bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nivolumab (NIVO) + low-dose ipilimumab (IPI) as first-line (1L) therapy in microsatellite instability-high/DNA mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): Clinical update.
Authors: Lenz Heinz-Josef , Lonardi Sara , Zagonel Vittorina , Van Cutsem Eric , Limon M. Luisa , Wong Ka Yeung Mark , Hendlisz Alain , Aglietta Massimo , Garcia-Alfonso Pilar , Neyns Bart , Cardin Dana Backlund , Spallanzani Andrea , Dragovich Tomislav , Shah Usman , Atasoy Ajlan , Ledeine Jean-Marie , Overman Michael J. 
Published: May 2019

3521 Background: In the phase 2 CheckMate 142 trial, NIVO + low-dose IPI provided robust and durable clinical benefit and was well tolerated as 1L therapy for MSI-H/dMMR mCRC (Lenz et al. Ann Oncol 2018;29:LBA18). Longer follow-up data will be presented. Methods: Patients with MSI-H/dMMR mCRC and no prior treatment for metastatic disease received NIVO 3 mg/kg every 2 weeks + low-dose IPI 1 mg/kg every 6 weeks until disease progression or discontinuation. The primary endpoint was investigator-assessed objective response rate (ORR). Results: For all 45 patients (median follow-up was 13.8 months), ORR was 60% (95% CI 44.3–74.3). Responses were consistent with the overall population across subgroups including age, Eastern Cooperative Oncology Group (ECOG) performance status, prior adjuvant/neoadjuvant therapy, and mutation status (Table). Seven patients (16%) had grade 3–4 treatment-related adverse events (TRAEs); 3 (7%) had any grade TRAEs leading to discontinuation. Updated response, survival, and safety data after a longer follow-up (median 19.9 months) will be presented. Conclusions: NIVO + low-dose IPI demonstrated robust and durable clinical benefit and was well tolerated. Evaluated subgroups had responses consistent with the overall population. NIVO + low-dose IPI may represent a new 1L treatment option for patients with MSI-H/dMMR mCRC. Clinical trial information: NCT02060188. [Table: see text]
Apatinib monotherapy for chemotherapy-refractory metastatic colorectal cancer: A multicenter, single-arm, prospective study.
Authors: Wang Fen , Wang Shubin , Yuan Xia , Jia Jun , Bi Xiaoxia , Zhou Zeqiang , Zhou Qiming , Luo Changguo , Deng Minghui , Yi Liangjie , Li Yong , Li Xia , Lu Jianxin , Su Wenzhi , Chen Hanbin , Zhu Yu 
Published: May 2019

3527 Background: Apatinib is an oral highly-selective tyrosine kinase inhibitor (TKI) that blocks vascular endothelial growth factor receptor 2 (VEGFR-2). This exploratory study evaluated the efficacy and safety of apatinib monotherapy in patients with chemotherapy-refractory metastatic colorectal cancer. Methods: In this multicenter, single-arm, prospective study, 48 patients with metastatic colorectal cancer who had failed at least two lines standard chemotherapies including fluorouracil, oxaliplatin and irinotecan were recruited from 14 centers in Guangdong, China. Apatinib at a 500mg dose was administered daily continuously. Each cycle was 4 weeks (28 days). The primary endpoint was progression free survival (PFS). Secondary end points included overall survival (OS), objective response rate (ORR), disease control rate (DCR), quality of life (QoL) and toxicity. Results: A total of 48 patients was enrolled in the study from September 3, 2015 to June9, 2017. Four patients achieved a partial response, and 22 achieved stable disease, representing a response rate of 8.3% and a disease control rate of 60.4%. Median follow-up time was 10.3 months. Median progression-free survival (PFS) and overall survival (OS) of evaluable patients (n=41) were 4.7 months (95% confidence interval [CI] 3.7-5.9) and 9.7 months (95% CI 5.9-13.6). The most common grade 3 or 4 adverse events (AE) were hypertension (12.5%), hand-foot syndrome (10.4%), thrombocytopenia (10.4%), proteinuria (8.3%) and mucositis oral (6.3%). Conclusions: Apatinib monotherapy shows promising efficacy and manageable toxicities in patients with chemotherapy-refractory metastatic colorectal cancer. Further phase 3 trial is warranted. Clinical trial information: ChiCTR1900020503.
