bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of safety, immunogenicity, and preliminary efficacy of PolyPEPI1018 off-the-shelf vaccine with fluoropyrimidine/bevacizumab maintenance therapy in metastatic colorectal cancer (mCRC) patients.
Authors: Hubbard Joleen Marie , Cremolini Chiara , Graham Rondell P. , Moretto Roberto , Mitchell Jessica L , Wessling Jaclynn , Toke Eniko Rita , Csiszovszki Zsolt , Lőrincz Orsolya , Molnar Levente , Somogyi Eszter , Megyesi Mónika , Pantya Kata , Tóth József , Páles Péter , Miklós István , Falcone Alfredo 
Published: May 2020

4048 Background: PolyPEPI1018 is an off-the-shelf, multi-peptide vaccine containing 12 immunogenic epitopes derived from 7 cancer testis antigens (CTAs) frequently expressed in patients with CRC. Here we report the final results of the phase I study of PolyPEPI1018 vaccine as an add-on to maintenance therapy in mCRC patients. Methods: 11 patients with MSS mCRC were vaccinated with PolyPEPI1018 just after the transition to maintenance therapy with fluoropyrimidine/bevacizumab after first-line combo chemotherapy and bevacizumab. Part A: n = 5, single dose; Part B: n = 6, 3 doses, Q12W. Primary endpoint was safety. Immunomonitoring was performed at both blood and tumor levels, as well as prospectively predicted. Results: The vaccine was well tolerated; most common side effects were transient skin reactions. No vaccine-related SAE occurred. Pre-existing immune responses were boosted by the vaccine for 7/10 patients. De novo responses were also induced, overall, 80% of patients had CD8+ T cell responses against at least 3 CTAs. The magnitude of immune responses as well as the density and the ratio of CD8+/CD3+ tumor infiltrating T cells increased with multiple vaccine doses. Three patients had objective tumor response according to RECIST v1.1: one of them in the single dose group and two of them in the 3 doses group. Both patients in the 3 doses group qualified for curative surgery. One of them had no viable tumor cells in his primary tumor at the time of surgery. Post-trial follow-up revealed PFS of at least 12 months for 3 patients. mPFS was longer for patients receiving multiple doses (9.9 months) compared to single dose (6.1 months). Both measured and predicted multiantigenic immune responses tend to correlate with PFS and tumor volume reduction. Conclusions: PolyPEPI1018 was effective in restoring immunological responses to CTAs in patients’ with spontaneous immunity against. Treatment with PolyPEPI1018 vaccine and maintenance therapy was safe and demonstrated evidence of early clinical activity in MSS mCRC tumors. Data support further randomized trials with PolyPEPI1018. Clinical trial information: NCT03391232 .
Prognostic effect of specific RAS/BRAF mutations in patients (pts) with metastatic colorectal cancer (mCRC).
Authors: George Ben , Taylor Bradley W , Lasowski Matthew , Ritch Paul S. , Shreenivas Aditya Varnam , Chakrabarti Sakti , Kamgar Mandana , Zimmermann Michael T , Reddi Honey V , Urrutia Raul , Thomas James P. 
