bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of plasma protein biomarkers from the phase 3 CONCUR study of regorafenib in Asian patients with metastatic colorectal cancer (mCRC).
Authors: Teufel Michael , Kalmus Joachim , Rutstein Mark Daniel , Koechert Karl , Seidel Henrik , Reischl Joachim , Skubala Adam , Vonk Richardus , Wilhelm Scott , Kobina Svetlana , Qin Shukui , Xu Rui-hua , Kim Tae Won , Li Jin 
Published: February 2017

672 Background: In the randomized phase 3 CONCUR trial (NCT01584830), regorafenib significantly improved overall survival (OS) and progression-free survival (PFS) vs placebo (PBO) in Asian patients (n = 136 regorafenib; n = 68 PBO) with treatment-refractory mCRC (HR [95% CI]: OS 0.55 [0.40‒0.77]; PFS 0.31 (0.22‒0.44]). Protein biomarker data from the phase 3 CORRECT trial of mostly Western patients with mCRC identified TIE-1 as a potential predictor of clinical response to regorafenib; however, this association was not significant in multivariable analyses. We present an exploratory protein biomarker analysis of patients in CONCUR. Methods: Sixteen proteins of interest, many of which are involved in angiogenesis, were quantified by multiplex immunoassay or ELISA in plasma samples collected at study entry from 121/204 (59%) patients (n = 83 regorafenib; n = 38 PBO). Potential predictive and prognostic effects were evaluated. Results: The biomarker cohort was representative of the overall study population in major baseline demographic factors, OS (HR 0.61; 95% CI 0.40‒0.93), and PFS (HR 0.25; 95% CI 0.16‒0.39). Elevated levels of ANG-2 (HR 2.46; p = 0.0016) and VEGF-A (HR 1.38; p = 0.03) were associated with poor OS prognosis; however, no significant association with treatment OS benefit for regorafenib vs PBO was observed for either marker (ANG-2: HR 0.76; p = 0.3307; VEGF-A: HR 0.83; p = 0.20). Elevated levels of five plasma proteins were associated with poor PFS prognosis: ANG-2 (HR 1.73; p = 0.0085), VEGF-A (HR 1.30; p = 0.0308), IL-8 (HR 1.67; p = 0.0014), VWF (HR 2.39; p = 0.0029), and IGF-BP2 (HR 1.71; p = 0.0384). Elevated levels of IL-8 (HR 0.70; p = 0.019), VWF (HR 0.53; p = 0.0312), and IGF-BP2 (HR 0.60; p = 0.0336) showed a modest interaction with regorafenib PFS; however, these results did not reach statistical significance after adjustment for multiple testing (p = 0.0045). Conclusions: None of the plasma proteins analyzed were predictive of regorafenib clinical benefit as measured by both OS and PFS in Asian patients with mCRC. These results, as well as those in CORRECT, suggest that rationally selected protein markers are not suitable to predict treatment benefit of regorafenib. Clinical trial information: NCT01584830.
Safety and efficacy of regorafenib in Japanese patients with metastatic colorectal cancer (mCRC) in clinical practice: Interim result from postmarketing surveillance (PMS).
