bluuebunny/crossref_metadata_2025_split huggingface dataset:
Updated results from a phase Ib trial of regorafenib plus nivolumab in patients with advanced colorectal or gastric cancer (REGONIVO, EPOC1603).
Authors: Shitara Kohei , Hara Hiroki , Takahashi Naoki , Kojima Takashi , Kawazoe Akihito , Asayama Masako , Yoshii Takako , Kotani Daisuke , Tamura Hitomi , Mikamoto Yuichi , Hirano Nami , Wakabayashi Masashi , Nomura Shogo , Sato Akihiro , Nishikawa Hiroyoshi , Fukuoka Shota 
Published: February 2020

135 Background: In the phase 1 REGONIVO study, regorafenib of 80 mg/day plus nivolumab showed manageable safety profiles and encouraging anti-tumor activity for advanced colorectal cancer (CRC) or gastric cancer (GC) with objective response rate (ORR) of 36% in CRC and 44% in GC (Fukuoka, et al. ASCO 2019). Updated efficacy results are presented. Methods: Enrolled patients (pts) received regorafenib plus nivolumab in a dose-finding phase to estimate the maximum tolerated dose (MTD). Additional pts were enrolled in a dose-expansion phase. Regorafenib of 80 to 160 mg was administered once daily for 21 on 7 days off with nivolumab 3 mg/kg every 2 weeks. The primary endpoint was dose-limiting toxicity (DLT) during cycle one to estimate the MTD and the recommended dose. PD-L1 combined positive score (CPS) was assessed using the anti–PD-L1 28-8 antibody. Tumor mutation burden (TMB) was measured using Oncomine tumor mutation load assay. Results: Fifty pts were enrolled (25 CRC; 25 GC) until October 2018 with median prior treatment line of 3. Efficacy results were updated as of September 1st 2019. One CRC pt was with MSI-high but all other pts were with MSS or MMR-proficient. Among the 20 pts (9 CRC and 11 GC) with objective response (40%), responses are still ongoing in 13 pts (7 CRC and 6 GC) and the median duration of response was not reached (NR). Median progression free survival (PFS) was 7.8 months in CRC (95% CI, 2.8- NR) and 5.5 months (95% CI, 2.6-10.2 months) in GC. One-year PFS rate was 41.7% in CRC and 22.4% in GC. Median overall survival (OS) was not reached in CRC (95% CI, 9.7-NR) and 12.1 months (95% CI, 5.2-NR) in GC. One-year OS rate was 68% in CRC and 55.3% in GC. No significant difference of PFS and ORR was observed in CRC according to PD-L1 and TMB. Conclusions: Encouraging anti-tumor activity of the combination of regorafenib plus nivolumab had been maintained with long-term follow-up. A randomized study for MSS CRC is under planning. Clinical trial information: NCT03406871.
Factors associated with effectiveness of trifluridine/tipiracil versus regorafenib in patients with pretreated metastatic colorectal cancer (mCRC).
Authors: Grell Peter , Borilova Simona , Schwanzerova Renata , Kukolikova Sabina , Dvorak Josef , Vocka Michal , John Stanislav , Buchler Tomas , Selingerova Iveta , Petruzelka Lubos B. , Vyzula Rostislav , Kiss Igor , Obermannova Radka 
Published: February 2020

137 Background: Trifluridine/tipiracil (T) and regorafenib (R) are indicated for patients with refractory mCRC. Currently, no biomarkers are used to select which patient will benefit from which treatment. Methods: We retrospectively evaluated 212 patients who received T and/or R. Different factors associated with progression-free survival (PFS) and overall survival (OS) were analyzed. Results: T received 132, R 52, both drugs 28 patients. Median age was 64 (range 28-83), male 64%, PS 0 37%, median line of treatment 3, characteristic was similar between treatment groups. Median follow-up was 16.5 months. Median OS for T was 10.2, for R 6.9 months, P = 0.03. Factors significantly associated with OS were: ≥ 24 months from diagnosis of mCRC (0.49, P < 0.001), PS 0 (HR 1.54, P = 0.007), baseline WBC < 8 × 109/L (HR 0.47, P < 0.001), normal baseline CRP (HR 0.47, P < 0.001), ≥ 3 months from last therapy (fluoropyrimidine for T, anti-VEGF for R) (HR 0.66, P = 0.006). We developed a scoring system TASREG from these factors, 1 point for each factor, the overall score was the sum of these points and patients were divided into 3 groups: high risk group with 0 to 1 point, intermediate with 2 to 3, favorable with 4 or more points. OS for all patients according to risk group was 4.6 for high risk, 7.9 intermediate, 11.8 months favorable risk (P < 0.001). Score was also significant for T and R group evaluated separately. Score was also significant for PFS. Factors associated with OS specific for T were neutropenia G≥2 (HR 0.34, P < 0.001); for R normal baseline LDH (HR 0,40. P < 0.001), no liver metastases (HR 0.45, P = 0.002), non-synchronous disease (HR 0,40, P < 0.001). Conclusions: We could find factors associated with better outcomes for both treatment groups and factors specific for T or R. TASREG is simple prognostic tool for patients with refractory mCRC.
