in comparison to pN0-2, HR, 1.865; 95% CI, 1.275-2.727; p = 0.0013), and undifferentiated type (HR, 2.674; 95% CI, 1.628-4.394; p = 0.0001). Extended lymph node metastasis (pN3) was the only risk factor (in comparison to pN0-2, HR, 8.030; 95% CI, 4.605-14.002; p < 0.0001) for lymph node recurrence. Conclusions: The risk factors for recurrence differed according to the patterns of recurrence. Vigilant follow-up with an understanding of patterns of recurrence is required, especially for high-risk patients.
IMbrave150: Exploratory efficacy and safety results of hepatocellular carcinoma (HCC) patients (pts) with main trunk and/or contralateral portal vein invasion (Vp4) treated with atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in a global Ph III study.
Authors: Breder Valeriy Vladimirovich , Vogel Arndt , Merle Philippe , Finn Richard S. , Galle Peter R. , Zhu Andrew X. , Cheng Ann-Lii , Feng Yin-Hsun , Li Daneng , Gaillard Vincent E. , Li Lindong , Nicholas Alan , Lencioni Riccardo 
Published: June 2021

4073 Background: Atezo + bev has been approved in >60 countries for pts with unresectable HCC who have not received prior systemic therapy, based on IMbrave150 (NCT03434379; Finn RS NEJM 2020). Due to their poor prognosis and the hemodynamic changes from increased portal vein pressure, pts with main portal vein tumor thrombus are often excluded from pivotal HCC trials. Here, we report exploratory efficacy and safety results of pts with Vp4 (presence of a tumor thrombus in the main trunk and/or contralateral portal vein) using updated IMbrave150 data (Finn RS ASCO GI 2021). Methods: Pts were randomized 2:1 to atezo 1200 mg IV q3w + bev 15 mg/kg IV q3w or sor 400 mg bid until unacceptable toxicity or loss of clinical benefit per investigator. IMbrave150 enrolled 501 systemic treatment (tx)–naive unresectable HCC pts, ≥1 measurable untreated lesion (RECIST 1.1), Child-Pugh class A liver function and ECOG PS 0/1, including 73 (15%) Vp4 pts. This post hoc exploratory analysis was conducted with a median follow-up of 15.6 mo in ITT pts. Results: Of the Vp4 pts, 48 received atezo + bev and 25 received sor. Median OS (mOS) was 7.6 vs 5.5 mo (HR, 0.62; 95% CI: 0.34, 1.11) and median PFS (mPFS) per independent review facility (IRF)–assessed RECIST 1.1 was 5.4 vs 2.8 mo (HR, 0.62; 95% CI: 0.35, 1.09) with atezo + bev and sor, respectively. ORR per IRF RECIST 1.1 was 23% (11/47) with atezo + bev (2 [4%] pts had CR) vs 13% (3/23) with sor (1 [4%] pt had CR). All-grade variceal bleeding was higher with atezo + bev in Vp4 (13.6%) vs rest of ITT pts (2.5%). See table for further efficacy and safety data. Conclusions: The benefits of atezo + bev over sor in Vp4 pts are consistent with those in ITT pts across all efficacy endpoints, despite the expected disease-intrinsic increase in variceal bleeding in Vp4 vs rest of ITT pts. The overall positive benefit-risk profile supports the use of atezo + bev in pts with Vp4. Clinical trial information: NCT03434379. [Table: see text]
A phase II trial of lenvatinib plus toripalimab and hepatic arterial infusion chemotherapy as a first-line treatment for advanced hepatocellular carcinoma (LTHAIC study).