Impact of age on safety and efficacy of first-line FOLFOXIRI/bevacizumab in mCRC: A pooled analysis of TRIBE and TRIBE2 studies.
Authors: Marmorino Federica , Rossini Daniele , Aprile Giuseppe , Casagrande Mariaelena , Lonardi Sara , Murgioni Sabina , Dell'Aquila Emanuela , Tomasello Gianluca , Antoniotti Carlotta , Borelli Beatrice , Zucchelli Gemma , Urbano Federica , Ronzoni Monica , Zaniboni Alberto , Manglaviti Sara , Buonadonna Angela , Ritorto Giuliana , Allegrini Giacomo , Falcone Alfredo , Cremolini Chiara 
Published: May 2019

3536 Background: FOLFOXIRI/bevacizumab is a valuable upfront option in mCRC based on results of phase III TRIBE and TRIBE2 studies: 1187 pts aged 18–70 years with ECOG performance status (PS) ≤ 2 or between 71–75 years with an ECOG PS of 0 were randomized to receive first-line FOLFOXIRI/bevacizumab or a doublet (FOLFIRI in TRIBE and mFOLFOX6 in TRIBE2)/bevacizumab. Here, we aimed at assessing the effect of the intensification of the upfront chemotherapy (triplet versus doublet) in terms of safety and efficacy in pts aged < 70 versus 70-75. Methods: Subgroup analyses for ORR, PFS, G3/4 overall adverse events (AEs), chemo-related and bevacizumab-related AEs were performed according to baseline age. Results: 182 (15%) out of 1187 pts were 70-75 years old (97 in the FOLFOXIRI/bevacizumab and 85 in the doublets/bevacizumab arms). The benefit provided by the intensification of the upfront chemotherapy was independent of the age subgroup in terms of both ORR (p for interaction = 0.684) and PFS (p for interaction = 0.634). The risk of overall and chemo-related G3/4 AEs was increased with the triplet independently of age (p for interaction = 0.736 and 0.790), while no difference in bevacizumab-related AEs was observed in both subgroups (p for interaction = 0.566). In the overall population, as compared to younger pts, those aged 70-75 were more susceptible to overall G3/4 AEs (70% vs 57%, p = 0.001). In the FOLFOXIRI/bevacizumab arm a higher incidence of G3/4 diarrhea (27% vs 17%, p = 0.016) and febrile neutropenia (16% vs 6% p = 0.001) and a lower incidence of all grade nausea (51% vs 65%, p = 0.009) and vomiting (26% vs 44% p = 0.001) were reported among elderly pts. Conclusions: The activity and efficacy of FOLFOXIRI/bevacizumab are confirmed among selected pts between 70 and 75 years old, with a relative increase in the risk of chemo-related AEs similar to that of younger pts. However, elderly pts are more susceptible to experience AEs independently of the treatment arm. Considering the increased incidence of febrile neutropenia and diarrhea with FOLFOXIRI/bevacizumab, the use of G-CSF as primary prophylaxis or an initial dose reduction of irinotecan and 5-fluorouracil might be considered in this population.
Evaluating gender as a predictive marker for response to bevacizuamb (Bev) in metastatic colorectal carcinoma (mCRC): Pooled analysis of 3369 patients (pts) in the ARCAD database.