Published: May 2020

4050 Background: Somatic mutations in KRAS, HRAS, NRAS (extended RAS) and BRAF have prognostic and predictive impact in pts with mCRC. We analyzed the prognostic impact of specific somatic mutations in extended RAS and BRAF. Methods: We retrospectively reviewed the electronic medical records of pts with mCRC at our institution who underwent comprehensive genomic profiling (CGP) utilizing the Foundation One assay. DNA was extracted from clinical specimens and CGP was performed on hybrid-capture, adaptor ligation-based libraries for up to 315 genes plus 47 introns from 19 genes frequently rearranged in cancer. BRAF mutations were classified as class I, II and III according to accepted nomenclature. Fisher’s exact test and Kaplan Meier estimates were used for statistical analyses. This project was approved by the Medical College of Wisconsin Institutional Review Board. Results: 273 pts were identified - median age at diagnosis was 57, 48% were male. Somatic mutations in extended RAS were found in 138 (50%) pts, majority being mutations in KRAS (46%). Among pts with KRAS mutations, codon 12, 13, 61 and 146 mutations accounted for 73%, 11%, 4% and 6% respectively while KRAS G12C mutations accounted for 9%. BRAF mutations were detected in 22 (8%) pts - BRAF V600E and non–V600E mutations accounting for 4.4% and 3.6% respectively. Among pts with BRAF mutations, 17 (77%) were kinase domain mutations, 16 of which could be further classified as class I (12/16), II (1/16) and III (3/16). Median overall survival (mOS) for the entire cohort was 26.4 months (mo). KRAS mutated pts had a mOS of 25.8 mo; pts with KRAS G12C mutation had a mOS of 23 mo compared to 27.1 mo for pts with other KRAS mutations (p < 0.001).Pts with BRAF mutation had a mOS of 26.2 mo; pts with BRAF V600E mutation had a mOS of 14.1 mo compared to 30.6 mo for pts with BRAF non-V600E mutations (p = 0.1). Conclusions: The poor prognosis of pts with KRAS G12C and BRAF V600E mutations compared to pts with other KRAS and BRAF mutations merit further biologic characterization with functional assays. Individualized therapeutic strategies must be conceptualized for mCRC pts with specific RAS/BRAF mutations, considering their widely disparate prognosis and putative downstream signaling mechanisms. Dynamic molecular simulation to understand conformational changes in proteins associated with specific mutations will be pivotal to optimizing precision therapeutic strategies.
The mutation of homologous recombination repair genetics is a potential biomarker for immunotherapy in microsatellite stable colon cancer.
Authors: Wu Xueying , Mao Beibei , Zhang Henghui 
Published: May 2020

4076 Background: Patients with microsatellite instability-high (MSI-H) colonic adenocarcinoma (COAD) are always immunotherapy-sensitive for the use immune checkpoint inhibitors, however, the vast majority of COAD patients (85%) are microsatellite stable (MSS). Homologous recombination deficiency (HRD) is demonstrated to be a response predictor to immunotherapies in gynecologic cancers, while limited studies were reported in colon cancer. We focus herein on the mutational pattern of HRR related genes in a large Chinese COAD cohort and further analyze the relationship between HRR-gene mutations and clinical response to immunotherapy in MSS COAD. Methods: The genomic profiling of Genecast cohort which is consisted of 406 Chinese patients with COAD were analyzed in a panel of 543 cancer related genes via next generation sequencing (NGS). The correlation between HRR-gene mutations and tumor immunity or clinical outcome using two COAD genomics datasets (TCGA and MSK-COAD) by the bioinformatic approach. Results: In Genecast Cohort, seventy of 406 (17.2%) patients were identified genomic alterations in HRR-gene, the most frequently mutated genes were ATM (9%), BRCA2 (4%), ATR (3%), RAD50 (3%) and BRIP1 (3%). In MSK-COAD cohort (treated with immune checkpoint inhibitors), HRR-mut group (n = 34) had a significantly better OS than HRR-wt group (n = 50) (log-rank test, P = 0.0087). From the analysis of TCGA cohort, we found that mutations of HRR-gene could increase immune activity in MSS COAD, including increased cytotoxic cells infiltration ( P = 0.035), increased exhausted CD8 T cells infiltration ( P = 0.0098) and higher IFN-g score ( P = 0.03). In contrary, similar results were not found in MSI-H COAD (all P > 0.05). Conclusions: Mutations of HRR-gene could significantly increase immune activity in patients with MSS COAD, implying the feasibility of using HRR-mut as a response predictor of immunotherapy in MSS-COAD.
Short-term results of VOLTAGE-A: Nivolumab monotherapy and subsequent radical surgery following preoperative chemoradiotherapy in patients with microsatellite stable and microsatellite instability-high locally advanced rectal cancer.