Authors: He MinKe , Ming Shi , Lai Zhicheng , Li QiJiong 
Published: June 2021

4083 Background: Combining systemic and locoregional therapies represents a promising treatment strategy for patients with advanced hepatocellular carcinoma (HCC). We investigated the efficacy and safety of combined lenvatinib and toripalimab (recombinant, humanized programmed cell death receptor-1 monoclonal antibody) plus hepatic arterial infusion chemotherapy (HAIC) as a first-line treatment in this patient population. Methods: This single-arm, phase II study included treatment-naive adult (≥18 years) patients with advanced HCC, Eastern Cooperative Oncology Group performance status 0–2, and Child-Pugh Class A liver function (NCT04044313). Patients initiated lenvatinib (8 mg for bodyweight < 60 kg or 12 mg for bodyweight ≥60 kg, orally once daily) 3-7 days prior to initial HAIC to confirm tolerability, and then received 21-day treatment cycles of lenvatinib (day 1 to day 21), toripalimab (240 mg by IV infusion, on day 1), and HAIC (day 1 to day 2) with the FOLFOX regimen (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil bolus 400 mg/m2 on day 1, and 5-fluorouracil infusion 2400 mg/m2 for 24 hours) until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS) at six months, evaluated using RECIST 1.1. Secondary endpoints were median PFS and overall survival (OS), objective response rate (ORR) per RECIST 1.1 and mRECIST, and safety. Results: Between August 2019 and May 2020, 36 patients (33 men and 3 women; median age, 49 years) were enrolled. The median tumor size was 11.2 cm, 86.1% of patients had portal vein invasion, and 27.8% had extrahepatic metastasis. The primary endpoint showed a 6-month PFS rate of 80.6%. After a median follow up of 11.2 months, the median PFS was 10.5 months (95% CI, 6.21−14.79), and the median OS was not reached. The ORR per RECIST was 63.9% (95% CI, 40.9−73.0), and per mRECIST was 66.7% (95% CI, 43.3−75.1) including five (13.9%) patients who achieved a complete radiological response. The median duration of response was 12.1 months (95% CI, 4.52−19.69). Furthermore, eight patients achieved sufficient downstaging to be converted to resectable disease. Among them, one patient received liver transplantation, and four received curative surgical resection. One of them achieved pathological complete response. Grade 3-4 treatment-related adverse events (AEs) occurred in 72.2% of patients, and the most common were thrombocytopenia (13.9%), elevated aspartate aminotransferase (13.9%), and hypertension (11.1%). All AEs were expected and manageable, and no treatment-related deaths were reported. Conclusions: Combination treatment with lenvatinib and toripalimab plus HAIC showed promising antitumor activity and manageable toxicity in patients with advanced HCC. Further randomized, controlled trials are warranted to validate our findings. Clinical trial information: NCT04044313.
Phase I study of H3B-6527 in hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC).
Authors: Macarulla Teresa , Moreno Victor , Chen Li-Tzong , Sawyer Michael B. , Goyal Lipika , Muñoz Martín Andres J. , Sheng-Shun Yang , Le Sourd Samuel , Morris John , Fuchs Michael , Karasic Thomas Benjamin , Kang Yoon-Koo , Yong Wei-Peng , Selvaraj Anand , Destenaves Benoit , Xiao Jianjun Alan , Gomez Ronald , Gualberto Antonio , Pipas J. Marc Marc , Finn Richard S. 
Published: June 2021

4090 Background: Evidence suggests that hyperactivated fibroblast growth factor 4 (FGFR4) signaling pathway leads to enhanced tumor growth. Targeting FGFR4 may have therapeutic benefit in tumors with altered FGF19 signaling. A phase I study (NCT02834780) was undertaken to assess H3B-6527, a highly selective covalent FGFR4 inhibitor, in patients with HCC/ICC. Methods: Adults with advanced HCC/ICC, ECOG PS 0-1, well compensated liver function, who progressed after > one prior therapy, received H3B-6527 po daily (QD) or twice-daily (bid) on a 21-day cycle following a 3+3 design. Doses ranged from 300-2000mg QD or 500-700mg BID. Patients in dose escalation were treated regardless of FGF19 status. Patients in expansion had FGF19+ tumors by mRNA testing. Adverse events (AEs), and pharmacokinetics (PK) were assessed. Response was determined by RECIST 1.1/mRECIST imaging every 6 weeks. Results: Study enrollment is complete at 128 patients. Ninety HCC patients were treated (QD = 48, bid = 42). ICC enrollment was suspended after 38 patients due to limited efficacy. No dose-limiting toxicities were seen and no grade 4-5 treatment related AEs have been observed. Recommended Phase II dose for H3B-6527 is 1000mg QD based upon safety, efficacy, and PK data. Grade 3 TEAEs have occurred in 12.5% of patients on QD dosing. Treatment related TEAEs were seen in 62.5% of patients on the QD schedule, with diarrhea (45.8%), fatigue (12.5%), and nausea (12.5%) most frequent. Drug discontinuation due to AEs for QD dosing was 8.3%. Interim data analysis shows that, for HCC patients with >2 prior lines of therapy treated on QD schedule, overall survival was 10.6m, progression-free survival 4.1m, overall response rate 16.7% (all partial responses), and clinical benefit rate 45.8% (responders + durable stable disease >17 weeks). H3B-6527 Cmax and AUC were lower at 300 mg dose but then similar across 500–2000 mg doses. Following oral administration of 1000 mg fasted, H3B-6527 plasma concentration reached peak at a Tmax of ̃2-3 hours and then decayed exponentially, with terminal half-life of ̃4-5 hours. There was no accumulation following QD dose. Dosing with food did not meaningfully change H3B-6527 plasma exposure. Conclusions: H3B-6527 was well tolerated and demonstrated a favorable toxicity and safety profile and encouraging clinical activity in heavily pretreated HCC patients. Final trial results will be presented at conference. Clinical trial information: NCT02834780.