Authors: Margalit Ofer , Harmsen William S. , shacham-Shmueli Einat , Petersen Molly , Boursi Ben , Saltz Leonard B. , Adams Richard , Maughan Tim , Douillard Jean-Yves , Van Cutsem Eric , Hurwitz Herbert , Bokemeyer Carsten , Tebbutt Niall C. , Kabbinavar Fairooz F. , De Gramont Aimery , Shi Qian , Lenz Heinz-Josef 
Published: May 2019

3539 Background: Previous studies suggest a possible gender-specific response to Bev in mCRC, showing a benefit in males, while the effect in females is less significant. Therefore, we evaluated response to Bev according to gender. Methods: Data from 3369 mCRC patients enrolled on 4 first-line randomized trials testing Bev (2000-2007) were pooled. Association between gender and progression-free survival (PFS)/overall survival (OS) was evaluated by stratified Cox regression model, adjusted for potential confounders. Predictive value was evaluated by interaction (inter.) effect between gender and treatment. In a pre-planned secondary analysis, analyses were stratified using an age cut-point of 60 years (commonly used in breast cancer trials) to evaluate the possible role of menopausal-related effects. Results: OS was not statistically different between males and females (median OS [mOS], 18.8 vs. 17.6 months [mo], adjusted hazard ratio [HRadj], 0.93, 95% confidence interval [CI], 0.84-1.03, p, 0.15) in the overall population. Bev was associated with an improved mOS in males and females, with a 2.3 and 0.6 mo benefit, respectively, as well as an improved PFS. There was no statistically significant interaction effect between gender and treatment (see table). Further stratified by age (< vs. ≥ 60 years), Bev resulted in improved PFS and OS in both genders, at all ages, except for the effect in young females which did not reach statistical significance (see table). Conclusions: Our results confirmed the mOS benefit from addition of Bev to first-line chemotherapy in mCRC in both genders, although the benefit in females was < 1 month. For females under the age of 60, there are uncertainties for mOS benefit from addition of Bev and further evaluation is needed. [Table: see text]
Development and validation of a prognostic score for overall survival integrating baseline metabolically active tumor volume measured by 18F-FDG PET/CT and clinical factors for metastatic colorectal cancer patients.
Authors: Woff Erwin , Hendlisz Alain , Salvatore Lisa , Marmorino Federica , Falcone Alfredo , Genovesi Dario , Giorgetti Assuero , Critchi Gabriela , Ameye Lieveke , Paesmans Marianne , Guiot Thomas , Levillain Hugo , Flamen Patrick 
Published: May 2019

3543 Background: This study aimed to develop and validate a prognostic score integrating baseline metabolically active tumor volume (MATV) and clinical factors in metastatic colorectal cancer (mCRC) patients. Methods: The development cohort included chemorefractory mCRC patients enrolled in two prospective multicenter non-randomized trials evaluating sorafenib/regorafenib as last line therapy. The validation cohort included mCRC patients from another center, treated with chemotherapy and bevacizumab as first line. Baseline MATV was defined as the sum of metabolically active volumes of all target lesions identified on the baseline 18F-FDG PET/CT. MATV optimal cutoff for OS prediction was determined from the development cohort with Contal and O’Quigley’s method. MATV, age, gender, BMI, ECOG PS, years since diagnosis, and KRAS status were included in a multivariate analysis. A prognostic score to predict OS was developed from the development cohort using Cox proportional hazards model. Results: MATV and clinical factors were evaluable respectively in 155 and 122 patients of the development and validation cohorts. In univariate analysis, MATV with cutoff set at 100 cm³ identified two risk groups with different median OS (mOS) in both the development (4.5 vs 10.9 months, HR: 2.64; p < 0.001) and validation cohorts (20.9 vs 42.9 months, HR: 2.39; p < 0.001). A multivariate analysis identified four independent negative predictors of OS (high MATV, short time since diagnosis, poor PS, BMI < 25). Combining these factors in a prognostic score for OS (best cutoff:-2) allowed to identify two risk groups with different mOS in the development (4.4 vs 13.4 months, HR: 3.67; p < 0.001) and validation cohorts (25 vs 63.8 months, HR: 2.5; p = 0.001). Conclusions: In mCRC patients, the high prognostic value of baseline MATV found in the development cohort was confirmed by external validation, independently of patients’ treatment. In both the development and validation cohorts the prognostic score for OS allowed to identify two risk groups of mCRC patients with significantly different mOS. MATV and our prognostic score for OS should provide a firm basis for risk stratification, in clinical practice and research trials.
Who can benefit from a liver surgery for metastatic colorectal cancer in the era of modern chemotherapy? A post hoc analysis of the MIROX phase III trial.