The impact of body mass index (BMI) on the safety and outcomes of small molecule inhibitors (SMI) in gastrointestinal cancer.
Authors: McCabe Colleen , Patel Urvi , Beardslee Tyler , Caulfield Sarah , Lee Christin , Pruitt Rosie , Chen Zhengjia , Goyal Subir , Draper Amber , Shaib Walid Labib 
Published: February 2020

144 Background: A number of studies have demonstrated that overweight and early obese states are associated with improved survival in renal and melanoma cancer patients. The purpose of this study was to investigate the impact of BMI on outcomes of GI cancers treated with SMIs. Methods: A retrospective chart review was conducted to compare outcomes between patients with BMIs ≥ 25 and < 25 who received treatment at Winship between 1/2010-8/2019. The primary objective was to determine the PFS, OS, and ADR rates of patients with BMI ≥ 25 treated with SMIs compared to patients with BMIs < 25. PFS and OS rates were estimated with the Kaplan-Meier method and compared between the groups using the log-rank test. The incidence of adverse events was estimated as frequency and percentage and logistic regression was used to estimate the impact of BMI on adverse effects. Results: 269 patients were included in analysis for PFS, 61 for OS and 281 for ADR rate analysis. Diagnoses included HCC (n = 123, 44%) and CRC (n = 158, 56%). There was no significant difference seen in PFS and OS between the BMI < 25 and BMI ≥ 25 groups (HR 1.17 (0.87-1.56), p = 0.291, HR 1.10 (0.66-1.84), p = 0.713, respectively). A significant difference was demonstrated in the rates of adverse reactions between the two groups (OR 0.31 (0.19-0.52), p<.001) with BMI < 25 having a lower rate of ADRs. After adjusting for covariates, HCC vs CRC diagnosis (p = 0.002) and not requiring dose reduction or delay due to toxicity (p<0.001) were significantly associated with better PFS. Conclusions: Based on the multiple regression analysis, patients with a BMI ≥ 25 do not have improved outcomes over those with a BMI < 25 when taking SMIs for their GI malignancies. Patients with BMI < 25 experienced less drug toxicity that required dose reduction, discontinuation, or treatment delays. [Table: see text]
Identification of the optimal patients for trifluridine/tipiracil (FTD/TPI) treatment in mCRC: A Spanish real-world analysis.