Authors: Yuki Satoshi , Bando Hideaki , Tsukada Yuichiro , Inamori Koji , Komatsu Yoshito , Homma Shigenori , Uemura Mamoru , Kato Takeshi , Kotani Daisuke , Fukuoka Shota , Nakamura Naoki , Fukui Makoto , Wakabayashi Masashi , Kojima Motohiro , Togashi Yosuke , Sato Akihiro , Nishikawa Hiroyoshi , Ito Masaaki , Yoshino Takayuki 
Published: May 2020

4100 Background: Chemoradiotherapy (CRT) followed by radical surgery (S) is standard therapy for patients (pts) with locally advanced rectal cancer (LARC). Sequential use of an anti-PD-1 antibody after radiation demonstrates synergistic effects in in vivo models, and an anti-PD-1 antibody is effective in pts with microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). We studied nivolumab (nivo) and radical S following CRT (50.4 Gy with capecitabine 1,650 mg/m2) in T3–4 NanyM0 LARC. Methods: After the quality-assured CRT, 240 mg q2 weeks x 5 cycles of nivo and radical S were investigated. In cohort A-1, for pts with microsatellite stable (MSS) LARC, the primary endpoint was a centrally confirmed pathological complete response (pCR) rate using AJCC tumor regression grading. The estimated required sample size assuming null and alternative hypotheses pCR = 10% and 30% was 37 pts, with a 1-sided alpha of 5% and power of 90%. In Cohort A-2, 5 pts with MSI-H LARC were included in an exploratory manner. Results: From Jan/2017 to Oct/2019, a targeted number of pts was included and assessed. In cohort A-1, 30% (11/37; 90% CI 18-44%) of pCR (AJCC grade (gr) 0) rate and 38% (14/37) of major pathological response (MPR) (AJCC gr 0+1) rate were observed. Clinical CR was observed in one additional pt (3%) refusing S after nivo. In cohort A-2, 60% (3/5) of pCR rate and 60% (3/5) of MPR rate were observed. As of Jan/2020, only 2 pts (1 local and 1 metastatic) in cohort A-1 and none in cohort A-2 recurred. Immune-related severe adverse events were observed in 3 pts (gr 3 myasthenia, gr 3 interstitial nephritis, and gr 2 peripheral motor neuropathy); all fully recovered and received radical S. During the follow-up period, one additional pt with gr 2 colitis was observed. No treatment-related deaths were observed. Conclusions: Promising pCR rates of 30% and 60%, with mild toxicities, were shown in MSS and MSI-H LARC pts treated with nivo plus radical S after CRT, suggesting the candidate therapy for the future non-surgical approach. Clinical trial information: NCT02948348 .
ARISTOTLE: A phase III trial comparing concurrent capecitabine with capecitabine and irinotecan (Ir) chemoradiation as preoperative treatment for MRI-defined locally advanced rectal cancer (LARC).