Phase I result of ICP-192 (gunagratinib), a highly selective irreversible FGFR inhibitor, in patients with advanced solid tumors harboring FGFR pathway alterations.
Authors: Guo Ye , Yuan Chunwang , Ying Jieer , Zhu Xu , Luan Guodong , Zhang Bin , Zhao Renbin , Li Jin 
Published: June 2021

4092 Background: ICP-192 (gunagratinib), developed by InnoCare Pharma, is a novel pan-FGFR (fibroblast growth factor receptors) inhibitor that potently and selectively inhibits FGFR activities irreversibly by covalent binding. Preclinical data showed that gunagratinib overcomes the acquired resistance to the first-generation reversible FGFR inhibitors, e.g., infigratinib. ICP-CL-00301 is a phase I, first-in-human, clinical study which includes a dose escalation followed by dose expansion. The safety and tolerability as well as pharmacokinetics/pharmacodynamics (PK/PD) of gunagratinib were evaluated in patients with advanced solid tumors, and the preliminary anti-tumor activity was evaluated by RECIST1.1 in patients with FGF/FGFR gene aberrations. Methods: In the dose-escalation stage, patients with advanced solid tumors with or without FGF/FGFR alterations were treated with escalating doses (2, 4, 8, 10, 12, 14, 16 mg etc.) of gunagratinib once daily in 21-day cycles until disease progression or unacceptable toxicity. During the dose-expansion stage, patients with cholangiocarcinoma harboring FGFR2 gene fusion/translocation received the treatment of gunagratinib daily at 12 mg continuously. Results: As of February 2021, a total of 30 patients had received the treatment of gunagratinib. The median age of the treated patients was 55.0 (range: 28 to 75 years) with 56.7% male and ECOG performance status between 0-1. The maximum tolerated dose (MTD) had not been reached. The most common treatment-related adverse events (TRAEs) ( > 20%) included hyperphosphatemia, hypercalcemia, increased ALT or AST, diarrhea and hypertriglyceridemia. Hyperphosphatemia is a commonly reported AE from other trials targeting FGFR and here serves as a PD biomarker of FGFR inhibition. This PD biomarker was observed in 73.3% of the patients treated with gunagratinib at all dose levels and was consistently observed at doses of 8 mg QD and above. Hyperphosphatemia was well managed with oral phosphate binders when necessary. The plasma exposure increased proportionally to the oral dosage levels of gunagratinib. Among the 12 patients with FGF/FGFR gene aberrations who have completed at least one tumor assessment, the overall response rate (ORR) was 33.3%, including 1 patient (8.3%) of cholangiocarcinoma with complete response (CR) and 3 patients (25%) with partial response (PR). The disease control rate (DCR) was 91.7% (11 of 12 patients). Conclusions: Gunagratinib is safe and well-tolerated in patients with advanced solid tumors. Anti-tumor activity was demonstrated in patients with FGF/FGFR gene aberrations in multiple tumor types, including cholangiocarcinoma (NCT03758664). Better response is expected with the increase of treatment durations. Clinical trial information: NCT03758664.