Authors: Fernandez Montes Ana Fernandez , Vazquez Rivera Francisca , Martinez Lago Nieves , Covela Rúa Marta , Castiñeiras Antia Cousillas , Gonzalez Villarroel Paula , De la camara Juan , Méndez Méndez Carlos , Salgado Fernandez Mercedes , Candamio Folgar Sonia , Reboredo Lopez Margarita , Carmona Campos Marta , Gallardo Martin Elena , Jorge Fernandez Monica , Pellon Augusto Maria Luz , Garcia Gomez Jesus ,   Galician Research Collaborative Group
Published: February 2020

146 Background: FTD/TPI has demonstrated significantly overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC) refractory to standard therapies. Nevertheless, data regarding the pt profile that benefits most from this FTD/TPI is scarce. Some reports have shown optimal benefit for pts with low tumor burden indolent disease, ECOG PS 0-1, and no liver metastasis. Methods: We conducted a retrospective, multicenter, observational study of pts treated with FTD/TPI at eight hospitals from the Galician Research Group on Digestive Tumours (GITuD). Data were analyzed for a correlation between prognostic characteristics (good prognostic characteristics (GPC) vs. poor prognostic characteristics (PPC)), clinicopathological characteristics and survival. The GPC group was composed of pts who have one or two metastatic sites and time from diagnosis of 1st metastases to treatment ≥ 18 months. Results: Between January 1, 2017 and August 20, 2018, 160 pts were included in the study, of which 85 pts (53.1%) were classified as PPC and 75 pts (46.9%), as GPC. Pts with PPC were associated with younger age (60.5 vs. 63.7 years, p=0.034), higher presence of liver metastases (83.5% vs. 60%, p=0.001) and lower incidence of primary tumor resection (34.1% vs. 17.3%, p=0.019), without differences in ECOG PS, RAS mutation, tumor stage at diagnosis, lung metastases and sidedness. In the whole population of pts median OS and PFS were 7.63 months and 2.75 months, respectively. However, in the GPC and PPC groups mPFS were 2.64 vs. 2.33 months, respectively (p=0.311). Also, median OS was 8.23 months for GPC and 6.75 months for PPC, respectively. Interestingly,the mOS reached 10.5 months in those patients in the GPC group without liver metastasis. OS according ECOG PS 0/1/2 were 10.9 vs. 7.8 vs. 4.4 months, respectively (p=0.004) in the GPC group of pts. Conclusions: We have identified a subgroup of pts who most benefit from FTD/TPI, characterized by ECOG PS 0, low tumor burden, indolent disease and no liver metastasis.
Phase Ib study to test the safety and activity of pembrolizumab (anti-PD-1) and trebananib (angiopoietin-2 inhibitor [Ang-2]) in patients with advanced solid tumors: Updated analysis of the colorectal cancer (CRC) cohort.
Authors: Rahma Osama E. , Cleary James M. , Ng Kimmie , Schlechter Benjamin L. , Eno Jessica , Maloney Anna , Giobbie-Hurder Anita , McDermott David F. , Hodi F. Stephen 
Published: February 2020

155 Background: Ang-2 is produced by endothelial cells, predominantly in tissues undergoing vascular remodeling. Current studies suggest that Ang-2 partially suppresses T cell activation by increasing PD-L1 expression and decreasing activation of monocytes. We demonstrated that high pre-treatment serum Ang-2 is associated with reduced overall survival in patients treated with PD-1 blockade. We therefore hypothesized that the combination of Ang-2 and PD-1 blockade may be effective for treatment of patients with advanced cancer. Methods: We initiated a phase 1b trial of the combination of pembrolizumab and trebananib, an Ang-1/2 neutralizing peptibody in advanced solid tumors. Treatment consisted of an induction phase of pembrolizumab 200 mg every 3 weeks and trebananib weekly (with an initial run-in dose escalation of 15-30 mg/kg) for 12 weeks followed by pembrolizumab alone for 2 years. Here we present the updated data in the fully enrolled CRC expansion cohort. Results: The study enrolled 18 microsatellite stable (MSS) CRC patients. There were no DLTs in the dose escalation phase, and 30mg/kg was deemed to be the MTD. This summary is based on 15 CRC patients treated with 30 mg/kg trebananib plus pembrolizumab. The most common treatment-related adverse events (AEs) were abdominal distension, diarrhea, limb edema, transaminitis, and proteinuria, each reported in 40% of the patients. As of September 2019 (median follow up of 10 months), 13 patients were off treatment and two were continuing. Eleven patients were off treatment due to disease progression and 2 due to unacceptable toxicities (grade 4 pneumonitis and grade 3 transaminitis). The response rate was 7% (1 partial response for 23.8+ months) and the disease control rate was 27%, with 4 stable disease for a median of 10 months (4-18 months). Median time to progression and overall survival were 2.8 months (90% CI: 1.5 to 8.1 months) and 9.0 months (90% CI: 2.6 months to ∞), respectively. Conclusions: The combination of pembrolizumab and trebananib is well tolerated and demonstrated promising activity in patients with heavily treated MSS CRC. Clinical trial information: NCT03239145.