Authors: Sebag-Montefiore David , Adams Richard , Gollins Simon , Samuel Leslie M. , Glynne-Jones Robert , Harte Robert , West Nicholas , Quirke Philip , Myint Arthur Sun , Bach Simon P , Parsons Philip , Falk Stephen , Dhadda Amandeep Singh , Misra Vivek , Brown Nick , Brown Gina , Harrison Mark , White Laura , Duggan Marian , Lopes Andre ,   ARISTOTLE Trial Management Group
Published: May 2020

4101 Background: Phase II studies reported high pathological complete response (pCR) rates and acceptable toxicity using irinotecan and fluoropyrimidine chemoradiation in LARC (ISRCTN:09351447). Methods: This phase III, multicentre, open-label trial funded by Cancer Research UK, randomly assigned (1:1) patients with MRI defined LARC threatening or involving resection margins without metastases, to pre-operative radiotherapy (RT) 45Gy/25 fractions combined with either capecitabine 900mg/m2(CRT) or 650 mg/m2 bd weekdays with Irinotecan iv once-weekly 60mg/m2 weeks 1-4 (IrCRT). The primary endpoint is disease-free survival (DFS). Secondary endpoints include treatment compliance, safety and pCR. Results: 75 UK sites randomised 564 eligible patients from Oct/11 to July/18; 284 to CRT and 280 to IrCRT. 370 (66%) male; median age 61 years (range:29-83). Staging in both arms was similar: mrT3 (432/564(77%), mrT4 (89/564(16%); mrCRM involved (275/564(49%); threatened ≤1mm (215/564(38%). Compared with CRT, IrCRT patients were less likely to receive 45Gy RT (207/276(75%) vs 251/283(89%), p < 0.001) or receive ≥90% capecitabine dose in 188/276(68%) vs 253/283(89.4%)p < 0.001). A total of 204/276(74%) received ≥90% irinotecan dose. The grade 3-4 gastrointestinal adverse event rate was 21%(58/276) with IrCRT and 12%(34/283) with CRT (p = 0.004). Patients receiving IrCRT had significantly more diarrhoea 38/276(13.8%) vs 10/283(3.5%)p < 0.001) and neutropenia 27/276(9.8%) vs 3/283 (1.1%) p < 0.001). Two CRT and three IrCRT patients experienced a treatment related death. 237/276(86%) IrCRT and 241/283(85%) CRT patients had surgery. The median time from end of RT to surgery(10.6 weeks), the surgical procedure APE 262/478(55%), AR 189/478(40%), Hartmann’s 10/478(2%); and the surgical complications(any event) 38%(181/478) were similar in both arms. The pCR rate is available in > 95% patients and is 20.2%(46/228) for IrCRTvs.17.4%(40/230) for CRT (p = 0.45), A > 84% CRM-ve resection rate is similar in both arms. Conclusions: For patients with MRI defined high risk LARC low rates of CRM involvement were observed in both arms reflecting high quality multidisciplinary care. The addition of irinotecan did not significantly improve the pCR rate, was associated with a decrease in the RT and capecitabine compliance and a higher rate of adverse events. Surgical procedure or complications were unaffected. Longer follow-up is required to assess DFS and translational data. Clinical trial information: 09351447 .
Perioperative ramucirumab in combination with FLOT versus FLOT alone for resectable esophagogastric adenocarcinoma (RAMSES/FLOT7): Results of the phase II-portion—A multicenter, randomized phase II/III trial of the German AIO and Italian GOIM.
Authors: Al-Batran Salah-Eddin , Hofheinz Ralf Dieter , Schmalenberg Harald , Strumberg Dirk , Goekkurt Eray , Angermeier Stefan , Zander Thomas , Potenberg Jochem , Kopp Hans Georg , Pink Daniel , Siegler Gabriele Margareta , Schenk Michael , De Vita Ferdinando , Maiello Evaristo , Gaiser Timo , Sookthai Disorn , Bankstahl Ulli Simone , Pauligk Claudia , Goetze Thorsten Oliver , Homann Nils 
Published: May 2020

4501 Background: Periop. FLOT has become SOC for resectable, esophagogastric adenocarcinoma. However, patient’s outcome is still poor. This trial evaluates the addition of the VEGF-R2 inhibitor ramucirumab (RAM) to FLOT for resectable patients (pts). Methods: This is a prospective, international, randomized, investigator-initiated phase II/III trial. Pts with resectable, Her2-negative, adenocarcinoma of the stomach and GEJ (≥ cT2 or cN+) were enrolled. Pts were randomized to 4 pre-and post-operative cycles of FLOT (docetaxel 50 mg/m²; oxaliplatin 85 mg/m²; leucovorin 200 mg/m²; 5-FU 2600 mg/m², q2w) alone (Arm A) or the same regimen with RAM 8mg/kg q2w, followed by 16 cycles RAM (Arm B, FLOT-RAM). Important endpoints of phase II (exploratory) were major pathological (complete and nearly complete) response, centrally assessed acc. to Becker criteria, R0-resection rate, and safety. GEJ type I tumors and pts requiring trans-thoracic esophagectomy were excluded for safety reasons during the conduct of the study. Results: In total, 180 pts were randomized. Baseline characteristics were similar between arms (male, 73%; median age, 60y; cT3/T4, 83%; cN+, 78%; GEJ, 54%; signet-ring cells, 40%). However, the FLOT-RAM arm included more unfavorable pts with T4 (9% vs. 4%), Siewert type I tumors (18% vs. 13%), impaired ECOG PS of 1 (34% vs. 20%), and concomitant disease (87% vs. 79%). 