Authors: Komatsu Yoshito , Muro Kei , Yamaguchi Kensei , Uetake Hiroyuki , Satoh Taroh , Yoshino Takayuki , Nishida Toshirou , Yamazaki Naoya , Takigawa Hajime , Hamada Yoko , Chosa Masayuki , Sunaya Toshiyuki , Yamamoto Yuka , Ito Yuichiro , Watanabe Toshiaki , Sugihara Kenichi 
Published: February 2017

680 Background: The oral multikinase inhibitor regorafenib (REG) was approved for unresectable mCRC in Japan in 2013 based on results of the global CORRECT phase 3 trial of 760 patients (pts), which included 100 Japanese pts. A Japanese PMS (NCT01843400) has been conducted since approval, to assess the safety and efficacy of REG for the treatment of mCRC in clinical practice. Methods: Pre-registration was applied in the PMS. Adverse events (AEs), laboratory tests, drug exposure and anti-tumor effects were prospectively monitored for 6 months after initiating REG. One-year survival data was also collected. The target enrollment was 1,250 Japanese pts. Results: A total 1,307 pts were enrolled in the PMS from March 2013 to May 2015. At the interim analysis as of June 2014, 545 pts were evaluable for safety and efficacy: male 59%; age ≥ 65 yrs 48%; Eastern Cooperative Oncology Group Performance Status 0/1/2 40%/51%/9%; KRAS status wild-type/mutant 50%/47%; treatment line of REG 3rd/4th/ ≥ 5th line 33.8%/37.6%/27.7%; initial dose of REG 160 mg/120mg 76%/17%. Drug related AEs were reported in 483 patients (89%). The most common events were hand foot skin reaction [(HFSR) 57%], liver dysfunction [31.8% (including hepatic laboratory abnormalities (15%)], hypertension (28%), platelets count decreased (16%) and fatigue (15%). The incidence of major AEs of any grade typically peaked the first 2 months after starting REG and was relatively stable afterwards. Median time to treatment failure was 2.3 months [range 2.1– 2.4]; median overall survival (OS) was 6.9 months [range 6.0– 7.7]. Exploratory analysis suggested that pts who experienced HFSR had a significantly longer OS than pts who did not (hazard ratio 0.351; 95% confidential interval0.253– 0.488; p < 0.0001). Conclusions: Interim results suggested that the safety and efficacy profile of REG in Japanese pts in clinical practice was consistent with those of Japanese pts in the CORRECT trial. Follow-up and data collection are ongoing. Updated data will be presented. Clinical trial information: NCT01843400.
Impact of first-line bevacizumab therapy on the efficacy of subsequent anti-epidermal growth factor antibodies (anti-EGFR) in metastatic colorectal cancer (mCRC).
Authors: Burge Matthew E. , Wong Hui-Li , Lee Belinda , Tie Jeanne , Kosminder Suzanne , Field Kathryn Maree , Tran Ben , Desai Jayesh , Ananda Sumitra , Gibbs Peter 
Published: February 2017

685 Background: The FIRE3 study reported that cetuximab added to first line combination chemotherapy versus the addition of bevacizumab to the same chemotherapy backbone, with a planned switch to the alternative biologic in second line therapy, resulted in improved overall survival. One possible explanation is that the sequence of biologic administration in mCRC impacts on treatment benefit. Examination of the efficacy of anti-EGFR therapy in cohorts where patients have and have not received prior bevacizumab will inform this. Methods: We interrogated our prospective database (ACCORD), which records comprehensive detail on demographics, treatments received and patient outcomes for consecutive mCRC patients in real world practice across multiple institutions in Australia. We included patients receiving 2nd and subsequent line anti-EGFR monotherapy. Disease control rate (DCR) (partial response plus stable disease), progression free survival (PFS) and overall survival (OS) from the start of anti-EGFR were determined as a function of prior bevacizumab use. Results: From a total of 1511 patients treated between 01/10/2002 and 31/12/2014,129 patients treated with single agent anti- EGFR were identified, 75 had received prior bevacizumab. Demographics, performance status and tumour characteristics were similar between the 2 groups. 84% were confirmed KRAS exon 2 wild type. Prior treatment with bevacizumab did not impact DCR (35% vs 40%, p = 0.5065), median PFS (3.0 vs 3.0 months, p = 0.9460) or OS (8.6 vs 8.4 months, HR 0.95, p = 0.8073). Similarly, for bevacizumab treated patients, the time since last dose of bevacizumab to start of anti-EGFR ( < 3 months (n = 26) vs 3-6 months (n = 17) vs > 6 months (n = 32)) did not impact PFS (2.3 vs 3.6 vs 3 months) or OS (8.9 vs 10.1 vs 7.1 months, HR: 0.88, p = 0.82). Conclusions: There was no evident impact of previous bevacizumab treatment, or time from previous bevacizumab treatment, on the efficacy of single agent anti-EGFR therapy in a routine clinical practice cohort. Our data do not support the notion that prior bevacizumab renders tumors more or less sensitive to subsequent anti EGFR therapy.