Regorafenib with TAS-102 (REGOTAS) in metastatic colorectal cancer patients who progressed after at least two standard therapies: Efficacy and safety results of a multicenter phase I study (REMETY).
Authors: Moehler Markus H. , Stein Alexander , Trojan Jorg , Marquardt Jens Uwe , Quidde Julia , Waidmann Oliver , Weinmann Arndt , Woerns Marcus , Schroeder Helge , Maenz Martin , Karatas Aysun , Foerster Friedrich 
Published: February 2020

158 Background: The multi-kinase inhibitor regorafenib (REGO) and oral fluoropyrimidine TAS-102 (TAS) show efficacies as single agents in treatment of refractory metastatic CRC patients (pts). We conducted a conventional 3+3 dose finding to determine a recommended phase II dose (RP2D) of its combination REGOTAS and efficacy in 3-4.-line. Methods: Eligible patients with ECOG 0-1, measurable mCRC, not amenable to surgery had at least 3rd-line treatments. Prior fluoropyrimidine-based and anti-VEGF (R) combinations were mandatory, and anti-EGFR for RAS WT tumors. TAS was given on days 1-5 and 8-12 (28-days cycle); REGO on days 2-22 (dose levels see table below). The following major AE categories were used to define DLTs if they occurred during the first 2 treatment cycles: any grade ≥3 non-hematologic toxicity (except vomiting, nausea, non-significant lab abnormalities), grade ≥3 hematological toxicities, grade ≥3 bleeding. Tumor response was assessed Q8W as per RECIST1.1. EudraCT 2016-001968-11; NCT03305913. Results: All observed toxicities were consistent with safety profile of individual IMPs. 6 pts were enrolled into each DL1 and DL2 (n=12 in total). One DLT was observed in 1/6 pts in DL1; 2 DLTs in 2/6 pts in DL2. All DLTs were only grade 3 hypertension was well manageable, causality was attributed to REGO. No DLT resulted in treatment discontinuation. Results indicate a RP2D of 25mg/m² TAS-102 BID + 120mg REGO daily. No remissions were observed. Overall disease control rate (DCR) after 8 weeks was promising with 58.3% (DCR of 33.3% for DL1 and 83.3% in DL2) and remarkably better as historical data with 41/44% for REGO/TAS102 alone, respectively (Lancet 2013/NEJM 2015). Conclusions: Toxicities of REGOTAS were consistent with safety profiles of REGO and TAS alone. No additional DLTs were attributed to REGOTAS. Thus, the risk-benefit assessment of REGOTAS was positive. DCR was clinically quite meaningful. Mature PFS and OS will be presented at the meeting. Clinical trial information: NCT03305913. [Table: see text]
Impact of antibiotic exposure on the efficacy of immune checkpoint blockade in MSI-H metastatic CRC.