Authors: Makhloufi Samira , Turpin Anthony , Andre Thierry , Pruvot Francois-Rene , Martinage Geoffrey , Truant Stephanie , Bachet Jean-Baptiste , Vernerey Dewi , Hebbar Mohamed 
Published: May 2019

3547 Background: Despite improvement in colorectal liver metastasis (CLM) treatment, survival after liver surgery remains highly variable. Several clinicopathologic prognostic factors have been reported whose validity in the era of modern chemotherapy remains to be defined. This study aimed to analyze the prognostic factors associated with survival after CLM resection. Methods: Clinicopathologic data of patients included in the MIROX phase III trial who underwent surgery for isolated CLMs were analyzed. The primary endpoints were 5-year overall survival (OS) and disease-free survival (DFS). Univariate Cox analysis was performed to identify associations with OS and DFS and select variables included in a multivariate model to determine their independent prognostic value. Results: A total of 181 patients were analyzed. The median follow-up period was 6.42 years (95% CI: 5.15-8.71), and the 5-year OS and DFS rates were 67.1% and 35.4%, respectively. On multivariate analysis, Fong's clinical risk score (CRS) as a categorical variable (CRS 0-1 vs 2-3 vs 4-5, p = 0.036) and polymorphonuclear neutrophil (PMN) count (>6000/mm3vs ≤6000/mm3, p = 0.006) before chemotherapy were found to be independent prognostic factors for OS. However, only Fong's CRS remained significantly associated with DFS (p = 0.027). The final OS model was used to establish a nomogram that allows individual OS estimations at 1, 3, 5, and 10 years. Conclusions: Fong's CRS and PMN count were independently associated with poor OS after CLM resection. Fong's CRS was also associated with DFS. The established prognostic nomogram could predict OS more accurately before CLM treatment.
Randomized phase II study on the influence of BRAF and PIK3CA mutations on the efficacy of FOLFIRI plus bevacizumab (Bev) or cetuximab (Cet), as first line therapy of patients (pts) with RAS wild-type metastatic colorectal carcinoma (mCRC) and <3 baseline circulating tumor cells (bCTCs).
Authors: Aranda Enrique , Garcia-Alfonso Pilar , Vieitez Jose María , Ortiz Maria Jose , López-López Carlos , Reina-Zoilo Juan José , Salud Salvia Antonieta , Quintero Aldana Guillermo Alfonso , Robles Luis , Safont Maria Jose , La Casta Munoa Adelaida , Alés Inmaculada , Polo Marques Eduardo , Gallego Plazas Javier , García de Paredes Beatriz , Lopez Rafael , Mónica Guillot , Valladares-Ayerbes Manuel , Sastre Javier , Díaz-Rubio Eduardo ,   Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD)
Published: May 2019

3549 Background: The outcome for mCRC has changed since the introduction of new chemotherapy schedules and targeted therapies, however new predictive biomarkers are needed. bCTCs and BRAF / PIK3CA mutations have been studied as a potential predictive biomarkers. The primary endpoint was progression-free survival (PFS) in pts WT KRAS and <3 bCTCs, according to BRAF/ PIK3CA status. Methods: This is an open, multicentric, randomized phase II trial and included wildtype KRAS mCRC pts (RAS after approval of protocol amendment), younger than ≤70 with <3 bCTCs, ECOG 0-1 and available tissue for molecular analyses. Pts were stratified per number of metastatic organs involved (1 vs >1) and mutation status of BRAF and/or PIK3CA (WT vs MUT) and randomized to group A (FOLFIRI+Bev) or group B (FOLFIRI+Cet). Results: 240 pts (196 WT and 44 MUT: 6 BRAF, 12 PIK3CA and 6 BRAF + PIK3CA) were included. General characteristics per mutation status (WT vs MUT): Mean age (59 vs 61 years), gender (Male/Female 68/32 vs 70/30%), ECOG 0/1 (57/43 vs 66/34%), primary tumor unresected (48 vs 64%), RAS MUT in 12 pts (11 and 1 pts, respectively), previous chemotherapy (12 vs 9%). Overall response rate (ORR) was 52 and 41% in the WT and MUT groups, respectively. PFS and overall survival (OS) are presented in the table. Conclusions: In the low risk mCRC pts according to bCTCs, BRAF and/or PIK3CA MUT have a negative impact in OS and a trend to worse PFS in the ITT population. The impact of treatment is under evaluation and will be provided during the meeting. Clinical trial information: 2012-000840-90. [Table: see text]
Bevacizumab (BV) maintenance (M) after first-line chemotherapy (CT) plus BV for metastatic colorectal cancer (mCRC) patients (pts): A meta-analysis of individual pts data (IPD) from three phase III studies.