Updated results for the advanced esophageal carcinoma cohort of the phase Ib KEYNOTE-028 study of pembrolizumab (MK-3475).
Authors: Doi Toshihiko , Piha-Paul Sarina Anne , Jalal Shadia Ibrahim , Mai-Dang Hieu , Saraf Sanatan , Koshiji Minori , Csiki Ildiko , Bennouna Jaafar 
Published: February 2017

7 Background: PD-L1 and PD-L2 expression have been associated with poor prognosis in esophageal cancer. Pembrolizumab (pembro) is a humanized monoclonal antibody against PD-1 that blocks interaction with PD-L1 and PD-L2. The multicohort, phase Ib KEYNOTE-028 (NCT02054806) trial was designed to evaluate the safety and efficacy of pembro in patients (pts) with PD-L1+advanced solid tumors. We report updated results from the esophageal carcinoma cohort of this study. Methods: Key eligibility criteria included advanced squamous cell carcinoma or adenocarcinoma of the esophagus or gastroesophageal junction, PD-L1 expression in tumor or stroma determined centrally by IHC, failure of standard therapy, and ECOG PS 0-1. Pts received pembro 10 mg/kg every 2 wk for up to 2 y or until confirmed progression, intolerable toxicity, or investigator decision. Response was assessed every 8 wk for the first 6 mo and every 12 wk thereafter. Primary end point was ORR per RECIST v1.1 by investigator review. Results: Of the 23 pts enrolled, median age was 65 y, 82.6% were men, 73.9% had squamous histology, and 87.0% received ≥ 2 prior therapies for metastatic disease. As of the Aug 4, 2015 data cutoff date, median follow-up duration was 31 wk (range 5.7-71). Nine pts (39.1%) had drug-related adverse events (DRAEs), most commonly decreased appetite (n = 3, 13.0%). Four pts (17.4%) had grade 3 DRAEs, with only decreased lymphocytes reported in > 1 pt (n = 2, 8.7%). No pts died or discontinued pembro due to a DRAE. Immune-mediated AEs, regardless of attribution by investigator, were grade 2 hypothyroidism (n = 2, 8.7%) and adrenal insufficiency (n = 1, 4.3%). ORR was 30.4% (95% CI 13.2-52.9), and the stable disease rate was 13.0% (n = 3, 95% CI 2.8-33.6); 6-mo and 12-mo PFS rates were 30.4% and 21.7%. Five of 7 responses were ongoing at data cutoff, with a median duration of response of 40.0 wk (range 24.1+ to 46.1+). Analysis of the relationship between PD-L1 expression level and antitumor activity is ongoing. Conclusions: Pembro continued to show manageable toxicity and durable antitumor activity in pts with heavily pretreated, PD-L1+ advanced esophageal carcinoma. Phase II and III trials of pembro in pts with esophageal carcinoma are ongoing. Clinical trial information: NCT02054806.
Race-based socioeconomic and treatment disparities in adolescent and young adults with stage II-III rectal cancer.