Authors: Serpas Victoria , Rogers Jane Elizabeth , Xiao Lianchun , Mola-Rudd Kerri , Dasari Arvind , Kee Bryan K. , Overman Michael J. , Johnson Benny 
Published: February 2020

161 Background: Immunotherapy has improved outcomes for many patients (pts) with advanced cancers found to be microsatellite instability high (MSI-H). However, not all MSI-H pts exhibit the same efficacy from immunotherapy. Previous studies have suggested that concomitant antibiotic use while receiving immunotherapy may result in poorer outcomes. We aimed to evaluate what factors impacted immune checkpoint blockade (ICB) response in pts with MSI-H metastatic colorectal cancer (mCRC) treated at a large academic referral center. Methods: We completed a single-site, retrospective review of 45 pts with MSI-H mCRC that received ICB. Data was collected including patient demographics, tumor and mutational data, ICB agent, length of treatment, and antibiotic use. Both single and multi-course antibiotic use was included from 2 weeks prior until 6 weeks following ICB treatment. Fisher’s exact test was used to evaluate the association of response and covariables. Log rank test was used to compare progression free survival (PFS) between subgroups. Results: A majority of pts were male (n = 25, 56%) and Caucasian (n = 30, 66%) with right sided tumors (n = 26, 62%). Combination Nivolumab and Ipilimumab was used in 7 (16%) with single agent Nivolumab in 10 (22%) and single agent pembrolizumab in 28 (62%). Of the pts in this cohort, 28 (62%) received antibiotics with 11 (39%) receiving a single round of antibiotics and 17 (61%) receiving multiple courses. Those that did not receive antibiotics had a greater response (partial or complete) at first scan while on ICB therapy (75% vs 32%, p = 0.01). No significant difference was noted between class of antibiotic, age, sex, or tumor sidedness. The median 12 month PFS (12-PFS) was also higher in the group that did not require antibiotics but was not statistically significant (82% vs 72%, p = 0.298). Conclusions: This study shows that MSI-H mCRC pts that received antibiotics while on ICB had impaired response rate and a trend towards lower PFS. This suggests alteration of the gut microbiome may impact ICB response warranting a larger, prospective study.
Skeletal muscle index (SMI) status and survival in patients undergoing surgery for colorectal cancer (CRC): A longitudinal study.
Authors: Abbass Tanvir , Dolan Ross , McSorley Stephen Thomas , Horgan Paul G. , McMillan Donald C. 
Published: February 2020

175 Background: There is now good evidence that low skeletal muscle index (SMI) using established thresholds is associated with poor survival in patients undergoing surgery for CRC. However, to date few studies have carried out longitudinal analyses. Such studies also inform, the determinants of SMI status. Methods: From prospectively maintained database, pre-operative and 1 year follow up CT scans were analysed at L3 level for SMI (n=794).The relationship between SMI status before and after surgery (both high (n=366)/high then low (n=52)/low then high (n=108) and both low (n=268), clinicopathological parameters and overall survival was analysed. Results: The majority of patients were > 65 years of age (75%), male (56%), ASA<3 (67%), had TNM stage <3 (65%) and were not systemically inflamed (mGPS = 0 in 73%, and NLR <3 in 53%). Patients with low SMI at any time point (before surgery, after surgery, or both) had significantly poorer survival (p<0.001), were more likely to be over 65 years (p<0.001), and with mGPS>0 (p<0.001) than those who had high SMI at both time points. In those patients who were high then low SMI, they had poor survival (p<0.001) and were more likely >65 years old (p<0.001) compared with high high SMI. There was no difference in survival between those with low high SMI compared with low low SMI status (p=0.296). Conclusions: In this longitudinal study, low SMI status was associated with older age, increased systemic inflammatory response and poorer survival whether prior to or following surgery for CRC. Interestingly, surgery did not affect preoperative SMI status in the majority of patients, suggesting that host responses perhaps have a greater effect than the presence of the tumour itself. Reference: Martin L, Birdsell L, Macdonald N, et al. Cancer cachexia in the age of obesity: skeletal muscle depletion is a powerful prognostic factor, independent of body mass index. J Clin Oncol. 2013;31: 1539-1547.
Immune modulation after Toca 511 and Toca FC treatment of colorectal cancer patients.
Authors: Falchook Gerald Steven , Rodon Ahnert Jordi , Venkat Shree , Donahue Arthur , Horner Peder , Thomassen Amber , Accomando William , Rodriguez-Aguirre Maria , Bentley Cornelia , Hogan Daniel , Ostertag Derek , Yavrom Sharon , Kheoh Thian , Jolly Douglas J. , Gruber Harry E. , Shorr Jolene , Merchan Jaime R. 