Authors: Salvatore Lisa , Bria Emilio , Sperduti Isabella , Hinke Axel , Hegewisch-Becker Susanna , Aparicio Thomas , Le Malicot Karine , Boige Valerie , Koeberle Dieter , Baertschi Daniela , Dietrich Daniel , Tortora Giampaolo , Arnold Dirk 
Published: May 2019

3550 Background: Although CAIRO3 and AIO KRK 0207 trials demonstrated the benefit of BV + fluoropyrimidine as a M regimen after induction CT + BV, the role of BV alone is not clear. Indeed, SAKK 41/06 and PRODIGE 9 trials failed to demonstrate the superiority of BV alone vs no M, while AIO KRK 0207 showed the non-inferiority of BV alone vs combo M. Thus, in order to evaluate the magnitude of the eventual benefit of M with BV alone vs no M, an IPD meta-analysis was performed. Methods: Trials whereas mCRC pts were prospectively randomized to receive BV M or not were considered eligible. Primary end-points were PFS and OS, both from the start of induction and M. Univariate and multivariate analyses for PFS and OS were performed, with the following variables: baseline ECOG PS; age ( > vs ≤ 65 years); RAS and BRAF status; LDH and CEA baseline level; RR (PR or CR vs SD) during induction; induction CT (oxa- vs iri-based); resected primary tumor; primary tumor side; synchronous vs metachronous; adjuvant treatment; number (N) of metastatic sites; liver-only disease. Results: IPD of 1,064 pts enrolled in the PRODIGE 9, AIO KRK 0207 and SAKK 41/06 trials were collected. Considering the different timing of randomization in PRODIGE 9 (at the start of induction) vs AIO KRK 0207 and SAKK 41/06 (at the start of M), IPD of pts not progressed during induction and starting M phase entered the analysis. 909 pts were included, 457 (50%) received BV M. Median PFS from induction start was 9.6 and 8.9 months in BV group vs no M group, respectively (HR 0.78; 95%CI: 0.68-0.89; p < 0.0001). At the multivariate PFS analysis, BV M, resected primary tumor, N of metastatic sites and liver-only disease were significant. No difference in terms of OS between the 2 groups was observed. Conclusions: This is the first IPD meta-analysis investigating the role of BV alone M vs no M after first-line induction CT+BV in mCRC pts. Despite the significant PFS improvement in favor of BV M, the absolute benefit appears limited, and without a clear clinical relevance. On these bases, a predictive nomogram to identify pts most likely to benefit from BV M is under evaluation and will be presented during the Congress.
Exosomes as novel prognostic biomarker in potentially resectable colorectal cancer liver metastatic (CCLM) patients.