91% of pts with FLOT and 92% with FLOT-RAM completed the 4 pre- cycles. R0-resection (in the full set) could be achieved in 83% of pts with FLOT and 97% of pts with FLOT-RAM (p = 0.0049). The rate of major path response was similar in both arms and was 30% for FLOT and 27% for FLOT-RAM. Surgical morbidity was observed in 37% of pts with FLOT and 44% of pts with FLOT-RAM. Mortality was 2.5% with FLOT and 5.9% with FLOT-RAM including GEJ type I tumors and dropped to 2.9% in both arms after excluding type I tumors per amendment. There was bit more G≥3 adverse events with FLOT-RAM (78% vs. 89%). Conclusions: In this phase II trial, the addition of ramucirumab to perioperative FLOT significantly improved R0-resection rates without an impact on path response, mainly because more patients could proceed to operation. The FLOT-RAM is safe, when type I tumors are excluded. Clinical trial information: NCT02661971 .
ESPAC-5F: Four-arm, prospective, multicenter, international randomized phase II trial of immediate surgery compared with neoadjuvant gemcitabine plus capecitabine (GEMCAP) or FOLFIRINOX or chemoradiotherapy (CRT) in patients with borderline resectable pancreatic cancer.
Authors: Ghaneh Paula , Palmer Daniel H. , Cicconi Silvia , Halloran Christopher , Psarelli Eftychia Eirini , Rawcliffe Charlotte Louise , Sripadam Rajaram , Mukherjee Somnath , Wadsley Jonathan , Al-Mukhtar Ahmed , Jiao Long R. , Wasan Harpreet Singh , Carter Ross , Graham Janet Shirley , Ammad Farooq , Evans Jonathan , Tjaden Christine , Hackert Thilo , Buchler Markus W. , Neoptolemos John P. ,   European Study Group for Pancreatic Cancer (ESPAC)
Published: May 2020

4505 Background: Patients with borderline resectable pancreatic cancer have poor survival and low resection rates. Neoadjuvant therapy may improve the outcome for these patients. The aim of this trial was to determine the feasibility and efficacy of a comparison of immediate surgery versus neoadjuvant GEMCAP or FOLFIRINOX or CRT. Methods: Eligible patients with NCCN defined borderline resectable (following central review of the baseline CT scan) and biopsy proven pancreatic cancer were randomised (stratified by centre) to receive immediate surgery, or neoadjuvant therapy of either 2 cycles of GEMCAP, or 4 cycles of FOLFIRINOX or 50.4Gy capecitabine-based CRT in 28 daily fractions over 5 ½ weeks. Patients were restaged at 4-6 weeks and underwent surgical exploration if still borderline resectable. Resected patients received adjuvant therapy. Follow up was 12 months. There was quality assurance of surgery and CRT. Primary endpoints were recruitment rate and resection rate (R1/R0). Secondary endpoints included overall survival and toxicity. A target of 90 patients was set to determine feasibility and resection rates. Rates will be presented as point estimates and survival compared across treatment arms using a log-rank test. Analyses will be on an ITT basis. Results: Between August 2014 and December 2018, 90 patients were randomised with 88 included in the full analysis set (32 immediate surgery, 20 GEMCAP, 20 FOLFIRINOX, 16 CRT). Median age was 63 years, 44% were men. WHO performance status was 0 and 1 in 45% and 55% respectively. Median CA19-9 was 603 kU/L at baseline. 44 (79%) patients completed neoadjuvant therapy. Recruitment rate was 21 patients per year. Resection rate was 62% for immediate surgery and 55% for neoadjuvant therapy (p=0.668). R0 resection rate on resected patients was 15% and 23% respectively (p=0.721). One year survival rate was 40% [95% CI, 26% – 62%] for immediate surgery and 77% [95%CI, 66% - 89%] for neoadjuvant therapy. Log-rank analysis showed an HR=0.27 [95% CI, 0.13 – 0.55]; χ2 (1) = 14.91, P<0.001. 9 out of the 51 neoadjuvant patients included in the safety set reported 12 serious adverse events of grade 3 or above. Conclusions: There was no difference in resection rate between arms, however neoadjuvant therapy had a significant survival benefit compared with immediate surgery. Clinical trial information: 89500674 .