Authors: Lee David Y , Teng Annabelle , Pedersen Rose C , Tavangari Farees R , Attaluri Vikram , McLemore Elisabeth C , Stern Stacey , Bilchik Anton J. , Goldfarb Melanie R 
Published: February 2017

714 Background: Stage II-III rectal cancer (CA) requires a multidisciplinary approach to optimize outcomes. This study explores whether treatment disparities account for racial differences in outcomes of AYA (ages 15-39) patients. Methods: AYAs with clinical stage II-III rectal CA were identified in the National Cancer Database. Demographic, clinical, and pathologic features predictive of receipt of adjuvant and surgical therapies were examined as well as factors associated with overall survival (OS). Results: Most of the 3,295 patients were white (72.0%), male (57.5%) and free of comorbidities (93.8%). Income, education levels, and rates of health insurance coverage were higher for whites than for blacks or Hispanics. Clinical stage was balanced by race, but more blacks and Hispanics did not receive radiation (24.5% and 27.1%, respectively, vs 16.5% for whites), surgery (22.4% and 15.3%, vs 12.3%), or chemotherapy (21.5% and 24.1%, vs 16.7%; p < 0.05). Additionally, the average number of days before treatment was 34.0 for blacks and 33.3 for Hispanics, versus 27.5 for whites (p < 0.05). Multivariate analysis showed that receipt of neoadjuvant chemoradiation was less likely when patients were black (OR 0.7, 95%CI 0.5-0.9, p = 0.014), Hispanic (OR 0.6, 95%CI 0.4-0.9, p = 0.012), female (OR 0.8, 95% CI 0.63-0.94, p = 0.011), without insurance (OR 0.5, 95%CI 0.36-0.69, p < 0.001), or treated at a community cancer center (OR 0.5, 95%CI 0.36- 0.74, p < 0.05). Race significantly influenced treatment, regardless of disease stage. Although 5-year OS was lower (p < 0.05) in blacks (59.8±3.3%) and Hispanics (65.9±3.5%) compared to whites (74.9±1.1%), race did not impact mortality on Cox regression. Instead, mortality was associated with male sex (HR 1.5, 95%CI 1.1-2.0, p = 0.009), nodal positivity (HR 2.6, 95%CI 1.9-3.6, p < 0.001), nonsurgical therapy (HR 7.1, 95%CI 2.8-18.2, p < 0.001), no chemotherapy (HR 1.9, 95%CI 1.03-3.6, p = 0.04), poorly differentiated histology (HR 3.0, 95%CI 1.3-6.5, p = 0.007), and no insurance (HR 1.7, 95%CI 1.1-2.7, p = 0.022). Conclusions: Race-based socioeconomic and treatment disparities may contribute to survival differences among AYAs with rectal cancer.
Palliative radiotherapy and chemotherapy instead of surgery in symptomatic rectal cancer with synchronous unresectable metastases: Final overall survival analysis of phase II study.
Authors: Wyrwicz Lucjan , Tyc-Szczepaniak Dobromila , Mydlowska Magdalena , Pietrzak Lucyna , Rutkowski Andrzej , Bujko Krzysztof , Michalski Wojciech , Olszyna-Serementa Marta , Palucki Jakub 
Published: February 2017

726 Background: A palliative surgery and chemotherapy is the standard of care in stage IV rectal cancer patients with pelvic symptoms. Recently we published primary results of the single-arm phase II study on combination of short-course radiation (5x5 Gy) with an oxaliplatin-based chemotherapy started after one-week rest (NCT01157806). The study met its primary end-point with only 17.5% (95% CI 13% to 22%) of patients (pts) who needed stoma throughout the observation and 67% (95% CI 58% to 76%) of pts having significant resolution of pelvic symptoms. Here we provide the long-term follow up data after median 60 months of observation. Methods: 40 consecutive patients with symptomatic rectal cancer with unresectable distant metastases were enrolled from September 2009 to February 2011. The time of treatment failure on chemotherapy (TTF3) was measured from the start of radiation to disease progression on fluoropiridine, oxaliplatin and irinotecan. All eligible patients were assessed for KRAS/NRAS status. Due to limitations in access to targeted agents none of patients were treated with anti-angiogenic agents and anti-EGFR treatment was restricted to third line. Results: Total 40 pts were assessed for pelvic symptoms, chemotherapy response and overall survival. In the group of patients with survival reaching over 2 years we have not observed any additional local complications which were treated surgically. The patients with total symptoms’ resolution after one month had significantly longer time-to-treatment failure (TTF3) than non-responders (median 22.5 vs 5 months, p < 0.05), while patients with minor local response had intermediate TTF3. The subgroup of patients who experienced clinical complete response of rectal tumor had a median TTF3 and overall survival reaching median 40 months. Conclusions: In the palliative setting short-course radiotherapy and early chemotherapy allowed for acceptable and durable local control. Metastatic rectal cancer patients with early symptomatic response of primary tumor had significantly better prognosis. Clinical trial information: NCT01157806.