Lenvatinib plus toripalimab as first-line treatment for advanced intrahepatic cholangiocarcinoma: A single-arm, phase 2 trial.
Authors: Jian Zhou , Fan Jia , Shi Guo-Ming , Huang Xiao-Yong , Wu Dong , Liang Fei , Yang Guo-Huan , Lu Jia-Cheng , Chen Yi , Ge Ning-Ling , Ji Yuan , Hou YY , Sun Hui-Chuan , Qiu Shuang-Jian , Ye Qing-Hai , Huang Xiao-Wu , Shi Ying-Hong , Gao Qiang , Yang Xin-Rong , Wang Xiao-Ying 
Published: June 2021

4099 Background: Lenvatinib monotherapy and lenvatinib plus PD-1 antibody have shown some clinical benefit for advanced intrahepatic cholangiocarcinoma (ICC) in the second-line setting. Our study assesses the role of lenvatinib plus toripalimab (PD-1 antibody) for advanced ICC patients as the first line therapy. Methods: Patients (pts) with locally advanced or metastatic ICC received 12 mg/day (Body Weight ≥60 kg) or 8 mg/day (Body Weight <60 kg) oral lenvatinib daily plus 240 mg intravenous toripalimab every 3 weeks. The primary endpoint was objective response rate (ORR) and evaluated according to Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1). Secondary endpoints included safety, progression-free survival (PFS) and overall survival (OS). Treatment continued until confirmed disease progression, unacceptable toxicity, or voluntary withdrawal. This trial is registered with ClinicalTrials.gov (NCT04361331). Results: From March 2020 to Sep. 2020, 31 pathologically confirmed advanced ICC pts with a mean age of 58.4 (range, 25-73) years, including 18 women (58.0%), were enrolled at Zhongshan Hospital, Fudan University. At the end of last follow-up (February 10, 2021), the ORR was 32.3% (10/31; 95% CI: 16.7%-51.4%) and the disease control rate (DCR) was 74.2% (23/31; 95% CI: 55.4%-88.1%). Median follow-up was 6.9 months. Two pts with locally advanced disease were down-staged and then underwent resection. They remained disease-free survival at the end of last follow-up. 11 pts exerted disease progression and 7 pts died. The median PFS and OS have not been reached. Median duration of response (DOR) has not been reached and responses were ongoing in 9/10 (90.0%) pts at data cutoff. 6-months OS rate was 87.1%. No grade 5 adverse event (AE) was observed in present study. 32.3% (10/31) of pts experienced Grade 3 or higher AEs and 1 pts discontinued the treatment owing to severe fatigue. Conclusions: As the first-line therapy, lenvatinib plus toripalimab provided promising efficacy with reasonable safety profile in advanced ICC patients. It offered an alternative treatment for advanced ICC who cannot tolerate gemcitabine-based chemotherapy. Clinical trial information: NCT04361331.
Genomic alterations for novel targeted therapies in pancreatobiliary cancers from real-world data.