Donafenib versus sorafenib as first-line therapy in advanced hepatocellular carcinoma: An open-label, randomized, multicenter phase II/III trial.
Authors: Bi Feng , Qin Shukui , Gu Shanzhi , Bai Yuxian , Chen Zhendong , Wang Zishu , Ying Jieer , Lu Yinying , Meng Zhiqiang , Pan Hongming , Yang Ping , Zhang Helong , Chen Xi , Xu Aibing , Liu Xiufeng , Meng Qiu , Wu Liqing , Chen Feng 
Published: May 2020

4506 Background: Sorafenib is still the standard first-line therapy for advanced hepatocellular carcinoma (HCC). Donafenib, a novel multikinase inhibitor, showed potential benefits in a previous phase Ib study in HCC. Methods: In this open-label, randomized phase II/III trial (ZGDH3), patients with unresectable or metastatic HCC, a Child-Pugh liver function score ≤ 7, and no prior systemic therapy were enrolled from 37 sites across China and randomized (1:1) to receive oral donafenib (0.2 g) or sorafenib (0.4 g) twice daily until intolerable toxicity or disease progression. The primary endpoint was overall survival (OS). Efficacy analysis was primarily based on the full analysis set (FAS). Results: Between March 2016 and April 2018, 668 patients were randomized (donafenib, 334; sorafenib, 334) and included in the intention-to-treat (ITT) set, of whom 659 were analysed by FAS (328 vs 331). Donafenib was associated with a significantly longer median OS than sorafenib in both FAS (12.1 months vs 10.3 months, hazard ratio 0.831, 95% confidence interval 0.699–0.988, p = 0.0363) and ITT (12.0 months vs 10.1 months, 0.839, 0.706–0.996, p = 0.0446). There were no significant differences in median progression-free survival (3.7 months vs 3.6 months, p = 0.2824), objective response rate (4.6% vs 2.7%, p = 0.2448), and disease control rate (30.8% vs 28.7%, p = 0.5532). Grade 3 or worse adverse events (AEs) occurred in 191 (57.4%) and 224 (67.5%) patients ( p = 0.0082), respectively, and AEs of special interest and those leading to treatment interruption occurred in 287 (86.2%) vs 309 (93.1%, p = 0.0049) and 101 (30.3%) vs 141 (42.5%, p = 0.0013). A numerically lower number of patients reported serious AEs (55 [16.5%] vs 67 [20.2%], p = 0.2307) with donafenib. Common AEs with donafenib included hand-foot skin reaction (50.5%), aspartate aminotransferase increased (40.5%), blood bilirubin increased (39.0%), platelet count decreased (37.8%), and diarrhea (36.6%). Conclusions: Donafenib significantly improves OS over sorafenib with favourable safety and tolerability. Donafenib is a promising superior first-line therapy for advanced HCC. Funding: Zelgen. Clinical trial information: NCT02645981 .