Observational cohort study of first-line bevacizumab with oxaliplatin or irinotecan and fluoropyrimidines in metastatic colorectal cancer: HGCSG0802—Analysis of early tumor shrinkage (ETS).
Authors: Yuki Satoshi , Nakatsumi Hiroshi , Sawada Kentaro , Kato Takashi , Meguro Takashi , Nakamura Michio , Iwanaga Ichiro , Ehira Nobuyuki , Sonoda Norikazu , Kudo Mineo , Kato Kanji , Sogabe Susumu , Amano Toraji , Ono Kota , Sakamoto Keita , Miyamoto Noriyuki , Kudo Kohsuke , Sakamoto Naoya , Sakata Yuh , Komatsu Yoshito 
Published: February 2017

753 Background: It was reported that early tumor shrinkage (ETS) was associated with better overall survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC) receiving first line chemotherapy. We investigated association of ETS with progression-free survival (PFS) and OS in pts with mCRC treated with first-line bevacizumab (BV)-based chemotherapy (HGCSG0802). Methods: The objective of HGCSG0802 was to evaluate PFS, OS, response rate (RR), safety and so on. The key eligibility criteria were evaluable lesions, older than 20 years old, ECOG PS 0-2. This analysis evaluated the association of ETS at 8 weeks from the start of chemotherapy with pts characteristics, PFS and OS. To identify factors associated with ETS, if there were clinical variables with p < 0.2 in univariate analysis, we planned a multivariate analysis using the logistic regression model. To identify predictive and prognostic factors, a multivariate analysis was performed using Cox proportional hazard model with backward elimination for variables with p < 0.2 in univariate analysis. Results: Of 108 pts (the full analysis set), 99 pts were evaluable for ETS. Sixty-eight pts (68.7%) had ETS ≥20%. The pts characteristics between ETS ≥20% (ETS) and <20% (Non-ETS) were well balanced. In univariate analysis to identify factors associated with ETS, there were no clinical variables with p < 0.2. The median PFS and OS were 7.3/18.3 months in Non-ETS versus 10.0/25.2 months in ETS (HR 0.529; p=0.006 and HR 0.627; p=0.107). In multivariate analysis for PFS and OS, although there was no significant difference between ETS and Non-ETS for OS (HR 0.709; p=0.186), there was significant difference for PFS (HR 0.524; p=0.006). Conclusions: ETS was observed in 68.7% (68/99) and non-ETS in 31.3% (31/99) of patients with metastatic colorectal cancer received bevacizumab combined first line chemotherapy. In univariate analysis, it could not identify any factors associated with ETS. In the results of multivariate analysis, ETS showed an independent predictive impact, but not prognostic impact. Clinical trial information: UMIN000018935.
Pembrolizumab (MK-3475) for recurrent or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma: Multicohort phase II KEYNOTE-059 study.