Authors: Zurlo Ina Valeria , Di Salvatore Mariantonietta , Lucchetti Donatella , Colella Filomena , Ricciardi Tenore Claudio , Perelli Luigi , Ferrucci Massimo , Basso Michele , Vellone Maria , Calegari Maria Alessandra , Salvatore Lisa , Pozzo Carmelo , Giuliante Felice , Cassano Alessandra , Sgambato Alessandro , Tortora Giampaolo 
Published: May 2019

3558 Background: Target therapies and new surgical strategies deeply modify the history of CCLM patients (pts). Several prognostic scoring systems have been developed but no one is able to identify pts who should be excluded from a potentially useless surgery. Currently research is committed in identifying early biomarkers able to discern pts who could benefit from an aggressive approach. Exosomes are arising as promising biomarkers in cancer. The aim of this pivotal study was to analyze the association among exosome levels during CCLM-pts treatment, clinical outcomes and the KRAS status. Methods: We enrolled 22 pts with CCLM candidate to preoperative chemotherapy (pCT) and subsequent liver surgery. A blood sample was collected before pCT, after surgery, monthly during follow-up and at progression (PD). Exosomes were isolated by ultracentrifugation and characterized by standard methods. Exosomes concentration was assessed by Bradford assay. We adopted ddPCR™ KRAS G12/G13 Screening Kit to evaluate the KRAS status in exosomal DNA (e-DNA). Results: 22 CCLM pts received pCT and underwent liver surgery: 5 major hepatectomies and 17 multiple liver resections. Changes in exosomes plasma levels were found to correlate with each treatment step,resulting reduced after pCT and surgery and increased at PD, respectively (p = 0.0026). Pts with higher baseline exosome levels experimented shorter PFS than those with lower levels (p = 0.0033 HR 0.2). No association was found between exosome levels after liver surgery and disease free interval nor overall survival. KRAS status on e-DNA was evaluated on 10 pts in baseline, in pCT, after surgery, and in PD samples. In 8 out of 10 pts e-DNA displayed the same mutational status than the one detected on tumor DNA. Changes in e-DNA KRAS copies were found statistically significant in pCT vs surgery and pCT vs PD (p = 0.039; p = 0.04). Conclusions: Our study suggests a prognostic role of exosome levels in CCLM pts. Moreover, we showed that KRAS mutational status could be monitored during the post-surgery follow up by analyzing e-DNA. Overall, our data confirm the potential role of exosomes in liquid biopsy tool to monitor molecular changes during the treatment of CCLM pts.
Gender and survival benefit from initial irinotecan in metastatic colorectal cancer: Analysis of the XELAVIRI (AIOKRK0110) study.
Authors: Heinrich Kathrin , Modest Dominik Paul , Ricard Ingrid , Fischer von Weikersthal Ludwig , Decker Thomas , Vehling-Kaiser Ursula , Graeven Ullrich , Uhlig Jens , Schenk Michael , Freiberg-Richter Jens , Peuser Bettina , Denzlinger Claudio , Peveling genannt Reddemann Christina , Giessen-Jung Clemens , Stahler Arndt , Held Swantje , Jung Andreas , Kirchner Thomas , Stintzing Sebastian , Heinemann Volker 
Published: May 2019

3559 Background: XELAVIRI compared initial vs sequential irinotecan (iri) in combination with fluoropyrimidine (FP) plus bevacizumab (bev) in patients (pts) with mCRC, trial identification: NCT01249638. In the full analysis set of the study, non-inferiority of time to failure of strategy (TFS) was not shown (primary endpoint). Pts with RAS/BRAF wildtype (wt) tumors benefitted from initial iri. Methods: The study endpoints objective response rate (ORR), progression-free survival (PFS), time to failure of strategy (TFS) as well as overall survival (OS) were evaluated in female vs. male pts as well as molecular subgroups (i.e. RAS mutational status). Interaction of treatment and gender was tested by likelihood ratio tests. Results: Of 421 patients, 281/140 were male/female. In male patients, ORR was 33.6% without and 58.3% with initial iri (P < 0.001). PFS (HR: 0.54 (95%CI 0.42-0.69) P < 0.001) and OS (HR: 0.63 (95%CI 0.47-0.85), P = 0.002), were also significantly better with initial iri. In the subgroup analysis, this effect was especially pronounced in pts with RAS/BRAF wt tumors. In female pts, ORR was 43% in both arms, PFS was similar (HR: 1.09 (95%CI 0.76-1.55), P = 0.65) without and with initial iri. In OS, a strong trend for inferior outcome with initial iri was seen (HR: 1.46 (95%CI 0.95-2.24), P = 0.08) that reached significance in the multivariate analysis (HR: 1.73 (95%CI 1.04-2.86, P = 0.034). Female patients with RAS/BRAF wt tumors did not benefit from initial iri (HR 1.05 (95% CI 0.46-2.41), P = 0.903 for OS). Formal interaction of treatment and gender was seen for ORR (P = 0.018), PFS (P = 0.002) and OS (P = 0.001). There were some trends for more pronounced toxicities in female pts treated with Irinotecan. Conclusions: This unplanned exploratory analysis suggests that gender might interact with efficacy of initial iri when used in the context of FP and bev. While especially male RAS wild-type patients derived a significant and clinically meaningful benefit from initial use of iri, this was not observed in female patients with RAS wt tumors. Clinical trial information: NCT01249638.