Published: February 2020

186 Background: Toca 511 (vocimagene amiretrorepvec) is a cancer-selective, retroviral replicating vector encoding yeast cytosine deaminase that converts 5-fluorocytosine (5-FC) into 5-fluorouracil in the tumor microenvironment (TME). In animal models, Toca 511 and 5-FC kill dividing cancer and nearby immunosuppressive cells, leading to antitumor immune activity. A Phase 1 study of Toca 511 & Toca FC (extended-release 5-FC) in patients with recurrent high grade glioma revealed results consistent with this proposed mechanism. A Phase 3 trial is ongoing. Methods: Toca 6 (NCT02576665) is a Phase 1b, single-arm, multicenter study designed to investigate immunological changes after Toca 511 & Toca FC treatment in patients with advanced solid tumors, including colorectal cancer (CRC). Patients received intravenous (IV) Toca 511 for 3 days, and underwent biopsy of metastatic tumor before and ~ 4 weeks after starting oral Toca FC. Toca FC was repeated every 4-6 weeks. Peripheral blood mononuclear cells and tumor biopsies were evaluated for treatment related immune responses. Results: 17 CRC patients with a median 5 lines of prior chemotherapy were enrolled. At last data cut-off, 9 patients were alive and the median overall survival was 9.4 months. A patient receiving concomitant panitumumab had a partial response. IV Toca 511 led to viral expression in tumor, which decreased post-Toca FC while maintaining a reservoir of virus in the remaining tumor. T cells shifted from naïve to effector phenotypes, CD4 memory T cells expanded, and/or B cells increased after Toca FC treatment in 36% of patients. Marked changes in tumor infiltrating cells (CD11b myeloid cells, Tregs, exhausted T cells and CD8 T cells) occurred after Toca FC treatment. Treatment has been generally well tolerated. We also plan to report insights gained from RNA analysis of TME and update on clinical finding. Conclusions: Clinical data suggest a signal of activity in these heavily pretreated CRC patients warranting further exploration. IV Toca 511 administration showed viral infection of CRC metastatic tumor. Toca 511 & Toca FC may be associated with T cell mediated immune activity in peripheral blood and metastatic tumor, consistent with pre-clinical data in multiple tumor types. Clinical trial information: NCT02576665.
Allele frequencies of two dihydropyrimidine dehydrogenase (DPYD) risk variants, c.1905+1G>A (*2A) and c.2846A>T (D949V), in a direct-to-consumer genetic database.
Authors: Kosinski Cindy , Wen Jingran , Nhan Hoang , Chubb Alison , Wu Shirley ,   23andMe Health Team
Published: February 2020

2 Background: Pharmacogenetic (PGt) testing holds great potential for supporting clinical decision making and optimizing medication outcomes for cancer patients. Genetic variants in the DPYD gene are associated with reduced dihydropyrimidine dehydrogenase enzyme activity, and can cause severe fluoropyrimidine-related toxicity. However, the clinical uptake of PGt testing has been slow. Recent FDA authorization for a direct-to-consumer (DTC) PGt test will improve access to PGt testing. This study assessed the frequency of two DPYD variants, c.1905+1G > A (*2A) and c.2846A > T (D949V), in a generally unselected group of genotyped individuals who have used DTC genetic testing (23andMe, Inc. Sunnyvale, CA). Methods: Study participants were genotyped using Illumina genotyping arrays that included the DPYD c.1905+1G > A and c.2846A > T variants. Eligible subjects were 23andMe U.S. customers who were at least 18 years of age and consented to participate in research. IRB approval was obtained from Ethical & Independent Review Services. Results: Out of approximately 6.4 million eligible participants included in this analysis, the overall allele frequencies of DPYD c.1905+1G > A and c.2846A > T were 0.42% and 0.47%, respectively. People of Ashkenazi Jewish, South Asian, and European descent had the highest frequencies (0.56%, 0.56%, and 0.47%, respectively) for the DPYD c.1905+1G > A variant, and people of European and Hispanic/Latino descent had the highest frequencies (0.55% and 0.43%, respectively) for the DPYD c.2846A > T variant. Conclusions: This is the first description of an unselected cohort of individuals with DPYD c.1905+1G > A and c.2846A > T variants identified through DTC genetic testing. Preemptive DTC PGt testing can help disseminate potentially clinically useful information to a large number of consumers.