Authors: Fuchs Charles S. , Denker Andrew E. , Tabernero Josep , Van Cutsem Eric , Ohtsu Atsushi , Lam Baohoang , Koshiji Minori , Bang Yung-Jue 
Published: February 2017

TPS184 Background: Pembrolizumab (pembro) is a humanized monoclonal antibody that targets the PD-1 receptor and prevents it from interacting with its ligands, PD-L1 and PD-L2. In the phase I KEYNOTE-012 trial, pembro showed an acceptable safety profile and promising antitumor activity in patients (pts) with PD-L1+ metastatic gastric cancer. The multicohort, phase II KEYNOTE-059 (NCT02335411) trial was designed to further evaluate pembro as monotherapy or in combination with 5-fluorouracil (5-FU) and cisplatin in pts with advanced gastric cancer. Methods: Patients ≥ 18 y who have relapsed or metastatic gastric or GEJ adenocarcinoma, ECOG PS 0-1, no active autoimmune disease or brain metastases, and no prior chemotherapy within 2 wk of the first dose of pembro are eligible. PD-L1 expression status will be determined by IHC using the 22C3 antibody (Merck). In cohort 1 (C1), up to 180 pts with any PD-L1 status whose disease progressed on ≥ 2 prior chemotherapy regimens, including a fluoropyrimidine and platinum doublet and, if HER2+, trastuzumab, will receive pembro 200 mg Q3W. In cohort 2 (C2), ~12 Asian and ~6 non-Asian, treatment-naive, HER2– pts of any PD-L1 status will receive pembro 200 mg Q3W + infusional 5-FU or capecitabine and 6 cycles of cisplatin. In cohort 3 (C3), ~25 treatment-naive pts with HER2–/PD-L1+ tumors will receive pembro 200 mg Q3W. Treatment may continue for up to 24 mo or until progression, intolerable toxicity, or investigator decision. Response will be assessed at wk 9 and every 6 wk thereafter per RECIST v1.1 and RECIST v1.1 adapted for immunotherapy response patterns. Treatment may be discontinued for eligible pts who have a CR. Eligible pts may continue treatment beyond initial RECIST-defined progression. AEs will be collected throughout the study and for 30 d thereafter (90 d for serious AEs) and graded per NCI CTCAE v4.0. The primary efficacy end point for C1 and C3 is ORR per RECIST v1.1 by central review; the primary end point for C2 is safety and tolerability of the combination. Secondary end points include PFS, OS, DCR, and duration of response. Enrollment in KEYNOTE-059 is ongoing and will continue until up to 223 pts are enrolled across all cohorts. Clinical trial information: NCT02335411.
A multicenter phase II study of istiratumab (MM-141) plus nab-paclitaxel (A) and gemcitabine (G) in metastatic pancreatic cancer (MPC).
Authors: Ko Andrew H. , Murray James , Horgan Kerry E , Dauer Julia , Curley Michael , Baum Jason , Louis Chrystal Ursula , Lugovskoy Alexey 
Published: February 2017

TPS481 Background: Despite recent advances in the treatment of MPC, overall prognosis for patients remains poor. This may be attributed in part to the ability of pancreatic tumors to co-opt growth factor signaling pathways to counteract the activity of chemotherapy. We previously demonstrated that IGF-1 and heregulin, the ligands for IGF-1R and ErbB3, respectively, can decrease the cytotoxic activity of A/G (JCO 33 2015 s3 a289). Additionally, co-expression of IGF-1R and ErbB3 is known to be associated with poor survival prognosis in MPC patients (JCO 33 2015 s3 a295). Istiratumab, a fully human bispecific antibody directed at IGF-1R and ErbB3, produced significant tumor regression, including durable complete responses, when combined with A/G in preclinical models of pancreatic cancer, and has been shown to be safe and tolerable in a Phase 1 study (JCO 33 2015 s3 a384). On these bases, the current Phase 2 study was developed to evaluate istiratumab plus A/G in pts with MPC. Methods: Eligible patients have biopsy-confirmed MPC, ECOG PS 0-1, no prior therapy for advanced disease, and elevated serum levels of free IGF-1 (estimated to be ~40% of all screened patients). The study design includes two parts: Part 1 (n = 12) is an open-label assessment of the safety, tolerability, and pharmacokinetics (PK) of a fixed dose of istiratumab (2.8 grams IV q 2 weeks) in combination with A/G; in Part 2 (n = 146), pts are randomized 1:1 to receive A/G plus either istiratumab or placebo. The primary objective of Part 2 is to compare progression free survival (PFS) between the two treatment arms in two distinct cohorts: a) patients with high free serum IGF-1 levels (i.e., the entire study cohort), and b) patients with both high free serum IGF-1 levels and positive expression of heregulin in tumor tissue. Additional objectives include safety, overall survival, PK and immunogenicity analyses of istiratumab, and correlative analyses of pre-defined biomarkers and their potential correlation with study outcomes. The study is designed with 80% power to detect a hazard ratio of 0.63 in favor of the experimental arm (8 vs 5 months) at a one-sided significance level of 0.05. The study has been open to enrollment as of September 2015. Clinical trial information: NCT02399137.