Authors: Umemoto Kumiko , Yamamoto Hiroyuki , Oikawa Ritsuko , Takeda Hiroyuki , Doi Ayako , Horie Yoshiki , Ogura Takashi , Mizukami Takuro , Izawa Naoki , Moore Jay A. , Sokol Ethan , Sunakawa Yu 
Published: June 2021

4124 Background: Cancers of the pancreas and biliary tract remain one of the unfavorable malignant tumors with few driver genomic alterations. Tumor-agnostic approaches are promising for cancers with poor prognosis, with some potentially actionable alterations, such as BRCA1/2 mutations, ERBB2 amplification, MSI-High, or tumor mutational burden (TMB)-High. However, co-existing alterations, clinical significance of other genomic alterations, or frequency of alterations by clinical and genomic background are unclear. Here we investigated the genomic profile in a large cohort of advanced pancreatobiliary cancers to help refine and discover new targets for improved cancer therapies. Methods: Comprehensive genomic profiling was performed at Foundation Medicine, on patients with RWD tested during the course of routine clinical care. Hybrid capture was carried out on up to 395 cancer-related genes and select introns from up to 31 genes frequently rearranged in cancer. 16,913 pancreatic cancer (PC) patients and 3,031 biliary tract cancer (BTC) patients were available for analyses and were stratified by age (≥40/ < 40), MSI status, TMB status (High ≥10/Low < 10 Muts/Mb), and select gene alterations. Using a chi-square test with Yate’s correction, frequencies of genetic alterations were analyzed according to clinical or genomic background. Results: KRAS (84.8%), TP53 (73.3%), CDKN2A (51.2%), CDKN2B (26.5%), and SMAD4 (23.2%) were frequently altered in PC patients, versus TP53 (60.6%), CDKN2A (33.5%), KRAS (27.1%), CDKN2B (20.6%) and SMAD4 (16.9%) in BTC patients. The frequency of MSI-High and TMB-High in BTC was 1.2% and 5.7%, respectively, while these were lower in PC (0.48% and 2.1%, respectively). In PC patients, the KRAS alteration rate was significantly lower in both MSI-High (57.3%, P< 0.001) and TMB-High populations (51.3%, P< 0.001). In BTC patients, the rate of ERBB2 amplification was 6.4% in TMB-High and 8.6% in TMB-Low population. Interestingly, CDK12 rearrangement was observed in BTC patients with ERBB2 amplified tumors but not in those without ERBB2 amplified tumors. In patients of pediatric/adolescents and young adults ( < 40 years old), the mutation rate of KRAS/ TP53/ CDKN2A/ SMAD4 was lower, and FGFR2 rearrangement (4%) was observed in PC patients; GATA6 amplification (11.1%) and rearrangement of BRAF (2.8%), FGFR2 (5.6%) were observed in BTC patients. Conclusions: A large real-world dataset showed differences in genomic landscape according to clinical or genomic background, and some potential targets for the development of novel drugs in advanced pancreatobiliary cancers. These findings may lead to the improvement of cancer therapies in PC and BTC patients with poor prognosis.
Late relapse of germ cell tumors: Detection and treatment outcomes.
Authors: Richardson Noah Hunter , Althouse Sandra K. , Ashkar Ryan , Cary Clint , Masterson Timothy A. , Foster Richard , Hanna Nasser H. , Einhorn Lawrence H. , Adra Nabil 
Published: June 2021

5007 Background: Late relapse (LR) of germ cell tumors (GCT) is defined as relapsed disease > 2 years from initial treatment. LR remains a challenge both for optimal screening methods and treatment. We report the method of detection, treatments received, and outcomes in patients with LR GCT. Methods: The prospectively maintained Indiana University testicular cancer database was queried identifying 2712 pts with GCT treated at Indiana University from January 2000 to January 2019. Method of detection of LR was recorded along with site, treatment received, chemo-naive vs chemo-exposed LR, and survival outcomes. Results: 90 pts with LR were identified. Median age at LR was 35.2 yr (range, 19.2-56.8). Primary tumor site was testis in 88 (98%), retroperitoneum in 1 (1%), and mediastinum in 1 (1%). Chemo-exposed accounted for 42 (47%) and chemo-naïve for 48 (53%) of cases. Table compares clinical characteristics and survival outcomes of chemo-exposed vs. chemo-naïve late relapse. 62% of chemo-exposed LR were diagnosed with elevated AFP. For the 42 chemo-exposed LR pts, 2-yr PFS based on treatment: surgery vs. chemo vs surgery+chemo was 48% vs 10% vs 45% (p = 0.105). For the 48 chemo-naïve LR pts, 2-yr PFS based on treatment: surgery vs. chemo vs. surgery+chemo was 100% vs 74% vs 37% (p = 0.004). Next generation sequencing was available for 9 patients. No actionable findings were found. Tumor mutational burden was low in all patients where genomic testing was available. Conclusions: Most pts with chemo-exposed LR will be diagnosed with an elevated AFP. GCT pts require lifetime follow-up with annual physical exam and tumor markers. Surgical resection, when feasible, remains our preferred treatment for chemo-exposed LR as chemotherapy alone offers only brief responses. Pts with chemo-naïve LR have more chemo-sensitive biology.[Table: see text]